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Douglas E. Rollins, Donald K. Blumenthal - Workbook and Casebook For Goodman and Gilman's The Pharmacological Basis of Therapeutics-McGraw-Hill (2015)
Douglas E. Rollins, Donald K. Blumenthal - Workbook and Casebook For Goodman and Gilman's The Pharmacological Basis of Therapeutics-McGraw-Hill (2015)
EDITORS
Douglas E. Rollins, MD, PhD Donald K. Blumenthal, PhD
Professor Emeritus, Pharmacology &Toxicology Associate Professor of Pharmacology &Toxicology
University of Utah Associate Dean for Interprofessional Education &
Salt Lake City, Utah Assessment, College of Pharmacy
University of Utah
Salt Lake City, Utah
New York Chicago San Francisco Lisbon London Madrid Mexico City
Milan New Delhi San Juan Seoul Singapore Sydney oronto
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CONTENTS
v
PREFACE
T is Workbook and Casebook derives rom the 12th edition • Mechanisms o Action (and, where appropriate, Mechanisms
o Goodman & Gilman’s T e Pharmacological Basis of T era- o Resistance) able
peutics. T e organization o the parent text has been retained • Clinical Cases
and many o the tables and gures are the same. T e editors
• Key Concepts
have attempted to provide the most important concepts rom
the 12th edition o G&G in a user- riendly ormat without the • Summary Quiz
elimination o salient pharmacological in ormation. It is our • Summary able o Drugs that includes Drug Class, Drug
intention that the Workbook and Casebook will complement Name, Clinical Uses, and Common and Unique Clinically
the parent text and the second edition o Goodman & Gilman’s Important oxicities
Manual of Pharmacology and T erapeutics and be use ul to
Additional Side Bars are included to highlight signi cant phar-
students and educators who might need a companion text in
macological in ormation. Narrative pharmacological in orma-
an advanced pharmacology course.
tion is provided in the orm o Clinical Cases to give a clinical
T e number o chapters in the Workbook and Casebook has been context or the therapeutic use o drugs and their adverse events.
reduced rom 67 to 48 by combining the substance o multiple We have omitted research data, chemical structures, re erences,
chapters rom the 12th edition into one Workbook and Casebook and the pharmacokinetic data o Appendix II, all o which can
chapter. For example, Chapter 9 Muscarinic Receptor Agonists be ound on the G&G Web site on AccessMedicine.com and
and Antagonists, Chapter 10 Anticholinesterase Agents, and AccessPharmacy.com, along with pharmacotherapeutic updates
Chapter 11 Agents Acting at the Neuromuscular Junction and and mechanistic animations.
Autonomic Ganglia in the 12th edition have been combined
We thank the contributors and editors o the 12th edition
into one Workbook chapter entitled Cholinergic Pharmacology.
o G&G, Christie Naglieri and James Shanahan o McGraw
An additional chapter, Chapter 4 Special Populations: Children
Hill, and the long line o contributors and editors who have
and the Elderly, has been added to the Workbook and Casebook
worked on Goodman & Gilman over 12 editions. It is an
based in part on content that is published in Updates in the
honor to ollow in the path o Louis Goodman and Al red
online version o Goodman & Gilman (Accessmedicine.com
Gilman, and it is a tribute to their writing and editing that
and Accesspharmacy.com).
their book is use ul and relevant 74 years af er the publication
Each Workbook and Casebook chapter begins with a statement o the rst edition.
o how it di ers rom the 12th edition so that the reader can
re er to the parent text to obtain additional in ormation i nec-
Douglas E. Rollins
essary. Workbook and Casebook chapters (except or chapters
Donald K. Blumenthal
on general principles) are ormatted as ollows:
• Learning Objectives
• Drugs Included in the Chapter
vi
SECTION
General Principles I
1. Pharmacodynamics 1
2. Pharmacokinetics 18
1
CHAPTER
1 Pharmacodynamics
T is chapter will be most use ul a er having a basic understanding o the material in
PHARMACODYNAMIC Chapter 3, Pharmacodynamics: Molecular Mechanisms o Drug Action in Goodman
CONCEPTS AND & Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition Additional in or-
NOMENCLATURE (key terms mation related to this chapter is provided in Chapter 1, Drug Invention and the Phar-
a re indica ted in ita lics) maceutical Industry and Chapter 7, Pharmacogenetics T e drugs presented in this
• Pharmacodynamics is the studyo the bio- chapter are used to illustrate general pharmacodynamic principles T e mechanisms
chemical and physiological e ects o drugs o action and therapeutic uses o drugs described in this chapter are discussed in more
and their mechanisms o action. detail in subsequent chapters Neither a Mechanisms o Action able nor a Clinical
Summary able is included in this chapter because this in ormation is provided in
• Pharmacodynamics re ers to the e ects o subsequent chapters
a drug on the body; in contrast, the e ects
o the bodyon the actions o a drug are In addition to the material presented here, Goodman & Gilman’s T e Pharmacological
pharmacokineticprocesses (see Chapter 2). Basis of T erapeutics, 12th Edition contains:
• The termdrug receptor or drug target • A description in Chapter 1 o the process o drug invention and FDA approval
denotes the cellular macromolecule or • able 1-1, ypical Characteristics o the Various Phases o the Clinical rials
macromolecular complexwith which the Required or Marketing o New Drugs
drug interacts to elicit a cellular response.
• Figure 1-1, T e Phases, ime Lines, and Attrition T at Characterize the Invention o
• Drugs commonlyalter the rate or magni- New Drugs
tude o an intrinsiccellular response rather
• A comprehensive description in Chapter 3 o the various mechanisms o drug action,
than create newresponses.
including cellular pathways activated by physiological receptors, structural and unc-
• Drug receptors are o ten located on the tional amilies o physiological receptors, second messengers, ion channels, nuclear
sur ace o cells but mayalso be located in receptors, and transcription actors
speci cintracellular compartments.
• Chapter 3 also describes mechanisms o receptor desensitization and regulation, and
• Manydrugs also interact with acceptors an example o pharmacodynamic interactions in a multicellular context
within the body; acceptors are entities
• Chapter 7 includes a number o examples o genetic polymorphisms that a ect drug
that do not directlycause anychange in
pharmacodynamics, the impact o pharmacogenetics on drug development, and a
biochemical or physiological response.
discussion o pharmacogenetics in clinical practice
• Proteins ormthe most important class o
drug receptors. Examples include: LEARNING OBJECTIVES
»Physiological receptors or hormones, Understand key concepts and terms related to pharmacodynamics, including
growth actors, transcription actors, drug receptor agonism and antagonism
and neurotransmitters (see Table 1-1)
Know concepts and terms that are used to quanti y drug receptor interactions,
»Enzymes o crucial metabolicor including a nity, e cacy, potency, KD and Ki.
regulatorypathways (eg, dihydro olate
reductase, acetylcholinesterase, and Understand how drug pharmacodynamic in ormation is used to predict benef -
cyclicnucleotide phosphodiesterases) cial and toxic drug e ects
»Proteins involved in transport processes Know the modern process o drug invention and FDA approval, and post-market
(eg, Na+, K+-ATPase); secreted surveillance
glycoproteins (eg, Wnts) Know how genetic polymorphisms and other actors can a ect the pharma-
»Structural proteins (eg, tubulin) codynamic properties o drugs and lead to variability in individual patient
responses to drugs
• Speci cbindingo drugstoother cellular
constituentssuchasDNAisalsoexploited or Know how pharmacodynamics is applied to populations o patients to estimate
therapeuticpurposes(eg, manycancer che- population therapeutic windows or drug dosing
motherapeuticagentsandantiviral drugs).
• Antibioticand other anti-in ectives o ten
target enzymes and biochemical processes
that are unique to the pathogen, resulting
in cytotoxicityor inhibition o proli eration.
2
Pharmacodynamics CHAPTER 1
Eicosanoid receptors Prostaglandins, leukotrienes, Gs, Gi, and Gq proteins Misoprostol, montelukast
thromboxanes
Ion channels Ligand-gated ACh (M2), GABA, 5-HT Na+, Ca2+, K+, Cl– Nicotine, gabapentin
Voltage-gated None (activated by Na+, Ca2+, K+, other ions Lidocaine, verapamil
membrane depolarization)
Transmembrane Receptor tyrosine kinases Insulin, PDGF, EGF, VEGF, SH2 domain and PTB- Herceptin, imatinib
enzymes growth actors containing proteins
Toll-like receptors LPS, bacterial products MyD88, IARKs, NF-κB (in development)
Nuclear receptors Steroid receptors Estrogen, testosterone Co-activators Estrogens, androgens, Cortisol
AC, adenylyl cyclase; DA, dopamine; GC, guanylyl cyclase; GEF, guanine nucleotide exchange actor; LPS, lipopolysaccharide; NE, norepinephrine;
PAR, protease-activated receptor; PLC, phospholipase C; PPAR, peroxisome proli erator-activated receptor.
CASE 1-1
A man who su ers rom hay ever is at his local pharmacy looking or a nonprescrip- DRUG-RECEPTOR
tion drug that can provide relie o symptoms One o the allergy medicines he f nds on INTERACTIONS (key terms
the shel says the active ingredient is an antihistamine, diphenhydramine a re indica ted in ita lics)
a. What is an “active ingredient” in an allergy medication such as this? • Manydrugs act on physiological receptors
Pharmaceuticals contain 1 or more pharmacologically active ingredients, which are and are particularlyselective because
termed active ingredients. T e quantities o each active ingredient in each dose (eg, physiological receptors have evolved to
tablet, capsule, or volume o a liquid medication) are indicated on the packaging. In recognize and respond to individual signal-
addition to active ingredients, most medications also contain other ingredients that are ing molecules with great selectivity.
pharmacologically inactive, but may improve the pharmacokinetics, appearance, taste, • Drugs that bind to physiological receptors
shel -li e, or other properties that may enhance dosing and product e ectiveness. and mimicthe regulatorye ects o the
b. What kind o drug is an “antihistamine” and why is it so named? endogenous signaling compounds are
termed agonists.
As the name indicates, an antihistamine is an agent that antagonizes the action
o the endogenous mediator histamine. Histamine is released by mast cells and is » Adrug that binds to the same
involved in a variety o allergic and in ammatory responses (see Chapter 21). T is recognition site as the endogenous
man’s hay ever is caused by mast cell release o histamine and other substances that agonist (the primaryor orthosteric
result in his symptoms o sneezing, runny nose, itching o the nose and throat, and site on the receptor) is said to be
itchy, watery eyes. An antihistamine such as diphenhydramine will bind to hista- a primaryagonist.
mine receptors on cells throughout the body and block the e ects o histamine. (continues)
(Continued)
3
SECTION I General Principles
)
Ri
s
t
i
Drugs that can elicit the same maximal
n
u
»
y
response as the endogenous ligand are
r
L
a
150
r
termed ull agonists (see Figure 1-1) and
t
i
LR i LR a
b
r
are said to possess ull e cacy.
a
(
e
s
Drugs that are onlypartlye ective in 100 L
n
»
o
activating a receptor regardless o the
p
LR i LR a
s
e
concentration employed are termed
R
f
50
o
partial agonists (see Figure 1-1).
l
e
L
v
»Asyntopicinteraction is an interaction e
L
LR i Ra
between ligands that bind to the same 0
recognition site, or to recognition Log [Drug]
sites that overlap, on the receptor FIGURE 1-1 Regulation o the activity o a receptor with con ormation-selective drugs. The ordi-
macromolecule (see Figure 1-2). nate is the activity o the receptor produced by Ra, the active receptor con ormation (eg, stimu-
»Allosteric(allotopic) agonists bind to an lation o adenylyl cyclase by a β adrenergic receptor). I a drug Lselectively binds to Ra, it will
allostericor allotopicsite, a region on produce a maximal response. I Lhas equal a nity or Ri and Ra, it will not perturb the equilibrium
the receptor that is di erent romthe between them and will have no e ect on net activity; Lwould appear as an inactive compound.
I the drug selectively binds to Ri, then the net amount o Ra will be diminished. I Lcan bind to
primarysite (see Figure 1-2). receptor in an active con ormation Ra but also bind to inactive receptor Ri with lower a nity, the
• Manyreceptors exhibit some constitutive drug will produce a partial response; Lwill be a partial agonist. I there is su cient Ra to produce
activityin the absence o a regulatory an elevated basal response in the absence o ligand (agonist-independent constitutive activity),
ligand; drugs that stabilize such receptors then activity will be inhibited; Lwill then be an inverse agonist. Inverse agonists selectively bind
in an inactive con ormation are termed to the inactive orm o the receptor and shi t the con ormational equilibrium toward the inactive
state. In systems that are not constitutively active, inverse agonists will behave like competitive
inverse agonists (see Figure 1-1). antagonists, which helps explain why the properties o inverse agonists and the number o such
• Drugs that blockor reduce the action agents previously described as competitive antagonists were only recently appreciated. Recep-
o an agonist are termed antagonists tors that have constitutive activity and are sensitive to inverse agonists include benzodiazepine,
(see Figure 1-2). histamine, opioid, cannabinoid, dopamine, bradykinin, and adenosine receptors.
»Antagonismmost commonlyresults
romcompetition o a drug with an
agonist or the primarysite on the c. What are histamine receptors and what kind o an antagonist is diphenhydramine?
receptor (re erred to as competitive
Histamine receptors are G protein–coupled receptors (GPCRs; see able 1-1). H 1
antagonists because o a syntopic
receptors couple to Gq/11 and activate the PLC–IP3–Ca2+ pathway and its many pos-
interaction; see Figure 1-2).
sible sequelae, including activation o PKC, Ca2+–calmodulin–dependent enzymes
»Noncompetitive antagonismresults rom (eNOS and various protein kinases), and PLA2. H 2 receptors link to Gs to activate
an antagonist that covalentlybinds the the adenylyl cyclase–cyclic AMP–PKA pathway, whereas H 3 and H 4 receptors
receptor or dissociates extremelyslowly couple to Gi/o to inhibit adenylyl cyclase and decrease cellular cyclic AMP. Activa-
romthe receptor (pseudo-irreversible) tion o H 3 receptors also can activate mitogen-activated protein (MAP) kinase and
such that the maximal response o the inhibit the Na+/H + exchanger, and activation o H 4 receptors mobilizes stored Ca2+
receptor is diminished with increasing in some cells.
concentration o antagonist (see
All the available H 1 receptor “antagonists” are actually inverse agonists (see Side
Figure 1-2).
Bar DRUG-RECEP OR IN ERAC IONS and Figure 1-1) that reduce constitutive
»Noncompetitive antagonismcan also activity o the receptor and compete with histamine. Whereas histamine binding to
occur with antagonists that interact the receptor induces a ully active con ormation, antihistamine binding yields an
with allostericsites on the receptor inactive con ormation (see Figure 1-1). At the tissue level, the e ect seen is propor-
(allostericantagonists), reducing the tional to receptor occupancy by the antihistamine.
a nityo the receptor or agonist.
d. T e warning on the medication package says “marked drowsiness may occur.” T e
Drugs that act bycombining with the
package label also warns that “excitability may occur, especially in children.” How
»
4
Pharmacodynamics CHAPTER 1
D
100 Po te ntiatio n
t
c
e
f
f
E
l
a
m
50
xi
a
M
%
0
Log [A]
e
QUANTITATIVE ASPECTS
s
A B
n
o
100 100
OF DRUG RECEPTOR
p
s
e
INTERACTIONS
R
l
50 50
a
m
• Receptor occupancytheoryassumes that
xi
EC 50 EC 50
a
response emanates roma receptor occu-
M
0 0
%
pied bya drug, a concept that has its basis [A] Log [A]
in the lawo mass action. FIGURE 1-3 Graded responses (y axis as a percentage o maximal response) expressed as a
• The dose-response (or concentration- unction o the concentration o drug A present at the receptor. The hyperbolic shape o the
response) curve is a depiction o the curve in panel A becomes sigmoid when plotted semi-logarithmically, as in panel B. The con-
observed e ect o a drug as a unction o centration o drug that produces 50% o the maximal response quanti es drug activity and is
its concentration in the receptor compart- re erred to as the EC50 (ef ective concentration or 50% response). The range o concentrations
needed to ully depict the dose-response relationship (~3 log 10 units) is too wide to be use ul in
ment (see Figure 1-3). the linear ormat o Figure 1-3A; thus, most dose-response curves use log [Drug] on the x axis,
» The maximal asymptoticresponse as in Figure 1-3B. Dose-response curves presented in this way are sigmoidal in shape and have
occurs when the drug occupies all the 3 properties: threshold, slope, and maximal asymptote. These 3 parameters quantitate the activity
receptor sites. o the drug.
»Some drug-receptor systems exhibit
an inverted U-shaped dose-response T e rst-generation H 1 antagonists can both stimulate and depress the CNS.
relationship with low-dose stimulation Stimulation occasionally is encountered in patients given conventional doses; they
and high-dose inhibition o response, become restless, nervous, and unable to sleep. Central excitation also is a strik-
an e ect known as hormesis. ing eature o overdose, which commonly results in convulsions, particularly in
• The bimolecular drug-receptor interaction in ants. Central depression, on the other hand, usually accompanies therapeutic
that results in receptor activation can be doses o the older H 1 antagonists. Diminished alertness, slowed reaction times,
described as a series o 2 equilibrium and somnolence are common mani estations. Patients vary in their susceptibility
reactions as shown in Equation 1-1. and responses to individual drugs. T e ethanolamines (eg, diphenhydramine) are
k+1 k+2
particularly prone to causing sedation. T us, the development o second-generation
L+ R LR LR* “nonsedating” antihistamines was an important advance that allowed their general
k−1 k−2
(Equation 1-1)
use. T ese newer H 1 antagonists do not cross the blood-brain barrier appreciably.
• The initial reaction is the reversible binding T eir sedative ef ects are similar to those o placebo.
o drug (L) toa receptor (R) which leads to
the ormation o the drug-receptor complex e. Are there other pharmacological properties of H1 antagonists that are clinically
(LR), and depends on both the orward or useful?
associationrate (k+1) and the reverse or Many o the rst-generation H 1 antagonists tend to inhibit responses to acetylcho-
dissociationrate (k−1). line (ACh) that are mediated by muscarinic receptors and may be mani est during
»The equilibriumdissociation constant clinical use (see Chapter 6). Some H 1 antagonists also can be used to treat motion
(KD) is de ned as the ratio o the sickness; the anticholinergic properties o H 1 antagonists may be largely responsible
o and on rate constants (k−1/k+1; or this ef ect. Indeed, promethazine (a rst-generation H 1 antagonist) has perhaps
Equation 1-2); the af nityor equilibrium the strongest muscarinic-blocking activity among these agents and is the most
association constant (KA) is the reciprocal ef ective H 1 antagonist in combating motion sickness. T e second-generation H 1
o the equilibriumdissociation constant. antagonists have no ef ect on muscarinic receptors.
[L][R] k−1
KD = = CASE 1-2
[LR] k+1 (Equation 1-2)
A pharmaceutical company research and development team is working to develop new
» Thus a high-af nitydrug has a low drugs that target a novel molecular entity that might play a role in diabetes. Preclini-
KDand will bind a greater number cal data regarding the pharmacodynamics of a number of small molecules have been
o a particular receptor at a low collected and are being analyzed to determine which lead compounds might be worth
concentrationthana low-af nitydrug. carrying forward into clinical trials in humans.
» Depending on the characteristics
a. What are the steps that the team has taken to this point and what must be done
o the drug (eg, ull agonist, partial
before the drug is tested in humans?
agonist, antagonist, inverse agonist; see
Figure 1-1), the drug-receptor complex Modern drug invention usually starts with a statement (or hypothesis) that a cer-
mayundergo a con ormational change tain protein or pathway plays a critical role in the pathogenesis o a certain disease,
that leads to the ormation o the and that altering the protein’s activity would there ore be ef ective against that
activated complex(LR*). disease. T e usual approach to invention o a small-molecule drug is to screen
a collection o chemicals (“library”) or compounds with the desired eatures.
(Continued)
6
Pharmacodynamics CHAPTER 1
7
SECTION I General Principles
Be ore being administered to people, potential drugs are tested or general toxicity
by monitoring the activity o various systems in 2 species o animals or extended
periods o time. Compounds also are evaluated or carcinogenicity, genotoxicity,
and reproductive toxicity. Animals are used or much o this testing, although the
predictive value o results obtained in nonhuman species is certainly not per ect.
Usually 1 rodent (usually mouse) and 1 nonrodent (of en rabbit) species are used.
In vitro and ex vivo assays are utilized when possible, both to spare animals and to
minimize cost. I an unwanted e ect is observed, an obvious question is whether it
is mechanism-based (ie, caused by interaction o the drug with its intended target)
or due to an o -target e ect o the drug. I the latter, there is hope o minimizing
the e ect by urther optimization o the molecule.
Be ore clinical trials o a potential new drug may proceed in the United States (ie,
be ore the drug candidate can be administered to a human subject), the sponsor
must le an IND (Investigational New Drug) application, which is a request to the
United States. Food and Drug Administration (FDA) or permission to administer
the drug to human test subjects. T e IND describes the rationale and preliminary
evidence or e cacy in experimental systems, as well as pharmacology, toxicology,
chemistry, manu acturing, and so orth. It also describes the plan or investigating
the drug in human subjects (see Chapter 3).
b. In vitro binding studies show that KD values o the drugs that are being consid-
ered or clinical studies range rom 0.9 nM to 0.4 mM. What does a KD measure
and why is that value important to know?
In general, the drug-receptor interaction is characterized by (1) binding o drug to
receptor and (2) generation o a response in a biological system, as illustrated in
Equation 1-1 where the drug or ligand is denoted as L and the inactive receptor as
R. T e equilibrium dissociation constant (KD) is then described by ratio o the o
and on rate constants (k–1/k+1) when L and R are at equilibrium with LR.
T e a nity constant or equilibrium association constant (KA) is the reciprocal o
the equilibrium dissociation constant (ie, KA = 1/KD); thus a high-a nity drug has
a low KD and will bind a greater number o a particular receptor at a low concentra-
tion than a low-a nity drug. As a practical matter, the a nity o a drug is in u-
enced most of en by changes in its o -rate (k- 1) rather than its on-rate (k+1).
Equation 1-3 shows the relationship o the ractional occupancy (f) o receptors
by agonist L in terms o the concentration o L (ie, [L]), and either KD (or KA). T is
relationship illustrates that when the concentration o the drug equals the KD (or
1/KA), f = 0.5, that is, the drug will occupy 50% o the receptors. Note that this rela-
tionship describes only receptor occupancy, not the eventual response that is of en
ampli ed by the cell. Many signaling systems reach a ull biological response with
only a raction o receptors occupied (a phenomenon that might occur in a system
with “spare receptors”).
c. Other preclinical studies were conducted with the target protein expressed in
cultured cells. T ese studies were used to determine dose-response curves or
each lead compound. What is a dose-response curve and what in ormation can it
provide regarding the drug-receptor interaction?
T e basic currency o receptor pharmacology is the dose-response (or concentration-
response) curve, a depiction o the observed e ect o a drug as a unction o its
concentration in the receptor compartment (see Figures 1-1 through 1-4). Drugs
that bind to physiological receptors and mimic the regulatory e ects o the endog-
enous signaling compounds are termed agonists. I the drug binds to the same
recognition site as the endogenous agonist (the primary or orthosteric site on the
receptor), the drug is said to be a primary agonist. Allosteric (allotopic) agonists
bind to a di erent region on the receptor re erred to as an allosteric or allotopic
site. Drugs that block or reduce the action o an agonist are termed antagonists.
Antagonism most commonly results rom competition with an agonist or the same
or overlapping site on the receptor (a syntopic interaction), but can also occur by
(Continued)
8
Pharmacodynamics CHAPTER 1
CASE 1-3
Following the FDA approval o a new short-acting hypnotic drug to enhance sleep ol-
lowing pain ul surgical procedures, postmarketing surveillance shows that toxic side
e ects are relatively common among elderly patients, but uncommon in younger adults
a. What is postmarketing surveillance?
No drug is totally sa e; all drugs produce unwanted e ects in at least some people
at some dose. Many unwanted and serious e ects o drugs occur so in requently,
perhaps only once in several thousand patients, that they go undetected in the
relatively small populations (a ew thousand) in the standard Phase III clinical trial
(see able 1-1 in Goodman & Gilman’s T e Pharmacological Basis of T erapeutics,
12th Edition). o detect and veri y that such events are in act drug-related would
require administration o the drug to tens or hundreds o thousands o people
(Continued)
9
SECTION I General Principles
β2 Adrenergic receptor (ADBR2) β 2 Antagonists (eg, albuterol, terbutaline) Bronchodilation, susceptibility to agonist-induced
desensitization, cardiovascular e ects (eg, increased heart
rate, cardiac index, peripheral vasodilation)
β1 Adrenergic receptor (ADBR1) β 1 Antagonists Blood pressure and heart rate a ter β 1 antagonists
Dopamine receptors D2, D3, D4 Antipsychotics (eg, haloperidol, clozapine, Antipsychotic response (D2, D3, D4), antipsychotic-
thioridazine, nemonapride) induced tardive dyskinesia (D3) and acute akathisia (D3),
hyperprolactinemia in emales (D2)
Serotonin transporter 5-HTT (SLC6A4) Antidepressants (eg, clomipramine, Clozapine e ects, 5-HT neurotransmission,
f uoxetine, paroxetine, f uvoxamine) antidepressant response
Modif ers
Apolipoprotein E Statins (eg, simvastatin), tacrine Lipid-lowering; clinical improvement in Alzheimer disease
Cholesteryl ester trans er protein Statins (eg, pravastatin) Slowing atherosclerosis progression
Ion channels (HERG, KvLQT1, Erythromycin, cisapride, clarithromycin, Increased risk o drug-induced torsade de pointes,
Mink, MiRP1) quinidine increased QT interval (Roden, 2003; Roden, 2004)
Stromelysin-1 Statins (eg, pravastatin) Reduction in cardiovascular events and in repeat angioplasty
10
Pharmacodynamics CHAPTER 1
during clinical trials, adding enormous expense and time to drug development, and
delaying access to potentially bene cial therapies. In general, the true spectrum
and incidence o untoward e ects becomes known only af er a drug is released to
the broader market and used by a large number o people (Phase IV, postmarketing
surveillance; see Chapter 3, Case 3-2).
b. T e preclinical trials o this drug showed a therapeutic index o 25. What is the
therapeutic index and how is it calculated?
In preclinical studies o drugs, the median lethal dose (LD50) is determined in
experimental animals (see Figure 1-5, panel B). T e LD50/ED50 ratio is an indication
o the therapeutic index, which is a quantitative statement o how selective the drug
is in producing its desired e ects versus its adverse e ects. A therapeutic index o
25 indicates that the concentration o drug that is lethal in 50% o animals (LD50) is
25- old higher than the dose required to achieve a speci c therapeutic e ect in 50%
o the population tested (the median e ective dose, ED50).
A similar term to therapeutic index, the therapeutic window, is the range o steady-
state concentrations o drug that provides therapeutic e cacy with minimal toxic-
ity (see Figure 1-6). In clinical studies, the dose, or pre erably the concentration, o
a drug required to produce toxic e ects can be compared with the concentration
required or therapeutic e ects in the population to evaluate the clinical therapeutic
index. Since pharmacodynamic variation in the population may be marked, the
concentration or dose o drug required to produce a therapeutic e ect in most o
the population usually will overlap the concentration required to produce toxicity
in some o the population, even though the drug’s therapeutic index in an indi-
vidual patient may be large. Also, the concentration-percent curves or e cacy and
toxicity need not be parallel, adding yet another complexity to determination o
the therapeutic index in patients. Finally, no drug produces a single e ect, and the
therapeutic index or a drug will vary depending on the e ect being measured.
(Continued)
100 A 100 B
g
g
Hypnos is De a th
n
n
Cumula tive
i
i
d
d
n
n
80 fre que ncy 80
o
o
p
p
dis tribution
s
s
e
e
R
R
s
s
l
l
60 60
a
a
u
u
d
d
vi
vi
i
i
d
d
n
n
I
I
40 40
f
f
Fre que ncy
o
o
e
e
dis tribution
g
g
a
a
t
t
ED50 ED50 ED99
n
n
20 20
e
e
c
c
r
r
LD1 LD50
e
e
P
P
0 0
5 7 10 20 50 100 200 400 800
Conce ntra tion (mg/L) Dos e (mg/kg)
FIGURE 1-5 Frequency distribution curves and quantal concentration-e ect and dose-e ect
curves. A. Frequency distribution curves An experiment was per ormed on 100 subjects, and the
e ective plasma concentration that produced a quantal response was determined or each
individual. The number o subjects who required each dose is plotted, giving a log-normal re-
quency distribution (blue bars). The gray bars demonstrate that the normal requency distribu-
tion, when summated, yields the cumulative requency distribution—a sigmoidal curve that is
a quantal concentration-e ect curve. B. Quantal dose-ef ect curves. Animals were injected with
varying doses o a drug and the responses were determined and plotted. The calculation o the
therapeutic index, the ratio o the LD50 to the ED50, is an indication o how selective a drug is
in producing its desired e ects relative to its toxicity. See Chapter 3 in Goodman &Gilman’s The
Pharmacological Basis o Therapeutics, 12th Edition or additional explanation.
11
SECTION I General Principles
The ra pe utic
g
window
n
i
d
n
100
o
p
s
e
R
s
t
n
The ra pe utic
e
i
t
a
re s pons e
P
50
f
o
e
g
a
Adve rs e
t
n
e
e ffe cts
c
r
e
P
1 2 3 4 6
Conce ntra tion of drug in pla s ma (ng/mL)
FIGURE 1-6 The relation o the therapeutic window o drug concentrations to the therapeutic
and adverse e ects in the population. The ordinate is linear; the abscissa is logarithmic.
c. Why might this toxicity primarily be seen in elderly patients in Phase IV trials?
Data on the correlation o drug levels with e cacy and toxicity must be interpreted
in the context o the pharmacodynamic variability in the population (eg, genetics,
age, disease, and the presence o coadministered drugs), as well as pharmacokinetic
variables. Determinants o inter-individual variation in response to drugs that are
due to pharmacokinetics include disease-related alterations such as impaired renal
and liver clearance due to renal and hepatic disease, circulatory ailure, altered drug
binding to plasma proteins, impaired GI absorption, and pharmacokinetic drug
interactions. T e e ects o these actors on variability o drug pharmacokinetics are
described more thoroughly in Chapters 2 and 5 to 7 in Goodman & Gilman’s T e
Pharmacological Basis of T erapeutics, 12th Edition.
I the Phase III clinical trials did not include large numbers o elderly patients,
toxicities in this patient population might not be apparent until postmarketing sur-
veillance has indicated an increased risk o toxicities in the elderly. Elderly patients
may be more susceptible to toxicities or a variety o reasons, including age-related
decreases in cardiac, renal and hepatic unction, disease comorbidities, and poor
nutritional status (see Chapter 3).
T ere is a quantal concentration-response curve or e cacy and adverse e ects
(see Figure 1-5B); or many drugs, the concentration that achieves e cacy in all the
population may produce adverse e ects in some individuals. T us, a population
therapeutic window expresses a range o concentrations at which the likelihood o
e cacy is high and the probability o adverse e ects is low (see Figure 1-6), but it
does not guarantee either e cacy or sa ety. T ere ore, use o the population thera-
peutic window to adjust dosage o a drug should be complemented by monitoring
appropriate clinical and surrogate markers or drug e ect(s).
CASE 1-4
A 64-year-old male patient diagnosed with atrial f brillation is started on anticoagulant
therapy with war arin to lower his risk o stroke due to f brin clots Despite calculating
initial war arin dosing based on the patient’s age, weight, and sex, laboratory monitoring
o anticoagulant activity a er the f rst week o therapy shows that the patient is receiving
too much war arin (his INR was too high indicating he is “over anti-coagulated”) A er
several weeks o dose adjustment, the patient’s anticoagulant therapy is optimized at a
war arin concentration that is 10- old lower than the initial dose
a. What actors might have contributed to this patient’s high sensitivity to war arin?
Both pharmacokinetic and pharmacodynamic polymorphisms a ect war arin dosing
(see Chapter 19). T e anticoagulant war arin is catabolized by CYP2C9, and war arin’s
(Continued)
12
Pharmacodynamics CHAPTER 1
5
CYP 2C9
wa rfa rin hydroxywa rfa rin
)
g
m
(
e
s
o
D
VKORC1
g
n
i
t
r
vita min K
a
vita min K
t
e poxide
S
d
e
d
n
e
m
m
o
c
e
R
prothrombotic a ntithrombotic
(a ctiva te d clotting (hypofunctiona l clotting
fa ctors ) fa ctors ) 0
CYP 2C9 AA AB BB AA AB BB AA AB BB
ge notype
VKORC1 homozygous he te ro- homozygous
va ria nt zygous common
ge notype BB AB AA
FIGURE 1-7 Pharmacogenetics o war arin dosing. War arin is metabolized by CYP2C9 to inactive
metabolites, and exerts its anticoagulant e ect partly via inhibition o VKORC1 (vitamin Kepoxide
hydrolase), an enzyme necessary or reduction o inactive to active vitamin K. Common polymor-
phisms in both genes, CYP2C9 and VKORC1, impact on war arin pharmacokinetics and pharmaco-
dynamics, respectively, to a ect the population mean therapeutic doses o war arin necessary to
maintain the desired degree o anticoagulation (o ten measured by the international normalized
ratio [INR] blood test) and minimize the risk o too little anticoagulation (thrombosis) or too much
anticoagulation (bleeding).
13
SECTION I General Principles
Based on evidence that genetic variations a ect war arin dose requirements and
responses to therapy, the FDA amended the prescribing in ormation or war arin in
2007 to indicate that lower war arin initiation doses be considered or patients with
CYP2C9 and VKORC1 genetic variations. E orts to acilitate the rational incorpo-
ration o genetic in ormation into patient care have included the development o a
war arin dosing algorithm and point-o -care methods or CYP2C9 and VKORC1
genotyping. In a 2009 study o more than 4000 patients, the International War arin
Pharmacogenetics Consortium compared the accuracy o a pharmacogenetic algo-
rithm that included VKORC1 and CYP2C9 genotypes with 2 conventional clinical
approaches: one based on clinical in ormation to adjust the initial dose, and the
other using a xed-dose approach. T e pharmacogenetic algorithm predicted the
war arin dose signi cantly better than the other 2 approaches. Moreover, the phar-
macogenetic algorithm signi cantly improved the dose prediction or patients who
required either high or low doses o war arin (<21 mg/wk or >49 mg/wk).
Vitamin K is required or synthesis o unctional clotting actors by serving as a
co actor (see Figure 1-7; Chapter 19). Relative de ciency o vitamin K may increase
the sensitivity o patients to war arin and may result rom inadequate diet (eg, post-
operative patients on parenteral uids), especially when coupled with the elimina-
tion o intestinal ora by antimicrobial agents. Gut bacteria synthesize vitamin K
and are an important source o this vitamin. Consequently, antibiotics can cause
a high INR in patients who were previously adequately controlled on war arin. In
addition to an e ect on reducing intestinal ora, cephalosporins containing het-
erocyclic side chains also inhibit steps in the vitamin K cycle. Low concentrations
o coagulation actors may result rom impaired hepatic unction, congestive heart
ailure, or hypermetabolic states, such as hyperthyroidism; generally, these condi-
tions increase the INR.
Frequently cited drug interactions that increase INR and enhance the risk o hem-
orrhage in patients taking war arin include decreased metabolism due to CYP2C9
inhibition by amiodarone, azole anti ungals, cimetidine, clopidogrel, cotrimoxa-
zole, disul ram, uoxetine, isoniazid, metronidazole, sul npyrazone, tolcapone, or
za rlukast, and displacement rom protein binding sites caused by loop diuretics
or valproate.
CASE 1-5
A 42-year-old man is diagnosed with chronic myelogenous leukemia (CML) He is
prescribed imatinib, a small molecule anticancer drug that targets a disease-causing
enzyme in leukemic cells
a. What is the molecular target o imatinib in CML?
T e molecular target o imatinib in CML is the abnormal protein tyrosine kinase
BCR-ABL, which is caused by a chromosomal translocation (see Chapter 46). BCR-
ABL is constitutively active which causes the uncontrolled proli eration o leuke-
mic cells. Imatinib binds at the active site o the kinase and blocks its activity, thus
blocking cell proli eration.
Imatinib mesylate was the rst molecularly targeted protein kinase inhibitor to
receive FDA approval. Imatinib was identi ed through high-throughput screening
against the BCR-ABL kinase. T e lead compound o this series, a 2-phenylamino-
pyrimidine, had low potency and poor speci city, inhibiting both serine/threonine
and tyrosine kinases. T e addition o a 3′-pyridyl group at the 3′ position o the
pyrimidine enhanced its potency. Further modi cations resulted in improved activ-
ity against PDGFR and c-KI (2 other disease-causing tyrosine kinases) and loss o
serine/threonine kinase inhibition. Introduction o N-methylpiperazine as a polar
side chain greatly improved water solubility and oral bioavailability, yielding ima-
tinib, an inhibitor o the closed, or inactive, con guration o the kinase.
(Continued)
14
Pharmacodynamics CHAPTER 1
b. T e patient’s cancer goes into remission or 24 months, but then comes back,
despite daily doses o imatinib. What is the likely mechanism o resistance to
imatinib that has developed in this patient?
Resistance to imatinib and other small molecule tyrosine kinase inhibitors arises
rom point mutations in 3 separate segments o the kinase domain. T e contact
points between imatinib and the enzyme become sites o mutations in drug-
resistant leukemic cells; these mutations prevent tight binding o the drug and
lock the enzyme in its open con guration, in which it has access to substrate. Such
mutations hold the enzyme in its open and enzymatically active con rmation. T e
most common resistance mutations a ect amino acids 255 and 315, both o which
serve as contact points or imatinib; these mutations con er high-level resistance to
imatinib. Some mutations, such as at amino acids 351 and 355, con er low levels o
resistance to imatinib.
c. What is the therapeutic strategy to overcome resistance to imatinib in this patient?
T e strategy depends on the sites o mutation in BCR-ABL that lead to the resis-
tance. Mutations at amino acids 351 and 355 might lead to a clinical response with
dose escalation o imatinib. Mutations at other amino acids that con er high resis-
tance to imatinib will require using a di erent tyrosine kinase inhibitor such as
nilotinib or dasatinib. Dasatinib is una ected by mutation at 255 but is ine ective
in the presence o mutation at 315. Nilotinib retains inhibitory activity in the pres-
ence o most point mutations (except at 315) that con er resistance to imatinib.
KEY CONCEPTS
Pharmacodynamics re ers to the e ects o a drug on the body
Most drugs act by binding to physiological receptors and alter the rate or mag-
nitude o an intrinsic cellular response rather than create new responses
Important pharmacodynamic properties o a drug include its a nity, e cacy,
and specif city
T e e ects o a drug depend on many pharmacodynamic actors, including
receptor specif city, the tissue-specif c expression o the receptor(s), drug con-
centration in the receptor compartment on target tissues, drug concentrations
in di erent tissues expressing the receptor, pharmacogenetics, and interactions
with other drugs at the receptor
No drug is totally sa e; all drugs produce unwanted e ects in at least some
people at some dose
T e concentration or dose o drug required to produce a therapeutic e ect in
most o the population usually will overlap the concentration required to pro-
duce toxicity in some o the population
SUMMARY QUIZ
QUESTION 1-1 Pindolol and some other β adrenergic receptor antagonists have an
additional property that is re erred to as intrinsic sympathomimetic activity (ISA) T is
additional property indicates these agents are
a ull agonists
b inverse agonists
c partial agonists
d neutral antagonists
e noncompetitive antagonists
15
SECTION I General Principles
16
Pharmacodynamics CHAPTER 1
Nonetheless, the clinical signif cance o partial agonism has not been substantially
demonstrated in controlled trials but may be o importance in individual patients
Agents such as pindolol block exercise-induced increases in heart rate and cardiac
output (see Chapters 15 and 16)
QUESTION 1-2 Answer is d. Naloxone is a competitive antagonist o various
opioid receptors (see Chapter 10) Opioid antagonists, particularly naloxone, have
an established use in the treatment o opioid-induced toxicity, especially respiratory
depression Its specif city is such that reversal by this agent is virtually diagnostic or
the contribution o an opiate to the depression Naloxone acts rapidly to reverse the
respiratory depression associated with high doses o opioids
It should be used cautiously because it also can precipitate withdrawal in dependent
subjects and cause undesirable cardiovascular side e ects By care ully titrating
the dose o naloxone, it usually is possible to rapidly antagonize the respiratory-
depressant actions without eliciting a ully expressed withdrawal syndrome T e
duration o action o naloxone is relatively short, and it o en must be given repeatedly
or by continuous in usion
Under ordinary circumstances, opioid antagonists such as naloxone produce ew
e ects in the absence o an exogenous agonist However, under certain conditions
(eg, shock), when the endogenous opioid systems are activated, the administration o
an opioid antagonist alone may have visible consequences
QUESTION 1-3 Answer is b. T e equilibrium dissociation constant (KD) is a measure
o a drug’s a nity or its receptor It is the reciprocal o the a nity constant or equilib-
rium association constant (KA; ie, KA = 1/KD) T us a high-a nity drug has a low KD
and will bind a greater number o a particular receptor at a low concentration than a
low-a nity drug
QUESTION 1-4 Answer is d. A population therapeutic window expresses a range o
concentrations at which the likelihood o e cacy is high and the probability o adverse
e ects is low (see Figure 1-6) It does not guarantee either e cacy or sa ety T ere ore,
use o the population therapeutic window to adjust dosage o a drug should be comple-
mented by monitoring appropriate clinical and surrogate markers or drug e ect(s)
QUESTION 1-5 Answer is e. Many receptors exhibit some constitutive activity in the
absence o a regulatory ligand Inverse agonists selectively bind to the inactive orm
o such receptors and shi the con ormational equilibrium toward the inactive state
(see Figure 1-1) Inverse agonists typically bind such receptors at the same site as the
endogenous agonist; ligands that interact syntopically with a ull agonist will behave as
competitive antagonists
T e characteristic pattern o competitive antagonism is the concentration-
dependent production o a parallel shi to the right o the agonist dose-response
curve with no change in the maximal response (see Figure 1-2A) T e magnitude o
the rightward shi o the curve depends on the concentration o the antagonist and its
a nity or the receptor
In systems that are not constitutively active, inverse agonists will behave like
competitive antagonists, which helps explain why the properties o inverse agonists
and the number o such agents previously described as competitive antagonists were
only recently appreciated Receptors that have constitutive activity and are sensitive to
inverse agonists include benzodiazepine, histamine, opioid, cannabinoid, dopamine,
bradykinin, and adenosine receptors
17
CHAPTER
2 Pharmacokinetics
T is chapter will be most use ul a er having a basic understanding o the material in
Chapter 2, Pharmacokinetics in Goodman & Gilman’s T e Pharmacological Basis of
T erapeutics, 12th Edition. T is chapter also draws rom content in Chapter 5, Mem-
brane ransporters and Drug Response; Chapter 6, Drug Metabolism; and parts o
Chapter 7, Pharmacogenetics. T e drugs presented in this chapter are used to illustrate
general pharmacokinetic principles. T e pharmacokinetic, pharmacodynamic, and
therapeutic uses o drugs described in Chapter 2 are discussed in more detail in subse-
quent chapters. Neither a Mechanisms o Action able nor a Clinical Summary able is
included in this chapter because this in ormation is provided in subsequent chapters.
In addition to the material presented here, the 12th Edition contains:
• A review in Chapter 2 o cell membranes and their physicochemical properties that
a ect the movement o drugs to their site o action
• A discussion in Chapter 2 o di erent routes o drug administration and their rela-
tive advantages and disadvantages
• A detailed discussion in Chapter 2 o renal drug excretion, biliary and ecal excre-
tion, and excretion by other routes
• A comprehensive discussion o design and optimization o dosage regimens in
Chapter 2, including examples o dosing calculations that take into consideration
bioavailability, clearance, and distribution
• Appendix II Design Optimization o Dosage Regimens: Pharmacokinetic Data in
Goodman & Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition pro-
vides a summary o basic pharmacokinetic data or a number o drugs that are in
common clinical use, as well as in ormation that is use ul in individualizing dosing
in a given patient
• Chapter 5 contains a detailed review o membrane transporters, including their role
in absorption, distribution, and clearance o xenobiotics, and their role in adverse
drug responses
• able 5-1 Regulation o ransporter Expression by Nuclear Receptors provides
detailed in ormation about drug regulation o transporter expression mediated
through speci c nuclear receptors
• A description in Chapter 5 o the role o e ux transporters in the blood-brain
barrier (BBB) and blood-cerebrospinal uid (CSF) barrier
• Chapter 6 provides a comprehensive discussion o drug metabolism enzymes
and illustrations that show many o the key chemical reactions catalyzed by
these enzymes
CHARACTERISTICS OF
A DRUG THAT PREDICT LEARNING OBJECTIVES
ITS MOVEMENT AND Understand key concepts and terms that determine drug pharmacokinetics,
AVAILABILITY AT ITS SITES including absorption, distribution, metabolism, and excretion.
OF ACTION Understand the mechanisms by which drugs cross membranes and the physico-
• Molecular size and structural eatures chemical actors that in uence this trans er.
• Degree o ionization Be able to predict the ionization state o a drug that is a weak acid or base
• Relative lipid solubilityo its ionized and knowing the drug’s pKa and the pH o the uid.
nonionized orms Describe the role o membrane transporters in drug absorption, distribution,
• Its binding to serumand tissue proteins and clearance.
18
Pharmacokinetics CHAPTER 2
Know the major mechanisms by which drugs are metabolized and excreted
PASSIVE TRANSPORT
rom the body.
VERSUS ACTIVE
Understand the major pharmacokinetic mechanisms that can result in drug TRANSPORT ACROSS
interactions. CELLULAR BARRIERS
Know the pharmacokinetic mechanisms that give rise to interpatient variability
• Passive transport is the dominant transport
in drug response and toxicity.
mechanismin the disposition o most
Understand the clinical pharmacokinetic principles used to calculate dosing drugs (Figure 2-1).
required to achieve steady-state drug concentrations in plasma. » In passive di usion, the drug molecule
Understand how route o administration can a ect the bioavailability and clear- usuallypenetrates cellular barriers by
ance o drugs. di usion along a concentration gradient
byvirtue o itssolubilityinthe lipidbilayer.
CASE 2 1 » Paracellular transport through
intercellular gaps occurs across capillary
In Case 1-1, a gentleman is seeking an allergy medicine at his local pharmacy to relieve
endotheliumand is important in
his hay ever symptoms. One o the nonprescription drugs he nds contains diphen-
ltration across the glomerulus in the
hydramine, which can cause drowsiness or other CNS e ects as discussed in part d o
kidneybut is limited in some tissues
Case 1-1.
such as the CNSwhere capillaries have
a. How is diphenhydramine able to cause CNS e ects? tight intercellular junctions.
First-generation antihistamines such as diphenhydramine can cross the BBB and » Facilitateddi usion describes a carrier-
cause CNS depression such as somnolence. Diphenhydramine and the other rst- mediated transport process in which
generation antihistamines contain a tertiary amino group linked by a 2- or 3-atom there is no input o energy, and there ore
chain to 2 aromatic substituents (see Figure 32-3 in Goodman & Gilman’s T e enhanced movement o the involved
Pharmacological Basis of T erapeutics, 12th Edition). T e only ionizable group in substance is down a chemical gradient.
(Continued) • Active transport is characterized bya direct
requirement or energy, movement against
an electrochemical gradient, saturability,
PAS S IVE TRANS P ORT ACTIVE selectivity, and competitive inhibition by
TRANS P ORT
cotransported compounds.
Pa ra ce llula r Diffus ion Fa cilita te d ABC
tra ns port diffus ion tra ns porte rs
WEAK ELECTROLYTES AND
THE INFLUENCE OF PH
• Manydrugs are weakacids or bases that
are present in solution as both the nonion-
ized and ionized species.
» Nonionized molecules are usuallymore
lipid soluble and can di use readily
across the cell membrane.
» Ionized molecules usuallyare less
able to penetrate the lipid membrane
because o their lowlipid solubility.
FIGURE 2-1 The variety o ways drugs move across cellular barriers in their passage through- • The transmembrane distribution o a weak
out the body. Transmembrane movement o drug generally is limited to unbound drug; thus electrolyte is in uenced byits pKa and the
drug-protein complexes constitute an inactive reservoir o drug. Unbound drugs cross mem-
pHgradient across the membrane.
branes either by passive processes or by mechanisms involving the active participation o
components o the membrane. In passive trans er, the drug molecule usually penetrates by di - • The ratio o nonionized to ionized drug
usion along a concentration gradient by virtue o its solubility in the lipid bilayer. Such trans er at a given pHis readilycalculated rom
is directly proportional to the magnitude o the concentration gradient across the membrane, the Henderson-Hasselbalch equation
to the lipid-water partition coe cient o the drug, and to the membrane sur ace area exposed (Equation 2-1), where pKa is the drug’s
to the drug. The greater the partition coe cient, the higher is the concentration o drug in the
acid dissociation constant.
membrane and the aster is its di usion. A ter a steady-state is attained, the concentration o
the unbound drug is the same on both sides o the membrane i the drug is a nonelectrolyte. [protonated form]
For ionic compounds, the steady-state concentrations depend on the electrochemical gradi- log = pKa − pH
[unprotonated form]
ent or the ion and on di erences in pH across the membrane, which will in uence the state o
ionization o the molecule disparately on either side o the membrane and can e ectively trap (Equation 2-1)
drug on 1 side o the membrane. Carrier-mediated active transport is characterized by a direct
(continues)
requirement or energy.
19
SECTION I General Principles
A
WEAK ELECTROLYTES AND
We a k Acid HA A– + H+ pKa = 4.4
THE INFLUENCE OF PH (Cont.) nonionize d ionize d
• Figure 2-2 illustrates the partitioning o a B [1] [1000] 1001 = [HA] + [A– ]
weakacid (pKa = 4.4) between plasma
(pH= 7.4) and gastricjuice (pH= 1.4). HA A– + H+
• At steadystate, an acidicdrug will accumu- P la s ma pH = 7.4
diphenhydramine and these other agents is the tertiary amino group, which has
DRUG ABSORPTION, a pKa ~9.0. T us, at physiological pH (pH 7.4), the drug is largely unionized
BIOAVAILABILITY, AND (see Figure 2-2) and very lipophilic and can easily di use through lipid membranes,
ROUTES OF ADMINISTRATION including the BBB.
• Absorptionis the movement o a drug rom b. Are there other antihistamines that this patient could take that do not cause
its site o administration intothe central drowsiness?
compartment (Figure 2-3). T e second-generation antihistamines, such as loratadine (see Chapter 21), do not
• Bioavailabilityis the ractional extent to cause drowsiness. T ese second-generation histamine H 1 antagonists are ionized at
which a dose o drug reaches its site o physiological pH and as a consequence do not readily cross the BBB. For example,
action or a biological uid romwhich the the pKa o loratadine is ~4.3, and is thus largely ionized at pH 7.4 and not able to
drug has access to its site o action. di use readily through lipid membranes.
• A raction o the administered and (Continued)
absorbed dose o drug will be inactivated
or diverted in the intestine and liver be ore
it can reach the general circulation and be TIS S UE RES ERVOIRS
distributed to its sites o action. bound fre e
THERAP EUTIC
UNWANTED S ITE
»I the metabolicor excretorycapacityo S ITE OF ACTION
OF ACTION
“Re ce ptors ”
the liver and the intestine or the drug bound fre e CENTRAL bound fre e
is large, bioavailabilitywill be reduced COMPARTMENT
substantially(frst-pass e ect).
• The route o drugadministration can a ect DRUG
ABS ORP TION
[FREE DRUG]
CLEARANCE
the time course o drug e ects, extent o DOS E
LIBERATION EXCRETION
absorption, bioavailability, rst-pass e ect,
variabilityo drug e ects, and adverse prote in bound me ta bolite s
e ects (see Table 2-1). drug
TABLE 2-1 Some Characteristics o Common Routes o Drug Administration DISTRIBUTION OF DRUGS
LIMITATIONS AND • Distribution re ers to the movement o
ROUTE ABSORPTION PATTERN SPECIAL UTILITY PRECAUTIONS drug into interstitial and intracellular uids
Intravenous Absorption circumvented Valuable or Increased risk o adverse ollowing absorption or systemicadminis-
Potentially immediate emergency use e ects tration (see Figure 2-3).
e ects Permits titration o Must inject solutions • Distribution re ects a number o physi-
Suitable or large dosage slowly as a rule ological actors and the particular physico-
volumes and or irritating Usually required or Not suitable or oily
substances, or complex high-molecular-weight solutions or poorly
chemical properties o the individual drug.
mixtures, when diluted protein and peptide soluble substances • Physiological actors that determine the
drugs rate o deliveryand potential amount o
drug distributed into tissue include:
Subcutaneous Prompt rom aqueous Suitable or some Not suitable or large
solution poorly soluble volumes » Cardiacoutput
Slow and sustained rom suspensions and or Possible pain or » Regional blood ow
repository preparations instillation o slow- necrosis rom irritating
release implants substances » Capillarypermeability
» Tissue volume
Intramuscular Prompt rom aqueous Suitable or moderate Precluded during
solution volumes, oily vehicles, anticoagulant therapy • During the initial distribution phase, the
Slow and sustained rom and some irritating May inter ere with liver, kidney, brain, and other well-per-
repository preparations substances interpretation o certain used organs receive most o the drug.
Appropriate or diagnostic tests (eg,
sel -administration creatine kinase)
• The second distribution phase to muscle,
(eg, insulin) most viscera, skin, and at is slower and
mayrequire minutes toseveral hours be ore
Oral ingestion Variable, depends on Most convenient and Requires patient the concentration o drug in tissue is in
many actors economical; usually compliance equilibriumwith that in blood.
more sa e Bioavailability
potentially erratic and » The second phase involves a ar larger
incomplete raction o bodymass (eg, muscle) than
does the initial phase and generally
accounts or most o the extravascularly
distributed drug.
• With exceptions such as the brain, di u-
c. Besides the CNS, where else in the body might the net charge o a drug be sion o drug into the interstitial uid occurs
a ected by pH? rapidlybecause o the highlyperme-
T e partitioning o a weak acid (pKa = 4.4) between plasma (pH = 7.4) and gas- able nature o the capillaryendothelial
tric juice (pH = 1.4) is depicted in Figure 2-2. Assume that the gastric mucosal membrane.
membrane behaves as a simple lipid barrier with a high electrical resistance that • Tissue distribution is determined bythe
is permeable only to the lipid-soluble, nonionized orm o the acid. T e ratio o partitioning o drug between blood and
nonionized to ionized drug at each pH is readily calculated rom the Henderson- the particular tissue.
Hasselbalch equation (see Equation 2-1). In the example o Figure 2-2, the ratio » Lipid solubilityand transmembrane pH
o nonionized to ionized drug in plasma is 1:1000; in gastric juice, the ratio is gradients are important determinants
1:0.001, as given in brackets in Figure 2-2. T e total concentration ratio between o tissue uptake or drugs that
the plasma and the gastric juice there ore would be 1000:1 i such a system came are either weakacids or bases;
to a steady-state. For a weak base with a pKa o 4.4 (eg, chlordiazepoxide), the however, ion trapping associated
ratio would be reversed, as would the thick horizontal arrows in Figure 2-2, which with transmembrane pHgradients is
indicate the predominant species at each pH. Accordingly, at steady state, an acidic generallynot large because the pH
drug will accumulate on the more basic side o the membrane and a basic drug on di erence between tissue and blood
the more acidic side. (~7.0 vs 7.4) is small.
T e e ects o net charge are observable elsewhere in the body, such as in the kidney » The most important determinant o
tubules. Urine pH can vary over a ride range, rom 4.5 to 8. As urine pH drops (as blood-tissue partitioning is the relative
[H +] increases), weak acids (A–) and weak bases (B) will exist to a greater extent in binding o drug to plasma proteins and
their protonated orms (HA and BH +); the reverse is true as pH rises, where A– and tissue macromolecules that limits the
B will be avored. In the kidney tubules where a lipid-soluble (uncharged) drug can concentration o ree drug.
be reabsorbed by passive di usion, excretion o the drug can be promoted by alter-
ing the pH o the urine to avor the ionized state (A– or BH +). T us, alkaline urine
(Continued)
21
SECTION I General Principles
avors excretion o weak acids; acid urine avors excretion o weak bases. Elevation
PLASMA PROTEIN BINDING
o urine pH (by giving sodium bicarbonate) will promote urinary excretion o weak
OF DRUGS
acids such as aspirin (pKa~3.5) and urate (pKa~5.8). T is principle o ion trapping is
• Manydrugs circulate in the bloodstream an important process in drug distribution.
bound to plasma proteins. T e establishment o concentration gradients o weak electrolytes across membranes
»Albumin is a major carrier or acidic with a pH gradient is a physical process and does not require an active electrolyte
drugs. transport system. All that is necessary is a membrane pre erentially permeable to
»α 1-Acid glycoprotein binds basicdrugs. one orm o the weak electrolyte and a pH gradient across the membrane. T e estab-
lishment o the pH gradient, however, is an active process.
»Certain drugs maybind to proteins
that unction as speci chormone
carrier proteins, such as the binding
o estrogen or testosterone to sex CASE 2 2
hormone–binding globulin or the A 68-year-old woman has symptoms o angina when she climbs stairs or engages in
binding o thyroid hormone to thyroxin- strenuous activity. She is prescribed nitroglycerin (glyceryl trinitrate, see Chapter 16)
binding globulin. to take prophylactically be ore she engages in any activity that might cause angina
• Plasma protein binding is a nonlinear, symptoms.
saturable process.
a. T e patient’s pharmacist instructs her that she is to place the nitroglycerin tab-
• Binding o a drug to plasma proteins limits let under her tongue a couple o minutes be ore strenuous activity to prevent
its concentration in tissues and at its site o angina. Why is this route o administration used or this drug?
action because onlyunbound ( ree) drug
Sublingual administration o nitroglycerin results in rapid onset o action (peak
is in equilibriumacross membranes (see
concentrations within 4 minutes o administration) and avoids the rst-pass
Figure 2-3).
e ect. Absorption rom the oral mucosa has special signi cance or certain
• AppendixIIin Goodman &Gilman’s The drugs despite the act that the sur ace area available is small. Venous drainage
Pharmacological Basis o Therapeutics, 12th rom the mouth is to the superior vena cava, bypassing the portal circulation
Edition provides plasma protein binding and thereby protecting the drug rom rapid intestinal and hepatic rst-pass
percentages or a number o commonly metabolism. Nitroglycerin is e ective when retained sublingually because it
used drugs. is nonionic and has very high lipid solubility. T us, the drug is absorbed very
• The extent o plasma protein binding also rapidly. Nitroglycerin also is very potent; absorption o a relatively small amount
maybe a ected bydisease-related actors. produces the therapeutic e ect (“unloading” o the heart; see Chapter 16).
»Changes in protein binding due Nitroglycerin that is swallowed undergoes nearly complete rst-pass metabolism
to disease states and drug–drug as the result o enzymatic denitration in the liver. T us, its bioavailability is only
interactions are clinicallyrelevant ~0.01 (ie, ~1%) when swallowed.
mainly or a small subset o the b. o prevent rst-pass e ects, what other routes o administration might be
so-called high-clearance drugs o e ective or this agent?
narrowtherapeuticindexthat are
Because nitroglycerin has very high lipid solubility, it can be absorbed through
administered intravenously.
the skin and administered via controlled-release transdermal patches. T is route
• Drug excretion bythe kidneys, transport, o administration is e ective or patients requiring chronic administration o
and metabolismcan be limited bybinding nitroglycerin to prevent symptoms o angina, but can result in the development
to plasma protein. o tolerance unless the patch is removed or 8-12 hours each day (see Case 16-1).
CASE 2 3
A 59-year-old man who was diagnosed with coronary artery disease undergoes angio-
plasty and receives a coronary stent. o prevent platelet thrombosis o the stent, he is
prescribed a standard dosing regimen o clopidogrel, a drug that inhibits platelet aggre-
TISSUE BINDING OF DRUGS gation (see Chapter 19). A er several weeks o clopidogrel therapy, his platelet unction
is measured and it is determined that the dose o clopidogrel is too low to e ectively
• Manydrugs accumulate in tissues at higher
inhibit platelet aggregation.
concentrations than those in the extracel-
lular uids and blood. a. What kind o drug is clopidogrel and how might this explain the poor response
• Tissue accumulation maybe a result o to therapy with this agent?
active transport or, more commonly, bind- Clopidogrel is a prodrug that requires bioactivation, primarily by CYP2C19. T ere
ing to cellular constituents such as proteins, is wide interindividual variability in the capacity o clopidogrel to inhibit platelet
phospholipids, or nuclear proteins. aggregation, and some patients are designated resistant to the antiplatelet e ects
(continues)
(Continued)
22
Pharmacokinetics CHAPTER 2
TABLE 2-2 ABC Transporters Involved in Drug Absorption, Distribution, and TISSUE BINDING OF DRUGS
Excretion Processes (Cont.)
TRANSPORTER TISSUE PHYSIOLOGICAL • Tissue binding is generallyreversible and
NAME GENE DISTRIBUTION FUNCTION SUBSTRATES can serve as a reservoir that prolongs drug
MDR1 (ABCB1) Liver Natural Characteristics: Neutral or action in that same tissue or at a distant
Kidney detoxi cation cationic compounds with bulky site reached through the circulation.
Intestine system against structure » Tissue binding and accumulation also
BBB xenobiotics Anticancer drugs: etoposide,
can produce local toxicity.
BTB doxorubicin, vincristine
BPB Ca2+ channel blockers: diltiazem, • Manylipid-soluble drugsare storedbyphysi-
verapamil cal solution in the neutral at; hence, at may
HIV protease inhibitors: indinavir, serve as a reservoir or lipid-soluble drugs.
ritonavir
• Some drugs, divalent metal ion chelating
Antibiotics/Antifungals:
erythromycin, ketoconazole agents, and heavymetals mayaccumulate
Hormones: testosterone, in bone by adsorption onto the bone
progesterone crystal sur ace and eventual incorporation
Immunosuppressants: cyclosporine, into the crystal lattice.
tacrolimus
Others: digoxin, quinidine,
exo enadine, loperamide DRUG MEMBRANE
TRANSPORTERS
MRP1 (ABCC1) Ubiquitous Leukotriene C4 Characteristics: Amphiphilic with at
(Kidney, BCSFB, secretion rom least one negative net charge • Transporters are membrane proteins that
BTB) leukocyte Anticancer drugs: vincristine (with control the in ux(uptake) o essential
GSH), methotrexate nutrients and ions, and the e uxo cellu-
Glutathione conjugates: lar waste, environmental toxins, drugs, and
leukotriene C4, glutathione conjugate
other xenobiotics.
o ethacrynic acid
Glucuronide conjugates: estradiol- • The unctions o membrane transport-
17-D-glucuronide, bilirubin mono(or ers maybe facilitated (equilibrative, not
bis)glucuronide requiring energy) or active (requiring
Sulfated conjugates: estrone-3- energy); see Figure 2-1.
sul ate (with GSH)
HIV protease inhibitors: saquinavir • The transport o drugsis primarilymediated
Antibiotics: grepa oxacin by2major super amilies, ABC(ATP-binding
Others: olate, GSH, oxidized cassette) andSLC(solute carrier) transporters.
glutathione » Most ABCproteins are primaryactive
MRP2 (ABCC2) Liver Excretion Characteristics: Amphiphilic with at transporters, which relyon ATPhydrolysis
Kidney o bilirubin least one negative net charge (similar toactivelypump their substrates across
Intestine glucuronide and to MRP1) membranes (Table 2-2).
BPB GSH into bile Anticancer drugs: methotrexate, There are 49 known genes or ABC
vincristine
protein which include P-glycoprotein
Glutathione conjugates:
leukotriene C4, glutathione conjugate (P-gp, encoded byABCB1, also
o ethacrynic acid termed MDR1) and the cystic brosis
Glucuronide conjugates: estradiol- transmembrane regulator (CFTR,
17-D-glucuronide, bilirubin mono(or encoded byABCC7).
bis)glucuronide » The SLCsuper amilyincludes genes that
Sulfate conjugate of bile salts:
taurolithocholate sul ate encode acilitated transporters and ion-
Amphipathic organic anions: coupled secondaryactive transporters
statins, angiotensin II receptor (Table 2-3).
antagonists, temocaprilat Approximately315 SLCtransporters
HIV protease inhibitors: indinavir, have been identi ed in the human
ritonavir
Others: GSH, oxidized glutathione
genome, manyo which serve as
drug targets or in drug absorption
and disposition, including the
serotonin (5-HT) and dopamine
transporters (SERT,encoded by
SLC6A4; DAT,encoded bySLC6A3).
(continues)
23
SECTION I General Principles
24
Pharmacokinetics CHAPTER 2
Representative substrates and cytotoxic drugs with increased resistance (*) are included in this
table (cytotoxicity with increased resistance is usually caused by the decreased accumulation
o the drugs). Although MDR3 (ABCB4), BSEP (ABCB11), ABCG5, and ABCG8 are not directly
involved in drug disposition, inhibition o these physiologically important ABC transporters will
lead to un avorable side e ects.
BBB, blood-brain barrier; BTB, blood-testis barrier; BPB, blood-placental barrier; BCSFB, blood-
cerebrospinal uid barrier.
SLC6 Na+- and Cl–-dependent 16 Paraoxetine, uoxetine X-linked creatine de ciency syndrome
neurotransmitter transporter
SLC10 Na+ bile salt cotransporter 6 Benzothiazepines Primary bile salt malabsorption
25
SECTION I General Principles
SLC22 Organic cation/anion/zwitterion 18 Pravastatin, met ormin Systemic carnitine de ciency syndrome
transporter
SLC26 Multi unctional anion exchanger 10 Salicylic acid, Congenital Cl–-losing diarrhea
cipro oxacin
SLC30 Zinc ef ux 9
26
Pharmacokinetics CHAPTER 2
CYP2C9 Tolbutamide, war arin,a phenytoin, nonsteroidal Anticoagulant e ect o war arin
anti-in ammatory
N-acetyltrans erase (NAT2) Isoniazid, hydralazine, sul onamides, amona de, Hypersensitivity to sul onamides, amona de
procainamide, dapsone, ca eine toxicity, hydralazine-induced lupus, isoniazid
neurotoxicity
Glutathione trans erases (GSTM1, Several anticancer agents Decreased response in breast cancer,
GSTT1,GSTP1) more toxicity and worse response in acute
myelogenous leukemia
Thiopurine methyltrans erase (TPMT) Mercaptopurine,a thioguanine,a azathioprine a Thiopurine toxicity and e cacy, risk o second
cancers
P-glycoprotein (ABCB1) Natural product anticancer drugs, HIVprotease Decreased CD4 response in HIV-in ected patients,
inhibitors, digoxin decreased digoxin AUC, drug resistance in
epilepsy
Organic anion transporter (SLC01B1) Statins, methotrexate, ACE inhibitors Statin plasma levels, myopathy; methotrexate
plasma levels, mucositis
Organic cation transporter (SLC22A1, Met ormin Pharmacologic e ect and pharmacokinetics
OCT1)
27
SECTION I General Principles
28
Pharmacokinetics CHAPTER 2
the important phase 2 enzymes that metabolizes acetaminophen are the sul otrans-
BIOTRANSFORMING
erase (SUL ) SUL 1 iso orms that are recognized as phenol SUL s, because they
ENZYMES (Xe nob iot ic
catalyze the sul ation o phenolic molecules such as acetaminophen, minoxidil, and
17α-ethinyl estradiol. Me t ab olizin g Enzyme s;
Tab le 2 5)
b. Package labels on products containing acetaminophen warn o possible liver
damage when daily dosing o acetaminophen exceeds 4000 mg. What is the • Phase 1 oxidation reactions are carried
mechanism o liver toxicity by acetaminophen? out bycytochrome P-450s (CYPs), avin-
containing monooxygenases (FMO), and
Acetaminophen, which is normally metabolized by glucuronidation and sul ation, epoxide hydrolases (EH).
is also a substrate or oxidative metabolism by CYP2E1 and CYP3A4, which gen-
erate the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) that, under • Phase 2 enzymes include the glutathione-
normal dosing, is readily neutralized through conjugation with glutathione (GSH). S-trans erases (GST), UDP-glucuronos-
However, an overdose o acetaminophen can lead to depletion o cellular GSH lev- yltrans erases (UGT), sul otrans erases
els, thereby increasing the potential or NAPQI to interact with other cellular com- (SULT), N-acetyltrans erases (NAT), and
ponents resulting in toxicity and cell death. Acetaminophen toxicity is associated methyltrans erases (MT).
with increased levels o NAPQI and hepatic necrosis (see Chapter 3). » Conjugation reactions usuallyrequire
the substrate to have oxygen (hydroxyl
or epoxide groups), nitrogen, or sul ur
CASE 2 5
atoms that serve as acceptor sites or a
A 26-year-old woman is lling a prescription or oral contraceptives and is asked by her hydrophilicmoiety, such as glutathione,
pharmacist whether she is taking any other medications, including herbal remedies. T e glucuronicacid, sul ate, or anacetyl group.
woman tells the pharmacist that she takes St John’s wort, an over-the-counter herbal • Xenobioticmetabolizing enzymes are
remedy used or depression. ound in most tissues in the bodywith the
a. What are the possible drug interactions that might occur with St. John’s wort? highest levels located in the GItract (liver,
small and large intestines).
Hyper orin, a component o St. John’s wort, activates a type 2 nuclear receptor,
the pregnane X receptor (PXR). T e type 2 nuclear receptors include the pregnane » The liver is considered the major
X receptor (PXR), constitutive androstane receptor (CAR), and the peroxisome “metabolicclearing house” or both
endogenous chemicals (eg, cholesterol,
(Continued)
steroid hormones, attyacids, and
proteins) and xenobiotics.
» Drugs that are orallyadministered are
TABLE 2-5 Xenobiotic Metabolizing Enzymes
absorbed bythe gut and taken to the
ENZYMES REACTIONS liver through the portal vein.
Pha se 1 “oxygena ses” » Xenobiotic-metabolizingenzymeslocated
in the epithelial cells o the GI tract are
Cytochrome P450s (P450 or CYP) C and O oxidation, dealkylation, others
responsible or the initial metabolic
Flavin-containing monooxygenases (FMO) N, S, and P oxidation processing o most oral medications.
» Following oral administration o a drug,
Epoxide hydrolases (mEH, sEH) Hydrolysis o epoxides
a signi cant portion o the dose maybe
Pha se 2 “tra nsfera ses” metabolicallyinactivated in either the
intestinal epitheliumor the liver be ore
Sul otrans erases (SULT) Addition o sul ate
the drug reaches the systemiccirculation;
UDP-glucuronosyltrans erases (UGT) Addition o glucuronic acid this so-called irst-pass metabolism
signi cantlylimits the oral bioavailability
Glutathione-S-trans erases (GST) Addition o glutathione o highlymetabolized drugs.
N-acetyltrans erases (NAT) Addition o acetyl group » Tissues o the nasal mucosa and lung
playimportant roles in the metabolism
Methyltrans erases (MT) Addition o methyl group
o drugs that are administered through
Other enzymes aerosol sprays and are also the rst line
o contact with hazardous chemicals
Alcohol dehydrogenases Reduction o alcohols that are airborne.
Aldehyde dehydrogenases Reduction o aldehydes • Phase 1 oxidation enzymes are located
primarilyin the endoplasmicreticulum,
NADPH-quinone oxidoreductase (NQO) Reduction o quinones
whereas the phase 2 conjugation enzyme
mEH and sEH are microsomal and soluble epoxide hydrolase. UDP, uridine diphosphate; systems are mainlycytosolic.
NADPH, reduced nicotinamide adenine dinucleotide phosphate.
29
SECTION I General Principles
30
Pharmacokinetics CHAPTER 2
31
SECTION I General Principles
Acetylation CoAS CO CH3 + RNH2 RNH CO CH3 + CoA-S H Sul onamides, isoniazid, dapsone, clonazepam
Methylation RO-, RS-, RN- + AdoMet → RO-CH3 + AdoHomCys L-Dopa, methyldopa, mercaptopurine, captopril
32
Pharmacokinetics CHAPTER 2
A
CYP 1A1/2 EXCRETION OF DRUGS
Es te ra s e s
CYP 1B1 • Drugs are eliminated romthe bodyeither
Epoxide
unchanged bythe process o excretion or
Othe rs hydrola s e converted to metabolites.
CYP 2A6
• Excretoryorgans, the lung excluded, elimi-
CYP 2B6 DPYD
nate polar compounds more ef ciently
than substances with high lipid solubility.
CYP 2C8/9 » Lipid-soluble drugs thus are not readily
eliminated until theyare metabolized to
more polar compounds.
CYP 2C10
• The most important organ or excreting
drugs and their metabolites is the kidney.
CYP 2D6 CYP 3A4/5
» Excretion o drugs and metabolites in
the urine involves 3 distinct processes:
CYP 2E1
Glomerular ltration
B TP MT NATs Active tubular secretion
GSTs
Passive tubular reabsorption
Othe rs
• Substances excreted in the eces are princi-
pallyunabsorbed orallyingested drugs or
drug metabolites excreted either in the bile
or secreted directlyinto the intestinal tract
and not reabsorbed.
• Excretion romthe lung is important mainly
or the elimination o anestheticgases.
S ULTs UGTs • Drugs excreted in breast milkare potential
sources o unwanted pharmacological
FIGURE 2-5 The raction o clinically used drugs metabolized by the major phase 1 and phase
e ects in the nursing in ant.
2 enzymes. The relative size o each pie section represents the estimated percentage o drugs
metabolized by the major phase 1 (panel A) and phase 2 (panel B) enzymes, based on studies
in the literature. In some cases, more than a single enzyme is responsible or metabolism o a
single drug. CYP, cytochrome P-450; DPYD, dihydropyrimidine dehydrogenase; GST, glutathione- CLINICAL
S-trans erase; NAT, N-acetyltrans erase; SULT, sul otrans erase; TPMT, thiopurine methyltrans erase; PHARMACOKINETICS
UGT, UDP-glucuronosyltrans erase
• Clinical pharmacokinetics attempts to pro-
vide a quantitative relationship between
dose and e ect, and a rameworkwithin
which to interpret measurements o con-
centrations o drugs in biological uids and
TABLE 2-7 Nuclear Receptors That Induce Drug Metabolism their adjustment through changes in dos-
ing or the bene t o the patient.
RECEPTOR LIGANDS
• The 4most important parameters governing
Aryl hydrocarbon receptor (AHR) Omeprazole drug disposition are:
Constitutive androstane receptor (CAR) Phenobarbital » Bioavailability, the raction o drug
absorbed as such into the systemic
Pregnane X receptor (PXR) Ri ampin circulation
Farnesoid X receptor (FXR) Bile acids » Volume o distribution, a measure o the
apparent space in the bodyavailable to
Vitamin D receptor Vitamin D
contain the drug based on howmuch
Peroxisome proli erator activated receptor (PPAR) Fibrates is given versus what is ound in the
systemiccirculation
Retinoic acid receptor (RAR) all-trans-Retinoic acid
» Clearance, a measure o the body’s
Retinoid X receptor (RXR) 9-cis-Retinoic acid ef ciencyin eliminating drug romthe
systemiccirculation
(continues)
33
SECTION I General Principles
CLINICAL RXR
PHARMACOKINETICS (Cont.)
PXR
» Elimination t1/2, the time it takes or Lig and Lig and
the plasma concentration o a drug to
OH
be reduced by50%and a measure o
CYP3A4
the rate o removal o drug romthe
systemiccirculation
VOLUME OF DISTRIBUTION
RNAPII
• The volume o distribution (V) relates the Lig and Co
-a c tiv
amount o drug in the bodyto the concen- PXR RXR a to TBP
r
tration o drug (C) in the blood or plasma. TATA
The volume o distribution de ned in
»
34
Pharmacokinetics CHAPTER 2
Lipid-soluble drugs are not readily excreted until they are metabolized to more
polar compounds.
T e kidney is the most important organ or excreting drugs and their
metabolites.
DRUG CLEARANCE
Pharmacokinetic drug–drug interactions are among the leading causes o
adverse drug reactions (ADRs). • Clearance romthe systemcirculation (CL)
is the most important concept to consider
When a constant drug dosage is given, steady state is not reached until at least when designing a long-termdrug dosing
our hal -lives have passed. rate that maintains steady-state concentra-
Genetic polymorphisms in membrane transporters and drug metabolizing tions o a drug (Css) within a therapeutic
enzymes can result in marked inter-patient responses to drugs, including serious window(see Chapter 1 or de nition o
drug toxicities. therapeuticwindow).
» Assuming complete bioavailability, the
steady-state concentration o drug in
SUMMARY QUIZ the body(Css) will be achieved when the
rate o drug elimination (CL) equals the
QUESTION 2-1 T e term “ rst-pass e ect” re ers to the rate o drug administration (dosing rate)
a. e ect a new drug has on the body a er its rst administration. as described in Equation 2-3.
b. time it takes or a drug to be detected in the urine or eces a er oral administration. Dosing rate= CLCss
c. ability o the intestines and liver to reduce the bioavailability o a drug.
(Equation 2-3)
d. time it takes or a drug to reach therapeutic concentrations in the target tissue.
e. initial e ect a drug has on target tissues.
» Systems or elimination o drugs such as
metabolizing enzymes and transporters
QUESTION 2-2 T e term “blood-brain barrier” (BBB) re ers to a usuallyare not saturated, thus the
absolute rate o elimination o the drug
a. noncellular barrier that prevents drugs rom entering the CNS unless transported by
is essentiallya linear unction o its
speci c carriers.
concentration in plasma ( rst-order
b. cellular barrier that includes brain capillary endothelial cells that limits drug entry kinetics), where a constant raction o
into the brain. drug in the bodyis eliminated per unit
c. virtual or conceptual barrier that can explain the behavior o some drug e ects on o time.
the CNS. » I mechanisms or elimination o a
d. physical barrier that prevents blood rom entering the brain. given drug become saturated, the
e. device that is used to prevent blood-borne drugs rom entering the brain. kinetics approach zero-order, in
which a constant amount o drug is
QUESTION 2-3 Phase 1 drug metabolism di ers rom phase 2 metabolism in that eliminated per unit o time, and the
relationship o clearance (CL) to drug
a. phase 1 metabolism always occurs prior to phase 2 metabolism.
concentration (C) is described by
b. phase 1 metabolism occurs in the intestine where orally administered drugs can rst Equation 2-4 which is analogous to the
be metabolized, whereas phase 2 metabolism occurs in the blood. Michaelis-Menten equation where Km
c. phase 1 metabolism occurs in the liver soon a er a drug is absorbed, whereas phase represents the concentration at which
2 metabolism occurs a er a drug is excreted into the urine. hal the maximal rate o elimination
d. phase 1 metabolic enzymes activate prodrugs, whereas phase 2 metabolic enzymes is reached (in units o mass/volume)
inactivate drugs. and vm is equal to the maximal rate o
elimination (in units o mass/time).
e. phase 1 metabolic reactions unctionalize drugs, whereas phase 2 metabolic reactions
conjugate drugs. CL= vm /(Km + C) (Equation 2-4)
QUESTION 2-4 T e most important pharmacokinetic concept to consider when » Clearance o a drug (CL) is its rate o
designing a rational long-term pharmacotherapy is
elimination byall routes normalized to
a. bioavailability. the concentration o drug (C) in some
b. route o administration. biological uid where measurement can
c. volume o distribution. be made as described in Equation 2-5.
d. clearance. CL= rate o elimination/C
e. elimination t1/2. (Equation 2-5)
(continues)
35
SECTION I General Principles
)
clearance maybe determined rom
p
e ffe ct The ra pe utic
C
(
mass balance and the integration o window
t
c
e
f
Equation 2-5 over time as described in
f
E
Equation 2-6 where AUCis the total area
g
u
r
MEC for
D
under the curve o drug concentration
de s ire d
in the systemiccirculation as a unction Dura tion of a ction re s pons e
o time romtime zero to in nityas
shown in Figure 2-7.
36
Pharmacokinetics CHAPTER 2
A B
32 32 RATE OF DISTRIBUTION
C op = 31 AND EQUILIBRIUM OF
N
N
o
C p
O
O
DRUG INTO TISSUES (Cont.)
I
I
T
T
16 16
A
A
o
V = Dos e / C
R
R
p
• The decline o drug plasma concentration
T
T
N
N
with time or a multicompartment system
E
E
8 8
C
C
)
)
N
N
is shown in Figure 2-8B.
L
L
O
O
m
m
C
C
/
/
g
g
• Two di erent terms have been used to
µ
µ
G
G
4 4
(
(
U
U
describe the volume o distribution or drugs
R
R
D
D
that ollowmultiple exponential decay.
A
A
M
M
2 2
Varea is the ratio o clearance to the
S
S
A
A
»
t1 /2 t1 /2
L
L
rate o decline in concentration during
P
P
1 1 the elimination ( nal) phase o the
0 2 4 6 8 10 12 0 2 4 6 8 10 12
logarithmicconcentration versus time
TIME (hours ) TIME (hours )
curve (see Equation 2-8).
FIGURE 2-8 Plasma concentration-time curves ollowing intravenous administration o a drug
(500 mg) to a 70-kg patient. A. Drug concentrations are measured in plasma at 2-hour intervals CL dose
Varea = =
ollowing drug administration. The semilogarithmic plot o plasma concentration (Cp) versus time k k AUC
appears to indicate that the drug is eliminated rom a single compartment by a rst-order pro- (Equation 2-8)
cess (see Equation 2-7) with a t1/2 o 4 hours (k = 0.693/t1/2 = 0.173 h -1). The volume o distribution
(V) may be determined rom the value o Cp obtained by extrapolation to t = 0 (Cp0 = 16 µg/mL). » The volume o distribution at steady-
Volume o distribution (see Equation 2-2) or the 1-compartment model is 31.3 L, or 0.45 L/kg state (Vss) represents the volume in
(V= dose/Cp0). The clearance or this drug is 90 mL/min; or a 1-compartment model, CL = kV.
which a drug would appear to be
B. Sampling be ore 2 hours indicates that in act the drug ollows multiexponential kinetics.
distributed during steadystate i the
The terminal disposition t1/2 is 4 hours, clearance is 84 mL/min (see Equation 2-6), Varea is 29 L
(see Equation 2-7), and Vss is 26.8 L. The initial or “central”distribution volume or the drug (V1 = drug existed throughout that volume
dose/Cp0) is 16.1 L. The example chosen indicates that multicompartment kinetics may be over- at the same concentration as that in
looked when sampling at early times is neglected. In this particular case, there is only a 10% error the measured plasma or blood (see
in the estimate o clearance when the multicompartment characteristics are ignored. For many Equation 2-9, where VCis the volume o
drugs, multicompartment kinetics may be observed or signi cant periods o time, and ailure distribution in the central compartment
to consider the distribution phase can lead to signi cant errors in estimates o clearance and and VTis the volume term or drug in
in predictions o the appropriate dosage. Also, the di erence between the “central”distribution
the tissue compartment).
volume and other terms re ecting wider distribution is important in deciding a loading dose
strategy. The idealized 1-compartment model discussed earlier does not describe the entire time
Vss = VC + VT
course o the plasma concentration. That is, certain tissue reservoirs can be distinguished rom
the central compartment, and the drug concentration appears to decay in a manner that can be (Equation 2-9)
described by multiple exponential terms (Figure 2-8B).
• Changesin the pattern or ratioo blood ow
tovarioustissueschangeswill leadtochanges
in the rates o drug distribution totissues.
takes place; other anatomical, physiological, and pathological actors can in uence
bioavailability, and the choice o the route o drug administration must be based on an » Disease states that cause altered
understanding o these conditions. Moreover, knowledge o drugs that undergo sig- regional blood owor reduced
ni cant metabolism or require active transport across the intestinal and hepatic mem- per usion can lead to altered e ects o
branes instructs our understanding o adverse events in therapeutics, because some drugs that varydepending on relative
drugs are substrates or the same drug metabolizing enzymes or drug transporters and per usion o speci ctissues.
thus compete or metabolism and transport.
Diseases such as hepatic cirrhosis may a ect “ rst-pass metabolism” by shunting
o blood away rom hepatic metabolizing enzymes.
QUESTION 2-2 Answer is b. T e distribution o drugs into the CNS rom the blood
is unique. One reason or this is that the brain capillary endothelial cells have continu-
ous tight junctions; there ore, drug penetration into the brain depends on transcel-
lular rather than paracellular transport. T e unique characteristics o brain capillary
endothelial cells and pericapillary glial cells constitute the BBB. At the choroid plexus,
a similar blood-CSF barrier is present, except that it is epithelial cells that are joined by
tight junctions rather than endothelial cells. T e lipid solubility o the nonionized and
unbound species o a drug is there ore an important determinant o its uptake by the
brain; the more lipophilic a drug, the more likely it is to cross the BBB. T is situation
37
SECTION I General Principles
2 Ste a d y-Sta te
DOSING REGIMENS TO •Atta ine d a fte r a pproxima te ly four ha lf-time s
ACHIEVE A STEADY-STATE •Time to s te a dy-s ta te inde pe nde nt of dos a ge
DRUG CONCENTRATION
Cs s
N
• Equation 2-3 indicates that a steady-
O
I
state concentration eventually will be
T
A
R
achieved when a drug is administered at
T
1
N
a constant rate, that is, when the rate o
E
C
Stea d y-Sta te Co nc e n tra tio n s
drug elimination equals the rate o drug
N
O
•Proportiona l to dose /dos age inte rva l
availability.
C
•Proportional to F/CL
• With regular intermittent dosage the Flu c tu a tio n s
•Proportiona l to dos e inte rva l/ha lf-time
concentration o drug rises with absorption •Blunte d by s low a bs orption
and alls byelimination during each dosing 0
cycle, and at steadystate, the entire cycle 0 1 2 3 4 5 6
is repeated identicallyin each interdose TIME (multiple s of e limina tion ha lf-time )
interval (see Figure 2-9). FIGURE 2-9 Fundamental pharmacokinetic relationships or repeated administration o drugs.
• Equation 2-10 provides an approxima- The blue line is the pattern o drug accumulation during repeated administration o a drug at
tion o the time required to reach steady intervals equal to its elimination hal -time when drug absorption is 10 times as rapid as elimina-
state a ter a dosage regimen is initiated tion. As the rate o absorption increases, the concentration maxima approach 2 and the minima
approach 1 during the steady state. The black line depicts the pattern during administration o
or changed (ie, our hal -lives to reach
equivalent dosage by continuous intravenous in usion. Curves are based on the 1-compartment
~94%o a newsteadystate) and a model. Average concentration (Css) when the steady state is attained during intermittent drug
means to estimate the appropriate administration:
dosing interval.
F•dosing rate = CL•Css
t1/2 0.693 Vss / CL where F is ractional bioavailability o the dose and T is dosage interval (time). By substitution o
(Equation 2-10) in usion rate or F•dosing rate, the ormula is equivalent to Equation 2-3 and provides the con-
centration maintained at steady state during continuous intravenous in usion.
• To maintain the chosen steady-state or
target plasma drug concentration (CP),
the dosing rate is adjusted according o en is used in drug design to alter drug distribution to the brain; or example, the
to Equation 2-11 (where Fis ractional so-called second-generation antihistamines, such as loratadine, achieve ar lower brain
bioavailability o the dose) such that concentrations than do agents such as diphenhydramine and thus are nonsedating (see
the rate o input equals the rate o loss; Case 2-1). Drugs may penetrate into the CNS by speci c uptake transporters normally
Equation 2-11 is a similar relationship involved in the transport o nutrients and endogenous compounds rom blood into the
to what was previously described in brain and CSF.
Equation 2-3.
Another important actor in the unctional BBB involves membrane transporters
Dosing rate = target Cp CL/F that are e ux carriers present in the brain capillary endothelial cell and capable o
(Equation 2-11) removing a large number o chemically diverse drugs rom the cell. MDR1 (P-gp) and
the organic anion–transporting polypeptide (OA P) are 2 o the more notable o these.
• The dosing interval or intermittent dosing
T e e ects o these exporters are to dramatically limit access o the drug to the tissue
depends on the total uctuation in drug
expressing the e ux transporter.
concentrations that can be tolerated.
I the dosing interval Twere chosen
» QUESTION 2-3 Answer is e. Drug metabolism or biotrans ormation reactions are
to be equal to the t1/2, then the total classi ed as either phase 1 unctionalization reactions or phase 2 biosynthetic
uctuation would be 2- old; this is o ten (conjugation) reactions.
a tolerable variation.
Phase 1 reactions introduce or expose a unctional group on the parent compound
» I a drug is relativelynontoxicsuch such as occurs in hydrolysis reactions. Phase 1 reactions generally result in the loss
that a concentration manytimes that o pharmacological activity, although there are examples o retention or enhancement
necessary or therapycan be tolerated o activity. In rare instances, metabolism is associated with an altered pharmacological
easily, the maximal-dose strategycan activity. Prodrugs are pharmacologically inactive compounds designed to maximize
be used, and the dosing interval can be the amount o the active species that reaches its site o action. Inactive prodrugs are
much longer than the elimination t1/2 converted rapidly to biologically active metabolites o en by the hydrolysis o an ester
( or convenience). or amide linkage.
38
Pharmacokinetics CHAPTER 2
39
CHAPTER
40
Clinical and Environmental Toxicity CHAPTER 3
41
SECTION I General Principles
De eroxamine Iron
Flumazenil Benzodiazepines
42
Clinical and Environmental Toxicity CHAPTER 3
Polycyclic aromatic Benzo[a]pyrene Fossil uel combustion, tobacco Metabolic activation to orm DNA adducts or ROS
hydrocarbons smoke, charbroiled ood
Fungal toxins A atoxin B1 Corn, peanuts, and other ood Metabolic activation to orm DNA adducts
Non-genotoxic
Liver toxicants Ethanol Beverages, environment Toxicity and compensatory proli eration; depletion o GSH
Phorbol esters Tetradecanoyl phorbol Horticulture; rubber and Activation o PKC iso orms
acetate gasoline production
Metals Arsenic Environment, occupation Inhibition o DNA repair; activation o signal transduction
pathways
Dioxins TCDD Waste incineration, herbicides, Activation o the aryl hydrocarbon receptor
paper-pulp bleaching
a
Compounds in this table are classi ed as group 1 carcinogens by the International Agency or Research on Cancer (IARC), with the exception
o the phorbol esters, which have not been examined. TCDD, 2,3,7,8 tetrachlorodibenzo-p-dioxin; ROS, reactive oxygen species; GSH,
glutathione; PKC, protein kinase C.
Pb 2 Paint, soil CNS, blood, CV, renal Group 2A, probably carcinogenic
Hg 3 Air, ood CNS, renal Group 2B, possibly carcinogenic (MeHg +); group 3,
not classi able (Hg 0, Hg 2+)
43
SECTION I General Principles
100
A
,
g
n
i
d
n
o
p
Y
s
T
e
I
R
L
A
50
n
T
o
R
i
t
a
O
l
M
u
p
o
P
f
o
%
0
2 5 10 20 50
7.0 98
B
95
)
s
)
t
90
s
i
6.0
t
n
i
n
u
u
80
t
i
t
b
i
b
o
r
o
p
r
(
p
5.0 50
(
Y
Y
T
I
T
L
I
L
A
A
T
20
T
R
R
O
4.0
O
M
10
M
%
LD50 5
3.0 2
2 5 10 20 50
DOS E (mg/kg, log s ca le )
Co mpo und A
Co mpo und B
7.0
98
90
)
80 EFFECTS
e
6.0
l
)
a
s
c
t
70
i
s
n
t
u
i
b
ED 60
t
o
i
b
r
p
DES IRABLE
o
5.0 50
(
r
UNDES IRABLE
p
(the ra pe utic)
g
(
40
n
e
i
d
s
LD
n
30
n
o
o
p
p
s
20
s
4.0
e
e
R
NON-DELETERIOUS DELETERIOUS
R
10
%
(s ide e ffe cts ) (toxic e ffe cts )
5
3.0 pha rma cologica l
2
10 20 50 100 200 800
pa thologica l
DOS E (mg/kg)
FIGURE 3-2 Comparison o e ective dose (ED), and lethal dose (LD). For a dis- ge notoxic
cussion o probit units, see Chapter 4 in Goodman and Gilman’s The Pharmacologi-
cal Basis of Therapeutics, 12th Edition. Note that the abscissa is a logarithmic scale. FIGURE 3-3 Spectrum o the e ects o pharmaceuticals.
44
Clinical and Environmental Toxicity CHAPTER 3
CASE 3-1
An w h l o o d o h n o hy n on.
a. Describe how the e ects o the chemical are initially quanti ed?
Ev lu on o h do - on o h do - l on h u lly o-
n o ox olog . T g d d do - on l on h n n nd v du l
nd qu n l do - on l on h n h o ul on ( Ch 1 nd 2).
G d d do o d ug g v n o n nd v du l u u lly ul n g gn ud
o on h do n d. In qu n l do - on l on h , h
n g o h o ul on d n h do d; h l on-
h qu n l n h h d o h n o n n gv n
nd v du l ( F gu 3-1). T qu n l do - on h no non x ly
o n n ox ology nd u d o d n h d n l h l do (LD50) o
d ug nd o h h l . T LD50 o o ound d n d x n lly,
u u lly y d n on o h h l o o (o lly o n on -
lly) v l do n h l h l ng .
b. Describe how the chemical’s toxicity and “therapeutic index” are determined?
F gu 3-2 llu h l on h w n qu n l do - on u v o h
h u o d ug o g n d n v do (ED50), h on n-
on o d ug wh h 50% o h o ul on w ll h v h d d on , nd
qu n l do - on u v o l h l y y h g n .T 2 u v n
u d og n h u nd x ( I), wh h qu n h l v y o d ug.
I = LD50/ED50
D ug how w d ng o I, o 1 o 2 o o h n 100. D ug w h low I
u d n d w h u on. Ag n h ll n o h go y n lud h
d gly o d d g l ( Ch 17) nd n h oh u gn (
Ch 45 nd 46). Ag n w h v y h gh I x ly nd n lud o
n o ( g, n ll n) ( Ch 39), unl h known ll g on .
Phase I Establish the e ects o the drug as a unction o dosage in 20-100 healthy volunteers:
• Designed to prevent severe toxicity
• Determine the probable limits o the sa e clinical dosage range
• Pharmacokinetic measurements are o ten conducted in this phase
45
SECTION I General Principles
Pharmacological Toxicity Progression o clinical e ects to toxic e ects CNS depression produced by barbiturates rom anxiolysis, to
dependent upon dose sedation, to somnolence, to coma
May also occur at therapeutic doses Phototoxicity associated with exposure to sunlight in patients
treated with tetracycline
Pathological Toxicity Drug in overdose produces a distinct Acetaminophen overdose producing hepatic necrosis
pathological reaction
Allergic Reactions Result rom previous sensitization to Type I: Anaphylactic reactions mediated by IgE antibodies
a particular chemical or to one that is Type II: Cytolytic reactions mediated by IgG and IgM antibodies
structurally similar Type III: Arthrus reactions mediated predominantly by IgG
Type IV: Delayed hypersensitivity reactions mediated by sensitized
T-lymphocyctes and macrophages
Idiosyncratic Reactions An abnormal reaction to a chemical that is Genetically determined resistance to the anticoagulant action o
peculiar to a given individual. May take the war arin due to an alteration in vitamin Kepoxide reductase (see
orm o extreme sensitivity to low doses or Chapter 19)
extreme insensitivity to high doses o drugs
a
A complete discussion o the types o drug toxicity can be ound in Goodman and Gilman’s The Pharmacological Basis of Therapeutics,
12th Edition, Chapter 4.
CASE 3-2
A 35-y -old wo n ng d o o h g l ux w h d ug h h n
n ly ov d y h Food nd D ug Ad n on (FDA). Af 2 on h o
h y h l ng nd n gh ly od o ux d n h d, u h
hy n ll o ll h h h d ug ng ll d u o o l w h
d hy h , nd n w d ug w ll d.
a. What is the process o drug approval by the FDA?
F w h n on - h d o h d ug d n ln l l h h k l .
F d l l w n h Un d S nd h l on d on qu h h udy
o n w d ug n hu n ondu d n od n w h ng n gu d l n . S
S d B GUIDELINES FOR HE S UDY OF NEW DRUGS IN HUMANS.
b. What are the di erent types o therapeutic drug toxicity?
In h u , d ug y lly odu nu ou , u u u lly only 1
ough h y go l o n; o o h oh und l
o h d ug o h h u nd on ( F gu 3-3). S d
o d ug u u lly oh o u no d l ou no do h y lw y n -
h d on nu on o h d ug; h y n lud u h d y ou h
o u ng w h yl n d n h y. O h und l y
h z d ox ( Sd B YPES OF HERAPEU IC
DRUG OXICI Y).
c. Why can a drug approved by the FDA or use in humans and still cause
serious toxicity?
So ox o h u l n d d d u on h known
h olog l h n ; how v , o n no un l h o k ng
od h h h u ox y o l o d ug o ully d.
(Continued)
46
Clinical and Environmental Toxicity CHAPTER 3
A
Me c hanis ms o f
Che mic al Inte rac tio ns
P HARMACO- P HARMACO-
KINETIC DYNAMIC
a bs orption
excre tion
B
Clas s ific atio n o f
Che mic al Inte rac tio ns
ADDITIVE
SYNERGISTIC
P OTENTIATION
ANTAGONIS M
functiona l
che mica l
re ce ptor
47
SECTION I General Principles
o d w h olong on o h Q n v l nd d o on o v n ul
hy h . I w w hd wn o h k , nd u qu n - on ol
ud d on d n d ko hy h .C d now l d
n d u on h ough n nv g on l og n g d y h
nu u .T u , h d n on o d ug ox y x nd yond h g
o d ug d v lo n nd ov l.
DRUG–DRUG INTERACTIONS
TYPE OF INTERACTION DESCRIPTION EXAMPLE
Absorption One drug causes an increase or decrease in Ranitidine increases GI pH and may increase absorption o basic
(Pharmacokinetic) the GI absorption o another drug drugs such as triazolam
Protein Binding One drug displaces another rom protein The anticoagulant e ects o war arin may be enhanced by
(Pharmacokinetic) binding sites displacement rom plasma proteins by valproic acid therapy
Metabolism A drug in uences the metabolism o one Phenobarbital, phenytoin, and valproate increase the metabolism
(Pharmacokinetic) or several other drugs by enhancing or o carbamazepine
inhibiting hepatic CYPs Metabolism o carbamazepine is inhibited by erythromycin
(see Chapter 12)
Receptor Binding One drug binds to a receptor and prevents Buprenorphine binds opioid receptors with high af nity, and can
(Pharmacodynamic) the pharmacological action o another drug prevent euphoria rom concomitant use o abused opioid drugs
at that receptor
Therapeutic Action The therapeutic e ect o 1 drug impacts the When aspirin, an inhibitor o platelet aggregation, is given
(Pharmacodynamic) therapeutic e ect o another drug concomitantly with heparin, an anticoagulant, there may be an
increased risk o bleeding
CASE 3-3
A 38-y -old n ng d o zu d o d w h z n .
CLASSIFICATION Al hough h zu qu n y d d, v l o d dd d o u h du
OF DRUG–DRUG h zu qu n y.
INTERACTIONS
a. Is a drug–drug interaction o concern in this patient?
• Additive—the combined ef ect o 2 drugs
equals the sumo the ef ect o each agent P n o only d w h o h n 1 d ug, h v nd v du l d y
given alone ho , nd y l o u ng ov - h - oun (O C) d on , v n ,
nd o h “n u l” u l n .T oly h u ln u o h l h
• Synergistic—the combined ef ect o qu on d on o o n l d ug n on ( F gu 3-4).
2 drugs exceeds the sumo the ef ects
o each drug given alone A d ug n qu n ly nf u n h ol o 1 o v l o h d ug (
Ch 2), nd h lly no l w h h CYP . A no h n
• Potentiation—the creation o a toxic lly n o d y CYP2E1 o h ox ol NAPQI ( F gu 3-6).
ef ect o 1 drug due to the presence o In k o h nol, o n ndu o h 2E1 o nzy , y l d o n d
another drug u l y o no h n o on ng ov do . S l ly, nu o
• Antagonism—the inter erence o 1 drug ond-g n on dn n h n ( n dn , zol ) w ov d
with the action o another drug o h k wh n h y w no d o l d o Q n v l olong on nd
»Chemicalantagonism—reactionbetween hydy hy h wh n o d n dw h ol d n o .
2 chemicals to neutralize their ef ects b. What are the di erent types o drug–drug interactions?
»Dispositional antagonism—alteration D ug n on g n lly nvolv d ug o on, o n nd ng, o-
o the disposition o a substance sothat l , o nd ng, o h u on ( S d B DRUG–DRUG
less o the agent reaches the target organ IN ERAC IONS). Fu h d ug–d ug n on n l d dd v ,
»Receptor antagonism—blockade o the yn g , o n on, o n gon ( S d B CLASSIFICA ION OF
ef ect o 1 drug with another drug that DRUG–DRUG IN ERAC IONS).
competes at the receptor site
48
Clinical and Environmental Toxicity CHAPTER 3
CH3 OH H3 C CH2 OH
Me tha nol Ethano l H2 O 2
+ NADP H
NAD
+ O2
Fome pizole Alcohol Ca ta la s e
X de hydroge na s e CYP 2E1
NADH
+ NADP H 2H2 O
H+ O + H2 O
H2 C O H3 C CH
Forma lde hyde Ac e talde hyde
NAD+
Alde hyde
de hydroge na s e X Dis ulfira m
NADH
+ O O
H+
HC OH H3 C C OH
Fola te -de pe nde nt Formic a cid Ac e tic ac id
pa thway CoA + ATP
CO 2
+ Thiokina s e
H2 O
AMP + 2P ;
C
β-hydroxy-β-me thyl CoA S C CH3 Trica rboxylic
gluta ryl CoA a cid cycle
Ac e tyl Co A
Fa tty a cids
Ke tone Chole s te rol
bodie s
CASE 3-4
A 20-y -old n go o oll g y. A on h yo o k h
un h o n unl l d k. An hou l h n x n ng n n n h d-
h nd lu d v on. H k n o h g n y oo wh d n d h
h h n o on d w h h nol.
a. How does methanol produce toxicity?
On on l ohol, h nol (CH 3OH), l o known hyl nd wood l ohol.
I n o n ndu l g n nd olv n ound n odu u h n
ov , h ll , nd n z ; h nol dd d o ndu l-u h nol o
k un o hu n on u on.
Sv ol do n d v lo du o h u ul on o o d(
F gu 3-5), nd h o yd on n v , lly n h on x
o o .T v u ld u n o dw h h nol n ox on o -
n n o h ln l u nd o u on qu n o nju y o g ngl on
ll o h n u d y h ol , o d, w h u qu n nf -
on, o hy, nd o n l l l l ndn .
b. What are the signs and symptoms o methanol poisoning?
M h nol o on ng on o h d h , GI d , nd n( lly l d o
n nju y), d ul y h ng, l n , nd lu d v on o d
w h hy o d k .T ln l u n l o n lud n o o
h n .
(Continued)
49
SECTION I General Principles
ac e tamino phe n
HNCOCH3
HNCOCH3 HNCOCH3
OH
CYP
s ulfa te glucuronide
NCOCH3
NAP QI
(toxic
inte rme dia te )
FIGURE 3-6 Pathways o acetaminophen metabolism and toxicity. The toxic intermediate
NAPQI is N-acetyl-p-benzoquinoneimine.
CASE 3-5
A 16-y -old wo n ough o h g n y oo u h ook n ov do
o no h n. H v l gn no l nd h l x o ng
d ugh h v ng d u d .
a. What are the general principles o the management o a poisoned patient?
T jo y o o on ng x o u o d o US o on on ol n
judg d o non ox o only n lly ox . Wh n ox y x d, o do
o u, h o y o o on ng n o u o v l un on un l h
d ug o h l l n d o h ody. B u o h u on o on
nd n du on o on o o d ug , h n o o on ng u
o nd go l d d. T go l o o v l hy olog l un on
o n .T ond go l o k h on n on o o on n u
low o l y v n ng o on nd nh n ng l n on. T h d
go l o o h ox olog l o h o on h o .
(Continued)
50
Clinical and Environmental Toxicity CHAPTER 3
Opioids
Benzodiazepines
Alcohol
Antidepressants
U.S. DHHS.
Knowl dg o h l v ox y o d ug h g nn ng o h o n g-
n o o on d n . T ollow ng l u hu n o on ng n -
v: l 3-4 l h o 5 g n nvolv d n d ug- l d d h ; l 3-5 l
h u n o qu n ly nvolv d n hu n o on ng x o u ; l 3-6
l h o on o d w h h l g nu o hu n l .
T “ABC” n on o gn y ( w y, h ng, ul on) o u-
l ly ugh nd l o h n o u o on ng, u w h h dd on
o l n D (d l y) nd E ( x o u ) ( l 3-7). In v , ndo -
h l nu on, h n l v n l on, h olog l lood u u o ,
nd/o x o o l ul o y u o y n y nd o .
A ully o n d d lh o y y l o v l l d on o
h l h gh l d n o on ng v n . O n, n o v on o
hy l y o nd gn y h only dd on l lu o o on ng d g-
no . G ou o hy l gn nd y o o dw h o on ng
ynd o known ox d o . l 3-8 d o only n oun d
ox d o .
T o y lly v l l u n d ug ox ology n uno y d gn d
od o on d ug o u u h h n , u , nzod -
z n , nn , o n , nd o .A u o on ng w h h u n
n u u lly d n d on l n l g ound , nd h ul o h y
n qu n ly v l l nough o gu d l z on. Add on lly, d on o
d ug o h ol on u n uno y do no n h h d d
d ug on l o h u n ly o v d o on ng lln . Wh n ng on
(Continued)
Sedatives/hypnotics/antipsychotics 6.2
Antidepressants 4.0
Data rom Bronstein AC, Spyker DA, Cantilena LR, et al. 2007. Annual Report o the American
Association o Poison Control Centers’National Poison Data System (NPDS): 25th annual report.
Clin Toxicol, 2008, 46:927–1057.
51
SECTION I General Principles
TABLE 3-6 Poisons Associated with the Largest Number of Human Fatalities
Sedatives/hypnotics/antipsychotics
Acetaminophen
Opioids
Antidepressants
Cardiovascular drugs
Alcohols
Bronstein AC, Spyker DA, Cantilena LR, et al. 2007. Annual Report o the American Association
o Poison Control Centers’National Poison Data System (NPDS): 25th annual report. Clin Toxicol,
2008, 46:927–1057.
o no h n o n nno l ly x lud d v h x o u h o y,
u qu n on o h d ug o nd d. An l o d og (ECG)
y u ul d ng h lo k , N + h nn l lo k d , o K+ h nn l lo k-
d o dw h d on l . Fu h l o o y n ly , u h
u o lood g d n on , u h , o l lood oun , nd
oh ng, hould lo d o h nd v du l o on ng u n .
b. How are the principles o absorption, distribution, metabolism, and elimination
di erent or a drug a er excessive exposure than a er a therapeutic dose?
T n l o h ok n ( o on, d u on, ol , nd
l n on) d d n Ch 2. ox ok n (h h ok n o
d ug und u n h odu ox y o x v x o u ) yd
gn n ly o on ng, nd h d n y o oundly l n
d on nd ogno . Ing ng l g h n h u do o h u -
l y olong o on, l o n nd ng nd n volu o
d u on, nd h ng ol .
Wh n on on d w h o n l o on ng, 2 ox ok n qu on hould
o o n h l n n’ nd:
• How long do n y o n n d o on o d (d ug o on
nd dyn )?
• How long w ll k n n ox d n og (d ug l n on nd
dyn )?
(Continued)
52
Clinical and Environmental Toxicity CHAPTER 3
HR, heart rate; BP, blood pressure; RR, respiratory rate; T, temperature. aSLUDGE, muscarinic e ects o Salivation, Lacrimation, Urination,
De ecation, Gastric cramping, and Emesis.
CASE 3-6
A 2-y -old-g l ough o h g n y oo f ng ng o o h g-
n n o h ’ on l .
a. How should iron poisoning be established in this patient?
A h o y o ng on y n qu n ly u n o n h y. A on-
on o h d gno d w h h u n o l on.
In h v lu on o h ld hough o h v ng d on, olo o on n
h g on n nd n g n yd n on o h on n on o on
n l n o d. I h l l h n 63 µ ol (3.5 g/L), h h ld
no n d d ng . How v , vo ng hould ndu d wh n h
on n h o h, nd n x- y hould k n o v lu h nu o ll
n ng n h ll ow l ( on l d o qu ).
L g oun o ou l ox , u l n dul . Mo d h
o u n h ld n, ul ly w n h g o 12 nd 24 on h . A l l 1
o 2 g o on y u d h, u 2 o 10 g u u lly ng d n l .T
qu n y o on o on ng l o v l l y n h hou hold, ul ly
(Continued)
54
Clinical and Environmental Toxicity CHAPTER 3
h u ly h n gn n y. T olo d ug o ng o ny o h
o lly v l l l gv h h n o ndy. All on -
on hould k n h ld oo o l .
b. What are the signs and symptoms o iron poisoning and how does iron produce
toxicity?
S gn nd y o o v o on ng y o u w h n 30 nu ng -
on o y d l y d o v l hou . T y n lud do n l n, d h , o
vo ng o own o loody o h on n on n ng ll . O ul on-
n llo o y no , l ud , d ow n , hy v n l on du o do ,
nd d ov ul oll . I d h do no o u w h n 6 hou , h y
n n od o n ov y, ollow d y d h n 12 o 24 hou . T o-
o v nju y o h o h y ul n ylo no o g ng. H -
o h g g o n nd h d g o n n nd ng u o y.
c. How should this patient be treated?
I on n h u GI n d y l v g w h od u on o
ho h olu on, l hough h l n l n qu on l . Wh n h l
on n on o on g h n h o l on- nd ng y (63 µ ol; 3.5
g/L), d ox n hould d n d. Sho k, d hyd on, nd d-
no l hould d n h onv n on l nn . Mo o n h
d o d gno nd h y. W h ly v n, h o l y o
on o on ng n du d o h gh 45% o low 1%.
D ox n ol d h on h l o Streptomyces pilosus nd
d h lly o o n h l- l g nd. D ox n h h d l
o o k ly h gh n y o on (K = 1031) ou l d w h
v y low n y o l u (K = 102). In v o, ov on o h o d n
nd n nd, o l x n, o n n. I on n h oglo n o y o-
h o no ov d y d ox n .
D ox n oo ly o d o l d n on, nd n l d n -
on qu d. Fo v on ox y ( u on l v l g h n 500 µg/dL), h
n v nou ou d. T d ug d n d 10 o 15 g/kg/hou y on-
n n u on. F o n u on (45 g/kg/h) h v nu d n w ; d
olu u u lly o d w h hy o n on. D ox n y gv n n u-
ul ly n od ly ox ( u on 350-500 µg/dL) do o 50 g/kg w h
x u do o 1 g. Hy o n on l o n o u w h h n u ul ou .
d. What are the toxic e ects o de eroxamine therapy?
D ox n u nu o ll g on , n lud ng u u , wh l , h,
nd n hyl x . O h dv n lud dy u , do n l d o o , d h ,
v ,l g , nd hy d . O on l o o on h v n
o d. D ox n y u n u o ox y du ng long- , h gh-do h y
o n u on-d nd n h l jo ; o h v u l nd ud o y h ng h v
nd d. A “ ul on y ynd o ” h n o d w h h gh-do (10-25
g/kg/h) d ox n h y; hy n , hy ox , v , nd o no h l
o n n y o . Con nd on o h u o d ox n n lud n l n u -
n y nd nu ; du ng gn n y, h d ug hould u d only l ly nd d.
CASE 3-7
A 48-y -old nh o un y- qu d n u on . H d no l
n ll n odu . W h n 15 nu o k ng h do , h d v lo gh n n
h h , nd nu n nd w ll ng o h l . H w ll g n y v ;h
d n h ho nd n o d o h ho l.
a. What are the di erent types o adverse reactions to medications?
T d n y o ox y o d ug n lud do -d nd n on h y
n x n on o d ug’ h u , holog l ox y, g no ox y,
(Continued)
55
SECTION I General Principles
ll g on , nd d o yn on ( Sd B YPES OF HERA-
PEU IC DRUG OXICI Y).
b. He does not remember ever-receiving penicillin be ore so what type o reaction
is this?
H yh v v d n ll n h ld nd no known wh h d on
w . An ll gy n dv on h ul o v ou n z on
o ul h l o o on h u u lly l . Su h on
d d y h un y . Fo low- ol ul -w gh h l o u
n ll g on, o ol odu u u lly h n, o n ng
w h n ndog nou o n o o n n g n o l x. Su h n g n ndu
h yn h o n od , u u lly l n od o l 1 o2w k .
Su qu n x o u o h h l ul n n n g n- n ody n on h
ovok h y l n on o ll gy. Do - on l on h u u lly
no n o h ovo on o ll g on . All g on h v
n d vd d n o4g n l go d on h h n o unolog l
nvolv n ( Sd B YPES OF HERAPEU IC DRUG OXICI Y).
An hyl x d d y IgE n od . T F o on o IgE n nd o -
o on ll nd o h l .I h F o on o h n ody ol ul h n
nd n g n, v ou d o ( g, h n , l uko n , nd o gl nd n )
l d nd u v od l on, d , nd n nf o y on . T
n g o h y o on h g on n l (GI) ( ood ll -
g ), h k n (u nd o d ), h o y y (hn nd
h ), nd h v ul u ( n hyl ho k). T on nd o o u
qu kly h ll ng w h n n g n o wh h h nd v du l h n n z d
nd d d hy n v y on .
c. What would be the treatment or this type o reaction?
T u o n h n o d ly d ug- ndu d n hyl x n o-
du d n Ch 7 o Goodman and Gilman’s T e Pharmacological Basis o T era-
peutics, 12 h Ed on.
CASE 3-8
A 56-y -old wo n v ou ly d v lo d v h o o yo n f v ng
ul hox zol - ho x d-do odu (sept r a ) o u n y n -
on. Sh now n h ho l o h l n u g y. H ho l h h
k “All g o sept r a ” on h on ov . Follow ng h u g y h d v lo
u n y n on nd g v n ba ct r im.
a. What is the issue with the administration o BACTRIM to this patient?
ba ct r im no h d n o x d-do o n on o ul hox zol -
ho ( Ch 38). So h hould on n h ba ct r im w ll u
h y o dv on sept r a . T y o d on o o v -
ou ly v n l nd o h l k o knowl dg y ho l ou h
d on ng d n d. In h , n ly h h y h
d d no know h h n h d h o yo o on o sept r a , o h
ba ct r im w l odu .
b. How can medication errors be avoided?
Ov h d d on d l n on h n g v n o h du on o d-
on o nd dv d ug v n (ADE ). M d on o n o u n ny
o h d on ng o u o , wh l ADE nju l d o
h u o nonu o d on . I l vd h d on o 50 o 100
o o on h n ADE . So ADE , u h v ou ly unknown ll g ,
un v n l , u o d on o n v n d. d on lly, h
“5 R gh ” o d on d n on h v n ugh on ho lw d :
Right drug, right patient, right dose, right route, right time. (Continued)
56
Clinical and Environmental Toxicity CHAPTER 3
Good medication use practices have mandatory and redundant checkpoints, such
in children
as having a pharmacist, a doctor, and a nurse all review and con rm that an ordered
dose o a medication is appropriate or a patient prior to the drug’s administration. » Neuromuscular de ects—lead palsy
In such a system, medication errors occur only when several “holes” in the medica- » Encephalopathy
tion administration sa eguards exist and are simultaneously aligned. Several practical • Cardiovascular e ects
strategies have been suggested to reduce medication errors within hospitals and other » Increased blood pressure
health care settings (see able 3-9), and these strategies are being constantly revised.
• Renal e ects
Depressed glomerular fltration
CASE 3-9
»
• Hematological e ects
A 3-year-old boy is brought to a medical clinic because of the recent onset of lethargy
and behavior changes. T e diagnosis of lead intoxication is made.
» Hypochromicmicrocyticanemia
» Immunosupression
a. How could this child have been exposed to lead?
• Gastrointestinal e ects
In the United States, paint containing lead or use in and around households was
» Severe intestinal pain—lead colic
banned in 1978, while the use o tetraethyl lead in gasoline was phased out and even-
tually eliminated between 1976 and 1996. T e economic bene t o the reduction in • Carcinogenesis
lead exposure due to these 2 measures is estimated at hundreds o billions o dollars » Probablycarcinogenicto humans—
per year. Despite these bans, past use o lead carbonate and lead oxide in paint and cancers o lung, brain, kidney,
tetraethyl lead in gasoline remain the primary sources o lead exposure. Lead is not and stomach
degradable and remains throughout the environment in dust, soil, and the paint o
older homes. Young children of en are exposed to lead by nibbling sweet-tasting paint
chips or eating dust and soil in and around older homes. Renovation or demolition
o older buildings may cause substantial lead exposure. etraethyl lead was used as
an antiknock agent in gasoline, which resulted in high levels o lead in air pollution.
Removal o lead rom gasoline caused lead levels in air pollution to drop by more
than 90% between 1982 and 2002. Lead was commonly used in plumbing and can
leach into drinking water. Acidic oods and beverages dissolve lead when stored in
containers with lead in their glaze or lead-soldered cans, which was a signi cant
problem through the middle o the 20th century and remains a problem in develop-
ing countries. Lead exposure also has been traced to other sources such as lead toys,
(Continued)
TABLE 3-9 Best Practice Recommendations to Reduce Medication Administration
Errorsa
Short Term
• Maintain unit-dose distribution systems for nonemergency medications
• Have pharmacies prepare intravenous solutions
• Remove inherently dangerous medications (eg, concentrated KCl) from patient care areas
• Develop special procedures for high-risk drugs
• Improve drug-related clinical information resources
• Improve medication administration education for clinicians
• Educate patients about the safe and accurate use of medications
• Improve access of bedside clinicians to pharmacists
Long Term
Implement technology-based safeguards:
• Computerized order entry
• Computerized dose and allergy checking
• Computerized medication tracking
• Use of bar codes or electronic readers for medication preparation and administration
http://macoalition.org/documents/Best_Practice_Medication_Errors.pdf
57
SECTION I General Principles
S uccinyl CoA + Glycine non-Western olk medicines, cosmetics, retained bullets, artists’ paint pigments,
ashes and umes rom painted wood, jewelers’ wastes, home battery manu acture,
δ-a minolevulina te syntha s e
and lead-type. Blood lead levels in the general population have steadily decreased
δ-Aminolevulina te (δ-ALA) since the 1970s. Between 1976 and 2002, mean blood levels in children 1 to 5 years o
age dropped rom 15 to 1.9 µg/dL. T e Centers or Disease Control and Prevention
δ-a minolevulina te de hydra ta s e (CDC) recommends screening o children at 6 months o age and the use o aggres-
sive lead abatement or children with blood lead levels greater than 10 µg/dL.
Porphobilinoge n
porphobilinoge n de a mina s e
Lead exposure occurs through ingestion or inhalation. GI absorption o lead var-
uroporphyrinoge n III cosyntha s e ies considerably with age and diet. Children absorb a much higher percentage o
ingested lead (~40% on average) than adults (<20%).
Uroporphyrinoge n III
uroporphyrinoge n de ca rboxyla s e
b. What is the mechanism o lead toxicity?
Lead toxicity results rom molecular mimicry o other divalent metals. Lead takes
Coproporphyrinoge n III the place o zinc or calcium in a number o important proteins. Because o its size
coproporphyrinoge n oxida s e and electron a nity, lead alters protein structure and can inappropriately activate
or inhibit protein unction. Speci c organ systems that are targets or lead are CNS,
Protoporphyrin IX cardiovascular, renal, hematopoietic, and gastrointestinal.
fe rroche la ta s e + Fe 2+ c. What are the health ef ects o lead poisoning?
Figure 3-7 shows the sites o action o the actions o lead on heme biosynthesis.
He me Lead causes a hypochromic microcytic anemia. Figure 3-8 shows the health e ects
Action produce d by le a d:
o lead poisoning in relation to the blood lead concentration.
Inhibition
Pos tula te d inhibition
d. What are the treatment options or this patient?
FIGURE 3-7 Heme biosynthesis and T e most important response to lead poisoning is removal o the source o lead
actions o lead. Lead inter eres with the exposure. Supportive measures should be undertaken to relieve symptoms.
biosynthesis o heme at several enzymatic Chelation therapy is warranted or children and adults with high blood lead levels
steps. Steps that def nitely are inhibited (>45 µg/dL and >70 µg/dL, respectively) and/or acute symptoms o lead poisoning.
by lead are indicated by black blocks.
Although chelation therapy is e ective at lowering blood lead levels and relieving
Steps at which lead is thought to act but
where evidence or this is inconclusive are immediate symptoms, it does not reduce the chronic e ects o lead beyond the bene t
indicated by blue blocks. o lead abatement alone. In rats, chelators enhance mobilization o lead rom the sof
tissues to the brain and may increase the adverse neurodevelopmental e ects o lead.
Chelators e ective in treating acute lead poisoning are listed in the Summary able
at the end o the chapter.
de a th
100 e nce pha lopa thy
e nce pha lopa thy fra nk a ne mia
ne uropa thy
fra nk a ne mia longevity
colic 50 he moglobin synthe s is
CASE 3-10
A 12-month-old boy is brought to the hospital because of weakness, nausea, vomiting,
diarrhea, and dyspnea for the past week. His father admitted to bringing home elemen-
tal mercury so that his older children could shine silver coins. T e older children
admitted to pushing the liquid mercury around the table some of which fell onto the
carpet. So that it would not be detected the older children spread it around with their
feet. Neither the parents nor the 3 older children were ill. A 24-hour urine collected
from the toddler showed an elevated mercury concentration.
a. Why was the youngest child intoxicated when the older children or the adults
were not?
Most likely it is because he was crawling or close to the oor which would have the
highest concentration o mercury vapor.
Figure 3-9 shows the health e ects o mercury in relation to the concentration in
air and the corresponding urinary concentrations.
Metallic mercury (Hg0) vapor is readily absorbed through the lungs (~70-80%),
but GI absorption o metallic mercury is negligible. Once absorbed, Hg0 distributes
throughout the body and crosses membranes such as the blood-brain barrier (BBB)
and the placenta via di usion. Hg0 is oxidized by catalase in the erythrocytes and
other cells to orm Hg2+. Shortly a er exposure, some Hg0 is eliminated in exhaled
air. A er a ew hours, distribution and elimination o Hg0 resemble the properties
o Hg2+. A er exposure to Hg0 vapor, it is oxidized to Hg2+ and retained in the brain.
Inhalation o high levels o mercury vapor over a short duration is acutely toxic to
the lung. Respiratory symptoms o mercury exposure start with cough and tight-
ness in the chest and can progress to interstitial pneumonitis and severely com-
promised respiratory unction. Other initial symptoms include weakness, chills,
metallic taste, nausea, vomiting, diarrhea, and dyspnea. Acute exposure to high
doses o mercury is toxic to the CNS with symptoms, including tremor, emotional
lability, insomnia, muscular atrophy, parathesia, and cognitive def cits.
b. How can this exposure be limited?
It is unlikely that the metallic mercury can be removed by cleaning the carpet in
place. T e carpet will need to be removed rom the house and discarded properly.
(Continued)
Co nc e ntratio n o f Me rc ury
Air (µg/m 3 ) Urine (µg/L)
TARGET ORGAN EFFECTS
lung 1100 a cute a ffe cts : pne umonitis
ne rvous sys te m e re this m; gros s tre mors
ora l tis s ue s gingivitis
kidneys ne phrotic syndrome
le ns of eye 500 me rcuria le ntis
200
pe riphe ra l ne uropa thy
100 de cre a s e d ve rba l e nzymuria
ne rvous sys te m inte llige nce s core s
& kidneys
50 EEG cha nge s
(s lowe r &
tre mor a tte nua te d
25 re s pons e )
59
SECTION I General Principles
CASE 3-11
A 33-y -old n, n ly vd o K ny , u d o h v ng l v n
du o ox n B1 x o u .
a. What are some common carcinogens? How do environmental contaminants
cause cancer?
F gu 3-10 how h h l d o n nv on n l nog n x o u
o nog n . l 3-2 l o o n nog n .
b. How do humans become exposed to excessive amounts o af atoxin B1?
Af ox n odu d y Aspergillus f avus, ungu h o on on -
n n o ood , lly o n, nu , o on d, nd nu . A. f avus un-
d n n g on w h ho nd w l , nd ul , h o llul no
ou o l n u o l nd o l g on o L n A ,A ,
nd Sou h A . Hu n x o u o f ox n n h Un d S v y
nd no hough o h v gn n on h l h.
c. What is the mechanism by which af atoxin B1 is thought to be carcinogenic?
T h n o f ox n nog n h n x n v ly ud d (
F gu 3-11). T 8,9- ox d o f ox n B1 d ly w h n n olog -
l o ol ul . Af ox n B1 8,9- ox d o ddu w h d oxygu no n
nd l u n h n d d n h lood o u n o hu n nd l o o y
n l x o d o f ox n, ov d ng v d n o h v yo h hw y n
v vo. Af ox n ly o DNA ddu d oxygu no n du , -
ng h h N1 o N7 o on. T N7-gu n n ddu w h d nn ,
l d ng o G → n v on . Hu n f ox n x o u o dw hh -
o llul no ng n AGG o AG u on n odon 249 o h 53
(Continued)
Ce ll
De ath
Me tabo lic
Ac tivatio n
Ca rcinoge n
DNA Adduc t Clo nal Ang io g e ne s is
Expos ure Abs o rptio n Mutatio ns Me tas tas is
Fo rmatio n Expans io n & Invas io n
(Ge notoxic)
Me tabo lic
De to xific atio n
DNA Re pair
FIGURE 3-10 Carcinogenesis: initiation and promotion. There are many steps that occur
between the exposure to a genotoxic carcinogen and the development o cancer. Processes
in gray lead to the development o cancer, while those in blue reduce the risk. Nongenotoxic
carcinogens act by enhancing steps leading to cancer and/or inhibiting protective processes.
A chemopreventive agent acts by inhibiting steps leading to cancer or by increasing protective
processes.
60
Clinical and Environmental Toxicity CHAPTER 3
O DNA
O O
A. fla vus H
in fo o d DNA Adduc ts
Abs o rptio n CYPs
O 1A2, 3A4 O
CH3 CH3
P rima ry H O O O O
P re ve ntion Aflato xin B 1 Aflato xin B 1
in live r e po xide
Albumin
Albumin
adduc ts
FIGURE 3-11 Metabolism and actions o a atoxin B1. Following absorption, a atoxin B1 under-
goes activation by CYPs to its 8,9-epoxide, which can be detoxi ed by glutathione S-trans erases
(GSTs) or by spontaneous hydration. Alternatively, it can react with cellular macromolecules such
as DNA and protein, leading to toxicity and cancer. Oltipraz, green tea polyphenols (GTPs), and iso-
thiocyanates (ITCs) decrease a atoxin carcinogenesis by inhibiting the CYPs involved in activating
a atoxin and increasing the synthesis o the co actor GSH or GSTs involved in detoxi cation.
u o u o g n , ul ng n h l n o n gn n w h y n .
T u on l o n v o v d n g og h l g on w h l d
f ox n x o u .
Af ox n x o u nd h B v u wo k yn g lly o u h o llul
no . M ny o h g on w h l v d f ox n x o u l o h v h gh
l v l o nd h B n on. S ly, f ox n o h B x ou
n h ko h o llul no 3.4- o 7.3- old, v ly; ho
x o d o o h h v 59- old n d ko n o d o un x o d
nd v du l .
T n on w n f ox n nd h B h on l o h
n d n d n o h o llul no no w ll und ood. H
B nf u n h ol o f ox n B1 y u gul ng CYP , n lud ng 3A4,
nd d ng glu h on S- n v y. In dd on, h o llul ol -
on o d g don y h B n on n h l k l hood h
f ox n- ndu d DNA ddu w ll u u on . T h o ox nd u o -
o o ng o h B l o ould ov d o vo l nv on n
o h ol on nd nv on o n d ll .
d. What treatment options are available or a person likely to be exposed to af atoxin?
T l l on h w n f ox n ol ( F gu 3-11) nd -
nog n y k n l ng g o h o v n v g h od y
ol . Inh ng CYP v yo n ng glu h on onjug on w ll
du h n llul on n on o h 8,9- ox d nd hu v n DNA
ddu o on. Ol z, g n oly h nol (G P ), nd o h o y n
(I C ) d f ox n nog n y nh ng h CYP nvolv d n v -
ng f ox n nd n ng h yn h o h o o GSH o GS nvolv d n
d ox on ( F gu 3-11).
Ch o v n on o h o llul no n o l x o d o f ox n l o
n h v d yl ng n on w h h B. B u o h ong n -
on w nh B nd f ox n n nog n , h h Bv n
w ll du h n v y o o l o h ndu on o n y f ox n. P y
v n on o f ox n x o u h ough h nd o f uo n o ng o o o
ov ho w h ung l on n on n l o du hu n x o u . A o
o - v y v n on o h o ov ood o g o l h
d o A. f avus, wh h qu w nd hu d nv on n .
(Continued)
61
SECTION I General Principles
Y no h o h u d o h h o v n on o f ox n h o no-
gn h u o “n o ol ul .” Chlo o hyll n, n ov - h - oun
x u o w - olu l hlo o hyll l , nd gh ly o f ox n n h GI ,
o ng o l x h no o d ( F gu 3-11).
KEY CONCEPTS
Ph ology n w h ox ology wh n h hy olog l on o
d ug n dv .
T h u nd x ( I) qu n h l v yo d ug.
ox ok n (h h ok n o d ug und u n h o-
du ox y o x v x ou ) yd gn n ly f o on ng.
T o h l o v d nl o oy n l , wh n o ly qu l -
d, ly o hu n ox y.
Ex o u o x n l n l o ox g n n h gh do n y
nd v l d hod o d ov o l h z d o hu n x o d o u h
low do .
F d l l w n h Un d S nd h l on d on qu h h udy
o n w d ug n hu n ondu d n o d n w h ng n gu d l n (
S d B GUIDELINES FOR HE S UDY OF NEW DRUGS IN HUMANS).
M d on o l vd o 50 o 100 o o on h n
dv d ug v n .
T o yo o on ng n o u o v l un on un l h d ug o
h l l n d o h ody; n do un o only n d d.
W h nv on n l x o u , on h o on d o ul on x o u o
low-do ox n ov long od o .
T n o on o no l ll o l gn n y ul g o ,
nd xog nou h l n 1o o o h g .
M l n o n l o nv on n l ox n ; h y u qu ou nv -
on n l on n n h o o o h n u l nd n h o og n ou .
T o o n on o x ou o l o l n h ou o
h x ou .
n o u l n ox on of n nvolv h u o h l o .
Follow ng h on x o u o ox l , h l on h y do no how
ln l n yond ho o on o x o u lon , nd n o
y do o h h n good.
SUMMARY QUIZ
QUESTION 3-2 A o h w h 3 h ld n l h n h g o 5y on n d
ou g o v n o on ng n h h ld n. On v gy o
. ll h h ld n no o k d n unl gv n o h y n dul .
. k ll d n n h gh n .
62
Clinical and Environmental Toxicity CHAPTER 3
. k n h ll d n n h ld- n k g.
d. k ll l n ng odu und h k h n nk nd ll h h ld n no o o n
h doo .
. k d n h g g.
63
SECTION I General Principles
. y n .
d. l u n .
. do n .
QUESTION 3-2 An w c. Po on ng v n on g y go z d ng
v , qu ng no h v o h ng on h o h nd v du l, o v , qu -
ng u n d d on o u ul. P v v n on g h o
v , nd v l y o v o on ng v n on d d n l 4-7
n Ch 4 o Goodman and Gilman’s T e Pharmacological Basis o T erapeutics, 12 h
Ed on. On v gy o k n h ll d on n h ld-
n on n .
QUESTION 3-3 An w d. Of n, n o v on o hy l y o nd gn y
h only dd on l lu o o on ng d gno . G ou o hy l gn nd
y o o dw h o on ng ynd o known ox d o .
l 3-8 d o only n oun d ox d o .T n h h h -
gn nd y o o o g no ho h o on ng.
QUESTION 3-4 An w b. T
“ABC” n on o gn y o ul ly
ugh nd l o h n o u o on ng ( l 3-7). In v ,
ndo h l nu on, h n l v n l on, h olog l lood u u -
o , nd/o x o o l ul o y u o y n y nd o .
QUESTION 3-5 An w e. ED A C N 2 v o h n o u l d o-
on ng, ul ly n o n on w h d ol, u no n v h l o o
u yo n n v vo.
64
Clinical and Environmental Toxicity CHAPTER 3
65
SECTION I General Principles
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE: CLINICALLY IMPORTANT
Heavy Metal Dimercaprol Used to treat acute exposures Increased blood pressure Pain ul sterile abscess at injection site
Chelators to arsenic, gold, mercury, and Nausea, vomiting, Contraindicated or treatment o
in combination with EDTA headache, burning chronic exposure to heavy metals
CaNa2 to treat lead exposure sensation in mouth and because it does not prevent
throat, and abdominal pain neurotoxic e ects
Penicillamine Used or treatment o Dryness and scaling o skin Long-term treatment results in
exposure to copper, mercury, cutaneous reactions such as urticaria,
zinc, and lead maculopapular reactions, pemphigoid
lesions, lupus erythematosus, and
dermatomyositis
Dimercaptosuccinic acid Approved or the treatment Nausea, vomiting, diarrhea, Transient elevations in hepatic
(DMSA), Succimer o children with acute lead and loss o appetite transaminases
poisoning
Used o label or treatment o
adults with lead, arsenic, and
mercury poisoning
a
carcinogens are not appropriate or this summary table. Only the toxicities o select heavy metals are shown.
66
CHAPTER
Special Populations
(Children and Elderly) 4
T ere is no speci c chapter on the topic o pharmacotherapy o special populations
PEDIATRIC
(children and elderly) in Goodman & Gilman’s T e Pharmacological Basis of T era-
peutics, 12th Edition. However, this is an important area o clinical pharmacology PHARMACOKINETICS—
because the pharmacotherapy o children and the elderly requires consideration o the ABSORPTION
di erences in pharmacokinetics and pharmacodynamics that can signi cantly a ect • Absorption o drugs romthe gastrointes-
the sa ety and e cacy o drugs used in these special populations. Moreover, most ran- tinal (GI) tract is reduced in neonates and
domized controlled clinical trials exclude young children and the aged, which makes it changes with maturation making predic-
di cult or the clinician to make evidence-based decisions regarding appropriate drugs tion o medication bioavailabilityo orally
and dosing regimens to use in these patients. administered drugs verydi cult.
T e content o this chapter is drawn rom a variety o sources, including a number o » Young children have higher gastricpH
chapters in Goodman & Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edi- than adults; adult levels o gastricacidity
tion including Chapters 1 to 3 in Section I: General Principles, and later chapters in are not reached until 3to7years o age.
which the pharmacotherapy o children or the elderly is discussed in the context o » Acid-labile drugs (eg, penicillin,
speci c agents. Content regarding general principles o pharmacotherapy in these ampicillin, and na cillin) have greater
special populations is drawn rom online Updates published as part o the online version bioavailability.
o Goodman & Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition related to » Weakacids (eg, phenobarbital,
pediatric pharmacology (speci cally, T e History of Pediatric Drug T erapy: Learning from phenytoin) are ionized in the GI tract
Errors Not rials and Pediatric Pharmacokinetics: Why Kids Are Not Small Adults), and rom o the neonate and young child and
Hazzard’s Geriatric Medicine and Gerontology, 6th Edition (speci cally, Chapter 8 General thus are more slowlyabsorbed than
Principles o Pharmacology and Chapter 24 Appropriate Approach to Prescribing). in adults.
Neither a Mechanisms o Action able nor a Clinical Summary able is included in this
» Weakbases(eg, penicillin, ampicillin,
chapter because this in ormation is provided or speci c agents in subsequent chapters.
anderythromycin) will be more quickly
In addition to the material provided here, Goodman & Gilman’s T e Pharmacological
absorbedthaninthe adult GItract.
Basis of T erapeutics, 12th Edition contains:
» Neonatesandin antshave prolongedrates
• Appendix II with pharmacokinetic data or a number o drugs with di erences in
o gastricemptyingcomparedtoadults,
pharmacokinetic parameters that occur in children, the aged, and individuals with
withadult rateso gastricemptyingnot
speci c disease states
developinguntil 6to8monthso age.
Hazzard’s Geriatric Medicine and Gerontology, 6th Edition contains: » Biliary unction develops over the rst
• able 8-5 Changes in Pharmacokinetics and Pharmacodynamics with Aging and month o li e; the reduced levels o bile
Suggested Dose Adjustments or Older Patients acid salts and pancreaticenzymes in the
neonate mayreduce the absorption o
LEARNING OBJECTIVES lipophilicdrugs.
Describe the important pharmacokinetic and pharmacodynamic di erences » β-Glucuronidase and UDP-glucuronyl
between adults and children that can a ect sa ety and e cacy o drugs used in trans erase have higher activities in the
in ants and children. neonate GItract than in adults which
mayreduce drug absorption.
Know the FDA’s role in providing in ormation to clinicians to improve sa e and
e ective use o drugs in young children, including breast- eeding in ants. » The development o intestinal ora in
the neonate, which depends primarily
Describe the important changes in the pharmacokinetics and pharmacodynamics
on diet, can contribute to dif erences in
o drugs that occur in older adults.
drug metabolismcompared with adults.
Know the classes o medications that should be avoided in older adults because • Dermal absorption is higher in neonates
o central nervous system (CNS) e ects. and in ants due to underdeveloped stra-
Know the steps that should be taken to optimize drug regimens in older adults. tumcorneumand increased skin hydration.
• Intramuscularinjectionsare generallyavoided
inneonates, in ants, andchildrenbecause
intramuscularabsorptionisunpredictable due
todecreasedmuscle tone andcontraction,
andvariable blood owandoxygenation.
67
SECTION I General Principles
68
Special Populations (Children and Elderly) CHAPTER 4
NSAIDs are labeled with a black box warning related to cardiovascular risks and
PEDIATRIC
are speci cally contraindicated ollowing coronary artery bypass gra (CABG)
PHARMACOKINETICS—
surgery. Patients at increased risk o cardiovascular disease or thrombosis are
likely to be particularly prone to cardiovascular adverse events while on NSAIDs. EXCRETION
T is includes patients with rheumatoid arthritis as the relative risk o myocardial • In ants and small children have reduced
in arction is increased in these patients compared to patients with osteoarthritis renal unction (20-40%o adult unction).
or no arthritis. T e risk appears to be related to actors inf uencing drug • Adult ltration rates are not reached until
exposure, such as dose, t 1/2, degree o COX-2 selectivity, potency, and treatment approximately3 years o age.
duration. T us, the lowest possible dose should be prescribed or the shortest
• Reduced renal unction in children is due to:
possible period.
» Reduced glomerular ltration rate (GFR)
b. What are the alternatives to NSAIDs in this patient?
» Tubular cell immaturity
Alternative approaches should be considered be ore NSAIDs are prescribed or
» Reduced nephron length
indications such as osteoarthritis in elderly patients. Possible non-pharmacologic
approaches, such as gentle exercise and weight reduction, may be bene cial alterna- » Reduced solute gradient
tives to treatment with NSAIDs. » Decreased responsiveness to
When pharmacologic therapy is required, a drug therapy with a less-adverse event antidiuretichormone
pro le, such as acetaminophen, should be used. • Even when normalized or bodysur ace area,
renal plasma ow, glomerular ltration,
CASE 4-3 tubular secretion, tubular reabsorption, and
the concentrating and acidi ying unctions
A 90-year-old woman develops symptoms o a cold and buys an over-the-counter cold o the kidneyare lowcompared with adults.
medication at the grocery store. T e medication contains diphenhydramine, acet-
• Renal clearance o drugs excreted almost
aminophen, and phenylephrine. She takes the recommended adult dose but soon a er
entirelybyglomerular ltration (eg, ami-
taking the medication she becomes very con used and disoriented.
noglycosides and vancomycin) will change
a. What is likely causing the signs o con usion? in a manner that corresponds to matura-
Diphenhydramine is a rst-generation antihistamine that is a common ingredient tion o renal unction.
in over-the-counter cold and allergy medications (see Chapter 21). T is agent is • Premature in ants have lower ltration
able to cross the BBB where it has signi cant anticholinergic e ects, including rates and are slowto develop the renal
con usion and somnolence. T e elderly have reduced BBB unction and are also at capacitythat termneonates will have
a higher risk o adverse drug e ects when taking drugs that have anticholinergic developed by1 weeko age.
properties. » Premature in ants require lower doses,
b. What symptoms are associated with strong anticholinergic drugs in longer dosing intervals, or both to
older patients? maintain the same steady-state plasma
concentrations as the ull-termin ant.
In the elderly, drugs with strong anticholinergic properties are associated with
adverse e ects such as con usion, dry mouth, dry eyes, urinary retention, constipa- • Excretion o drugs that depend on tubular
tion, and postural hypotension. secretion (eg, penicillins, sul onamides,
urosemide, and chloramphenicol) has
c. What other drugs have strong anticholinergic properties that should be avoided reduced rates o clearance in the neonate.
in elderly patients?
T e 2012 Beers Criteria (see Side Bar PO EN IALLY INAPPROPRIA E
MEDICA IONS FOR HE ELDERLY) lists the ollowing medications with strong
anticholinergic properties that should be avoided in older adults.
First-generation antihistamines, as a single agent or as part o a combination prod-
uct (see Chapter 21):
Brompheniramine
Carbinoxamine
Chlorpheniramine
Clemastine
Cyproheptadine
(Continued)
69
SECTION I General Principles
Dexbrompheniramine
PEDIATRIC
PHARMACKINETICS— Dexchlorpheniramine
METABOLISM Diphenhydramine (oral)
• In ants have reduced hepaticdrug metabo-
Doxylamine
lismenzymes.
• Neonatal phase 1 activity( unctionaliza- Hydroxyzine
tion reactions catalyzed byCYPs, see Promethazine
Chapter 2) are intact but not at ull
capacityuntil 6 months to 1 year o age. riprolidine
As a result, oxidation o manydrugs is
» Antispasmodics (see Chapter 6)
impaired in the neonate.
Belladonna alkaloids
Lacko one CYPenzyme maybe
»
70
Special Populations (Children and Elderly) CHAPTER 4
Reduced hepatic and renal clearance are generally the most signi cant
PEDIATRIC MEDICATION
pharmacokinetic changes in aging, which can a ect maintenance dose and
SAFETY AND THE FDA
dosing interval.
(CONT.)
Available methods to estimate renal unction in older adults are not reliable,
• The FDASa etyand Innovation Act o 2012 particularly in rail or acutely ill older adults.
has had a dramaticimpact on pediatric
labeling o drugs, and labeling o drugs or T ere is an increased risk o adverse drug e ects in older adults.
breast- eeding women. When prescribing drug therapies in older adults, it is important to use the
• FDA’s O ce o PediatricTherapeutics (OPT) minimal dose required to obtain bene t.
was created bya mandate o Congress to Optimal drug therapy in the older patient should include:
assure access or children toinnovative, An assessment o the aims o therapy in the individual
sa e and ef ective medical products, and in
collaboration with another branch o the Risks o drug therapy
agency(Center or Drug Evaluation and Possible drug–drug interactions
Research [CDER]) developed the NewPedi- T e e ect o disease on drug e ects
atricLabeling In ormation Database which
contains pediatriclabeling changes based Monitoring o drug e cacy and adverse drug e ects once drug therapy
on keypediatricin ormation romthe stud- is initiated
ies submitted in response toPREAand BPCA
(http://www.accessdata. da.gov/scripts/sda/ SUMMARY QUIZ
sdNavigation.c m?sd=labelingdatabase).
• In 2014, FDApublished a nal rule setting QUESTION 4-1 T e dosing o morphine in an in ant to control pain typically requires
standards or howin ormation about medi- using higher doses than an adult. T e major reason or the higher dosing is
cines used during pregnancyand breast- a. increased binding o drug to plasma proteins.
eeding is presented in the labeling o
prescription drugs and biological products. b. reduced entry o drug into the CNS.
» This labeling replaces the previous c. reduced opiate sensitivity in young children.
product letter categories—A, B, C,D, d. reduced metabolism o drug.
and X—used toclassi ythe risks o using e. increased clearance o drug.
prescription drugs during pregnancy.
QUESTION 4-2 T e bioavailability o orally administered drugs is di cult to predict in
» The nal rule requires the use o 3
subsections in the labeling titled in ants because
“Pregnancy,”“Lactation,”and“Females a. the rate o transit o drugs through the in ant GI tract is very rapid.
and Males o Reproductive Potential” b. in ants have very high rst-pass metabolism.
that provide details about use o the c. absorption o drugs rom the GI tract is reduced in neonates and changes with
drug or biological product. maturation.
» The“Pregnancy”and“Lactation” d. the clearance o drugs by the kidney is very rapid in in ants.
subsections also includes 3
subheadings:“risksummary,”“clinical e. all o the above.
considerations,”and“data.” QUESTION 4-3 Nonsteroidal anti-inf ammatory drugs (NSAIDs) such as ibupro en
should be avoided in the elderly because NSAIDs
a. have little e cacy in treating pain in older adults.
b. are more readily converted to toxic metabolites in older adults.
c. impair renal unction in older adults.
d. impair hepatic unction in older adults.
e. impair uptake o many nutrients rom the GI tract in older adults.
12
AUC IV
PHARMACOKINETICS
IN THE ELDERLY—
AUC EV (young)
10 ABSORPTION AND
AUC EV (old)
BIOAVAILABILITY
n
o
8 • Absorption o drugs is o ten slower in
i
t
a
r
the aged (see Figure 4-1) so the maximal
t
n
e
plasma concentration is reached later (lon-
c
6
n
o
ger Tmax) and is lower (lower Cmax).
C
a
• The extent o absorption is usuallycom-
m
4
s
plete in older adults so the area under the
a
l
P
curve (bioavailability) is not af ected.
2 • Oral bioavailabilitymaybe decreased or
drugs that require an acidicenvironment
0 in older adults with age-related hypo-
0 2 4 6 8 10 chlorhydria secondarytoatrophicgastritis
Time (5-10%o older adults) and in those taking
medications that raise gastricpHsuch as
FIGURE 4-1 Theoretical plasma concentration–time curves or the same drug given intravas-
H2-antagonists and proton pump inhibitors.
cularly (IV) and extravascularly (EV) in a young adult versus an elderly adult. The bioavailability is
the ratio o the area under the curve (AUC) or the EVroute to the AUC or the IVroute. The intra- • Factors associated with age-related
vascular AUC is not a ected by age. With aging, the extravascular curve shows delayed and lower changes in absorption and bioavailability
maximal plasma concentration and AUC may be increased or drugs that undergo rst-pass are shown inTable 4-1.
hepatic metabolism. (Reproduced with permission from Halter JB, Ouslander JG, Tinetti ME, Studenski
S, High KP, &Asthana S (Eds). Hazzard’s Geriatric Medicine and Gerontology, 6th ed. McGraw-Hill,
Inc., 2009. Fig 8-1.)
TABLE 4-1 Factors Associated with Bioavailability o Drugs Administered Through Common Extravascular Routes and
Description o Age-Related Changes
ABSORPTION FIRST-PASS CLEARANCE
AGE RELATED
ROUTE PROPERTIES OF DRUG DESCRIPTION AGE RELATED CHANGES DESCRIPTION CHANGES
Oral Particle size ormulation Gut lumen Gastric pH may be less acidic, Gut wall CYP450 Not known
Lipid solubility decomposition altering ionisation metabolism
Ionization
Sublingual Particle size Rapid into blood Not known ?Reduced Nil
Lipid solubility vessels at base o per usion
Potency tongue
Rectal (local and Lipid solubility Varies with rectal Not known Nil
systemic action) Ionisation contents ?Reduced per usion
(Continued)
73
SECTION I General Principles
Inhaled (local Particle size Minimal systemic Not known Lung metabolism and Not known
and systemic) – Powders absorption ?E ects o reduced alveolar clearance
– Aerosol solutions inhaler area, low-grade inf ammation,
(type and how used) ventilation/per usion
Gases: gas partition mismatch, decreased di usion
coe cient (blood) and transport across alveolar
capillary membrane
Reproduced with permission rom Halter JB, Ouslander JG, Tinetti ME, Studenski S, High KP, &Asthana S (Eds). Hazzard’s Geriatric Medicine and
Gerontology, 6th ed. McGraw-Hill, Inc., 2009. Table 8-1.
74
Special Populations (Children and Elderly) CHAPTER 4
Lipid: water Lipid soluble drugs Relative increase in Loading dose o water
coe cient can pass through lipid proportion o body at soluble drugs, eg,
membranes o cells and decrease in body gentamicin, digoxin,
more easily and have water (muscle mass). decreased with aging
higher Vthan water There ore, higher V to avoid toxicity rom
soluble drugs or lipid soluble high initial Cp.
drugs and lower V or
water soluble drugs
with aging.
Reproduced with permission rom Halter JB, Ouslander JG, Tinetti ME, Studenski S, High KP, &
Asthana S (Eds). Hazzard’s Geriatric Medicine and Gerontology, 6th ed. McGraw-Hill, Inc., 2009.
Table 8-2.
75
SECTION I General Principles
A B
PHARMACOKINETICS IN
10 10
THE ELDERLY—EXCRETION
9
• Renal drug clearance is reduced with aging
8
(Table 4-4).
• GFRis reduced by10 to 40%with aging. 7
e
e
c
c
n
n
a
Much o the age-related decline in renal 6
a
r
r
»
a
a
e
e
unction maybe related to disease,
l
l
5
C
C
c
particularlyhypertension, atherosclerosis,
c
i
i
t
t
4
a
a
andheart ailure, ratherthannormalaging.
p
p
e
e
H
H
3
• Available methodstoestimate renal unction
in older adults are not reliable, particularlyin 2
rail or acutelyill older adults. 1
»The Cockcro t–Gault equation(see below) 0 0
can give an estimate o renal unction 0 Old Young Old P ha s e I Young
or dose adjustment o renallyexcreted Old P ha s e II
drugs; however, the maintenance dose He pa tic Blood Flow Enzyme Ca pa city
o drugswith narrowtherapeuticindices
Flow-limite d drug Ca pa city-limite d drug
shouldbe guidedbytherapeuticdrug
monitoringandclinical response. FIGURE 4-2 The e ects o normal aging on hepatic drug clearance. With aging, hepatic blood
f ow is reduced by approximately 50%, which is associated with a 50% reduction in clearance
• Tubular secretion is reduced with aging, to o f ow-limited drugs, but has little e ect on clearance o capacity-limited drugs (A). In normal
a similar or greater extent than GFR. aging, phase 1 metabolism is reduced, which reduces hepatic clearance o capacity-limited drugs
• Tubular secretion maybe urther reduced metabolized by these enzymes, while phase 2 metabolism is probably preserved, although it may
bypolypharmacythat increases competi- be reduced in railty. Changes in enzyme capacity do not a ect the clearance o f ow-limited drugs
tion o drugs or transporters. (B). (Reproduced with permission from Halter JB, Ouslander JG, Tinetti ME, Studenski S, High KP, &Asthana
S [Eds]. Hazzard’s Geriatric Medicine and Gerontology, 6th ed. McGraw-Hill, Inc., 2009. Figs 8-3A&B.)
• Overall tubular unction is decreased in the
elderly, with impaired abilitytoconcentrate
or dilute urine maximally. TABLE 4-3 Changes in Hepatic Clearance with Aging
Cockcro t–Gault Equation PROCESS OF AGE RELATED
HEPATIC CLEARANCE DESCRIPTION CHANGES CLINICAL APPLICATION
Creatinine clearance (mL)/min
Hepatic blood f ow Portal venous f ow Decreases by 30-50% Reduced clearance
(140 − age) × weight (kg) (~80%) and hepatic by 30-50% o high
=
72× serumcreatinine (mg/dL) arterial f ow (~20%) extraction ratio drugs,
× 0.85 or emales eg, morphine and
verapamil. Less impact
on low extraction
ratio drugs, eg,
carbamazepine, war arin,
diazepam.
Protein binding Only ree drug Decreased albumin: Only signi cant or drugs
is cleared. acidic drugs have that are highly protein
Protein binding higher raction bound (>90%) with low
a ected by disease unbound and hepatic extraction ratios,
and competition increased hepatic eg, war arin, phenytoin,
rom other drugs. clearance. diazepam.
Increased α1-acid
glycoprotein: basic
drugs have lower
raction unbound
and decreased
hepatic clearance.
Scavenger cells Kup er cells scavenge Possible reduction in Not known. May reduce
large protein drugs. scavenger unction hepatic clearance.
Liver sinusoidal (in animal studies).
endothelial cells
(LSECs) may scavenge
smaller particles.
(Continued)
76
Special Populations (Children and Elderly) CHAPTER 4
• The American GeriatricSociety(AGS) Glomerular Decreased GFR, Estimates used to Gentamicin clearance correlates
ltration extent unclear, adjust maintenance with Cockcro t-Gault estimates
has developed and regularlyupdates
~10-40% doses o drugs or renal o creatinine clearance.
the Beers Criteria (medication list o impairment
PotentiallyInappropriate Medications
or the Elderly) based on evidence-based Tubular secretion Decreased Reduction in renal Ratio o procainamide clearance
recommendations: (active) clearance may be to creatinine clearance decreases
greater than reduction with aging.
https://www.dcri.org/
»
in GFR. Digoxin excreted by passive
trial-participation/the-beers-list With polypharmacy, glomerular ltration and active
• The list is updated based on a comprehen- increased risk o drug- tubular secretion. Serum digoxin
sive, systematicreviewand grading o the drug interactions levels increase with number
through competition o concurrent P-gp inhibitors,
evidence on drug-related problems and or transporters. e.g., verapamil, erythromycin,
adverse drug events in older adult. amiodarone, spironolactone,
• The 2012 AGSBeers Criteria or Potentially atorvastatin.
Inappropriate Medication Use in Older
Tubular Unknown I impaired, would Changes in clearance o lithium,
Adults is available online at: reabsorption reduce the e ect o which, like sodium, is reely
http://www.americangeriatrics.org/
» (passive) reduced glomerular ltered at glomerulus and 80%
les/documents/beers/2012AGSBeersCr ltration on clearance. reabsorbed in the proximal
iteriaCitations.pd tubule, consistent with changes
in GFR with aging.
Reproduced with permission rom Halter JB, Ouslander JG, Tinetti ME, Studenski S, High KP, &
Asthana S (Eds). Hazzard’s Geriatric Medicine and Gerontology, 6th ed. McGraw-Hill, Inc., 2009.
Table 8-4.
78
SECTION
Neuropharmacology II
5. Neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
6. Cholinergic Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
8. Pyschopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
79
CHAPTER
5 Neurotransmission
DRUGS INCLUDED IN Chapter 5, Neurotransmission is a compilation o Chapter 8 Neurotransmission: T e
Autonomic and Somatic Motor Nervous Systems, and Chapter 14 Neurotransmission
THIS CHAPTER
and the Central Nervous System in Goodman & Gilman’s T e Pharmacological Basis of
The pharmacologyo specifcdrugs is not T erapeutics, 12th Edition. An understanding o the material in these chapters will be
included in this chapter. The drugs pre- help ul in ollowing the material presented in this chapter. In addition to the material
sented in the cases are used as examples to presented here, the 12th Edition includes:
illustrate various aspects o neurotransmis-
• A detailed discussion o the peripheral and central nervous systems (CNS)
sion; the specifcpharmacologyo these
drugs is presented in the subsequent • An intricate discussion o the neurotransmitters in the peripheral and CNS, their
chapters o this section. synthesis, storage, mechanisms o release and termination o e ect
• Details o the cholinergic, adrenergic, and somatic nervous systems that are also
addressed in Chapters 6 and 7 o this book
• A detailed discussion o chemical transmission o impulses in the CNS
LEARNING OBJECTIVES
Understand the characteristics o the parasympathetic, sympathetic, and enteric
nervous systems.
Understand the di erence between the autonomic and somatic nervous systems.
Know the predominant transmitters at ganglionic sites in the parasympathetic
and sympathetic nerves.
Know the transmitters and their target receptors in parasympathetic and
sympathetic nervous system.
Know the e ect that agonist and antagonists have at each target receptor.
Understand the blood-brain barrier (BBB).
Understand the intricacies o chemical transmission within the CNS and how
the interaction o central neurons control the pharmacological e ects o drugs
acting in the brain.
CASE 5-1
A 47-year-old woman is given a drug to treat her overactive bladder. She is told that the
drug is similar to atropine and that it will decrease her requency o urination. She is
cautioned to be aware o the possibility o dry eyes, dry mouth, blurred vision, consti-
pation, drowsiness, dizziness, and con usion.
a. What are the divisions o the peripheral autonomic nervous system that describe
the diverse actions o this drug?
T e e erent nerves o the involuntary (autonomic) nervous system supply all
innervated structures o the body except skeletal muscle, which is served by the
somatic nerves (see Figures 5-1 and 5-2). T e peripheral autonomic nervous system
is composed o the sympathetic, parasympathetic, and enteric divisions (see Side
Bar DIVISIONS OF HE PERIPHERAL AU ONOMIC NERVOUS SYS EM).
b. Why does this drug have such a broad constellation o side e ects involving so
many di erent organs?
Atropine is a drug that blocks cholinergic muscarinic receptors located on the
membranes o many e ector organs (see Figure 5-1 and able 5-1), and it blocks
all the peripheral actions o acetylcholine, the parasympathetic neurotransmitter
(Continued)
80
Neurotransmission CHAPTER 5
cilia ry ga nglion
iris
cilia ry body
t
t
e
e
la crima l gla nd III
c
c
t
t
mechano- and chemoreceptors
o
o
b
b
s phe nopa la tine ga nglion inte rna l ca rotid
u
u
of carotid sinus
l
l
b
b
and carotid body
a
a
chorda tympa ni
r
r
(
(
c
c
s ublingua l gla nd
r
r
VII
a
a
otic
n
n
i
i
IX
a
a
s ubma xilla ry gla nd ga nglion
l
l
)
)
pa rotid gla nd X
o
o
a rch of a orta
u
u
t
t
va s os e ns itive a nd
f
f
l
l
o
o
s upe
uperior
rior
w
w
che more ce ptive e ndings
c
c
e
e
middle
r
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cervica l ga nglia
v
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i
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a
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l
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c
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o
o
inferior
r
r
d
d
1
tra che a s te lla te ga nglion
bronchi
lungs 2
pulmona ry ve s s e ls
3
pa ra ve rte bra l
ga nglionic
live r 4 cha in
bile ducts
ga ll bla dde r 5 t
oo
lr
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sa
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p
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a
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sp
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l
l
u
u
ga nglion
m
m
2 blood ve s s e ls
b
b
a
a
re ctum
r
r
3
c
c
o
o
p
r
r
e
d
d
urina ry 4
l
v
bla dde r
i
c
5
n
e
r
e xte rna l
v
1
e
s
s
ge nita lia
a
a
2
c
c
r
r
s
a
a
a
3
l
l
infe rior
c
o
o
r
u
u
me s e nte ric
a
4
t
t
l
f
f
l
l
ga nglion
g
o
o
a
5
w
w
n
g
l
i
a
To blood ve s s e ls To s we a t gla nds a nd
a nd ha ir follicle s s pe cia lize d blood ve s s e ls
of lowe r limb of lowe r limb
S e gme nta l pos tga nglionic S e gme nta l pos tga nglionic
a dre ne rgic fibe rs from choline rgic fibe rs from
pa ra ve rte bra l ga nglia to pa ra ve rte bra l ga nglia to
blood ve s s e ls a nd ha ir s we a t gla nds a nd ce rta in
follicle s via gra y ra mii blood ve s s e ls via gra y
a nd s pina l ne rve s ra mi a nd s pina l ne rve s
FIGURE 5-1 The autonomic nervous system. Schematic representation o the autonomic nerves and e ector organs
based on chemical mediation o nerve impulses. Blue, cholinergic; grey, adrenergic; dotted blue, visceral a erent; solid lines,
preganglionic; broken lines, postganglionic. In the rectangle at the right are shown the ner details o the rami cations
o adrenergic bers at any 1 segment o the spinal cord, the path o the visceral a erent nerves, the cholinergic nature o
somatic motor nerves to skeletal muscle, and the presumed cholinergic nature o the vasodilator bers in the dorsal roots
o the spinal nerves. The asterisk (*) indicates that it is not known whether these vasodilator bers are motor or sensory or
where their cell bodies are situated.
81
SECTION II Neuropharmacology
S OMATIC S YS TEM
Va rious
le ve ls Motor ne uron S ke le ta l Nicotinic
of ACh (s tria te d) Re ce ptors
s pina l cord mus cle Nm
Nm
AUTONOMIC S YS TEM
P a ra s ympa the tic
Ga nglion
Cra nia l Mus ca rinic
a nd ACh Nn Re ce ptors
s pina l ACh M
S mooth
M mus cle ,
ca rdia c
tis s ue ,
S ympa the tic
s e cre tory
Ga nglion gla nds
Thora cic
a nd ACh Nn Adre ne rgic
lumba r Re ce ptors
Nn NE α /β
S ympa the tic
choline rgic fibe r Mus ca rinic
ACh
α /β Re ce ptors
Adre na l Epi/NE (s we a t gla nds )
me dulla (80%/20%)
ACh M
S we a t
gla nds
FIGURE 5-2 Schematic representation o the somatic motor nerves and the e erent nerves o the autonomic nervous system. The principal
neurotransmitters, acetylcholine(ACh) and norepinephrine (NE), are shown in grey. The receptors or these transmitters, nicotinic (N) and mus-
carinic (M) cholinergic receptors, α and β adrenergic receptors are shown in grey rectangles to the right. The somatic nerves innervate skeletal
muscle directly without a ganglionic relay. The autonomic nerves innervate smooth muscles, cardiac tissue, and glands. Both parasympathetic
and sympathetic systems have ganglia where ACh is the transmitter o the preganglionic bers; ACh acts on nicotinic receptors on the postgan-
glionic nerves. ACh is also the neurotransmitter at cells o the adrenal medulla, where it acts on nicotinic ACh receptors to cause release o the
catecholamines epinephrine (Epi) and NE into the circulation. Epi represents ~80% o the released catecholamines. ACh is the predominant neu-
rotransmitter o postganglionic parasympathetic nerves and acts on muscarinic receptors. NE is the principal neurotransmitter o postganglionic
sympathetic nerves, acting on α or β adrenergic receptors. Note that somatic nerves orm a specialized synaptic junction, termed the motor end
plate. Autonomic nerves orm a more di use pattern with multiple synaptic sites. The ganglia in the parasympathetic system are near or within
the organ being innervated with generally a one-to-one relationship between pre- and postganglionic bers. In the sympathetic system, the
ganglia are generally ar rom the e ector cells (eg, within the sympathetic chain ganglia). Preganglionic sympathetic bers may make contact
with a large number o postganglionic bers.
(see Chapter 6). T us, it is easy to see why its side e ects involve so many organs.
Although atropine has minimal e ects on the CNS, there are de nitely musca-
rinic receptors in the brain and their antagonism may lead to drowsiness and
con usion.
c. What is the enteric nervous system?
T e processes o mixing, propulsion, and absorption o nutrients in the GI tract
are controlled locally through a restricted part o the peripheral nervous system
called the enteric nervous system (ENS; see Chapter 33). T e ENS actually com-
prises components o the sympathetic and parasympathetic nervous systems and
has sensory nerve connections through the spinal and nodose ganglia.
(Continued)
82
Neurotransmission CHAPTER 5
(Continued)
83
SECTION II Neuropharmacology
ADRENERGIC CHOLINERGIC
ORGAN SYSTEM SYMPATHETIC EFFECT a
RECEPTOR SUBTYPEb PARASYMPATHETIC EFFECTa RECEPTOR SUBTYPEb
Sex Orga ns, male Ejaculation+++ α1 Erection+++ M3
Pancreas
Acini ↓ secretion+ α Secretion++ M3, M2
Islets (β cells) ↓ secretion+++ α2 —
↑ secretion+ β2
Fat Cellsl Lipolysis+++; thermogenesis α1; β 1, β 2, β3 — —
Inhibition o lipolysis α2
Sa livary Gla nds K+ and water secretion+ α1 K+ and water secretion+++ M3, M2
84
Neurotransmission CHAPTER 5
d. What are the di erences between the parasympathetic and sympathetic nervous
DIVISIONS OF THE
systems?
PERIPHERAL AUTONOMIC
T e sympathetic system is distributed to e ectors throughout the body, whereas NERVOUS SYSTEM
parasympathetic distribution is much more limited (see Figure 5-1). T e ganglia
in the parasympathetic system are near or within the organ being innervated with • Sympatheticnervous system
generally a one-to-one relationship between pre- and postganglionic bers (see • Parasympatheticnervous system
Figure 5-2). In the sympathetic system the ganglia are generally ar rom the e ec- • Entericnervous system
tor cells. Preganglionic sympathetic bers may make contact with a large number
o postganglionic bers.
In contrast to the parasympathetic and sympathetic nervous systems, somatic
nerves innervate skeletal muscle directly without a ganglionic relay (see Case 5-2).
STEPS INVOLVED
Acetylcholine (ACh) is the predominant neurotransmitter o postganglionic para- IN JUNCTIONAL
sympathetic nerves and acts on muscarinic receptors. Norepinephrine (NE) is the
TRANSMISSION
principal neurotransmitter o postganglionic sympathetic nerves acting on α or β
adrenergic receptors. • Transmitter synthesis
Both parasympathetic and sympathetic systems have ganglia where ACh is the • Transmitter storage
transmitter o the preganglionic bers; ACh acts on nicotinic receptors on the post- • Transmitter release
ganglionic nerves. ACh is also the transmitter at cells o the adrenal medulla, where
• Transmitter recognition and binding by
it acts on nicotinic receptors to cause release o epinephrine and norepinephrine into
target receptor
the circulation.
• Termination o action
CASE 5-2
A 35-year-old man is undergoing abdominal surgery. T e anesthesiologist explains
in a presurgery meeting with the patient that a neuromuscular blocking drug will be
administered to cause complete muscle relaxation prior to the initiation o surgery.
a. What is the di erence between the autonomic nervous system that innervates many
visceral organs and the somatic nervous system that innervates skeletal muscle?
T e somatic nerves innervate skeletal muscle directly without a ganglion relay (see
Figure 5-2). At each neuromuscular junction, the axon terminal loses its myelin
sheath and orms a terminal aborization that lies in apposition to a specialized
sur ace o the muscle membrane termed the motor end plate (see Chapter 6).
b. What are the steps involved in the transmission o a nerve impulse?
T e steps involved in excitatory and inhibitory neurotransmission are depicted
schematically in Figure 5-3. T e steps involved in the junctional transmission
o the nerve impulse are outlined in the Side Bar S EPS INVOLVED IN JUNC-
IONAL RANSMISSION, the details o which are characteristic o a speci c
nerve transmission system, that is, parasympathetic, sympathetic, somatic, and in
the CNS.
ransmitter synthesis: Small molecules like ACh and NE (see Side Bar NEU-
RO RANSMI ERS or a list o neurotransmitters) are synthesized in nerve ter-
minals; peptides are synthesized in cell bodies and transported to nerve terminals.
ransmitter storage: Synaptic vesicles store transmitters, o en in association with
various proteins and requently with A P.
ransmitter release: Release o transmitter occurs by exocytosis. Depolarization
results in an in ux o Ca++, which in turn appears to bind proteins called synapto-
tagmins. T e storage vesicles dock and then use with sca olding proteins on the
presynaptic membrane, which is ollowed by exocytotic release o their contents
into the synaptic cle (see Figure 5-3).
ransmitter recognition: Receptors exist on postsynaptic cells, which recognize the
transmitter (see Side Bar NEURO RANSMI ERS). Binding o a neurotransmit-
ter to its receptor initiates a signal transduction event (see Figures 5-4 and 5-6).
(Continued)
85
SECTION II Neuropharmacology
p
excita tory
a
+ syna ptobrevin
g
input Na + – syna ptota gmin
c
+
ti
–
p
n
a ne uro-
K+
y
tra ns mitte r
s
+
–
tra ns porte r
Ca 2+
Na + Ca 2+ volta ge -s e ns itive
Ca 2+ cha nne l
K+ volta ge -s e ns itive pos tsyna ptic
Na + cha nne l re ce ptor-ga te d
K+
Na + ion cha nne l
–
+
inhibitory +
– – β1 β2
– +
input Cl– + SYNAP TIC VES ICLES
excita tory
+ 1. AP 2. IP S P 3. Inhibition
E
L
α tra ns mitte r
A
N
I
A
T
)
V
R
inhibitory
N
0
B
m
E
M
T
(
tra ns mitte r
O
E
–
M
P
FIGURE 5-3 Steps involved in excitatory and inhibitory neurotransmission. 1. The nerve action
potential (AP) consists o a transient sel -propagated reversal o charge on the axonal membrane.
(The internal potential Ei goes rom a negative value, through zero potential, to a slightly positive
value primarily through increases in Na+ permeability and then returns to resting values by an
increase in K+ permeability.) When the AP arrives at the presynaptic terminal, it initiates release o
the excitatory or inhibitory transmitter. Depolarization at the nerve ending and entry o Ca2+ initiate
docking and then usion o the synaptic vesicle with the membrane o the nerve ending. Docked
and used vesicles are shown. 2. Combination o the excitatory transmitter with postsynaptic recep-
tors produces a localized depolarization, the excitatory postsynaptic potential (EPSP), through an
increase in permeability to cations, most notably Na+. The inhibitory transmitter causes a selective
increase in permeability to K+ or Cl−, resulting in a localized hyperpolarization, the inhibitory post-
synaptic potential (IPSP). 3. The EPSP initiates a conducted AP in the postsynaptic neuron; this can
be prevented, however, by the hyperpolarization induced by a concurrent IPSP. The transmitter is
dissipated by enzymatic destruction, by reuptake into the presynaptic terminal or adjacent glial
cells, or by di usion. Depolarization o the postsynaptic membrane can permit Ca2+ entry i voltage-
gated Ca2+ channels are present. (Reproduced with permission rom Brunton L, Parker K, Blumen-
thal D, Buxton I (eds). Goodman &Gilman’s Manual of Pharmacology and Therapeutics. New York:
McGraw-Hill, 2008, p 94. Copyright © 2008 by The McGraw-Hill Companies, Inc. All rights reserved.)
86
Neurotransmission CHAPTER 5
I II III IV
outs id e
me mb ra ne
ins id e
Volta ge C
s e ns ing
S 4 tra ns me mbra ne ina ctiva tion
s e gme nt re gion P KA s ite
P KC s ite
N
Ina ctiva tion trime r
β C N
2+ δ C
Ca
β
C
C N
N
FIGURE 5-4 Structural similarities o voltage-dependent Na+, Ca2+, and K+ channels. A. The α subunit in both Ca2+ and
Na+ channels contains 4 subunits, each with 6 transmembrane hydrophobic domains. The hydrophobic regions that con-
nect segments 5 and 6 in each domain orm the pore o the channel. Segment 4 in each domain includes the voltage-
sensor. (Adapted with permission rom Catterall W. From ionic currents to molecular mechanisms: The structure and
unction o voltage-gated sodium channels. Neuron, 2000, 26:13–25. Copyright © Elsevier.) B. The Ca2+ channel also requires
several auxiliary small proteins (α2, β, γ, and δ). The α2 and δ subunits are linked by a disul de bond. Regulatory subunits
also exist or Na+ channels. C. Voltage-sensitive K+ channels (Kv) and the rapidly activating K+ channel (KA) share a similar
putative hexaspanning structure similar in overall con guration to 1 repeat unit within the Na+ and Ca2+ channel struc-
ture, while the inwardly recti ying K+ channel protein (Kir) retains the general con guration o just loops 5 and 6. Regula-
tory β subunits (cystosolic) can alter Kv channel unctions. Channels o these 2 overall moti s can orm heteromultimers.
87
SECTION II Neuropharmacology
A TM2
Exte rior
Inte rior
Hydrophobic
ring
L
L L
L L
FIGURE 5-5 Predicted 3-D structure o a ligand-gated ion channel receptor in a postsynaptic membrane. A. These channels consist o a cylindrical
membrane-embedded structure with a central pore. The second transmembrane domain (TM2) o each subunit lines the pore and bends inward to
block ion f ow through the channel. B. A highly conserved leucine residue (L) in the TM2 bend o each subunit is believed to protrude into the pore
to orm a tight hydrophobic ring, which may act as a barrier to the f ow o hydrated ions across the channel. (Redrawn with permission rom Nestler
EJ, Hyman SE, Malenka RC (eds). Molecular Neuropharmacology, 2nd ed. New York: McGraw-Hill, 2009, p 174. Copyright © 2009 by The McGraw-Hill
Companies, Inc. All rights reserved.)
A B
Ne urotra ns mitte r
Re ce ptor
Ion
Re ce ptor Ion cha nne l cha nne l
P rote in S te roid
tyros ine re ce ptor
kina s e
Alte re d ge ne Effe cts on
e xpre s s ion othe r
S ubs tra te s , ne urona l
s ca ffold prote ins proce s s e s
Nucle us
DNA
FIGURE 5-6 General patterns o signal transduction in the brain. A. Neurotransmitter activation o a receptor that contains an integral ion channel.
B. Neurotransmitter activation o G protein–coupled receptor. A ter activation, the βγ subunits o the G protein can directly regulate an ion channel (left),
and the α subunit can activate second messenger-dependent signaling involving protein kinases and protein phosphatases, which can, in turn, a ect
ion channels and other neuronal processes (right). C. Neurotrophic actors promote receptor dimerization, which leads to activation o receptor protein
tyrosine kinase activity and its sequelae. D. Steroid hormone activation o a cytoplasmic receptor. A ter the receptor-hormone complex orms, it enters
the nucleus and regulates gene expression. (Redrawn with permission rom Nestler EJ, Hyman SE, Malenka RC (eds). Molecular Neuropharmacology,
2nd ed. New York: McGraw-Hill, 2009, p 76. Copyright © 2009 by The McGraw-Hill Companies, Inc. All rights reserved.)
88
Neurotransmission CHAPTER 5
Cav 2.1 SK1 P/Q Nerve terminals ω-Agatoxin IVA Neurotransmitter release
Dendrites Dendrite Ca2+ transients
Cav 3.1 Gardos channel T Cardiac muscle Mibe radil Repetitive ring o pacemaker
Skeletal muscle cells
Neurons
DHP = dihydropyridines (ni edipine). PAA = Phenylalkylamines (verapamil). BZP = benzothiazepines (diltiazem). ω-CTX = ω-conotoxin
a
Five classes o Ca2+ channel identi ed as L, P/Q, N, R, and T channels exist.
Pre s ynaptic
ne uro n
11 10
Ne urotra ns mitte r 9
Ca 2 +
2
AP Glial
1 c e ll
5 6
NT
8
3
4
G prote in Na +
Po s ts ynaptic
ne uro n
FIGURE 5-7 Transmitter release, action, and inactivation. Depolarization opens voltage-depen-
dent Ca2+ channels in the presynaptic nerve terminal. (1) The inf ux o Ca2+ during an action
potential (AP) triggers (2) the exocytosis o small synaptic vesicles that store neurotransmitter
(NT) involved in ast neurotransmission. Released neurotransmitter interacts with receptors in the
postsynaptic membranes that either couple directly with ion channels (3) or act through second
messengers, such as (4) GPCRs. Neurotransmitter receptors in the presynaptic nerve terminal
membrane (5) can inhibit or enhance subsequent exocytosis. Released neurotransmitter is inacti-
vated by reuptake into the nerve terminal by (6) a transport protein coupled to the Na+ gradient,
or example, DA, NE, and GABA; by (7) degradation (ACh, peptides); or by (8) uptake and metabo-
lism by glial cells (Glu). The synaptic vesicle membrane is recycled by (9) clathrin-mediated
endocytosis. Neuropeptides and proteins are stored in (10) larger, dense core granules within the
nerve terminal. These dense core granules are released rom (11) sites distinct rom active zones
a ter repetitive stimulation.
and she is unable to work productively (see Chapter 21). Her doctor recommends that
she switch to loratadine, which should make her less sleepy.
a. What is the di erence between diphenhydramine and loratadine?
T e antihistamines are discussed in detail in Chapter 21 (see speci cally Case
21-1). Both diphenhydramine and loratadine are antagonists o histamine H 1 recep-
tors. Diphenhydramine is an ethanolamine and readily penetrates the CNS causing
the drowsiness experienced by this patient. Loratadine is a tricyclic piperidine that
does not penetrate the CNS and does not cause drowsiness.
b. What process in the brain keeps loratadine rom producing sleepiness?
Drugs acting in the CNS have to cross the blood-brain barrier (BBB) or the
blood-CSF barrier (see Chapter 2). T ese 2 barriers are ormed by brain capillary
endothelial cells and epithelial cells o the choroid plexus, respectively. Lipophilic
molecules such as diphenhydramine di use reely across the BBB and accumulate
in the brain. Loratadine is less lipophilic and does not cross the BBB. In addition,
diphenhydramine is an anticholinergic and interacts with muscarinic receptors,
whereas loratadine does not inhibit muscarinic receptors.
90
Neurotransmission CHAPTER 5
CASE 5-5
A 62-year-old man with a diagnosis o Alzheimer’s disease has mild cognitive loss. He
is given a drug that may improve his cognition, but his doctor explains to the amily
that the patient’s loss o cognitive ability will likely progress (see Chapter 13).
a. How is the pharmacological treatment o a disorder o the CNS di erent rom
treating a disorder in the peripheral nervous system?
T e identi cation o targets or drugs that a ect the CNS and behavior is a dif -
cult scienti c challenge. Complicating this e ort is the act that a CNS-active drug
(such as this patient is receiving to improve cognition) may act at multiple sites
with disparate and even opposing e ects. In addition, many CNS disorders involve
multiple brain regions and pathways, which can rustrate e orts to use a single
therapeutic agent.
b. What are the neurotransmitters in the CNS?
T e neurotransmitters in the CNS are generally the same as in the peripheral ner-
vous system (see Side Bar NEURO RANSMI ERS). In addition, there are many
other neurotransmitters in the CNS such as amino acids and peptides (see able 5-3).
c. How does this di erence make it di cult to treat disorders o the CNS?
In the peripheral nervous system, there are limited transmitters and receptors
which recognize them; thus, agonists or antagonists have speci c predictable
e ects. In the CNS there are more transmitters and receptors that unction to regu-
late brain activity and behavior. Figure 5-6 shows the multiple patterns o signal
transduction in the brain. Speci c therapeutic approaches to neurological and psy-
chiatric disorders are discussed in Chapters 8, 9, 12, 13, and 14.
Modi ed with permission rom Nestler EJ, Hyman SE, Malenka RC (eds). Molecular
Neuropharmacology, 2nd ed. New York: McGraw-Hill, 2009, p 184, Table 7-1. Copyright © 2009
by The McGraw-Hill Companies, Inc. All rights reserved.
91
SECTION II Neuropharmacology
CASE 5-6
A 56-year-old woman with advanced breast cancer is prescribed morphine or pain.
Although the morphine e ectively di uses the pain, the patient develops severe
constipation.
a. What is meant by drug specif city and nonspecif city in the CNS?
T e e ect o a drug in the CNS is considered to be speci c when it a ects an identi -
able molecular mechanism unique to target cells that bear receptors or that drug.
Conversely, a drug is regarded as being nonspeci c when it produces e ects at a
variety o di erent target cells, thus a ecting a diverse set o neurobiological systems.
Although relie o pain is the goal when administering an opiate, one must also
contend with potential o -target e ects, including respiratory depression and con-
stipation (see Chapter 10).
CASE 5-7
A 75-year-old woman has been taking alprazolam or anxiety and sleep or the past
10 years. Lately she has developed mild dementia and has orgotten to re ll her pre-
scription. A er 3 days without taking her alprazolam, she becomes extremely anxious
and shaky and has a tonic-clonic seizure.
a. What property o CNS drugs has led to this state o hyperexcitability in
this patient?
Alprazolam is a CNS depressant used commonly to treat anxiety and insomnia (see
Chapter 9).
Acute, excessive stimulation o the cerebrospinal axis (not the case with this
patient) normally is ollowed by depression, which is in part a consequence o neu-
ronal atigue and exhaustion o stores o transmitters. Acute, drug-induced depres-
sion (also not the case with this patient) is not ollowed by stimulation. However,
chronic drug-induced sedation or depression (such as with this patient) may be
ollowed by prolonged hyperexcitability upon abrupt cessation o the medication.
T is e ect is also common in alcohol withdrawal (see Chapter 9).
KEY CONCEPTS
T e autonomic nervous system, also called the vegetative, visceral, or involuntary
nervous system, regulates body unctions that occur without control (see able 5-1).
T e autonomic nervous system consists o nerves, ganglia, and plexuses that
innervate the heart, blood vessels, glands, other visceral organs, and smooth
muscle in various tissues (see Figure 5-1).
T e autonomic nervous system comprises the parasympathetic, sympathetic,
and enteric nervous systems.
T e somatic nervous system innervates skeletal muscle.
T e CNS is made up o various anatomic regions—cerebral cortex, limbic sys-
tem, diencephalon, midbrain and brainstem, cerebellum, and spinal cord with a
complex assembly o interacting neurons and nuclei that regulate their own and
each other’s activities generally through chemical neurotransmission.
T e parasympathetic and sympathetic systems have ganglia where ACh is the
transmitter o the preganglionic bers (see Figure 5-2). In these ganglia, ACh
acts on nicotinic receptors on the postganglionic nerves.
ACh is also the neurotransmitter at cells o the adrenal medulla where it acts on
nicotinic ACh receptors.
92
Neurotransmission CHAPTER 5
SUMMARY QUIZ
QUESTION 5-1 A 42-year-old man has just been prescribed a new drug. A er several
doses he notices dry mouth, dry eyes, and a rapid heart rate. T is is most likely due to
an inhibition o which o the ollowing neurotransmitter:
a. Norepinephrine
b. Serotonin
c. Glutamate
d. Acetylcholine
e. Epinephrine
93
SECTION II Neuropharmacology
94
CHAPTER
CholinergicPharmacology 6
Chapter 6 Cholinergic Pharmacology is a combination o Chapter 9 Muscarinic
Receptor Agonists and Antagonists Chapter 10 Anticholinesterase Agents, and
DRUGS (OR AGENTS)
Chapter 11 Agents Acting at the Neuromuscular Junction and Autonomic Ganglia in INCLUDED IN
Goodman and Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition. An THIS CHAPTER
understanding o the material in these chapters will be help ul in ollowing the material Acetylcholine (MIOCHOL-E)
presented in this chapter. In addition to the material presented here the above chapters Aldicarb (TEMIK)—Insecticide
in the 12th Edition include:
Ambenoniumchloride (MYTELASE)
• A complete discussion o the properties and subtypes o muscarinic receptors
Atracurium(TACRIUM, others)
• T e pharmacological e ects o acetylcholine (ACh)
Atropine
• A detailed discussion o the pharmacological e ects o atropine, a muscarinic
receptor antagonist Benztropine mesylate (COGENTIN, others);
see Chapter 13
• A discussion o the toxicology o drugs with antimuscarinic properties
Bethanechol (URECHOLINE)
• A review o the structure o acetylcholinesterase (AChE)
Carbachol (MIOSTAT,ISOPTOCARBACHOL)
• A discussion o the mechanism o AChE
Carbaryl (SEVIN)—Insecticide
• A description o the nicotinic acetylcholine receptor
Cevimeline (EVOXAC)
• A description o the actions o neuromuscular blocking agents on various organ
systems Chlorpyri os (DURSBAN, LORSBAN)—
Insecticide
• A discussion o the pathophysiology and treatment o malignant hyperthermia
Cisatracurium(NIMBEX)
• A discussion o ganglionic transmission
Cyclopentolate hydrochloride
• A description o the pharmacological actions o nicotine (CYCLOGYL, others)
LEARNING OBJECTIVES Dantrolene (DANTRIUM, others)
Understand cholinergic pharmacology, including the di erent types and sub- Dari enacin (ENABLEX)
types o cholinergic receptors expressed in the central nervous system (CNS), Diazinon (SPECTRICIDE, others)—Insecticide
autonomic nervous system (ANS), and neuromuscular junction. Dicyclomine hydrochloride (BENTYL, others)
Know the mechanisms o synthesis, storage, release, and destruction o ACh Donepezil (ARICEPT)
in the CNS, parasympathetic and sympathetic ganglia, parasympathetic nerve Doxacurium
bers, and the neuromuscular junction.
Edrophonium
Know the uses and toxicities o muscarinic receptor agonists and antagonists.
Fesoterodine (TOVIAZ)
Know the uses and toxicities o drugs and agents that inhibit AChE. Flavoxate (Urispas)
Describe the uses and toxicities o drugs that block neuromuscular Galantamine (REMINYL)
transmission.
Glycopyrrolate (ROBINUL, others)
Homatropine hydrobromide (ISOPTO
MECHANISM OF ACTION MUSCARINIC AGONISTS AND ANTAGONISTS HOMATROPRINE)
DRUG CLASS DRUG MECHANISM OF ACTION Ipratropium(ATROVENT,others)
Muscarinic Receptor Acetylcholine Neurotransmitter at nicotinic and Malathion (CHEMATHION,
Agonists muscarinic receptors (see Figures 5-2, MALA-SPRAY)—Insecticide
6-1, and Table 6-1 or details)
Mecamylamine (INVERSINE)
Pilocarpine Muscarinic receptor agonist Methacholine (PROVOCHOLINE)
Methacholine Muscarinic receptor agonist Methscopolamine bromide (PAMINE)
Carbachol Muscarinic receptor agonist Mivacurium(Not available in the United States)
Neostigmine bromide (PROSTIGMIN-oral)
Bethanechol Muscarinic receptor agonist
(continues)
Cevimeline Muscarinic receptor agonist
95
SECTION II Neuropharmacology
Sarin—Nerve gas
Scopolamine (TRANSDERMSCOP)
Soli enacin (VESICARE) CASE 6-1
Soman—Nerve gas A 65-year-old man with urinary retention and inadequate emptying o the bladder is
Succinylcholine (ANECTINE, QUELICIN) being treated with bethanechol.
Tabun—Nerve gas a. Why is he treated with this drug?
Tacrine (COGNEX) Bethanechol is a muscarinic receptor agonist. Parasympathetic stimulation causes
Tiotropium(SPIRIVA) detrusor muscle contraction, increased voiding pressure, and ureteral peristalsis
Tolterodine (DETROL) (see ables 5-1, 6-2, and 6-3). Bethanechol has utility in treating urinary retention
Trihexyphenidyl hydrochloride (ARTANE, and inadequate emptying o the bladder when organic obstruction is absent, as in
others); see Chapter 13 postoperative retention, diabetic autonomic neuropathy, and certain types o neu-
rogenic bladder.
Trimethaphan
Tropicamide (MYDRIACYL, others) b. What side e ects should he be aware o while taking bethanechol?
Trospiumchloride (SANCTURA) T e side e ects this patient might experience are a predictable consequence o
muscarinic receptor stimulation (see able 5-1), or example, diaphoresis, diarrhea,
Varenicline (CHANTIX) abdominal cramps, lacrimation, salivation, bradycardia, and bronchial secretion.
Vecuronium(NORCURON, others)
c. What are the contraindications to the use o bethanechol?
T e important contraindications to using bethanechol are asthma, chronic obstruc-
tive pulmonary disease (COPD), urinary or GI tract obstruction, acid-peptic
disease, cardiovascular disease accompanied by bradycardia, hypotension, and
hyperthyroidism (muscarinic agonists may precipitate atrial brillation in hyper-
thyroid patients).
96
Cholinergic Pharmacology CHAPTER 6
He micholinium
ChAT Na +
Mitochondrion
ACh 3Na +
Ve s a micol
ADP Na + , K+
-ATP a s e
Choline rgic ACh ATP
va ricos ity Co-T
2K+
Ca 2+ N
M
VAMP S
Ca 2+ Co-T Choline
ACh
Ace ta te
Botulinium
toxin S NAP S
Effe ctor ce ll
ACh me mbra ne
AChE
nAChR
(N n -Nm )
mAChR
(M1 -M 5 )
FIGURE 6-1 A cholinergic neuroe ector junction showing eatures o the synthesis, storage, and release o acetylcholine (ACh) and receptors
on which ACh acts. The synthesis o ACh in the varicosity depends on the uptake o choline via a sodium-dependent carrier. This uptake can be
blocked by hemicholinium. Choline and the acetyl moiety o acetyl coenzyme A, derived rom mitochondria, orm ACh, a process catalyzed by
the enzyme choline acetyl trans erase (ChAT). ACh is transported into the storage vesicle by another carrier that can be inhibited by vesamicol.
ACh is stored in vesicles along with other potential cotransmitters (Co-T) such as ATP and VIP at certain neuroe ector junctions. Release o ACh
and the Co-T occurs on depolarization o the varicosity, which allows the entry o Ca2+ through voltage-dependent Ca2+ channels. Elevated
[Ca2+]in promotes usion o the vesicular membrane with the cell membrane, and exocytosis o the transmitters occurs. This usion process
involves the interaction o specialized proteins associated with the vesicular membrane (VAMPs, vesicle-associated membrane proteins) and the
membrane o the varicosity (SNAPs, synaptosome-associated proteins). The exocytotic release o ACh can be blocked by botulinum toxin. Once
released, ACh can interact with the muscarinic receptors (M), which are GPCRs, or nicotinic receptors (N), which are ligand-gated ion channels, to
produce the characteristic response o the e ector. ACh also can act on presynaptic mAChRs or nAChRs to modi y its own release. The action o
ACh is terminated by metabolism to choline and acetate by acetylcholinesterase (AChE), which is associated with synaptic membranes.
CASE 6-2
A 56-year-old man reports to the emergency room a er eating mushrooms that he has
oraged. He has brought some o the whole, uncooked mushrooms with him.
a. Although his symptoms now, one hour a er ingesting the mushrooms, only
include mild abdominal pain and diarrhea, what symptoms should one look or?
It is important to identi y the speci c mushroom, i possible, to be able to be aware
o the possible toxicities. Amanita muscaria mushrooms contain muscarine, a
potent muscarinic receptor agonist, and symptoms will be related to stimulation o
muscarinic receptors (see able 5-1). Mushrooms o the Psilocybe or Panaeolus spe-
cies contain psilocybin which will cause short-lasting hallucinations. Mushrooms
o the Amanita phalloides or related species contain amatoxins which can cause
hepatic and renal ailure, and ultimately death.
(Continued)
97
SECTION II Neuropharmacology
Central Neuronal CNS; pre- and Pre- and postsynaptic Increased cation Cytosine, epibatidine Mecamylamine
(CNS) postjunctional excitation permeability Anatoxin A Dihydro-β-erythrodine
(α4)2(β 4)3 Prejunctional control o (Na+; K+) Erysodine
(α-btox-insensitive) transmitter release Lophotoxin
(α7)5 (α-btox-sensitive) CNS; pre- and Pre- and postsynaptic Increased Anatoxin A Methyllycaconitine
postsynaptic excitation permeability α-Bungarotoxin
Prejunctional control o (Ca2+) α-Conotoxin ImI
transmitter release
a
Nine α (α2-α10) and three β (β 2-β 4) subunits have been identi ed and cloned in human brain, which combine in various con ormations to orm
individual receptor subtypes. The structure o individual receptors and the subtype composition are incompletely understood. Only a nite
number o naturally occurring unctional nAChR constructs have been identi ed. α-btox, β-bungarotoxin.
98
Cholinergic Pharmacology CHAPTER 6
M4 479 aa Pre erentially Couples by Gi/Go Autoreceptor- and heteroreceptor- Parkinson disease
11p 12–11.2 expressed in CNS, (PTX-sensitive) mediated inhibition o transmitter Schizophrenia
particularly orebrain, Inhibition o AC, ↓ cAMP release in CNS and periphery. Neuropathic pain
also striatum, Activation o inwardly Analgesia; cataleptic activity
cerebral cortex, recti ying K+ channels Facilitation o DA release
hippocampus Inhibition o voltage-gated
Ca2+ channels
Hyperpolarization and
inhibition
M5 532 aa Substantia nigra Couples by Gq/11 Mediator o dilation in cerebral Drug dependence
15q 26 Expressed in low Activation o PLC; arteries and arterioles (?) Parkinson disease
levels in CNS and ↑ IP3 and ↑ DAG → Facilitates DA release Schizophrenia
periphery ↑ Ca2+ and PKC Augmentation o drug-seeking
Predominant mAchR Depolarization and excitation behavior and reward (eg, opiates,
in neurons in VTA (↑ sEPSP) cocaine)
and substantia nigra Activation o PLD2, PLA2;
↑ AA
a
Most organs, tissues, and cells express multiple mAChRs.
b
M1, M3, and M5 mAChRs appear to couple to the same G proteins and signal through similar pathways. Likewise, M2 and M4 mAChRs couple
through similar G proteins and signal through similar pathways.
c
Despite the act that in many tissues, organs, and cells multiple subtypes o mAChRs coexist, one subtype may predominate in producing a
particular unction; in others, there may be equal predominance.
PLC, phospholipase C; IP3, inositol-1,4,5-triphosphate; DAG, diacylglycerol; PLD2, phospholipase D; AA, arachidonic acid; PLA, phospholipase A;
AC, adenylyl cyclase; DA, dopamine; cAMP, cyclic AMP; SA node, sinoatrial node; AVnode, atrioventricular node; HR, heart rate; PTX, pertussis
toxin; VTA, ventral tegmentum area.
TABLE 6-3 Some Pharmacological Properties o Choline Esters and Natural Alkaloids
MUSCARINIC ACTIVITY
MUSCARINIC SUSCEPTIBILITYTO URINARY EYE ANTAGONISM NICOTINIC
AGONIST CHOLINESTERASES CARDIOVASCULAR GASTROINTESTINAL BLADDER (TOPICAL) BY ATROPINE ACTIVITY
Acetylcholine +++ ++ ++ ++ + +++ ++
99
SECTION II Neuropharmacology
CASE 6-3
A 48-year-old woman is being treated with oxybutynin or low bladder capacity and
urinary requency.
a. What kind o drug is oxybutynin and why is it e ective in this patient?
Oxybutynin is a muscarinic receptor antagonist that is indicated or the treatment
o overactive bladder (see able 6-4). T is drug lowers intravesicular pressure,
increases bladder capacity, and reduces the requency o contractions by antagoniz-
ing parasympathetic control o the bladder (see ables 5-1 and 6-3).
b. What side e ects should she be cautioned about?
T e side e ects o oxybutynin are a predictable consequence o muscarinic recep-
tor antagonism (see able 5-1). T ese e ects include xerostomia, blurred vision,
constipation, and dyspepsia. CNS-related antimuscarinic e ects, including drowsi-
ness, dizziness, and con usion can occur and are particularly problematic in elderly
patients. Dry mouth and dry eyes are the most common reasons or discontinuation.
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Cholinergic Pharmacology CHAPTER 6
TABLE 6-4 Muscarinic Receptor Antagonists Used in the Treatment o Overactive Urinary Bladder
t 1/2
NONPROPRIETARY NAME TRADE NAME hours PREPARATIONSa DAILY DOSE ADULT
Oxybutynin DITROPAN, others 2-5 IR 10-20 mg b
ER 5-30 mg b
OXYTROL Transdermal patch 3.9 mg
GELNIQUE Topical gel 100 mg
1 De nite dryness o mouth; thirst; acceleration o heart, sometimes preceded by slowing; mild dilation o pupils
2 Rapid heart rate; palpitation; marked dryness o mouth; dilated pupils; some blurring o near vision
5 Above symptoms marked; di culty in speaking and swallowing; restlessness and atigue; headache; dry, hot skin; di culty in
micturition; reduced intestinal peristalsis
≥10 Above symptoms more marked; pulse rapid and weak; iris practically obliterated; vision very blurred; skin f ushed, hot, dry,
and scarlet; ataxia, restlessness, and excitement; hallucinations and delirium; coma
The clinical picture o a high (toxic) dose o atropine may be remembered by an old mnemonic device that summarizes the symptoms: Red as a
beet, Dry as a bone, Blind as a bat, Hot as f restone, and Mad as a hatter.
101
SECTION II Neuropharmacology
102
Cholinergic Pharmacology CHAPTER 6
TABLE 6-6 Chemical Classif cation o Representative Organophosphorus Compounds o Particular Pharmacological or
Toxicological Interest
R1 O (S )
General ormula P
R2 X
Group A, X = halogen, cyanide, or thiocyanate leaving group; group B, X = alkylthio, arylthio, alkoxy, or aryloxy leaving group; group C,
thionophosphorus or thio-thionophosphorus compounds; group D, quaternary ammonium leaving group. R1 can be an alkyl (phosphonates),
alkoxy (phosphorates) or an alkylamino (phosphoramidates) group.
GROUP STRUCTURAL FORMULA COMMON, CHEMICAL, AND OTHER NAMES COMMENTS
A i-C 3 H7 O O DFP; Isof urophate; diisopropyl f uorophosphate Potent, irreversible inactivator
P
i-C 3 H7 O F
(CH3 )2 N O
Tabun Extremely toxic “nerve gas”
P
Ethyl N-dimethylphosphoramidocyanidate
C 2 H5 O CN
i-C 3 H7 O O
P Sarin (GB) Extremely toxic “nerve gas”
CH3 F Isopropyl methylphosphonof uoridate
CH3 CH3
CH3 C C
Soman (GD) Extremely toxic “nerve gas”; greatest
O O
CH3 H Pinacolyl methylphosphonof uoridate potential or irreversible action/rapid aging
P
CH3 F
CH2 COOC 2 H5
103
SECTION II Neuropharmacology
A. As s ocia tion of ACh Te tra he dra l tra ns ition s ta te Ace tyl e nzyme Hydrolys is of a ce tyl e nzyme
Glu 334
Glu 334 Glu 334 S e r 203 Glu 334
S e r 203 S e r 203 His 447 S e r 203
His 447 His 447 His 447
Gly 122
Gly 121
choline
B. Edrophonium complex C. Reve rs ible ne os tigmine binding Dime thyl ca rba moyl e nzyme Hydrolys is of dime thyl
Glu 334 S e r 203 ca rba moyl AChE
Glu 334 Glu 334 Glu 334 S e r 203
S e r 203 S e r 203
His 447 His 447 His 447
His 447
FIGURE 6-2 Steps involved in the hydrolysis o acetylcholine by acetylcholinesterase and in the inhibition and reactivation o the enzyme.
Only the 3 residues o the catalytic triad are depicted. The associations and reactions shown are: A. Acetylcholine (ACh) catalysis: binding o ACh,
ormation o a tetrahedral transition state, ormation o the acetyl enzyme with liberation o choline, rapid hydrolysis o the acetyl enzyme with
return to the original state. B. Reversible binding and inhibition by edrophonium. C. Neostigmine reaction with and inhibition o AChE: revers-
ible binding o neostigmine, ormation o the dimethyl carbamoyl enzyme, slow hydrolysis o the dimethyl carbamoyl enzyme. D. Diisopropyl
f uorophosphate (DFP) reaction and inhibition o AChE: reversible binding o DFP, ormation o the diisopropyl phosphoryl enzyme, ormation
o the aged monoisopropyl phosphoryl enzyme. Hydrolysis o the diisopropyl enzyme is very slow and is not shown. The aged monoisopropyl
phosphoryl enzyme is virtually resistant to hydrolysis and reactivation. The tetrahedral transition state o ACh hydrolysis resembles the conjugates
ormed by the tetrahedral phosphate inhibitors and accounts or their potency. Amide bond hydrogens rom Gly121 and Gly122 stabilize the car-
bonyl and phosphoryl oxygens. E. Reactivation o the diisopropyl phosphoryl enzyme by pralidoxime (2-PAM). 2-PAM attack o the phosphorus
on the phosphorylated enzyme will orm a phospho-oxime with regeneration o active enzyme. The individual steps o phosphorylation reaction
and oxime reaction have been characterized by mass spectrometry.
CASE 6-6
A 35-year-old woman with myasthenia gravis is being treated with ambenonium
chloride.
a. What is myasthenia gravis?
Myasthenia gravis is a neuromuscular disease characterized by weakness and
marked atigability o skeletal muscle; exacerbations and partial remissions occur
requently. T e de ect in myasthenia gravis is in synaptic transmission at the neuro-
muscular junction (see Figure 6-3). Myasthenia gravis is caused by an autoimmune
response primarily to the ACh receptor at the postjunctional end plate. A related
disease is Lambert-Eaton syndrome, in which antibodies are directed against Ca++
channels that are necessary or presynaptic release o ACh.
b. How is edrophonium used in the diagnosis o myasthenia gravis?
Although the diagnosis o myasthenia gravis usually can be made rom the his-
tory, signs, and symptoms, the use o the anti-ChE medication, edrophonium,
is o en use ul in con rming the diagnosis. T e edrophonium test is per ormed
(Continued)
104
Cholinergic Pharmacology CHAPTER 6
FIGURE 6-3 Sites o action o agents at the neuromuscular junction and adjacent structures.
The anatomy o the motor end plate, shown at the le t, and the sequence o events rom lib-
eration o acetylcholine (ACh) by the nerve action potential (AP) to contraction o the muscle
ber, indicated by the middle column, are described in Chapter 8 o Goodman and Gilman’s
The Pharmacological Basis o Therapeutics, 12th Edition. The modi cation o these processes by
various agents is shown on the right; an arrow marked with an X indicates inhibition or block;
an unmarked arrow indicates enhancement or activation. The insets are enlargements o the
indicated structures. The highest magni cation depicts the receptor in the bilayer o the postsyn-
aptic membrane.
Nn M2 M1 Pe ptide rgic
FIGURE 6-4 Postsynaptic potentials recorded rom an autonomic postganglionic nerve cell
body a ter stimulation o the preganglionic nerve ber. The preganglionic nerve releases ACh
onto postganglionic cells. The initial excitatory postsynaptic potential (EPSP) results rom the
inward Na+ current (and perhaps Ca2+ current) through the nicotinic receptor channel. I the EPSP
is o su cient magnitude, it triggers an action potential spike, which is ollowed by a slow inhibi-
tory postsynaptic potential (IPSP), a slow EPSP, and a late, slow EPSP. The slow IPSP and slow EPSP
are not seen in all ganglia. The electrical events subsequent to the initial EPSP are thought to
modulate the probability that a subsequent EPSP will reach the threshold or triggering a spike.
Other interneurons, such as catecholamine-containing, small, intensely f uorescent (SIF) cells, and
axon terminals rom sensory, a erent neurons also release transmitters and that may inf uence
the slow potentials o the postganglionic neuron. A number o cholinergic, peptidergic, adrener-
gic, and amino acid receptors are ound on the dendrites and soma o the postganglionic neuron
and the interneurons. The preganglionic ber releases ACh and peptides; the interneurons store
and release catecholamines, amino acids, and peptides; the sensory a erent nerve terminals
release peptides. The initial EPSP is mediated through nicotinic (Nn) receptors, the slow IPSP and
EPSP through M2 and M1 muscarinic receptors, and the late, slow EPSP through several types o
peptidergic receptors.
MECHANISMS OF ACTION OF DRUGS ACTING AT THE NEUROMUSCULAR JUNCTION (NMJ) AND AUTONOMIC GANGLIA
DRUG CLASS DRUG MECHANISM OF ACTION
Depolarizing Neuromuscular Blocking Agents Succinylcholine (see Table 6-7) Block ACh at nicotinic receptors
Competitive Neuromuscular Blocking Agents Pancuronium (see Table 6-7) Block ACh at nicotinic receptors
Antispasticity and Antirigidity Agents Dantrolene Inhibits Ca++ release o sarcoplasmic reticulum o skeletal
muscle
Nicotinic ACh Receptor Agonists Varenicline Partial to ull agonist at nicotinic ACh receptors
Ganglionic Blocking Drugs Mecamylamine (see Table 6-8) Block ACh at ganglionic nicotinic receptors
106
Cholinergic Pharmacology CHAPTER 6
Succinyl choline Dicholine ester Ultrashort duration; 0.8-1.4 6-11 Hydrolysis by plasma
(ANECTINE, others) depolarizing cholinesterases
D-Tubocurarine b Natural alkaloid (cyclic Long duration; 6 80 Renal and hepatic elimination
benzyl-isoquinoline) competitive
Metocurine b Benzylisoquinoline Long duration; 4 110 Renal elimination
competitive
Atracurium (TRACRIUM, Benzylisoquinoline Intermediate duration; 3 45 Ho mann elimination;
others) competitive hydrolysis by plasma esterases
Cisatracurium (NIMBEX) Benzylisoquinoline Intermediate duration; 2-8 45-90 Ho mann and renal
competitive elimination
Doxacurium b Benzylisoquinoline Long duration; 4-8 120 Renal elimination
competitive
Mivacurium Benzylisoquinoline Short duration; 2-3 15-21 Hydrolysis by plasma
competitive cholinesterases
Pancuronium (generic) Ammonio steroid Long duration; 3-4 85-100 Renal and hepatic elimination
competitive
Pipecuronium b Ammonio steroid Long duration; 3-6 30-90 Renal elimination; hepatic
competitive metabolism and clearance
Rocuronium (ZEMURON, Ammonio steroid Intermediate duration; 0.9-1.7 36-73 Hepatic elimination
others) competitive
Vecuronium (NORCURON, Ammonio steroid Intermediate duration; 2-3 40-45 Hepatic and renal elimination
others) competitive
Gantacurium c Asymmetric mixed- Ultra-short duration, 1-2 5-10 Cysteine adduction and ester
onium chloro umarate competitive hydrolysis
a
Time o onset and clinical duration achieved rom therapeutic doses.
b
D-Tubocurarine, doxacurium, metocurine, and pipecuronium are no longer available in the United States.
c
Gantacurium is in investigational status.
TABLE 6-8 Usual Predominance o Sympathetic or Parasympathetic Tone at Various E ector Sites, and Consequences o
Autonomic Ganglionic Blockade
SITE PREDOMINANT TONE EFFECT OF GANGLIONIC BLOCKADE
Arterioles Sympathetic (adrenergic) Vasodilation; increased peripheral blood f ow; hypotension
Veins Sympathetic (adrenergic) Dilation: peripheral pooling o blood; decreased venous return;
decreased cardiac output
Heart Parasympathetic (cholinergic) Tachycardia
Iris Parasympathetic (cholinergic) Mydriasis
Ciliary muscle Parasympathetic (cholinergic) Cycloplegia— ocus to ar vision
Gastrointestinal tract Parasympathetic (cholinergic) Reduced tone and motility; constipation; decreased gastric and
pancreatic secretions
107
SECTION II Neuropharmacology
CASE 6-7
A 48-year-old man is undergoing abdominal surgery. Succinylcholine is used as a mus-
cle relaxant during the surgery.
a. What is succinylcholine and how does it act?
Succinylcholine is a depolarizing neuromuscular blocking agent. Its initial action is
to open channels in the same manner as ACh (see Figures 6-1 and 6-3). However, it
persists longer than ACh primarily because o its resistance to AChE. T e long-lasting
depolarization results in a brie period o repetitive excitation (resulting in muscle as-
ciculations) ollowed by block o neuromuscular transmission and f accid paralysis.
b. What are the contraindications or the use o succinylcholine?
Succinylcholine and other depolarizing agents can release K+ rom intracellular sites.
T is may be a actor in the production o the prolonged apnea in patients receiving these
drugs. T is is a li e-threatening complication and precludes the use o succinylcholine in
patients with so -tissue trauma, burns, or patients with congestive heart ailure who are
receiving digoxin or diuretics. Succinylcholine is also contraindicated or should be given
with great caution to patients with nontraumatic rhabdomyolysis, ocular lacerations,
spinal cord injuries with paraplegia or quadriplegia, or muscular dystrophies.
Hepatic disease that results in a de ciency o butyrylcholinesterase (which is
responsible or the rapid hydrolysis o succinylcholine) may also be responsible
or a prolonged apnea.
CASE 6-8
A 49-year-old man is undergoing abdominal surgery. Vecuronium is used as a muscle
relaxant during the surgery.
a. What is vecuronium, how does it act, and how does it di er rom
succinylcholine?
Vecuronium is a competitive blocker at the neuromuscular junction (see Figure 6-3).
It combines with the nicotinic ACh receptor at the end plate and thereby
competitively blocks the binding o ACh. able 6-7 shows the classi cation and
di erences between the neuromuscular blocking agents.
b. What are the contraindications or the use o vecuronium?
Vecuronium is eliminated by hepatic metabolism and caution should be exercised
when using this drug in patients with hepatic dys unction.
108
Cholinergic Pharmacology CHAPTER 6
KEY CONCEPTS
Muscarinic acetylcholine receptors in the peripheral nervous system are located
primarily on e ector organs that are innervated by postganglionic parasympa-
thetic nerves (see Figure 5-2).
Muscarinic acetylcholine receptors are also located in the CNS.
T e e ects o drugs that are muscarinic receptor agonists and antagonist can
be predicted rom knowledge o parasympathetic nerve innervation (see
ables 5-1 and 6-3).
Acetylcholine (ACh) is the neurotransmitter that interacts with muscarinic
receptors at the postganglionic parasympathetic nerve endings (see Figure 6-1).
ACh is also the neurotransmitter at nicotinic acetylcholine receptors o the
parasympathetic and sympathetic autonomic ganglia (see Figure 5-2).
ACh is also the neurotransmitter at nicotinic acetylcholine receptor at the
motor end plate o skeletal muscle (see Figures 5-2 and 6-3).
ACh at these synaptic sites is destroyed by acetylcholine esterase (AChE) (see
Figure 6-2).
Drugs and other agents that are inhibitors o AChE have e ects that are pre-
dicted rom knowledge o an excess o ACh at the above synaptic sites (see
able 5-1).
Drugs that block the nicotinic acetylcholine receptor at the motor endplate o
skeletal muscle are used as adjuvants during surgery to relax muscles.
SUMMARY QUIZ
QUESTION 6-5 T e patient in Question 6-4 should be treated with atropine and which
additional drug in the ollowing list?
a. Physostigmine
b. Bethanechol
c. Pralidoxime
d. Morphine
e. Gentamicin
QUESTION 6-6 A 65-year-old man with the diagnosis o Alzheimer’s disease is being
treated with donepezil. T is drug acts by
a. stimulating the release o ACh.
b. blocking the reuptake o norepinephrine.
c. inhibiting monamine oxidase.
d. blocking the release o ACh.
e. inhibiting AChE.
QUESTION 6-9 A 3-year-old boy is brought to the emergency room because he has
ingested a large amount o a nicotine-containing product. Serious nicotine toxicity in
this child is the result o
a. blockade o transmission at autonomic ganglia and neuromuscular junctions.
b. blockade o muscarinic receptors.
c. stimulation o adrenergic receptors.
d. blockade o adrenergic receptors.
e. stimulation o muscarinic receptors.
110
Cholinergic Pharmacology CHAPTER 6
111
SECTION II Neuropharmacology
Cevimeline Long-lasting sialogogic May have ewer side Caution should be taken in
e ect and enhances lacrimal e ects than pilocarpine patients with asthma, COPD,
secretions in Sjögren urinary or GI obstruction,
syndrome or cardiovascular disease
accompanied by hypotension or
bradycardia
Muscarinic Receptor Atropine Treatment o patients Predictable e ects o Urinary or GI obstruction, angle-
Antagonists with acute MI in whom muscarinic blockade closure glaucoma
excessive vagal tone causes (see Tables 5-1 and 6-2): Use with extreme caution in
bradycardia; treatment o xerostomia, constipation, patients with benign prostatic
Amanita muscaria poisoning; blurred vision, dyspepsia, hyperplasia
treatment o AChE poisoning and cognitive impairment
Scopolamine Treatment o motion sickness Xerostomia, drowsiness, Mydriasis and cycloplegia can
and blurred vision in some occur by inadvertent trans er o
individuals drug to the eye; rare but severe
psychotic episodes are possible
112
Cholinergic Pharmacology CHAPTER 6
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Dari enacin Treatment o overactive Predictable consequences Reduce dose in patients taking
bladder by increasing o muscarinic receptor drugs that inhibit CYP3A4 or
capacity and reducing blockade (see Tables 5-1 CYP2D6
requency and 6-2) Urinary or GI obstruction, angle-
closure glaucoma
Use with extreme caution in
patients with benign prostatic
hyperplasia
Soli enacin Treatment o overactive Predictable consequences Reduce dose in patients taking
bladder by increasing o muscarinic receptor drugs that inhibit CYP3A4
capacity and reducing blockade (see Tables 5-1
requency and 6-2)
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
“Reversible”AChE Edrophonium Used or the diagnosis o Predictable consequences See Side Bar POTENTIAL EFFECTS
Inhibitors myasthenia gravis o muscarinic receptor OF ANTI-CHE AGENTS
stimulation (see Tables 5-1
and 6-2)
Physostigmine Used to treat intoxication Predictable consequences See Side Bar POTENTIAL EFFECTS
salicylate by anticholinergic drugs or o muscarinic receptor OF ANTI-CHE AGENTS; cardiac
substances stimulation (see Tables 5-1 arrhythmias i administered rapidly
and 6-2)
Neostigmine Used or the treatment o Predictable consequences See Side Bar POTENTIAL EFFECTS
bromide (oral) myasthenia gravis o muscarinic receptor OF ANTI-CHE AGENTS
stimulation (see Tables 5-1
and 6-2)
Neostigmine Used or the treatment o Predictable consequences See Side Bar POTENTIAL EFFECTS
methylsul ate myasthenia gravis o muscarinic receptor OF ANTI-CHE AGENTS
(parenteral) stimulation (see Tables 5-1
and 6-2)
Ambenonium Used or the treatment o Predictable consequences See Side Bar POTENTIAL EFFECTS
chloride myasthenia gravis o muscarinic receptor OF ANTI-CHE AGENTS
stimulation (see Tables 5-1
and 6-2)
Pyridostigmine Used or the treatment o Predictable consequences See Side Bar POTENTIAL EFFECTS
bromide myasthenia gravis o muscarinic receptor OF ANTI-CHE AGENTS
stimulation (see Tables 5-1
and 6-2)
114
Cholinergic Pharmacology CHAPTER 6
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Tacrine Approved or the treatment Predictable consequences See Side Bar POTENTIAL EFFECTS
o Alzheimer’s disease o muscarinic receptor OF ANTI-CHE AGENTS
stimulation (see Tables 5-1
and 6-2)
Donepezil Approved or the treatment Predictable consequences See Side Bar POTENTIAL EFFECTS
o Alzheimer’s disease o muscarinic receptor OF ANTI-CHE AGENTS
stimulation (see Tables 5-1
and 6-2)
Rivastigmine Approved or the treatment Predictable consequences See Side Bar POTENTIAL EFFECTS
o Alzheimer’s disease o muscarinic receptor OF ANTI-CHE AGENTS
stimulation (see Tables 5-1
and 6-2)
Galantamine Approved or the treatment Predictable consequences See Side Bar POTENTIAL EFFECTS
o Alzheimer’s disease o muscarinic receptor OF ANTI-CHE AGENTS
stimulation (see Tables 5-1
and 6-2)
Carbamate Insecticides Carbaryl Insecticide Excessive muscarinic Acute toxicity results rom excessive
receptor stimulation stimulation o muscarinic and
(see Tables 5-1 and 6-2); nicotinic receptors
low toxicity rom dermal
absorption
115
SECTION II Neuropharmacology
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Organophosphate Tabun Nerve gas agent Potent toxin; toxicity is due to
Nerve Gases stimulation o muscarinic and
nicotinic receptors
Stability o phosphorylated
cholinesterase is enhanced
through “aging”
Competitive Pancuronium Competitive neuromuscular Should be administered Persistent blockade with di culty
Neuromuscular blocking agent used as an only by an anesthesiologist in complete reversal o blockade
Blocking Agents adjuvant during surgical in a setting where
anesthesia to obtain acilities or respiratory
relaxation o skeletal muscle; and cardiovascular
long duration o action resuscitation are available
(see Chapter 11)
Atracuium Competitive neuromuscular Should be administered Histamine release which may result
blocking agent used as an only by an anesthesiologist in bronchospasm, hypotension,
adjuvant during surgical in a setting where and excessive bronchial and
anesthesia to obtain acilities or respiratory salivary secretion
relaxation o skeletal muscle; and cardiovascular
intermediate duration o resuscitation are available
action (see Chapter 11)
116
Cholinergic Pharmacology CHAPTER 6
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Botulinum Toxins Onabotulinum Treatment o strabismus and Diplopia, eyelid drop, and distant
toxin A blepharospasm and as a spread o toxin with paralysis o
cosmetic procedure to reduce respiratory muscles
acial wrinkles (see Chapter 48)
Ganglionic Stimulating Nicotine Presence in tobacco products Nicotine poisoning rom the
Agents con erring dependence on accidental ingestion o nicotine-
its users (see Chapter 14) containing insecticides, or, in
children, rom ingestion o tobacco
products; death rom respiratory
ailure may occur rapidly
Nicotinic ACh Varenicline Used as an aid to smoking FDA has issued a warning about
Receptor Agonists cessation mood and behavioral changes
Ganglionic Blocking Mecamylamine Initially used to treat Visual disturbances, dry Marked hypotension, constipation,
Drugs hypertension, but now mouth, urinary hesitancy, syncope, urinary retention,
surpassed by sa er agents decreased sexual potency, paralytic ileus, and cycloplegia
(see Table 6-8) diarrhea, abdominal pain
Trimethaphan Initially used to treat Visual disturbances, dry Marked hypotension, constipation,
hypertension, but now mouth, urinary hesitancy, syncope, urinary retention,
surpassed by sa er agents decreased sexual potency, paralytic ileus, and cycloplegia
(see Table 6-8) diarrhea, abdominal pain
117
CHAPTER
118
Adrenergic, Dopaminergic, and Serotonergic Pharmacology CHAPTER 7
119
SECTION II Neuropharmacology
• Oxymetazoline (AFRIN, OCU-CLEAR, others) Ketanserin Antagonist at α1 receptors and 5-HT receptors
• Palonosetron (ALOXI) Urapidil Antagonist at α1 adrenergic receptors
• Paroxetine (PAXIL)
Bunazosin An α1 selective antagonist
• Pemoline (CYLERT,others)—discontinued
in the United States
• Pergolide (PERMAX) MECHANISM OF ACTION OF MISCELLANEOUS SYMPATHOMIMETIC AGONISTS
• Phenelzine (NARDIL) DRUG CLASS DRUG MECHANISM OF ACTION
• Phenoxybenzamine (DIBENZYLINE) Miscellaneous Amphetamine Amphetamine exerts most o its e ects in the CNS
• Phentolamine (ORAVERSE) Sympathomimetic through the release o biogenic amines rom their
Agonists storage sites by targeting the neuronal dopamine
• Phenylephrine (NEO-SYNEPHRINE, others) (see Figure 7-3) transporter (DAT) and the vesicular monoamine
• Pindolol (VISKIN, others) transporter 2 (VMAT2) (see Table 7-1 and Figure 7-2)
• Pirbuterol (MAXAIR) Methamphetamine In the brain, methamphetamine releases DA and
• Pramipexole (MIRAPEX) other biogenic amines, and inhibits neuronal and
vesicular monoamine transporters as well as MAO
• Prazosin (MINIPRES, others)
Methylphenidate In the brain, methylphenidate is predominantly a
• Procaterol (MASCACIN)—not available in dopamine and norepinephrine uptake inhibitor
the United States
• Propranolol (INDERAL, INDERALLA, others) Dexmethylphenidate Mechanism o action is similar to methylphenidate
120
Adrenergic, Dopaminergic, and Serotonergic Pharmacology CHAPTER 7
OH OH OH CH3
COMT COMT
AR AD
CH3 O H CH3 O H H
COMT
CH3 O H OH
HO C C H
OH H
MOPEG
ADH AR
CH3 O H O
MAO MAO
HO C C H
OH
MOPGAL
AD
CH3 O H O
HO C C OH
OH
VMA
FIGURE 7-1 Steps in the metabolic disposition o catecholamines. Norepinephrine and epinephrine are f rst oxidatively deaminated to a short-lived
intermediate (DOPGAL) by monoamine oxidase (MAO). DOPGALthen undergoes urther metabolism to more stable alcohol or acid deaminated metab-
olites. Aldehyde dehydrogenase (AD) metabolizes DOPGALto 3,4-dihydroxymandelic acid (DOMA) while aldehyde reductase (AR) metabolizes DOPGAL
to 3,4-dihydroxyphenyl glycol (DOPEG). Under normal circumstances DOMA is a minor metabolite with DOPEG being the major metabolite produced
rom norepinephrine and epinephrine. Once DOPEG leaves the major sites o its ormation (sympathetic nerves; adrenal medulla), it is converted to
3-methoxy, 4-hydroxyphenylglycol (MOPEG) by catechol-0-methyl trans erase (COMT). MOPEG is then converted to the unstable aldehyde (MOPGAL) by
alcohol dehydrogenase (ADH) and f nally to vanillyl mandelic acid (VMA) by aldehyde dehydrogenase. VMA is the major end product o norepinephrine
and epinephrine metabolism. Another route or the ormation o VMA is conversion o norepinephrine or epinephrine into normetanephrine or meta-
nephrine by COMT either in the adreneal medulla or extraneuronal sites, with subsequent metabolism to MOPGAL and thence to VMA.
121
SECTION II Neuropharmacology
TH
Dopa Tyros ine
ATP NP Y DA
VAMP S NP Y NE DβH
NE ATP NE NE
Re s e rpine
Coca ine
Ca 2+
Ca 2+ β2
P1
NP Y
NE
P
Ade nos ine
T
P
A
AT E
Y
P N
rNTP a s e
Y2 α2
A
E
T
N
P
NP Y NE
ATP
AMP
ADP
NP Y
Effe c to r c e ll
me mbrane
P 2X1 – P 2X7 P 2Y Y1 – Y5 α ,β
FIGURE 7-2 An adrenergic neuroe ector junction showing eatures o the synthesis, stor-
age, release, and receptors or norepinephrine (NE), the cotransmitters neuropeptide Y(NPY),
and ATP. Tyrosine is transported into the varicosity and is converted to DOPA by tyrosine
hydroxylase (TH) and DOPA to dopamine (DA) by the action o aromatic l -amino acid decar-
boxylase (AAADC). Dopamine is taken up into the vesicles o the varicosity by a transporter,
VMAT2, that can be blocked by reserpine. Cytoplasmic NE also can be taken up by this
transporter. Dopamine is converted to NE within the vesicle via the action o dopamine-
β-hydroxylase (DβH). NE is stored in vesicles along with other cotransmitters, NPY and ATP,
depending on the particular neuroe ector junction. Release o the transmitters occurs upon
depolarization o the varicosity, which allows entry o Ca2+ through voltage-dependent Ca2+
channels. Elevated levels o Ca2+ promote the usion o the vesicular membrane with the
membrane o the varicosity, with subsequent exocytosis o transmitters. This usion process
involves the interaction o specialized proteins associated with the vesicular membrane
(VAMPs, vesicle-associated membrane proteins) and the membrane o the varicosity (SNAPs,
synaptosome-associated proteins). In this schematic representation, NE, NPY, and ATP are stored
in the same vesicles. Di erent populations o vesicles, however, may pre erentially store di erent
proportions o the cotransmitters. Once in the synapse, NE can interact with α and β adrenergic
receptors to produce the characteristic response o the e ector. The adrenergic receptors are
GPCRs. α and β Receptors also can be located presynaptically where NE can either diminish
(α2), or acilitate (β) its own release and that o the cotransmitters. The principal mechanism
by which NE is cleared rom the synapse is via a cocaine-sensitive neuronal uptake trans-
porter, NET. Once transported into the cytosol, NE can be restored in the vesicle or metabo-
lized by monoamine oxidase (MAO). NPYproduces its e ects by activating NPY receptors, o
which there are at least f ve types (YI through Y2). NPY receptors are GPCRs. NPYcan modi y its
own release and that o the other transmitters via presynaptic receptors o the Y2 type. NPYis
removed rom the synapse by metabolic breakdown by peptidases. ATP produces its e ects
by activating P2X receptors or P2Yreceptors. P2X receptors are ligand-gated ion channels;
P2Yreceptors are GPCRs. There are multiple subtypes o both P2X and P2Y receptors. As with
the other cotransmitters, ATP can act prejunctionally to modi y its own release via receptors
or ATP or via its metabolic breakdown to adenosine that acts on P1 (adenosine) receptors.
ATP is cleared rom the synapse primarily by releasable nucleotidases (rNTPase) and by cell-
f xed ectonucleotidases.
122
Adrenergic, Dopaminergic, and Serotonergic Pharmacology CHAPTER 7
FIGURE 7-3 Classif cation o adrenergic receptor agonists (sympathomimetic amines) or drugs
that produce sympathomimetic-like e ects. For each category, a prototypical drug is shown.
(*Not actually sympathetic drugs but produce sympathomimetic-like e ects.)
output and rate, in contrast to vasodilators such as hydralazine that have minimal
dilatory e ects on veins (see Chapter 15).
b. What is prazosin’s mechanism o action?
Blockade o α1 adrenergic receptors inhibits vasoconstriction induced by endog-
enous catecholamines; vasodilation may occur in both arteriolar resistance ves-
sels and in veins. T e result is a all in blood pressure due to decreased peripheral
resistance. T e magnitude o such e ects depends on the activity o the sympathetic
nervous system at the time the antagonist is administered, and thus is less in supine
than in upright subjects and is particularly marked i there is hypovolemia. For
most α receptor antagonists, the all in blood pressure is opposed by baroreceptor
re exes that cause increases in heart rate as well as uid retention. Prazosin appears
to depress barore ex unction in hypertensive patients.
(Continued)
No n-s e le c tive α 1 -s e le c tive α 2 -s e le c tive No n-s e le c tive β 1 -s e le c tive No n-s e le c tive β 1 -s e le c tive
(Firs t Ge ne ra tion) (S e c ond Ge ne ra tion) (Third Ge ne ra tion) (Third Ge ne ra tion)
phe noxybe nza mine pra zos in yohimbine na dolol a ce butolol ca rte olol be ta xolol
phe ntola mine te ra zos in pe nbutolol a te nolol ca rve dilol* ce liprolol
doxa zos in pindolol bis oprolol bucindolol ne bivolol
a lfuzos in propra nolol e s molol la be ta lol*
ta ms ulos in timolol me toprolol
indora min s ota lol
ura pidil levobunolol
buna zos in me tipra nolol
FIGURE 7-4 Classif cation o adrenergic receptor antagonists. Drugs marked by an asterisk (*)
also block α1 receptors.
123
SECTION II Neuropharmacology
Non-neuronal
OCT2 DA >> NE > Epi Kidney Medullary proximal and distal tubules Isocyanines
Brain Glial cells o DA-rich regions, some Corticosterone
nonadrenergic neurons
NET, norepinephrine transporter, originally known as uptake 1; DAT, dopamine transporter; ENT (OCT3), extraneuronal transporter, originally
known as uptake 2; OCT 1, OCT 2, organic cation transporters; Epi, epinephrine; NE, norepinephrine; DA, dopamine.
c. What are the major side e ects o prazosin that this patient should be aware o ?
A major potential adverse e ect o prazosin and its congeners is the rst-dose
e ect; marked postural hypotension and syncope sometimes are seen 30 to 90 min-
utes a er an initial dose o prazosin. Syncopal episodes also have occurred with a
rapid increase in dosage or with the addition o a second antihypertensive drug to
the regimen o a patient who already is taking a large dose o prazosin. It is recom-
mended that patients take their rst dose immediately prior to bedtime.
CASE 7-2
A 48-year-old man with the diagnoses o essential hypertension is being treated with
clonidine.
a. What type o drug is clonidine?
Clonidine, an α2-selective adrenergic agonist (see Figure 7-3), is used primarily or the
treatment o systemic hypertension (see Chapter 15). Clonidine’s ef cacy as an anti-
hypertensive agent is somewhat surprising, because many blood vessels contain post-
synaptic α2 adrenergic receptors that promote vasoconstriction. Indeed, clonidine, the
prototypic α2 agonist, was initially developed as a vasoconstricting nasal decongestant.
b. What is clonidine’s mechanism o action?
Clonidine’s capacity to lower blood pressure results rom activation o α2 receptors in
the cardiovascular control centers o the CNS; such activation suppresses the out ow o
sympathetic nervous system activity rom the brain. Although the exact mechanism by
which clonidine lowers blood pressure is not completely understood, the e ect appears
to result, at least in part, rom activation o α2 receptors in the lower brainstem region.
(Continued)
124
Adrenergic, Dopaminergic, and Serotonergic Pharmacology CHAPTER 7
β2 Selective Adrenergic Receptor Metaproterenol Agonist at β2 adrenergic receptors (see Table 5-1)
Agonists (see Figure 7-3) See Chapter 24
Nonselective β Adrenergic Receptor Carteolol Antagonist at β 1 and β 2 adrenergic receptors (see Table 5-1)
Antagonists (see Figure 7-4) See Chapter 47
Antioxida nt
Ca 2 + Agonis t NO
Blocka de ROS
β2
L-type
VGCC Ce ll me mbra ne
AC s GC
Va s cula r
s mooth mus cle
Ca 2 + cAMP ATP cGMP GTP
CASE 7-3
A 62-year-old woman with chronic obstructive airway disease is being treated with
albuterol.
a. What kind o drug is albuterol?
Albuterolol, a selective β2 receptor agonist (see Figure 7-3), is administered either
by inhalation or orally or the symptomatic relie o bronchospasm. Some o the
major adverse e ects o β receptor agonists in the treatment o asthma or obstruc-
tive pulmonary disease (COPD) are caused by stimulation o β1 receptors in the
heart. Accordingly, drugs with pre erential af nity or β2 receptors compared with
β1 receptors have been developed. However, this selectivity is relative, not absolute,
and is lost at high concentrations o these drugs.
b. How does albuterol a ect airways so that this patient might expect
improvement?
In the treatment o asthma and COPD, β receptor agonists are used to activate
pulmonary receptors that relax bronchial smooth muscle and decrease airway
resistance. Although this action appears to be a major therapeutic e ect o these
drugs in patients with asthma, evidence suggests that β receptor agonists also may
suppress the release o leukotrienes and histamine rom mast cells in lung tissue,
enhance mucociliary unction, decrease microvascular permeability, and possibly
inhibit phospholipase A2. See Chapter 24 or a detailed discussion o the treatment
o pulmonary disease with β2 receptor agonists.
c. What adverse e ects should this patient be alerted to?
T e major adverse e ects o β receptor agonists occur as a result o excessive activa-
tion o β receptors. achycardia is a common adverse e ect o systemically admin-
istered β receptor agonists. Stimulation o heart rate occurs primarily by means o
β1 receptors. Patients with underlying cardiovascular disease are particularly at risk
or signi cant reactions. However, the likelihood o adverse e ects can be greatly
decreased in patients with lung disease by administering the drug by inhalation
rather than orally or parenterally.
T e risk o adverse cardiovascular e ects also is increased in patients who
are receiving MAO inhibitors. In general, at least 2 weeks should elapse
between the use o MAO inhibitors and administration o β2 agonists or other
sympathomimetics.
remor is a relatively common adverse e ect o the β2-selective receptor agonists.
olerance generally develops to this e ect. Feelings o restlessness, apprehension,
and anxiety may limit therapy with these drugs, particularly oral or parenteral
administration.
CASE 7-4
A 51-year-old man has su ered a myocardial in arction. In the intensive care unit, he is
started on the β blocker, metoprolol.
a. Why is this patient started on a β blocker soon a er the onset o his myocardial
in arction?
A great deal o interest has ocused on the use o β receptor antagonists in the treat-
ment o acute myocardial in arction and in the prevention o recurrences or those
who have survived an initial attack. Numerous trials have shown that β receptor
antagonists administered during the early phases o acute myocardial in arction
and continued long-term may decrease mortality by ~25%.
b. What is the mechanism o action o metoprolol?
T e pharmacodynamics and pharmacokinetic parameters o β receptor antagonists
are shown in able 7-2. T e precise mechanism by which β receptor antagonists
(Continued)
127
SECTION II Neuropharmacology
CASE 7-5
A 58-year-old woman has su ered rom mild heart ailure or 5 years. She has been
treated with carvedilol. She recently changed to a di erent physician who questions the
use o a β blocker to treat heart ailure.
a. Why would her new physician question the use o a β blocker to treat heart
ailure?
It is a common clinical observation that administration o β receptor antagonists
can worsen markedly or even precipitate congestive heart ailure in compensated
patients with multiple orms o heart disease, such as ischemic or congestive cardio-
myopathy. Consequently, the hypothesis that β receptor antagonists might be ef ca-
cious in the long-term treatment o heart ailure originally seemed counterintuitive
to many physicians.
Carvedilol, metoprolol, and bisoprolol all have been shown to reduce the mortality
rate in large cohorts o patients with stable chronic heart ailure regardless o sever-
ity. reatment o patients with congestive heart ailure with β receptor antagonists
should only be undertaken by physicians with experience in using these drugs or
this purpose.
b. What is the mechanism o action o carvedilol or this indication?
A number o mechanisms have been proposed to play a role in the bene cial e ects
o β receptor antagonists in heart ailure. Since chronic excess catecholamines may
be toxic to the heart, especially through activation o β1 receptors, inhibition o
the pathway may help preserve myocardial unction. Also, antagonism o β recep-
tors in the heart may attenuate cardiac remodeling, which ordinarily might have
deleterious e ects on cardiac unction. Interestingly, activation o β receptors and
elevation o cellular cyclic AMP may promote myocardial cell death by apoptosis.
In addition, properties o certain β receptor antagonists that are due to other, unre-
lated properties o these drugs may be potentially important. For example, a erload
reduction by drugs such as carvedilol may be clinically relevant (see able 7-3
and Figure 7-5).
TABLE 7-3 Third Generation β Receptor Antagonists with Putative Additional Mechanisms of Vasodilation
NITRIC OXIDE β 2 RECEPTOR α1 RECEPTOR Ca 2+ ENTRY K+ CHANNEL ANTIOXIDANT
PRODUCTION AGONISM ANTAGONISM BLOCKADE OPENING ACTIVITY
Celiprolola Celiprolola Carvedilol Carvedilol Tilisolola Carvedilol
Nebivolol Carteolol Bucindolola Betaxolol
Carteolol Bopindolola Bevantolola Bevantolola
Bopindolola Nipradilola
Nipradilola Labetalol
a
Not currently available in the United States, where most are under investigation or use.
129
SECTION II Neuropharmacology
MAO Inhibitors That Alter 5-HT Concentrations Phenelzine MAO inhibition that results in alteration o 5-HT (see
Tranylcypromine Figure 7-6)
Isocarboxazid
Ergot Alkaloid Derivative Methylsergide 5-HT2A/2C receptor antagonist with some partial agonist
activity (see Table 7-4)
5-HT Receptor Antagonists Ondansetron 5-HT3 receptor antagonist (see Table 7-4)
Dolasetron
Granisetrol
Palonosetron
Alosetron
Dopamine (DA) Receptor Agonists Bromocriptine Ergot derivative that is a D1/D2 receptor agonist
130
Adrenergic, Dopaminergic, and Serotonergic Pharmacology CHAPTER 7
H COOH
C C NH2
L-TRYP TOP HAN
H H
N
H
O2 tryptopha n
te tra hydropte ridine hydroxyla s e
H COOH
HO
L-5-HYDROXY- C C NH2
TRYP TOP HAN H H
N
H
L-a roma tic
vita min B6 a mino a cid
de ca rboxyla s e
H H
HO
5-HYDROXY- C C NH2
TRYP TAMINE H H 5-HT
(S EROTONIN, 5-HT) N N-a ce tyla s e
H
MAO
H O
HO
5-HYDROXYINDOLE C C
H H
ACETALDEHYDE
N
H
a lde hyde a lde hyde
NAD NADH
de hydroge na s e re ducta s e
H H H
HO O HO
C C C C OH
H OH H H
N N
H H
5-HYDROXYINDOLE 5-HYDROXY-
ACETIC ACID TRYP TOP HOL
(5-HIAA)
H H O
HO
C C NH C
H H CH3
N
N-ACETYL-5-HT
H
hydroxyindole
O-me thyltra ns fe ra s e
H H O
H3 CO
C C NH C
H H CH3
N
MELATONIN H
FIGURE 7-6 Synthesis and inactivation o serotonin. Enzymes and co- actors are shown in blue.
CASE 7-6
A 36-year-old woman has been going through a di cult divorce or the past year. wo
weeks ago her ather died. She now presents to her physician with moderate situational
depression and is started on the selective serotonin reuptake inhibitor (SSRI) uoxetine.
a. Why is a drug that modulates serotonin (5-HT) at nerve endings e ective in
treating depression?
T e synthesis and inactivation o serotonin is shown in Figure 7-6 and the actions
and clinical indications o serotonergic drugs are presented in able 7-5. A multitude
(Continued)
131
SECTION II Neuropharmacology
o brain unctions are in uenced by 5-H , including sleep, cognition, sensory per-
ception, motor activity, temperature regulation, nociception, mood, appetite, sexual
behavior, and hormone secretion. All o the cloned 5-H receptors are expressed in
the brain, o en in overlapping domains (see able 7-4). Although patterns o 5-H
receptor expression in individual neurons have not been extensively de ned, it is
likely that multiple 5-H receptor subtypes with similar or opposing actions are
expressed in individual neurons, leading to a tremendous diversity o actions.
(Continued)
132
Adrenergic, Dopaminergic, and Serotonergic Pharmacology CHAPTER 7
SERT (5-HT transporter) Inhibitor Fluoxetine, sertraline Depression, obsessive-compulsive disorder, panic disorder,
social phobia, post-traumatic stress disorder
T e e ects o 5-H –active drugs in anxiety and depressive disorders, like the e ects
o selective serotonin reuptake inhibitors (SSRIs), strongly suggest a role or 5-H EVIDENCE SUGGESTING
in the neurochemical mediation o these disorders. THAT 5-HT IS A KEY
b. What are the adverse e ects o f uoxetine? MEDIATOR IN THE
Excessive stimulation o brain 5-H 2 receptors may result in insomnia, increased PATHOGENESIS OF
anxiety, irritability, and decreased libido, e ectively worsening prominent depres- MIGRAINE
sive symptoms. Excess activity at spinal 5-H 2 receptors causes sexual side e ects, • Plasma and platelet concentrations o
including erectile dys unction, anorgasmia, and ejaculatory delay. 5-HTvarywith the di erent phases o the
Stimulation o 5-H 3 receptors in the CNS and periphery contributes to GI e ects, migraine attack.
which are usually limited to nausea but may include diarrhea and emesis. Some • Urinaryconcentrations o 5-HTand its
patients experience an increase in anxiety, especially with the initial dosing o metabolites are elevated during most
SSRIs. With continued treatment, some patients also report a dullness o intel- migraine attacks.
lectual abilities and concentration. In addition, a phenomenon o a residual “ at
• Migraine maybe precipitated byagents (eg,
a ect” can occur in an otherwise success ul treatment with SSRIs.
reserpine and enfuramine) that release
c. Although this patient is otherwise healthy and is taking no other drugs, o what 5-HT romintracellular storage sites.
drug interactions should she be warned?
Most antidepressants, including the SSRIs, exhibit drug–drug interactions based on
their routes o metabolism CYPs (see Chapter 8). Paroxetine and, to a lesser degree,
uoxetine are potent inhibitors o CYP2D6. T e other SSRIs, outside o uvoxamine,
are at least moderate inhibitors o CYP2D6. T is inhibition can result in dispropor-
tionate increases in plasma concentrations o drugs metabolized by CYP2D6.
Another important drug–drug interaction with SSRIs occurs via a pharmacody-
namic mechanism. MAOIs enhance the e ects o SSRIs due to inhibition o sero-
tonin metabolism (see Figure 7-6 and Chapters 5 and 8). Administration o these
drugs together can produce synergistic increases in extracellular brain serotonin,
leading to the serotonin syndrome. Symptoms o the serotonin syndrome include
hyperthermia, muscle rigidity, myoclonus, tremors, autonomic instability, con u-
sion, irritability, and agitation; this can progress toward coma and death.
CASE 7-7
A 23-year-old woman su ers rom migraine headaches. She is given a prescription or
the 5-H receptor agonist sumitriptan and told to take it as soon as a migraine starts.
a. Why is she given a drug that is a 5-HT receptor agonist?
T e evidence that 5-H is important in the pathogenesis o migraine headaches is
shown in the Side Bar EVIDENCE SUGGES ING HA 5-H IS A KEY MEDIA-
OR IN HE PA HOGENESIS OF MIGRAINE. Consistent with this 5-H
hypothesis, 5-H receptor agonists have become a mainstay or acute treatment
o migraine headaches. T e triptans are e ective, acute antimigraine agents. T eir
(Continued)
133
SECTION II Neuropharmacology
5-HT1A 5-HT1D/1B
Re ce ptor Re ce ptor
5-HT
– –
5-HT
FIGURE 7-7 Two classes o 5-HT autoreceptors with di erential localizations. Somatodendritic
5-HT1A autoreceptors decrease raphe cell f ring when activated by 5-HT released rom axon collat-
erals o the same or adjacent neurons. The receptor subtype o the presynaptic autoreceptor on
axon terminals in the orebrain has di erent pharmacological properties and has been classif ed
as 5-HT1D (in humans) or 5-HT1B (in rodents). This receptor modulates the release o 5-HT. Postsyn-
aptic 5-HT1 receptors are also indicated.
ability to decrease, rather than exacerbate, the nausea and vomiting o migraine is
an important advance in the treatment o the condition.
b. What is the mechanism o action o sumitriptan?
T ere remains a controversy about the relative importance o vascular versus neu-
rological dys unction in migraine; thus the mechanism o the ef cacy o 5-H 1B/1D
agonists in migraine is not resolved.
According to a prominent pathophysiological model o migraine, unknown events
lead to the abnormal dilation o carotid arteriovenous anastomoses in the head and
shunting o carotid arterial blood ow, producing cerebral ischemia and hypoxia.
Based on this model, an e ective antimigraine agent would close the shunts and
restore blood ow to the brain. Indeed, sumatriptan has the capacity to produce
this vascular e ect with a pharmacological speci city that mirrors the e ects o
these agents on 5-H 1B and 5-H 1D receptor subtypes.
An alternative hypothesis concerning the signi cance o one or more 5-H 1 receptors
in migraine pathophysiology relates to the observation that both 5-H 1B and 5-H 1D
receptors serve as presynaptic autoreceptors, modulating neurotransmitter release
rom neuronal terminals (see Figure 7-7). 5-H 1 agonists may block the release o
proin ammatory neuropeptides at the level o the nerve terminal in the perivascular
space, which could account or their ef cacy in the acute treatment o migraine.
c. What are the adverse e ects o sumitriptan?
Rare but serious cardiac events have been associated with the administration o
5-H 1 agonists, including coronary artery vasospasm, transient myocardial isch-
emia, atrial and ventricular arrhythmias, and myocardial in arction, predominantly
in patients with risk actors or coronary artery disease. Orally administered triptans
can cause paresthesias; asthenia and atigue; ushing; eelings o pressure, tightness,
or pain in the chest, neck, and jaw; drowsiness; dizziness; nausea; and sweating.
T e triptans are contraindicated in patients who have a history o ischemic or
vasospastic coronary artery disease (including history o stroke or transient isch-
emic attacks), cerebrovascular or peripheral vascular disease, hemiplegic or basilar
migraines, other signi cant cardiovascular diseases, or ischemic bowel diseases.
KEY CONCEPTS
Catecholamines and sympathomimetic drugs are classi ed as direct-acting,
indirect-acting, or mixed-acting (see Figures 7-3 and 7-4).
T e pharmacological e ects o adrenergic agonists and antagonists can be
predicted rom the distribution o α and β adrenergic receptors (see able 5-1).
(Continued)
134
Adrenergic, Dopaminergic, and Serotonergic Pharmacology CHAPTER 7
Drugs that are selective or a particular adrenergic receptor subtype may have
therapeutic bene ts, but the selectivity is relative, not absolute, and is of en lost
at higher concentrations.
Adverse e ects and toxicity o adrenergic agonists and antagonist can mostly be
predicted rom the distribution o α and β adrenergic receptors (see able 5-1).
Adrenergic agonists and antagonists have broad and varied therapeutic uses,
including the treatment o shock, hypotension, hypertension, cardiac arrhyth-
mias, congestive heart ailure, nasal decongestion, asthma and chronic pul-
monary disease (COPD), allergic reactions, glaucoma, narcolepsy, weight
reduction, and attention-de cit/hyperactivity disorder (ADHD).
Serotonin (5-H ) and dopamine (DA) are neurotransmitters in the CNS and
also have prominent peripheral actions.
T e multiple actions o 5-H and DA involve interaction with distinct 5-H
and DA receptor subtypes, respectively.
Many o the therapeutic e ects o 5-H and DA agonists and antagonists in the
CNS are discussed in detail in Chapter 8 Psychopharmacology and Chapter 13
Drug T erapy o Neurodegenerative Diseases.
SUMMARY QUIZ
QUESTION 7-1 Despite its ability to stimulate receptors in the sympathetic nervous
system, norepinephrine has relatively little capacity to increase bronchial air ow
because the receptors in bronchial smooth muscle are largely o the
a. β2 subtype.
b. α1 subtype.
c. D2 subtype.
d. 5-H 4 subtype.
e. M3 subtype.
135
SECTION II Neuropharmacology
QUESTION 7-5 A 34-year-old woman has been requently using a nasal spray contain-
ing the α adrenergic receptor agonist oxymetazoline or nasal decongestion. She has
recently noticed that it is less e ective and her symptoms are worse. T is loss o e cacy
is most likely due to
a. the act that her spray container is empty.
b. degradation o the oxymetazoline.
c. a manu acturing de ect in the nasal spray container.
d. a loss o innervation to her nasal mucosa.
e. rebound hyperemia o her nasal mucosa.
QUESTION 7-9 A 35-year-old man is taking buspirone or anxiety. T is drug acts as a(n)
a. partial agonist at 5-H 1A receptors.
b. inhibitor o 5-H reuptake into presynaptic nerve terminals.
c. agonist at dopamine receptors.
d. agonist at α2 adrenergic receptors.
e. antagonist at M3 receptors.
DA
D2
Ne uro nal re uptake a utore ce ptor
(DAT, NET), the n s tora ge
(VMAT2), or me ta bolis m
Syna ptic DA
Po s ts ynaptic uptake
D1/D2 fa mily [(OCT1, OCT2,
of re ce ptors ENT (OCT3)]
DA
Effe ctor
re s pons e COMT
ALDH
HVA HVA 3MT
MAO
FIGURE 7-8 Dopaminergic terminal. Illustrated are the sequence o events (synthesis, release,
postsynaptic receptors, reuptake, and metabolism) that take place at synaptic terminals.
138
Adrenergic, Dopaminergic, and Serotonergic Pharmacology CHAPTER 7
or DA; moreover, DA can also be cleared rom the synapse by the NE transporter,
NE . Reuptake o DA by the DA transporter is the primary mechanism or termination
o DA action and allows or either vesicular repackaging o transmitter or metabolism.
139
SECTION II Neuropharmacology
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Apraclonidine Used topically to reduce Minimal e ects on Use with caution in patients with
intraocular pressure systemic cardiovascular cardiovascular disease
parameters
Brimonidine Used topically to reduce Hypotension and Use with caution in patients with
intraocular pressure sedation cardiovascular disease
Guan acine Used to treat hypertension (see Dry mouth and sedation Marked bradycardia
Chapter 15) Sexual dys unction may Withdrawal reaction upon abrupt
Used o -label to treat diarrhea occur discontinuation o long-term therapy
in patients with autonomic Use with caution in patients with
neuropathy and use ul in treating cardiovascular disease
withdrawal in patients addicted to
narcotic, alcohol, and tobacco
A sustained-release orm is
approved or treatment o
attention def cit/hyperactivity
disorder (ADHD) in children aged
6-17 years
Guanabenz Used to treat hypertension (see Dry mouth and sedation Use with caution in patients with
Chapter 15) cardiovascular disease
Methyldopa Used to treat hypertension (see Use with caution in patients with
Chapter 15) cardiovascular disease
Tizanidine Muscle relaxant used or the Dry mouth and sedation Use with caution in patients with
treatment o spasticity cardiovascular disease
α1 Adrenergic Prazosin Used to treat hypertension Syncopal reaction a ter Orthostatic hypotension
Receptor f rst dose
Antagonists (see Headache and dizziness
Figure 7-4) rarely limit treatment
(Continued)
140
Adrenergic, Dopaminergic, and Serotonergic Pharmacology CHAPTER 7
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
α2 Adrenergic Yohimbine Although not approved, it is used Enhanced motor activity
Receptor o -label to treat male sexual and tremors
Antagonists (see dys unction
Figure 7-4)
Phenoxybenzamine Used in the treatment o Hypotension and re ex cardiac
pheochromocytoma stimulation may cause alarming
tachycardia, arrhythmias, or ischemic
cardiac events
Additional Ergot Alkaloids Used in the treatment o migraine Nausea and vomiting Contraindicated in women who
α Adrenergic (see narrative in Chapter 13 o Leg weakness, are, or who may become pregnant
Receptor Goodman and Gilman’s 12th numbness and tingling due to increased motor activity
Antagonists (see Edition) o f ngers and toes o the uterus
Figure 7-4) Contraindicated in patients
with coronary artery disease,
hypertension, impaired hepatic or
renal unction
Miscellaneous Amphetamine Used or the treatment o Excessive CNS Aggressiveness, changes in libido,
Sympatho- narcolepsy and ADHD stimulation, with paranoid hallucinations, panic
mimetic Agonists dizziness, tremor, and states, and suicidal tendencies
(see Figure 7-3) hyperactive re exes Cardiovascular e ects include
hypertension and arrhythmias
Potential or abuse (see Chapter 14)
Methylphenidate Used to treat narcolepsy and Insomnia, abdominal Large doses may lead to convulsions
Dex- ADHD pain, anorexia, weight Contraindicated in patients with
methylphenidate loss glaucoma
Lisdexamphetamine
Pemoline Used to treat ADHD; discontinued Insomnia, abdominal Large doses may lead to convulsions
or use in the United States pain, anorexia, weight
loss
(Continued)
141
SECTION II Neuropharmacology
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Propylhexedrine Used to treat allergic or Tachycardia and Loss o e cacy and rebound
vasomotor rhinitis restlessness hyperemia
Use with caution in patients
with cardiovascular disease and
men with prostatic enlargement
Contraindicated in patients taking
MAO inhibitors
Pseudoephedrine Used to treat allergic or Tachycardia and Use with caution in patients
vasomotor rhinitis restlessness with cardiovascular disease and
men with prostatic enlargement
Contraindicated in patients taking
MAO inhibitors
Modaf nil Used to treat narcolepsy Tachycardia and Use with caution in patients
restlessness with cardiovascular disease and
men with prostatic enlargement
Contraindicated in patients taking
MAO inhibitors
β Adrenergic Isoproterenol Used in emergencies to stimulate Palpitations, tachycardia, Cardiac ischemia and arrhythmias
Receptor Agonists heart rate in patients with headache, and ushing may occur in patients with coronary
(see Figure 7-3) bradycardia, heart block, or artery disease
torsades de pointes
Dobutamine Indicated or the short- Increased blood pressure Patients with atrial f brillation are at
term treatment o cardiac and heart rate risk o marked increases in ventricular
decompensation that may occur rate because dobutamine acilitates
a ter cardiac surgery or in patients AVconduction
with congestive heart ailure or May increase size o a myocardial
myocardial in arction in arct by increasing myocardial O2
demand
(Continued)
142
Adrenergic, Dopaminergic, and Serotonergic Pharmacology CHAPTER 7
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
β2-Selective Metaproterenol Used or the long-term treatment Muscle tremor, anxiety, Dysrhythmias and cardiac e ects
Adrenergic o obstructive airway diseases, restlessness, tachycardia
Receptor Agonists asthma, and acute bronchospasm Selectivity is relative
(see Figure 7-3) (see Chapter 24) and is lost at high
concentrations
Albuterol Used or the long-term treatment Muscle tremor, anxiety, Dysrhythmias and cardiac e ects
o obstructive airway diseases restlessness, tachycardia
and or treatment o acute Selectivity is relative
bronchospasm (see Chapter 24) and is lost at high
concentrations
Levalbuterol Used or the long-term treatment Muscle tremor, anxiety, Dysrhythmias and cardiac e ects
o obstructive airway diseases restlessness, tachycardia
and or treatment o acute Selectivity is relative
bronchospasm (see Chapter 24) and is lost at high
concentrations
Pirbuterol Used or the long-term treatment Muscle tremor, anxiety, Dysrhythmias and cardiac e ects
o obstructive airway diseases restlessness, tachycardia
and or treatment o acute Selectivity is relative
bronchospasm (see Chapter 24) and is lost at high
concentrations
Terbutaline Used or the long-term treatment Muscle tremor, anxiety, Dysrhythmias and cardiac e ects
o obstructive airway diseases restlessness, tachycardia
and or treatment o acute Selectivity is relative
bronchospasm (see Chapter 24) and is lost at high
concentrations
Isoetharine Used or the long-term treatment Muscle tremor, anxiety, Dysrhythmias and cardiac e ects
o obstructive airway diseases restlessness, tachycardia
and or treatment o acute Selectivity is relative
bronchospasm (see Chapter 24) and is lost at high
concentrations
Bitolterol Used or the long-term treatment Muscle tremor, anxiety, Dysrhythmias and cardiac e ects
o obstructive airway diseases restlessness, tachycardia
and or treatment o acute Selectivity is relative
bronchospasm (see Chapter 24) and is lost at high
concentrations
Fenoterol Used or the long-term treatment Muscle tremor, anxiety, Dysrhythmias and cardiac e ects
o obstructive airway diseases restlessness, tachycardia
and or treatment o acute Selectivity is relative
bronchospasm (see Chapter 24) and is lost at high
concentrations
Procaterol Used or the long-term treatment Muscle tremor, anxiety, Dysrhythmias and cardiac e ects
o obstructive airway diseases restlessness, tachycardia
and or treatment o acute Selectivity is relative
bronchospasm (see Chapter 24) and is lost at high
concentrations
Salmeterol Prolonged duration o action Muscle tremor, anxiety, Dysrhythmias and cardiac e ects
(>12 hours) restlessness, tachycardia Increased risk o atal or near atal
Used or the long-term treatment Selectivity is relative asthma attacks
o obstructive airway diseases and is lost at high
Agent o choice or nocturnal concentrations
asthma (see Chapter 24)
(Continued)
143
SECTION II Neuropharmacology
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Formoterol Prolonged duration o action (>12 Muscle tremor, anxiety, Dysrhythmias and cardiac e ects
hours) restlessness, tachycardia Increased risk o atal or near atal
Used or the long-term treatment Selectivity is relative asthma attacks
o obstructive airway diseases and is lost at high
Agent o choice or nocturnal concentrations
asthma
Approved or prophylaxis o
exercise-induced bronchospasm
(see Chapter 24)
Ar ormoterol Prolonged duration o action Selectivity is relative Dysrhythmias and cardiac e ects
(>12 hours) and is lost at high Increased risk o atal or near atal
Used or the long-term treatment concentrations asthma attacks
o obstructive airway diseases, Skeletal muscle tremor,
including chronic bronchitis (see insomnia, and increases
Chapter 24) in blood glucose
Ritodrine Used as a uterine muscle relaxant Muscle tremor, anxiety, May actually increase maternal
to arrest preterm labor restlessness, tachycardia morbidity
Selectivity is relative
and is lost at high
concentrations
Nonselective Carteolol Used in the treatment o chronic Use with caution in patients with
β Adrenergic open-angle glaucoma (see pulmonary disease or congestive
Receptor Chapter 47) heart ailure
Antagonists (see
Figure 7-4) Propranolol Used in the treatment o Use o β blockers may Use with caution in patients with
hypertension, angina, acute increase atigue, sleep congestive heart ailure
coronary syndromes and disturbances, and May exacerbate asthma or COPD
congestive heart ailure depression Abrupt discontinuation a ter long-
The later use should only be May blunt recognition o term use may exacerbate angina and
undertaken by physicians hypoglycemia increase the risk o sudden death
experienced in the use o β
blockers to treat CHF
(see Chapters 15, 16, 17, and 18)
Levobunolol Used in the treatment o chronic Use with caution in patients with
open-angle glaucoma (see pulmonary disease or congestive
Chapter 47) heart ailure
Metipranolol Used in the treatment o chronic Use with caution in patients with
open-angle glaucoma (see pulmonary disease or congestive
Chapter 47) heart ailure
Nadolol Used in the treatment o Use o β blockers may Used with caution in patients with
hypertension, angina, acute increase atigue, sleep congestive heart ailure
coronary syndromes and disturbances, and May exacerbate asthma or COPD
congestive heart ailure depression Abrupt discontinuation a ter long-
The later use should only be May blunt recognition o term use may exacerbate angina and
undertaken by physicians hypoglycemia increase the risk o sudden death
experienced in the use o β
blockers to treat CHF
(see Chapters 15, 16, 17, and 18)
(Continued)
144
Adrenergic, Dopaminergic, and Serotonergic Pharmacology CHAPTER 7
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Timolol Ophthalmic preparations used in Use o β blockers may Use with caution in patients with
the treatment o chronic open- increase atigue, sleep congestive heart ailure
angle glaucoma (see Chapter 47) disturbances, and May exacerbate asthma or COPD
Also used or the treatment o depression Abrupt discontinuation a ter long-
hypertension, angina, acute May blunt recognition o term use may exacerbate angina and
coronary syndromes and hypoglycemia increase the risk o sudden death
congestive heart ailure
The later use should only be
undertaken by physicians
experienced in the use o β
blockers to treat CHF
(see Chapters 15, 16, 17, and 18)
Pindolol Used in the treatment o chronic Use o β blockers Used with caution in patients with
open-angle glaucoma may increase atigue, congestive heart ailure
Also used or the treatment o sleep disturbances, May exacerbate asthma or COPD
hypertension, angina, acute and depression Abrupt discontinuation a ter long-
coronary syndromes and May blunt recognition o term use may exacerbate angina and
congestive heart ailure hypoglycemia increase the risk o sudden death
The later use should only be
undertaken by physicians
experienced in the use o β
blockers to treat CHF
(see Chapters 15, 16, 17, and 18)
β1 Selective Metoprolol Used to treat hypertension, Use o β blockers Selectivity is relative and dependent
Adrenergic angina, tachycardia, heart may increase atigue, on dose
Receptor ailure, vasovagal syncope, and sleep disturbances, Should be avoided i possible in
Antagonists (see as secondary prevention o and depression patients with asthma or COPD
Figure 7-4) myocardial in arction May blunt recognition o Contraindicated or the treatment
Also used or migraine prophylaxis hypoglycemia o acute myocardial in arction in
(see Chapters 15, 16, and 17) patients with heart rates <45 bpm,
heart block greater than f rst degree,
systolic blood pressure <100 mm Hg,
or moderate to severe chronic heart
ailure
Betaxolol Used to treat hypertension, Use o β blockers Selectivity is relative and dependent
angina pectoris, and glaucoma may increase atigue, on dose
sleep disturbances, Should be avoided i possible in
and depression patients with asthma or COPD
May blunt recognition o
hypoglycemia
Levobetaxolol Used to treat hypertension, Use o β blockers Selectivity is relative and dependent
angina pectoris, and glaucoma may increase atigue, on dose
sleep disturbances, Should be avoided i possible in
and depression patients with asthma or COPD
May blunt recognition o
hypoglycemia
Bisoprolol Used to treat hypertension and Use o β blockers Selectivity is relative and dependent
moderate to severe chronic heart may increase atigue, on dose
ailure, cardiac arrhythmias, and sleep disturbances, Should be avoided i possible in
ischemic heart disease and depression patients with asthma or COPD
(see Chapters 15, 16, 17, and 18) May blunt recognition o
hypoglycemia
(Continued)
145
SECTION II Neuropharmacology
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Acebutolol Used to treat hypertension, Use o β blockers Selectivity is relative and dependent
ventricular and atrial cardiac may increase atigue, on dose
arrhythmias, and acute myocardial sleep disturbances, Should be avoided i possible in
in arction and depression patients with asthma or COPD
(see Chapters 15, 16, and 18) May blunt recognition o
hypoglycemia
Atenolol Used to treat hypertension, Use o β blockers Selectivity is relative and dependent
angina, tachycardia, and as may increase atigue, on dose
secondary prevention o sleep disturbances, Should be avoided i possible in
myocardial in arction (see and depression patients with asthma or COPD
Chapters 15, 16, and 17) May blunt recognition o
Also used to treat Graves’disease hypoglycemia
until anti-thyroid medications can
take e ect (see Chapter 27)
β Adrenergic Labetalol Used to treat hypertension (see Use o β blockers Should be avoided in patients with
Receptor Chapter 15) may increase atigue, asthma or COPD
Antagonists sleep disturbances,
with Additional and depression
Cardiovascular May blunt recognition o
E ects (“Third hypoglycemia
Generation”β
Blockers) (see Carvedilol Used to treat hypertension, mild Use o β blockers Should be avoided in patients with
Figure 7-4) to severe congestive heart ailure, may increase atigue, asthma or COPD
and acute myocardial in arction sleep disturbances,
(see Chapters 15, 16, and 17) and depression
May blunt recognition o
hypoglycemia
Bucindolol Used to treat hypertension, mild Use o β blockers Should be avoided in patients with
to severe congestive heart ailure, may increase atigue, asthma or COPD
and acute myocardial in arction sleep disturbances,
(see Chapters 15, 16, and 17) and depression
May blunt recognition o
hypoglycemia
Celiprolol Used to treat hypertension and Use o β blockers Should be avoided in patients with
angina may increase atigue, asthma or COPD
sleep disturbances,
and depression
May blunt recognition o
hypoglycemia
Nebivolol Used to treat hypertension Use o β blockers Should be avoided in patients with
may increase atigue, asthma or COPD
sleep disturbances,
and depression
May blunt recognition o
hypoglycemia
Selective Fluoxetine Used to treat depression and Sedation (see Chapter 8) Signif cant drug interactions due to
Serotonin Citalopram anxiety (see Chapter 8) inhibition o CYPs (see Chapter 8)
(5-HT) Reuptake Escitalopram
Inhibitors (SSRIs) Fluvoxamine
Paroxetine
Sertraline
(Continued)
146
Adrenergic, Dopaminergic, and Serotonergic Pharmacology CHAPTER 7
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Serotonin(5-HT)/ Duloxetine Used to treat depression, anxiety, See Chapter 8 See Chapter 8
Norepinephrine peripheral neuropathy, and
(NE) Reuptake f bromyalgia (see Chapter 8)
Inhibitors (SNRIs)
Venla axine Used to treat depression, anxiety, See Chapter 8 See Chapter 8
and panic disorders (see Chapter 8)
Desvenla axine Used to treat depression, anxiety, See Chapter 8 See Chapter 8
and panic disorders (see Chapter 8)
MAO Inhibitors Phenelzine Used to treat depression (see See Chapter 8 See Chapter 8
That Alter 5-HT Tranylcypromine Chapter 8)
Concentrations Isocarboxazid
5-HT Receptor Buspirone Used to treat anxiety (see See Chapter 8 See Chapter 8
Agonists Chapter 8)
Almotripan Used to treat an acute attack o Paresthesias, asthenia Contraindicated in patients who
Eletriptan migraine, but not intended or use and atigue, ushing, have a history o ischemic or
Frovatriptan in the prophylaxis o migraine tightness in the chest, vasospastic coronary artery disease,
Naratriptan dizziness, nausea, and cerebrovascular or peripheral
Rizatriptan sweating vascular disease, hemiplegic or
Sumatriptan basilar migraines, or other signif cant
Zolmitriptan cardiovascular diseases, or ischemic
bowel disease
Naratriptan is also contraindicated
in patients with severe renal or
hepatic impairment
Eletriptan is contraindicated in hepatic
disease Almotriptan, rizatriptan,
sumatriptan, and zolmitriptan are
contraindicated in patients who have
taken an MAO inhibitor within the
preceding 2 weeks (see Chapter 8)
5-HT Receptor Ondansetron Used to treat chemotherapy- See Chapter 33 See Chapter 33
Antagonists Dolasetron induced nausea (see Chapter 33)
Granisetrol
Palonosetron
(Continued)
147
SECTION II Neuropharmacology
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Dopamine (DA) Bromocriptine Used or the treatment o Nausea, dizziness, and Hallucination and other CNS e ects
Receptor Agonists Parkinson’s disease (see headache such as psychosis
Chapter 13)
Also used to treat acromegaly (see
Chapter 26)
Cabergoline Used to treat hyper-prolactinemia Hypotension, nausea, Has been linked to valvular heart
(see Chapter 26) dizziness disease
148
CHAPTER
Psychopharmacology 8
Chapter 8 Psychopharmacology is a combination o Chapter 15, Drug T erapy o
DRUGS INCLUDED
Depression and Anxiety Disorders and Chapter 16, Pharmacology o Psychosis and
Mania rom Goodman and Gilman’s T e Pharmacological Basis of T erapeutics, 12th IN THIS CHAPTER
Edition. An understanding o the material in those chapters will be help ul in ollowing • Amitriptyline (ELAVIL, others)
the material presented in this chapter. In addition to the material presented here, the • Amoxapine (ASENDIN)
above chapters in the 12th Edition include:
• Aripiprazole (ABILIFY)
• A characterization o depressive and anxiety disorders
• Asenapine (SAPHRIS, others)
• able 15-2, T e Potencies o Antidepressants at the Human ransporters or Norepi-
• Atomoxetine (STRATTERA)
nephrine (NE ), Serotonin (SER ), and Dopamine (DA )
• Bupropion (WELLBUTRIN, ZYBAN, others)
• able 15-4, Potencies o Selected Antidepressants at Muscarinic, Histamine H 1, and
alpha1-Adrenergic Receptors • Buspirone (BUSPAR)
• A discussion o the long-term adaptive e ects o antidepressants that enhance the • Carbamazepine (TEGRETOL, others)
e ectiveness o therapy • Chlorpromazine (THORAZINE, others)
• A discussion o the pathophysiology o psychosis • Citalopram(CELEXA)
• A discussion o the chemistry o antipsychotic agents • Clomipramine (ANAFRANIL)
• T e role o dopamine and serotonin receptors in antipsychotic therapy • Clozapine (CLOZARIL, others)
• A detailed discussion o the use antipsychotic agents or nonpsychotic disorders • Desipramine (NORPRAMIN)
• A discussion o the adverse e ects o antipsychotic agents that are not predicted by • Desvenla axine (PRISTIQ)
monoamine receptor a nities • Doxepin (ADAPIN, SINEQUAN)
• Novel treatments or psychosis and mania • Droperidol (INAPSIN, others)
• Duloxetine (CYMBALTA)
LEARNING OBJECTIVES
• Escitalopram(LEXAPRO)
Understand the mechanisms o action, therapeutic uses, and adverse e ects o
antidepressant drugs. • Fluoxetine (PROSAC, SYMBYAX,others)
Know how antidepressant drugs are used to manage depression. • Fluphenazine (PROLIXIN, others)
• Fluvoxamine (LUVOX)
Know the mechanisms o action, therapeutic uses, and adverse e ects o
antipsychotic drugs and drugs used to treat mania. • Haloperidol (HALDOL, others)
Understand the pharmacotherapy o acute and chronic psychoses and • Iloperidone (FANAPT)
bipolar disorder. • Imipramine (TOFRANIL, others)
• Isocarboxazid (MARPLAN)
• Lamotrigine (LAMICTAL)
• Lithium
• Loxapine (LOXITANE)
• Maprotiline (LUDIOMIL)
• Mianserin (DEPNON, others)—not
approved in the United States
• Milnacipran (IXEL, others)—not approved
in the United States
• Mirtazapine (REMERON, others)
• Molindone (MOBAN)—use discontinued
• Ne azodone (DUTONIN, others)
(continues)
149
SECTION II Neuropharmacology
• Ziprasidone (GEODON) Atypical Antidepressants Duloxetine Inhibit the reuptake o both NE and
and SNRIs Venla axine 5-HT, but do not have a tricyclic
Desvenla axine structure and thus avoid some o
Milnacipran the side e ects o TCAs
150
Psychopharmacology CHAPTER 8
151
SECTION II Neuropharmacology
TCAs
S NRIs
Modula tion
of ce ll s igna ling
MAOIs S S RIs pa thways a nd
TCAs ce ll function
S NRIs
S ERT
MAO Re upta ke
S e rotone rgic
ne uron 5-HTR 1A/1D/7
α 2 AR
NE
FIGURE 8-1 Sites o action o antidepressants. Schematics representing noradrenergic (top) and
serotonergic (bottom) nerve terminals. SSRIs, SNRIs, and TCAs increase noradrenergic or seroto-
nergic neurotransmission by blocking the norepinephrine or serotonergic transporter at presyn-
aptic terminals (NET, SERT). MAOIs inhibit the catabolism o norepinephrine and serotonin. Some
antidepressants such as trazodone and related drugs have direct e ects on serotonergic recep-
tors that contribute to their clinical e ects. Chronic treatment with a number o antidepressants
desensitizes presynaptic autoreceptors and heteroreceptors, producing long-lasting changes in
monoaminergic neurotransmission. Post-receptor e ects o antidepressant treatment, including
modulation o GPCR signaling and activation o protein kinases and ion channels, are involved in
the mediation o the long-term e ects o antidepressant drugs. Note that NE and 5-HT also a ect
each other’s neurons.
CASE 8-1
A 39-year-old woman is taking amitriptyline or major depression.
a. How do antidepressants act to elevate the mood o patients?
Many di erent antidepressants have estab ished track records o e cacy or treat-
ing major depression. However, they a su er some imitations in e cacy, since at
east 20% o a depressed patients are re ractory to mu tip e di erent antidepres-
sants at adequate doses. In monoamine systems, reuptake o the transmitter is the
main mechanism by which neurotransmission is terminated; thus, inhibition o
reuptake can enhance neurotransmission, presumab y by s owing c earance o the
transmitter rom the synapse and pro onging the dwe -time o the transmitter
in the synapse. Enhancing neurotransmission may subsequent y ead to adaptive
changes (see Figure 8-1).
(Continued)
152
Psychopharmacology CHAPTER 8
S ome
S timula nts Anti-P sy
FIGURE 8-2 Sites o action o antipsychotic agents and Li+. In varicosities (“terminals”) along
terminal arborizations o dopaminergic neurons projecting rom midbrain to orebrain, DA is
synthesized and stored in vesicles. Following exocytotic release, DA interacts with postsynaptic
receptors (R) o D1 and D2 types, and presynaptic D2 and D3 autoreceptors. Termination o DA
action occurs primarily by active transport o DA into presynaptic terminals via the DA trans-
porter DAT, with secondary deamination by mitochondrial monoamine oxidase (MAO). Stimula-
tion o postsynaptic D1 receptors activates the Gs-adenylyl cyclase-cAMP pathway. D2 receptors
couple through Gi to inhibit adenylyl cyclase and through Gq to activate the PLC-IP3-Ca2+ path-
way. Activation o the Gi pathway can also activate K+ channels, leading to hyperpolarization.
Lithium inhibits the phosphatase that liberates inositol (I) rom inositol phosphate (IP). Li+ can
also inhibit depolarization-evoked release o DA and NE, but not 5-HT. D2-like autoreceptors sup-
press synthesis o DA by diminishing phosphorylation o rate-limiting TH, and by limiting DA
release. In contrast, presynaptic A2 adenosine receptors (A2R) activate AC and, through cyclic AMP
production, TH activity. All antipsychotic agents act at D2 receptors and autoreceptors; some also
block D1 receptors. Stimulant agents inhibit DA reuptake by DAT, thereby prolonging the dwell
time o synaptic DA. Initially in antipsychotic treatment, DA neurons release more DA, but ol-
lowing repeated treatment, they enter a state o physiological depolarization inactivation, with
diminished production and release o DA, in addition to continued receptor blockade. (“T-line”),
inhibition or blockade; +, elevation o activity; –, reduction o activity.
CASE 8-2
A 48-year-old man has developed depression a er the death o his wi e. He is prescribed
venla axine.
a. How does venla axine dif er rom other antidepressants?
Many o der CAs b ock both SER and NE , but with a high side e ect burden.
Four medications with a nontricyc ic structure that inhibit the reuptake o both
5-H and norepinephrine have been approved or use in the United States or treat-
ment o depression, anxiety disorders, and pain: ven a axine and its demethy ated
metabo ite, desven a axine; du oxetine; and mi nacipran (approved on y or bro-
mya gia pain in the United States). T e rationa e behind the deve opment o these
newer agents was that targeting both SER and NE , ana ogous to the e ects o
some CAs, might improve overa treatment response.
(Continued)
154
TABLE 8-1 Antidepressants: Chemical Structures, Dose and Dosage Forms, and Side E ects
DOSE AND DOSAGE AMINE
NONPROPRIETARY NAME t r a d e n a me FORMS EFFECTS SIDE EFFECTS
Norepinephrine Reupta ke Inhibitors: Usuala Dosage Agitation Seizures Sedation Hypo- Anticholinergic GI Ef ects Weight Sexual Cardiac
Tertiary Amine Tricyclics Dose Form tension Ef ects Gain Ef ects Ef ects
R1 (mg/day)
R3 R2
R1 R2 R3
P
s
y
(+)-Trimipramine (su r mo n t il ) 75-200 O NE, 5-HT 0 2+ 3+ 2+ 3+ 0/+ 2+ 2+ 3+
c
h
C H
o
p
h
Norepinephrine Reupta ke Inhibitors:
a
Secondary Amine Tricyclics
r
m
a
Amoxapine (a sen d in ) 200-300 O NE, DA 0 2+ + 2+ + 0/+ + 2+ 2+
c
o
l
o
Desipramine (n o r pr a min ) 100-200 O NE + + 0/+ + + 0/+ + 2+ 2+
g
y
Maprotiline (l u d io mil ) 100-150 O NE 0/+ 3+ 2+ 2+ 2+ 0/+ + 2+ 2+
C
H
(±)-Citalopram (c el exa ) 20-40 O 5-HT 0/+ 0 0/+ 0 0 3+ 0 3+ 0
A
P
T
(+)- Escitalopram (l exa pr o ) 10-20 O 5-HT 0/+ 0 0/+ 0 0 3+ 0 3+ 0
E
R
(±)-Fluoxetine (pr o za c ) 20-40 O 5-HT + 0/+ 0/+ 0 0 3+ 0/+ 3+ 0/+
8
Fluvoxamine (luvox) 100-200 O 5-HT 0 0 0/+ 0 0 3+ 0 3+ 0
1
(–)-Paroxetine (pa xil ) 20-40 O 5-HT + 0 0/+ 0 0/+ 3+ 0 3+ 0
5
5
1
DOSE AND DOSAGE AMINE
5
NONPROPRIETARY NAME FORMS EFFECTS SIDE EFFECTS
6
t r a d e n a me
S
E
C
T
I
O
N
I
I
Cl
Cl
Atypical Antidepressants
N
e
(–)-Atomoxetine (st r at t er a ) 40-80 O NE 0 0 0 0 0 0/+ 0 0 0
u
(children:
r
o
mg/kg)
p
h
a
Bupropion (wel l bu t r in ) 200-300 O DA, ?NE 3+ 4+ 0 0 0 2+ 0 0 0
r
m
a
(+)-Duloxetine (c ymba lt a ) 80-100 O NE, 5-HT + 0 0/+ 0/+ 0 0/+ 0/+ 0/+ 0/+
c
o
l
o
(±)-Mirtazapine (r emer o n ) 15-45 O 5-HT, NE 0 0 4+ 0/+ 0 0/+ 0/+ 0 0
g
y
Ne azodone (ser zo n e) 200-400 O 5-HT 0 0 3+ 0 0 2+ 0/+ 0/+ 0/+
Note: Most o the drugs are hydrochloride salts, but SURMONTIL and LUVOX are maleates; CELEXA is a hydrobromide, and REMERON is a ree-base. Selegiline is approved or early Parkinson
disease, but may have antidepressant e ects, especially at daily doses 20 mg, and is under investigation or administration by transdermal patch.
a
Both higher and lower doses are sometimes used, depending on an individual patient’s needs and response to the drug; see the literature and FDA-approved dosage recommendations.
O, oral tablet or capsule; I, injectable; NE, norepinephrine; 5-HT, serotonin, DA, dopamine; 0, negligible; 0/+, minimal; +, mild; 2+, moderate; 3+, moderately severe; 4+, severe.
Other signi cant side e ects or individual drugs are described in the Summary Table.
Psychopharmacology CHAPTER 8
b. Why is there a delay in the onset o antidepressant ef ect with SSRI antidepres-
sants and SNRIs such as venla axine?
SNRIs inhibit both SER and NE . Depending on the drug, the dose, and the
potency at each site, SNRIs cause enhanced serotonergic and/or noradrenergic
neurotransmission. Simi ar to the action o SSRIs, the initia inhibition o SER
induces activation o 5-H 1A and 5-H 1D autoreceptors. T is action decreases sero-
tonergic neurotransmission by a negative eedback mechanism unti these seroto-
nergic autoreceptors are desensitized. T en, the enhanced serotonin concentration
in the synapse can interact with postsynaptic 5-H receptors.
c. What side ef ects might this patient expect with venla axine?
T e side e ects o ven a axine are shown in ab e 8-1. Ven a axine dose reductions
are suggested or patients with rena or hepatic impairment (see ab e 8-2). T e
SNRIs have desirab e sa ety advantages over the CAs. SNRIs have a side e ect
pro e simi ar to that o the SSRIs, inc uding nausea, constipation, insomnia, head-
aches, and sexua dys unction. T e immediate re ease ormu ation o ven a axine
can induce sustained diasto ic hypertension (systo ic b ood pressure > 90 mm Hg
at consecutive week y visits) in 10 to 15% o patients at higher doses; this risk is
reduced with the extended-re ease orm.
CASE 8-3
A 53-year-old man with mild depression has been treated with a monoamine oxidase
inhibitor. His physician is now switching his antidepressant therapy to uoxetine.
a. What drug interactions should he be cautioned about while taking the SSRI?
Most antidepressants, inc uding the SSRIs, exhibit drug—drug interactions based
on their routes o metabo ism (see ab e 8-2). Paroxetine and, to a esser degree,
f uoxetine are potent inhibitors o CYP2D6. T e other SSRIs, outside o f uvox-
amine, are at east moderate inhibitors o CYP2D6. T is inhibition can resu t in dis-
proportionate increases in p asma concentrations o drugs metabo ized by CYP2D6
when doses o these drugs are increased. F uvoxamine direct y inhibits CYP1A2
and CYP2C19; f uoxetine and f uvoxamine a so inhibit CYP3A4. See Chapter 2 or
a ist o drugs metabo ized by these CYPs.
b. He had previously been taking tranylcypromine, an MAO inhibitor. What con-
cerns are there or switching his medication to an SSRI?
Another important drug–drug interaction with SSRIs occurs via a pharmacody-
namic mechanism. MAOIs enhance the e ects o SSRIs due to inhibition o sero-
tonin metabo ism. Administration o these drugs together can produce synergistic
increases in extrace u ar brain serotonin, eading to the serotonin syndrome.
Symptoms o the serotonin syndrome inc ude hyperthermia, musc e rigidity, myoc-
onus, tremors, autonomic instabi ity, con usion, irritabi ity, and agitation; this
can progress toward coma and death. Other drugs that may induce the serotonin
syndrome inc ude substituted amphetamines such as methy enedioxymetham-
phetamine (Ecstasy), which direct y re eases serotonin rom nerve termina s. T e
primary treatment is stopping a serotonergic drugs, administering nonse ective
serotonin antagonists, and supportive measures.
Since current y avai ab e MAOIs bind irreversib y to MAO and b ock the enzy-
matic metabo ism o monoaminergic neurotransmitters, SSRIs shou d not be
started unti at east 14 days o owing discontinuation o treatment with an
MAOI; this a ows or synthesis o new MAO. For a SSRIs but f uoxetine, at east
14 days shou d pass prior to beginning treatment with an MAOI o owing the end
o treatment with an SSRI. Since the active metabo ite o f uoxetine, norf uoxetine,
has a t1/2 o 1 to 2 weeks, at east 5 weeks shou d pass between stopping f uoxetine
and beginning an MAOI.
(Continued)
157
SECTION II Neuropharmacology
Desipramine 30 125-300
Maprotiline 48 200–400
Nortriptyline 31 60-150
Protriptyline 80 100-250
Duloxetine 11 — 2D6
Other Antidepressants
Mirtazapine 16 — 2D6
Reboxetine 12 — —
Values shown are elimination t1/2 values or a number o clinically used antidepressant drugs; numbers in parentheses are t1/2 values o active
metabolites. Fluoxetine (2D6), uvoxamine (1A2, 2C8, 3A3/4), paroxetine (2D6), and ne azodone (3A3/4) are potent inhibitors o CYPs; sertraline
(2D6), citalopram (2C19), and venla axine are less potent inhibitors. Plasma concentrations are those observed at typical clinical doses.
In ormation was obtained rom manu acturers’summaries and Appendix II in Goodman and Gilman’s The Pharmacological Basis of Therapeutics,
12th Edition, which the reader should consult or important details.
158
Psychopharmacology CHAPTER 8
CASE 8-4
A 49-year-old man is in hospital or surgery on a herniated vertebral disc. On the sec-
ond day ollowing surgery, he becomes agitated, belligerent, paranoid, and aggressive.
He is given haloperidol to control his behavior.
a. What kind o drug is haloperidol and how does it act?
Like most antipsychotic drugs ha operido is an antagonist at D2 receptors (see
Figure 8-2; ab es 8-3 and 8-4).
b. What are the advantages o using a drug such as haloperidol in this setting?
De irium o owing surgery genera y requires on y short-term therapy. Because
anticho inergic drug e ects may worsen de irium and dementia, high-potency typi-
ca antipsychotic drugs (eg, ha operido ) or atypica antipsychotic agents with im-
ited antimuscarinic properties (eg, risperidone) are o en the drugs o choice.
c. While not a consideration in this setting, what are the side ef ects o the chronic
use o haloperidol?
Excessive D2 b ockade, as is o en the case with the use o high-potency typica agents
(eg, ha operido ), not on y increases risk or motor neuro ogica e ects (eg, muscu ar
rigidity, bradykinesia, tremor, akathisia) (see Figure 8-3), but a so s ows mentation
(bradyphrenia), and inter eres with centra reward pathways, resu ting in patient
comp aints o anhedonia. Rare y used are ow-potency typica agents (eg, ch or-
promazine), which a so have high a nities or H 1, M, and α1 receptors that cause
many undesirab e e ects (sedation, anticho inergic properties, orthostasis). Concerns
regarding Q c pro ongation (eg, thioridazine) urther imit their c inica use u ness.
d. What are other options in treating this patient?
Intramuscu ar (IM) administration o ziprasidone, aripiprazo e, or o anzapine repre-
sents an option or treating agitated and minima y cooperative patients, and presents
ess risk o drug-induced parkinsonism than ha operido . Q c pro ongation associated
with intramuscu ar droperido and intravenous administration o ha operido have
curtai ed the use o those particu ar ormu ations. reatment continues unti agitated
or ha ucinatory behaviors are contro ed and the under ying etio ogies are addressed.
CASE 8-5
A 32-year-old woman with a long history o drug abuse has been diagnosed with
schizophrenia.
a. What are the goals o short-term therapy with this patient?
T e immediate goa s o acute antipsychotic treatment are the reduction o agi-
tated, disorganized, or hosti e behavior, decreasing the impact o ha ucinations,
the improvement o organization o thought processes, and the reduction o socia
withdrawa . Doses used are o en higher than those required or maintenance
treatment o stab e patients.
b. What are the goals o long-term therapy with this patient?
T e need or ong-term treatment poses issues a most exc usive y to the chronic
psychotic i nesses, schizophrenia and schizoa ective disorder, a though ong-term
antipsychotic treatment is sometimes used or manic patients, or ongoing psy-
chosis in dementia patients, or l -dopa psychosis, and or adjunctive use in SSRI-
unresponsive major depression.
T e choice o antipsychotic agents or ong-term schizophrenia treatment is based
primari y on avoidance o adverse e ects and, when avai ab e, prior history o
patient response. Since schizophrenia spectrum disorders are i e ong diseases,
treatment acceptabi ity is paramount to e ective i ness management. Whether
atypica antipsychotic agents are superior to typica antipsychotic agents has been
the subject o signi cant and contentious debate.
(Continued)
159
1
TABLE 8-3 Chemical Structures, Dosages or Acute Psychosis and Schizophrenia Maintenance, and Metabolic Risk Prof le a
6
0
ORAL DOSAGE (MG/DAY)
NONPROPRIETARY NAME t r a d e n a me ACUTE PSYCHOSIS MAINTENANCE METABOLIC SIDE EFFECTS
S
DOSAGE FORMS 1ST EPISODE CHRONIC 1ST EPISODE CHRONIC WEIGHT GAIN LIPIDS GLUCOSE
E
C
T
Typical Antipsychotic Agents
I
O
Phenothia zines
N
I
I
Chlorpromazine (t h o r a zin e) O, S, IM 200-600 400-800 150-600 250-750 +++ +++ ++
N
e
Fluphenazine decanoate Depot IM Not or acute use 5-75 mg/2 wks +/– – –
u
r
o
Other Typical Agents
p
h
a
Molindone (mo ba n ) O, S 15-50 30-60 15-50 30-60 – – –
r
m
a
Loxapine (l o xit a n e) O, S, IM 15-50 30-60 15-50 30-60 + – –
c
o
l
Haloperidol (h a l d o l ) 2.5-10 5-20 2.5-10 5-15 +/– – –
o
g
y
O
OH
F C (CH2 )3 N
Cl
O, S, IM
(Continued )
ORAL DOSAGE (MG/DAY)
NONPROPRIETARY NAME t r a d e n a me ACUTE PSYCHOSIS MAINTENANCE METABOLIC SIDE EFFECTS
DOSAGE FORMS 1ST EPISODE CHRONIC 1ST EPISODE CHRONIC WEIGHT GAIN LIPIDS GLUCOSE
Iloperidone (fa n a pt ) O 12-24b 8-16 + +/– +/–
Olanzapine (zypr exa ) O, ODT, IM 7.5-20 10-30 7.5-15 15-30 ++++ +++ +++
Dosage Forms: O, tablet; S, solution; IM, acute intramuscular; ODT, orally dissolving tablet.
a
For urther in ormation on antipsychotic dosing in psychotic disorders, see Expert Consensus Panel or Optimizing Pharmacologic Treatment o Psychotic Disorders. The expert consensus
guideline series. Optimizing pharmacologic treatment o psychotic disorders. J Clin Psychiatry, 2003, 64(Suppl 12):2–97.
P
s
y
Note that doses in rst-episode, younger, or antipsychotic-naïve patients are lower than or chronic schizophrenia patients. Dose in elderly schizophrenia patients is approximately 50% o that
c
h
used in younger adults with schizophrenia; dosing or dementia-related psychosis is approximately 25%.
o
Due to orthostasis risk, dose titration o iloperidone is 1 mg bid on day 1, increasing to 2, 4, 6, 8, 10, and 12 mg bid on days 2, 3, 4, 5, 6, and 7 (as needed). Sa ety data exist or daily doses up to
p
b
h
16 mg bid.
a
r
c
Paliperidone palmitate dosing: in acute schizophrenia, deltoid IM loading doses o 234 mg at day 1 and 156 mg at day 8 provide paliperidone levels equivalent to 6 mg oral paliperidone
m
during the rst week, and peaking on day 15 at a level comparable to 12 mg oral paliperidone. No oral antipsychotic needed in rst week. Maintenance IM doses can be given in deltoid or
a
c
gluteus every 4 weeks a ter day 8. Maintenance dose options: 39, 78, 117, 156, or 234 mg every 4 weeks. Failure to give initiation doses (except or those switching rom depot) will result in
o
l
o
subtherapeutic levels or months.
g
Not available in the United States.
y
d
e
Oral dose must be given with ood (500 kcal) to acilitate absorption. Food increases the absorption o single doses o 20-, 40-, and 80-mg capsules by 48%, 87%, and 101%, respectively.
C
H
A
P
T
E
R
8
1
6
1
SECTION II Neuropharmacology
Molindone 20 3800 >5000 10,000 >250 >10,000 >2000 >10,000 2600 1100 2130
Atypical Agents
Asenapine b 1.4 2.7 0.1 0.03 0.05 1.4 1.1 >10,000 1.2 1.2 1.0
Sertindole b 2.7 280 0.4 0.90 0.2 12 13 >5000 1.8 640 130
Zotepine b 8.0 470 2.7 3.2 0.3 71 39 330 6.0 210 3.2
Sulpiride b 6.4 >10,000 >10,000 >10,000 >1000 >10,000 54 >10,000 >10000 >5000 >10,000
Quetiapine 380 390 640 1840 2.0 990 2020 37 22 2900 6.9
c. She is prescribed the atypical antipsychotic drug aripiprazole. What is the mech-
anism o action o aripiprazole?
Present y, antipsychotic agents inc ude many di erent chemica structures with a
range o activities at di erent neurotransmitter receptors (eg, 5-H 2A antagonism,
5-H 1A partia agonism). As a resu t, structure- unction re ationships that were
re ied upon in the past have become ess important. Instead, receptor- unction re a-
tionships and unctiona assays are more c inica y re evant. Aripiprazo e represents
a good examp e o how an examination o the structure provides itt e insight into
its mechanism, which is based on dopamine receptor partia agonism. Detai ed
know edge o receptor a nities (see ab e 8-4) and the unctiona e ect at speci c
(Continued)
162
Psychopharmacology CHAPTER 8
A
100 USE OF ANTIPSYCHOTIC
AGENTS IN NONPSYCHOTIC
EP S
80 DISORDERS
5-HT2
y
Anti-psych • Anxietydisorders
c
60
n
a
D2 • Tourette disorder
p
u
c
c
40 • Huntington’s disease
O
%
• Autism
20
• Antiemeticuse
0
0 2 5 10 20 30 40
Ola nza pine dos e (mg/day)
B
100
EP S
80
5-HT2
Anti-psych
y
60
c
n
D2
a
p
u
c
40
c
O
%
20
0
1 2 4 6 8 10 15
Ris pe ridone dos e (mg/day)
FIGURE 8-3 Receptor occupancy and clinical response or antipsychotic agents. Typically, in D2
receptor occupancy by the drug more than 60% provides antipsychotic e ects, receptor occu-
pancy more than 80% causes extrapyramidal symptoms (EPS). Atypical agents combine weak
D2 receptor blockade with more potent 5-HT2A antagonism/inverse agonism. Inverse agonism
at 5-HT2 receptor subtypes may contribute to the reduced EPS risk o olanzapine (Panel A) and
risperidone (Panel B) and e cacy at lower D2 receptor occupancy (olanzapine, Panel A). Aripipra-
zole is a partial D2 agonist that can achieve only 75% unctional blockade.
163
SECTION II Neuropharmacology
Cardiovascular Benign and reversible T wave and the appearance o U waves on ECG;
rare reports o e ects on cardiac conduction
CASE 8-6
A 38-year-old woman is being treated with lithium or bipolar disorder.
a. What is bipolar disorder and how ef ective is Li+ in treating the mania and
depression associated with bipolar disorder?
Patients who experience periods o hypomania and major depression have bipo ar
II disorder, those with mania at any time have bipo ar I, and those with hypomania,
but ess severe orms o depression have cyc othymia.
reatment with Li+ idea y is conducted in patients with norma cardiac and rena
unction. Occasiona y, patients with severe systemic i nesses are treated with Li+,
provided that the indications are compe ing, but the need or diuretics, nonste-
roida anti-inf ammatory agents, or other medications that pose potentia phar-
macokinetic prob ems o en prec udes ithium use in those with mu tip e medica
prob ems. reatment o acute mania and the prevention o recurrences o bipo ar
i ness in adu ts or ado escents are uses o Li+ approved by the FDA.
Whi e Li+, va proate, and carbamazepine have e cacy in acute mania, in c ini-
ca practice these are usua y combined with atypica antipsychotic drugs, even in
manic patients without psychotic eatures, due to their de ayed onset o action. Li+,
carbamazepine, and va proic acid preparations are on y e ective with dai y dosing
that maintains adequate serum eve s, and require serum eve monitoring.
b. What are the options or this patient?
Li+ is e ective in acute mania but is rare y emp oyed as a so e treatment or reasons
noted above, and because 5 to 7 days are required or c inica e ect. T e anticonvu -
sant sodium va proate provides more rapid antimanic e ects than Li+, with thera-
peutic bene t seen within 3 to 5 days. T e most common orm o va proate in use is
diva proex sodium, which is pre erred over va proic acid due to ower incidence o
GI and other adverse e ects.
Carbamazepine is e ective or acute mania. Immediate re ease orms o carbamaze-
pine cannot be oaded or rapid y titrated over 24 hours as with va proate due to the
(Continued)
164
Psychopharmacology CHAPTER 8
deve opment o neuro ogica adverse e ects such as dizziness or ataxia, even within
the therapeutic range (6-12 µg/mL); the extended-re ease orm o carbamazepine is
FDA-approved or acute mania.
c. What therapeutic options are there or prophylaxis or uture depressive episodes?
T e choice o ongoing prophy axis is determined by the need or continued anti-
psychotic drug use and or use o a mood-stabi izing agent. Both aripiprazo e and
o anzapine are e ective as monotherapy or mania prophy axis, but o anzapine use
is eschewed out o concern or metabo ic e ects, and aripiprazo e shows no bene t
or prevention o depressive re apse.
T e overriding concern guiding bipo ar treatment is the high recurrence rate. Indi-
vidua s who experience mania have an 80 to 90% i etime risk o subsequent manic
episodes. As with schizophrenia, ack o insight, poor psychosocia support, and sub-
stance abuse a inter ere with treatment adherence. T e anticonvu sants amotrigine,
carbamazepine, and diva proex have data supporting their use in bipo ar prophy axis.
Lamotrigine was e ective in 2 arge, 18-month- ong maintenance tria s or bipo ar
patients whose most recent mood episode was manic or depressed, with greater
e ect on depressive re apse. T e abi ity to provide prophy axis or uture depressive
episodes combined with data in acute bipo ar depression has made amotrigine a
use u choice or bipo ar treatment, given that bipo ar I and II patients spend arge
amounts o time in depressive phases (32 and 50%, respective y).
Bipo ar disorder is a i etime i ness with high recurrence rates. Individua s who
experience an episode o mania shou d be educated about the probab e need or
ongoing treatment. Stopping mood stabi izer therapy can be considered in patients
who have experienced on y 1 i etime manic episode, particu ar y when there may
have been a pharmaco ogica precipitant (eg, substance or antidepressant use), and
who have been euthymic or extended periods. For bipo ar II patients, the impact o
hypomania is re ative y imited, so the decision to recommend pro onged mainte-
nance treatment with a mood stabi izer is based on c inica response and risk:bene t
ratio. Discontinuation o maintenance Li+ treatment in bipo ar I patients carries
a high risk o ear y recurrence and o suicida behavior over a period o severa
months, even i the treatment had been success u or severa years.
CASE 8-7
A 71-year-old man with bipolar disorder has been treated success ully with Li+
since age 40. He now has developed hypertension, mild congestive heart ailure,
and osteoarthritis.
a. What are issues that might arise rom the coadministration o drugs or
these conditions?
T e majority o o der patients on Li+ therapy are those maintained or years on the
medication. Less than 10% o individua s with bipo ar disorder experience their
rst manic episode at age 50 or above. E der y patients requent y take numer-
ous medications or other i nesses and the potentia or contraindications or
drug–drug interactions is substantia . For patients naïve to Li+, these issues can
be addressed re ative y easi y prior to commencement o Li+ treatment. T e more
di cu t c inica decision revo ves around switching treatment in stab e patients
who have taken Li+ or years or decades with exce ent c inica response. In addi-
tion, age-re ated reductions in tota body water and creatinine c earance reduce
the sa ety margin or Li+ treatment in o der patients. argeting ower maintenance
serum eve s (0.6-0.8 mEq/L) may reduce the risk o toxicity. As GFR drops be ow
60 mL/min, strong consideration must be given to a search or a ternative agents,
despite ithium’s therapeutic advantages. Li+ toxicity occurs more requent y in
e der y patients, in part as the resu t o concurrent use o oop diuretics and angio-
tensin-converting enzyme inhibitors. Anticonvu sants, especia y extended-re ease
diva proex, are a reasonab e a ternative to Li+.
(Continued)
165
SECTION II Neuropharmacology
Li+ is comp ete y tered, and 80% is reabsorbed in the proxima tubu es. Li+ competes
with Na+ or reabsorption, and Li+ retention can be increased by Na+ oss re ated to
diuretic use, or ebri e, diarrhea , or other GI i ness. Heavy sweating eads to a pre er-
entia secretion o Li+ over Na+; however, the rep etion o excessive sweating using ree
water without e ectro ytes can cause hyponatremia, and promote Li+ retention. T iazide
diuretics dep ete Na+ and can cause signi cant reductions in Li+ c earance that resu t
in toxic eve s. T e K+-sparing diuretics triamterene, spirono actone, and ami oride
have modest e ects on the excretion o Li+, with concomitant y sma er increases in
serum eve s. Loop diuretics such as urosemide seem to have imited impact on Li+
eve s. Rena excretion can be increased by administration o osmotic diuretics or
acetazo amide, but not su cient y or the management o acute Li+ intoxication.
T rough a teration o rena per usion, some nonsteroida anti-inf ammatory agents
can aci itate rena proxima tubu ar resorption o Li+ and thereby increase serum con-
centrations. T is interaction appears to be particu ar y prominent with indomethacin,
but a so may occur with ibupro en, naproxen, and COX-2 inhibitors, and possib y ess
so with su indac and aspirin. Angiotensin-converting enzyme inhibitors, particu ar y
the rena y c eared isinopri , a so cause Li+ retention, with iso ated reports o toxicity
among stab e ithium-treated patients switched rom osinopri to isinopri .
b. How should his bipolar disorder be managed in light o his age and coexisting
medical conditions?
Because o the ow therapeutic index or Li+, periodic determination o serum con-
centrations is crucia . Li+ cannot be used with adequate sa ety in patients who cannot
be tested regu ar y. Concentrations considered to be e ective and acceptab y sa e are
between 0.6 and 1.5 mEq/L. T e range o 1.0 to 1.5 mEq/L is avored or treatment
o acute y manic or hypomanic patients. Somewhat ower va ues (0.6-1.0 mEq/L) are
considered adequate and are sa er or ong-term prophy axis. Serum concentrations
o Li+ have been ound to o ow a c ear dose-e ect re ationship between 0.4 and 1.0
mEq/L, but with a corresponding dose-dependent rise in po yuria and tremor as
indices o adverse e ects. Nonethe ess, patients who maintain trough eve s o 0.8 to
1.0 mEq/L experience decreased re apse risk compared to those maintained at ower
serum concentrations. T ere are patients who may do we with serum eve s o 0.5
to 0.8 mEq/L, but there are no current c inica or bio ogica predictors to permit a
priori identi cation o these individua s. Individua ization o serum eve s is o en
necessary to obtain a avorab e risk-bene t re ationship.
T e concentration o Li+ in b ood usua y is measured at a trough o the dai y osci -
ations that resu t rom repetitive administration (ie, rom samp es obtained 10-12
hours a er the ast ora dose o the day). Peaks can be 2 or 3 times higher than trough
eve s at steady state. When the peaks are reached, intoxication may resu t, even when
concentrations in morning samp es o p asma at the dai y nadir are in the acceptab e
range o 0.6 to 1 mEq/L. Sing e dai y doses generate re ative y arge osci ations o
p asma Li+ concentration but ower mean trough eve s than with mu tip e dai y dos-
ing and are associated with a reduction in the extent and risk or po yuria; moreover,
sing e night y dosing means that peak serum eve s occur during s eep, so comp aints
regarding CNS adverse e ects are minimized. Whi e re ative y uncommon, GI com-
p aints are a compe ing reason or mu tip e dai y dosing or using de ayed re ease Li+
preparations, bearing in mind the increased po yuria risk rom these strategies.
CASE 8-8
A 28-year-old woman is taking lithium or management o the mania phase o bipolar
disorder. She has entered the depressive phase o the disorder and takes an overdose o
her lithium.
a. What are the acute toxic ef ects o lithium overdose?
T e occurrence o toxicity is re ated to the serum concentration o Li+ and its rate
o rise o owing administration. Acute intoxication is characterized by vomiting,
(Continued)
166
Psychopharmacology CHAPTER 8
pro use diarrhea, coarse tremor, ataxia, coma, and convu sions. Symptoms o mi der
toxicity are most ike y to occur at the absorptive peak o Li+ and inc ude nausea,
vomiting, abdomina pain, diarrhea, sedation, and ne tremor. T e more serious
e ects invo ve the nervous system and inc ude menta con usion, hyperref exia,
gross tremor, dysarthria, seizures, and crania nerve and oca neuro ogica signs,
progressing to coma and death. Sometimes both cognitive and motor neuro ogica
damage may be irreversib e, with persistent cerebe ar tremor being the most com-
mon. Other toxic e ects are cardiac arrhythmias, hypotension, and a buminuria.
b. What is the treatment or acute overdose o lithium?
T ere is no speci c antidote or Li+ intoxication, and treatment is supportive (see
Chapter 3), inc uding intubation i indicated, and continuous cardiac monitoring.
Leve s greater than 1.5 mEq/L are considered toxic, but inpatient medica admission
is usua y not indicated (in the absence o symptoms) unti eve s exceed 2 mEq/L.
Care must be taken to assure that the patient is not Na+- and water-dep eted. Dia ysis
is the most e ective means o removing Li+ and is necessary in severe poisonings,
that is, in patients exhibiting symptoms o toxicity or patients with serum Li+ con-
centrations more than or equa to 3 mEq/L in acute overdoses. A review o 213 case
reports o acute Li+ toxicity between 1948 and 1984 ound that comp ete recovery
occurred with an average maxima eve o 2.5 mEq/L, permanent neuro ogica
symptoms with mean eve s o 3.2 mEq/L, and death with mean maxima eve s o
4.2 mEq/L. T e most common neuro ogica seque ae are due to cerebe ar damage,
and mani est c inica y as ataxia, tremor, dysarthria, and dysmetria.
KEY CONCEPTS
Inhibition o monoamine reuptake is a major mechanism by which antidepres-
sant drugs enhance neurotransmission (see Figure 8-1).
Monoamine oxidase inhibitor (MAOI) antidepressants inhibit monoamine
metabolism (see Figure 8-1).
With antidepressant drugs there is a “therapeutic lag” lasting 3 to 4 weeks
be ore a measurable response becomes evident.
Sudden withdrawal o antidepressants can precipitate a withdrawal syndrome.
CAs are potent antagonists at histamine H 1 and muscarinic receptors that
account or many o their side e ects (see Chapters 6 and 21).
MAOIs have many serious ood and drug interactions.
All antipsychotic drugs reduce dopaminergic neurotransmission by D2 block-
ade (or in the case o aripiprazole modulation o DA activity by virtue o being
a partial D2 agonist).
A Parkinson-like syndrome, a risk o long-term therapy with antipsychotic
drugs that is dose- and drug-dependent, can be predicted based on receptor
occupancy (see Figure 8-3).
Alteration o a patient’s metabolic prof le (see able 8-3) is also a serious side
e ect o some antipsychotic medications.
Bipolar disorder is generally treated with Li+; the anticonvulsants valproic acid and
carbamazepine, and antipsychotic drugs are use ul to manage the acute manic phase.
T e narrow therapeutic indices or Li+, valproic acid, and carbamazepine
requires care ul monitoring o their plasma concentrations.
SUMMARY QUIZ
QUESTION 8-1 A 56-year-old man who has a 30-year history o smoking cigarettes is
being treated or schizophrenia with clozapine. He is hospitalized or an acute exac-
erbation o his psychoses; his clozapine therapy is continued. During the third week
167
SECTION II Neuropharmacology
o his hospital stay, he has a seizure that is thought to be due to clozapine toxicity. T e
clozapine toxicity in this patient is likely due to
a. increased GI absorption o clozapine.
b. decreased renal excretion o clozapine.
c. a decrease in his blood-brain barrier unction.
d. decreased metabolism o clozapine.
e. a pharmacy mistake.
QUESTION 8-2 A 54-year-old woman is taking Li+ or bipolar disorder. Her Li+ plasma
concentrations have consistently been 0.8 mEq/L (therapeutic range 0.6-1.5 mEq/L). She
has developed osteoarthritis or which she is prescribed ibupro en. One week later dur-
ing a routine visit it is noted that her Li+ plasma concentration is 1.5 mEq/L. T e cause
o the rise in this patient’s plasma Li+ concentration is due to the e ect o ibupro en to
a. increase Li+ GI absorption.
b. acilitate Li+ reabsorption in the renal proximal tubule.
c. decrease Li+ metabolism in the liver.
d. displace Li+ rom serum albumin.
e. acilitate Li+ reabsorption rom the distal colon.
QUESTION 8-3 A 22-year-old woman is being treated with amitriptyline or depres-
sion. She, and her amily, should be cautioned about not seeing a therapeutic e ect or
a. 24 hours.
b. 12 hours.
c. 3 days.
d. 1 week.
e. 3 to 4 weeks.
QUESTION 8-4 A 75-year-old man with obsessive compulsive disorder is treated with
risperidone. A er 3 weeks o therapy, he develops bradykinesia, masked acies, and
reduced arm movements when walking. T ese symptoms are due to
a. α1-adrenergic receptor antagonism.
b. β-adrenergic receptor antagonism.
c. 5-H receptor stimulation.
d. D2 receptor antagonism.
e. blockade o norepinephrine uptake into presynaptic terminals.
QUESTION 8-5 An 86-year-old man with severe dementia has become very aggressive
and poses a danger to himsel and his amily. His geriatrician is reluctant to prescribe
an antipsychotic medication to control his behavior because o the risk o
a. increased mortality.
b. increased dementia.
c. decreased peripheral blood per usion.
d. skin cancer.
e. glaucoma.
QUESTION 8-6 A 43-year-old woman is being treated with olanzapine or schizophrenia.
Although olanzapine appeared to be improving her behavioral symptoms, she stopped
using the drug likely due to
a. an unusual taste.
b. increased libido.
c. weight gain.
d. her urine turned green.
e. hirsutism.
168
Psychopharmacology CHAPTER 8
(Continued)
169
SECTION II Neuropharmacology
Aripiprazole 2D6 and 3A4 convert aripiprazole to active 2D6 PMs experience 80% ↑ in 3A4 induction ↓ maximum
metabolite dehydro-aripiprazole. Metabolite aripiprazole AUC, and 30% ↓ in concentration and AUC o
has longer t1/2 (75 vs. 94 hours) and represents metabolite AUC (net e ect is aripiprazole and metabolite
40% o AUC at steady state. 60% ↑ in AUC or active moiety). by 70%.
Aripiprazole t1/2≈ 146 hrs in PM.
2D6 inhibitors ↑ aripiprazole
AUC by 112% and ↓ metabolite
AUC by 35%.
Ketoconazole (a potent 3A4
inhibitor) with a 15-mg single
dose o aripiprazole ↑ the AUC
o aripiprazole and its active
metabolite by 63% and
77%, respectively.
Asenapine Primarily glucuronidation (UGT 1A4), and Fluvoxamine, 25 mg twice daily or Smoking had no e ect on
limited oxidation via CYP 1A2, and to a lesser 8 days, ↑ Cmax by 13% and AUC 29%. clearance or other kinetic
extent 2D6 and 3A4. No active metabolites. Paroxetine ↓ both Cmax and AUC by parameters. Carbamazepine ↓
13%. Valproate, a UGT 1A4 inhibitor, both Cmax and AUC by 16%.
↑ Cmax 2%, and ↓ AUC 1%.
Clozapine Multiple enzymes convert clozapine to active Fluvoxamine ↑ Cp 5-10 old. 2D6 Loss o smoking-related 1A2
metabolite N-desmethylclozapine. The mean inhibition may ↑ levels as induction ↑ serum levels by
contributions o CYPs 1A2, 2C19, 3A4, 2C9, much as 100%. 50%. Carbamazepine ↓ clozapine
and 2D6 are 30%, 24%, 22%, 12%, and 6%, levels on average by 50%.
respectively. CYP1A2 is the most important
orm at low concentrations, which is in
agreement with clinical ndings.
Iloperidone 2D6 and 3A4 convert iloperidone to active Ketoconazole ↑ AUC o a single Impact o 3A4 inducers
metabolites P88 and P95. In 2D6 EM, the t1/2 o 3-mg iloperidone dose and its not documented.
P88 and P95 are 26 and 23 hours, respectively; metabolites P88 and P95 by 57%,
in PM, 37 and 31 hours, respectively. Only 55%, and 35%, respectively.
P88 has a nity or D2. P88 accounts or 19.5% Fluoxetine ↑ 3-mg single dose AUC
and 34.0% o total exposure in EM and PM, o iloperidone and P88 metabolite
respectively. P95 has Ki o 3.91 nM or 5HT2A and 2-3 old, and P95 AUC by 50%.
4.7 nM or α1A, and accounts or Paroxetine ↑ AUC o iloperidone
48% and 25% o total exposure in EM and and P88 metabolite 1.6- old, and
PM, respectively. reduces P95 AUC by 50%. Paroxetine
(8-12 mg twice daily) ↑ steady state
Cmax o iloperidone and P88 by 1.6-
old, and ↓ steady state Cmax o P95
by 50%. Combined use ↑ steady
state Cmax o iloperidone and P88
by 1.4- old, and ↓ steady state Cmax
o P95 1.4- old.
Olanzapine Direct glucuronidation or 1A2 mediated Increase in olanzapine Cmax Carbamazepine use ↑ clearance
oxidation to N-desmethylolanzapine (inactive). ollowing uvoxamine is 54% in by 50%. Olanzapine Cp lower in
emale nonsmokers and 77% in smokers (with equal dosing).
male smokers. The mean increase
in olanzapine AUC is 52% and
108%, respectively.
Paliperidone 59% excreted unchanged in urine, 32% Unlikely to have much o an e ect. Carbamazepine use ↓ steady state
excreted as metabolites. Phase 2 metabolism Cmax and AUC by 37%.
accounts or no more than 10%.
170
Psychopharmacology CHAPTER 8
Risperidone 2D6 converts risperidone to active metabolite Fluoxetine and paroxetine ↑ In a drug interaction study
9-OH risperidone. risperidone concentration ~ 2.5 old o risperidone 6 mg/day × 3
In 2D6 PMs, hal -lives are: risperidone, 20 hours; and 3-9 old, respectively. Fluoxetine weeks, ollowed by 3 weeks o
9-OH risperidone, 30 hours did not a ect 9-OH risperidone carbamazepine, concentration o
conc., but paroxetine lowered 9-OH active moieties (risperidone + 9-OH
risperidone (13%). Net e ect: 2D6 risperidone) was decreased 50%.
inhibition ↑ levels o active moiety
up to 75%.
Ziprasidone 3A4 (~1/3) Aldehyde Oxidase (~2/3) Concomitant ketoconazole ↑ AUC Carbamazepine ↓ AUC by 35%.
by 35%
Haloperidol Multiple CYP pathways, particularly 2D6, Hal -li e prolonged in CYP 2D6 PMs Carbamazepine and phenytoin ↑
3A4, and minor pathway 1A2. Only active Individuals with only one unctional haloperidol clearance ~32%, with
metabolite, reduced haloperidol ( ormed 2D6 allele experience 2- old greater ↓ Cp (mean, 47%). Discontinuation
by ketone reductase). Reduced haloperidol trough serum levels, those with no o carbamazepine ↑ Cp 2-3 old.
inhibits CYP2D6 and may be re-oxidized unctioning alleles 3-4 old higher.
to the parent drug.
Therapeutic serum levels not well de ned; 5-20
ng/mL used as a target or dosing.
Chlorpromazine CYP2D6. Over 10 identi ed human metabolites, Case report o uoxetine- 3A4/PGP inducers (eg,
most inactive. chlorpromazine interaction, but no phenobarbital, carbamazepine)
Chlorpromazine is a moderate 2D6 inhibitor, serum level data on extent o e ect. decrease chlorpromazine
and also induces its own metabolism. Levels levels by ~35%.
drop 25-33% during weeks 1-3 o treatment. Carbamazepine discontinuation ↑
Cp (30-80%).
AUC, area under the curve; PM, poor metabolizer; EM, extensive metabolizer; t1/2, hal li e; Cp , plasma concentration; Cmax, maximum plasma
concentration.
a
May have multiphasic elimination with much longer terminal t1/2.
warning indicates a 1.6 to 1.7- old increased mortality risk or drug versus placebo.
Mortality is due to heart ailure, sudden death, or pneumonia. T e underlying etiol-
ogy or antipsychotic-related cerebrovascular and mortality risk is unknown, but the
f nding o virtually equivalent mortality risk or typical agents compared to atypical
antipsychotic drugs (including aripiprazole) suggests an impact o reduced D2 signaling
regardless o individual antipsychotic mechanisms.
QUESTION 8-6 Answer is c. Weight gain is a signif cant problem during long-term use
o antipsychotic drugs and represents a major barrier to medication adherence, as well
as a signif cant threat to the physical and emotional health o the patient (see able 8-3).
Weight gain has e ectively replaced concerns over EPS as the adverse e ect causing
the most consternation among patients and clinicians alike. Appetite stimulation is the
primary mechanism involved, with little evidence to suggest that decreased activity (due
to sedation) is a main contributor to antipsychotic-related weight gain. Recent animal
studies indicate that medications with signif cant H 1 antagonism induce appetite stimu-
lation through e ects at hypothalamic sites. T e low-potency phenothiazine chlorprom-
azine and the atypical antipsychotic drugs olanzapine and clozapine are the agents o
highest risk, but weight gain o some extent is seen with nearly all antipsychotic drugs,
partly related to the act that acutely psychotic patients may lose weight; in placebo-
controlled acute schizophrenia trials, the placebo cohort inevitably loses weight. For
clozapine and olanzapine, massive weight gains o 50 kg or more are not uncommon,
(Continued)
171
SECTION II Neuropharmacology
Akathisia Subjective and objective Time: 5-60 days Unknown Reduce dose or change
restlessness; not anxiety drug; clonazepam,
or “agitation” propranolol more e ective
than anti-parkinsonian
agentsb
Parkinsonism Bradykinesia, rigidity, Time: 5-30 days. Elderly at DA antagonism Dose reduction;
variable tremor, mask greatest risk change medication;
acies, shuf ing gait anti-parkinsonian agentsc
Perioral tremor Perioral tremor (may Time: months or years o Unknown Anti-parkinsonian agents
(“rabbit syndrome”) be a late variant o treatment o ten help c
parkinsonism)
Tardive dyskinesia Oro acial dyskinesia; Time: months, years o Postsynaptic DA Prevention crucial;
rarely widespread treatment. Elderly at 5- old receptor supersensitivity, treatment unsatis actory.
choreoathetosis greater risk. Risk potency up-regulation May be reversible with
or dystonia o D2 blockade early recognition and drug
discontinuation
a
Treatment: diphenhydramine 25-50 mg IM, or benztropine 1-2 mg IM. Due to long antipsychotic t1/2, may need to repeat, or ollow with
oral medication.
b
Propranolol o ten e ective in relatively low doses (20-80 mg/day in divided doses). β 1-Selective adrenergic receptor antagonists are
less e ective.
Non-lipophilic β adrenergic antagonists have limited CNS penetration and are o no bene t (eg, atenolol).
c
Use o amantadine avoids anticholinergic e ects o benztropine or diphenhydramine.
d
Despite the response to dantrolene, there is no evidence o abnormal Ca2+ transport in skeletal muscle; with persistent antipsychotic e ects
(eg, long-acting injectable agents), bromocriptine may be tolerated in large doses (10-40 mg/day). Anti-parkinsonian agents are not e ective.
and mean annual weight gains o 13 kg are reported in schizophrenia clinical trials, with
20% o subjects gaining more than or equal to 20% o baseline weight.
QUESTION 8-7 Answer is e. Clozapine possesses a host o unusual adverse e ects
aside rom seizure induction, the most concerning o which is agranulocytosis.
Clozapine’s introduction in the United States was based on its e cacy in re ractory
schizophrenia, but came with FDA-mandated CBC monitoring that is overseen by
industry-created registries. Now that several generic orms o clozapine are available in
addition to proprietary CLOZARIL, clinicians must veri y with each manu acturer the
history o prior exposure. T e overall agranulocytosis incidence is slightly under 1%,
with highest risk during the initial 6 months o treatment, peaking at months 2 to 3 and
diminishing rapidly therea er. T e mechanism is immune-mediated, and patients who
have verif able clozapine-related agranulocytosis should not be rechallenged. Increased
risk is associated with certain HLA types and advanced age. An extensive algorithm
guiding clinical response to agranulocytosis, and lesser orms o neutropenia, is avail-
able rom manu acturer Web sites, and must be ollowed, along with the current rec-
ommended CBC monitoring requency.
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Psychopharmacology CHAPTER 8
Serotonin, Amitriptyline Used to treat depression Blurred vision, dry mouth, Quinidine-like e ects on cardiac
Norepinephrine Reuptake Doxepin tachycardia, di culty conduction
Inhibitors (SNRIs)— Imipramine urinating, constipation, Lowering o seizure threshold
Tertiary Amine Tricyclics Clomipramine and sedation Orthostatic hypotension
(TCAs) Trimipramine Weight gain (see rom antagonism o
Table 8-1) α1-adrenergic receptors
Serotonin, Amoxapine Used to treat depression Blurred vision, dry mouth, Quinidine-like e ects on cardiac
Norepinephrine Reuptake Desipramine tachycardia, di culty conduction
Inhibitors (SNRIs)— Maprotiline urinating, constipation, Lowering o seizure threshold
Secondary Amine Nortriptyline and sedation Orthostatic hypotension
Tricyclics (TCAs) Protriptyline Weight gain (see rom antagonism o
Table 8-1) α1-adrenergic receptors
173
SECTION II Neuropharmacology
TOXICITIES
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE: CLINICALLY IMPORTANT
Selective Serotonin Fluoxetine E ective in treating depression, Insomnia, increased Abrupt withdrawal may
Reuptake Inhibitors Fluvoxamine generalized anxiety, panic anxiety, irritability, and precipitate dizziness, headache,
(SSRIs) Paroxetine social anxiety, and obsessive decreased libido nervousness, nausea, and
Sertraline compulsive disorder (OCD) (see Table 8-1) insomnia
Citalopram Fluvoxamine is approved or This withdrawal may be more
Escitalopram OCD but not or depression intense or paroxetine
Citalopram is approved or Paroxetine is associated with an
use in premenstrual increase risk o congenital cardiac
dysphoric disorder mal ormations
Serotonin- Venla axine Treatment o depression, Nausea, constipation, The immediate release orm o
Norepinephrine Reuptake Desvenla axine anxiety disorders, and insomnia, headache, and venla axine can induce sustained
Inhibitors (SNRIs) Duloxetine bromyalgia and neuropathic sexual dys unction diastolic hypertension
Milnacipran pain (duloxetine) (see Table 8-1) Abrupt withdrawal o venla axine
Milnacipran is approved only may precipitate a withdrawal
or bromyalgia pain syndrome
Atypical Antidepressants Atomoxetine Approved or attention de cit Insomnia, nausea, Suicide-related events, emotional
hyperactivity disorder in constipation, headache, lability
children, adolescents, and erectile dys unction Contraindicated in patients with
adults (see Table 8-1) symptomatic cardiovascular
disease
Bupropion Used to treat depression, See Table 8-1 Seizures at high doses
prevention o seasonal (see Table 8-1)
depressive disorder, and as a
smoking cessation treatment
Anxiolytic Drugs See Chapter 9 See Chapter 9 See Chapter 9 See Chapter 9
(Benzodiazepines)
Anxiolytic Drugs (Not Buspirone Used to treat general anxiety Dizziness Contraindicated in patients with
benzodiazepines) disorder Somnolence severe renal or liver impairment
and in patients with symptomatic
cardiovascular disease
Typical Antipsychotic Chlorpromazine Low-potency drugs used or Anticholinergic Lowers seizure threshold
Drugs—Phenothiazines Perphenazine the treatment o acute and symptoms o dry (see Tables 8-3 and 8-6)
Tri uoperazine chronic psychoses, including mouth, blurred vision,
Fluphenazine schizophrenia constipation, and urinary
retention
174
Psychopharmacology CHAPTER 8
TOXICITIES
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE: CLINICALLY IMPORTANT
Atypical Antipsychotic Aripiprazole Used or the treatment o acute Weight gain, anxiety, Extrapyramidal symptoms at
Drugs Olanzapine and chronic psychoses insomnia doses that exceed 80% receptor
Quetiapine Most antipsychotics (except occupancy (see
Risperidone quetiapine) are ine ective Figure 8-3) Metabolic side e ects
Asenapine as monotherapy or bipolar (see Table 8-3)
Clozapine depression
Ziprasidone
Paliperidone
Iloperidone
Sertindole
Anticonvulsants Used to Valproic acid Used to treat acute mania See Chapter 12 See Chapter 12
Treat Mania Carbamazepine (valproic acid, carbamazepine)
Lamotrigine and or bipolar maintenance
(lamotrigine) (see Chapter 12)
Lithium Lithium Treatment o bipolar disorder See Side Bar ADVERSE See Side Bar ADVERSE EFFECTS
carbonate Also used or augmentation o EFFECTS OF LITHIUM OF LITHIUM
Lithium citrate unipolar depression in patients Fine postural hand tremor Low therapeutic index and
who are inadequate responders Ataxia, slurred speech, requires periodic measurement o
to antidepressant therapy and incoordination serum concentrations
Weight gain Seizures reported at therapeutic
concentrations
Nephrogenic diabetes insipidus
175
CHAPTER
176
Hypnotics, Sedatives, and Ethanol CHAPTER 9
177
SECTION II Neuropharmacology
GABA s ite
CATEGORIES OF
Be nzo diaze pine s ite Barbiturate s ite
BENZODIAZEPINES BASED
ON THEIR ELIMINATION t 1/2
• Ultra-short acting—midazolam
S te ro id s ite
• Short-acting agents (t 1/2 <6 hours)— a ne s the tics
triazolam, the nonbenzodiazepine or a nxioge nics
zolpidem(t 1/2 ~2 hours), and eszopiclone
(t 1/2 5-6 hours)
• Intermediate-acting agents (t 1/2 6-24
hours), including estazolamand Pic ro toxin s ite
temazepam Cl– convuls a nts
Alde hyde
de hydroge na s e X Dis ulfira m
NADH
+ O O
H+
HC OH H3 C C OH
Fola te -de pe nde nt Formic a cid Ac e tic ac id
pa thway CoA + ATP
CO 2
+ Thiokina s e
H2 O
AMP + 2P ;
C
β-hydroxy-β-me thyl CoA S C CH3 Trica rboxylic
gluta ryl CoA a cid cycle
Ac e tyl Co A
Fa tty a cids
Ke tone Chole s te rol
bodie s
CASE 9-2
A 23-year-old male college student is brought to the ER because he cannot be aroused.
T e patient has a history o depression and he has been acting depressed over his
classes lately. T e patient has a prescription or lorazepam or anxiety and insomnia. In
the ER he is given umazenil intravenously.
a. What type o drug is f umazenil and what is its role in treating a benzodiazepine
overdose?
Flumazenil, the only member o this class, is an imidazobenzodiazepine that
behaves as a speci c benzodiazepine receptor antagonist. Flumazenil binds with
high a nity to speci c sites on the GABAA receptor, where it competitively antago-
nizes the binding and allosteric e ects o benzodiazepines and other ligands. Flu-
mazenil antagonizes both the electrophysiological and behavioral e ects o agonist
and inverse-agonist benzodiazepines. T e drug is given intravenously.
(Continued)
179
SECTION II Neuropharmacology
CASE 9-3
A 66-year-old man is brought to the ER with extreme anxiety, agitation, irritation, and
con usion. It is learned that, because o early dementia, he recently did not renew his
prescription or alprazolam, which he had been taking or the past 3 years or anxiety.
a. What is the likely cause o this patient’s change in mental status?
Chronic benzodiazepine use poses a risk or development o dependence and
abuse. Mild dependence may develop in many patients who have taken therapeutic
doses o benzodiazepines on a regular basis or prolonged periods. Withdrawal
symptoms may include temporary intensi cation o the problems that originally
prompted their use (eg, insomnia or anxiety). Dysphoria, irritability, sweating,
unpleasant dreams, tremors, anorexia, and aintness or dizziness also may occur,
especially when withdrawal o the benzodiazepine occurs abruptly. Hence, it is
prudent to taper the dosage gradually when therapy is to be discontinued.
b. What are the options or treating this patient?
One option would be to reinstitute the alprazolam and once it has its calming
e ects, begin a slow tapering o the dose. Another option would be to begin a ben-
zodiazepine with a longer t1/2 such as f urazepam and once it has its calming e ects,
discontinue its use and let the long hal -li e taper the e ects and avoid withdrawal.
Each o these options would depend on the ability o the patient or a caregiver to
administer the drug.
CASE 9-4
A 43-year-old woman has been treated with secobarbital or insomnia or the past
10 years.
a. What distinguishes secobarbital rom other barbiturates?
able 9-1 shows the distinguishing eatures o selected barbiturates, including seco-
barbital. Secobarbital has a relatively short t 1/2 compared to other barbiturates such
as phenobarbital.
b. What is the mechanism o action o barbiturates?
See the Mechanisms o Action able above. T e barbiturates reversibly depress
the activity o all excitable tissues. T e barbiturates exert several distinct e ects on
excitatory and inhibitory synaptic transmission. For example, (–)-pentobarbital
(Continued)
180
Hypnotics, Sedatives, and Ethanol CHAPTER 9
TABLE 9-1 Structures, Trade Names, and Major Pharmacological Properties o Selected Barbiturates
R3 O
N C R 5a
3
(or S )a O C2 5C
N C R 5b
H O
COMPOUND DOSAGE
(TRADE NAMES) R3 R5a R5b FORMSb t 1/2 (hours) THERAPEUTIC USES COMMENTS
Amobarbital —H —C2H5 —CH2CH2CH(CH3)2 IM, IV 10-40 Insomnia, pre-op Only Na+ salt administered
(AMYTAL) sedation, emergency parenterally
management o
seizures
Methohexital —CH3 —CH2CH=CH2 —CH(CH3)C ≡ CCH2CH3 IV 3-5c Induction and Only Na+ salt available;
(BREVITAL) maintenance o single dose provides 5-7
anesthesia min o Anesthesiac
Pentobarbital —H —C2H5 —CH(CH3)CH2CH2CH3 Oral, IM, IV, 15-50 Insomnia, pre-op Only Na+ salt administered
(NEMBUTAL) rectal sedation, emergency parenterally
management o
seizures
Secobarbital —H —CH2CH=CH2 —CH(CH3)CH2CH2CH3 Oral 15-40 Insomnia, Only Na+ salt available
(SECONAL) preoperative
Sedation
Thiopental —H —C2H5 —CH(CH3)CH2CH2CH3 IV 8-10c Induction and Only Na+ salt available;
(PENTOTHAL) maintenance o single dose provides brie
anesthesia, pre-op o anesthesiac
sedation, emergency
management o
seizures
a
O except in thiopental, where it is replaced by S. bIM, intramuscular injection; IV, intravenous administration. c Value represents terminal t1/2 due
to metabolism by the liver; redistribution ollowing parenteral administration produces e ects lasting only a ew minutes
181
SECTION II Neuropharmacology
olerance to the e ects on mood, sedation, and hypnosis occurs more readily
and is greater than that to the anticonvulsant and lethal e ects; thus, as toler-
ance increases, the therapeutic index decreases. Pharmacodynamic tolerance
to barbiturates con ers cross-tolerance to all general CNS-depressant drugs,
including ethanol.
Chronic administration o barbiturates markedly increases the protein and lipid
content o the hepatic smooth endoplasmic reticulum, as well as the activities
o glucuronyl trans erase and CYPs 1A2, 2C9, 2C19, and 3A4. T e induction o
these enzymes increases the metabolism o a number o drugs and endogenous
substances, including steroid hormones, cholesterol, bile salts, and vitamins K and
D. T is also results in an increased rate o barbiturate metabolism, which partly
accounts or the tolerance to barbiturates. Repeated administration, especially o
phenobarbital, shortens the t1/2 o barbiturates that are metabolized as a result o the
induction o microsomal enzymes.
Like other CNS depressant drugs, barbiturates are abused, and some individuals
develop a dependence on them (see Chapter 14). Moreover, the barbiturates may
have euphoriant e ects.
Withdrawal rom barbiturates can be serious, resulting in seizures and death.
e. What are the adverse e ects that can be seen with the chronic use o
barbiturates?
Drowsiness may last or only a ew hours a er a hypnotic dose o barbiturate,
but residual CNS depression sometimes is evident the ollowing day, and subtle
distortions o mood and impairment o judgment and ne motor skills may be
demonstrable. Residual e ects also may take the orm o vertigo, nausea, vomiting,
or diarrhea, or sometimes may be mani ested as overt excitement. T e user may
awaken slightly intoxicated and eel euphoric and energetic; later, as the demands o
daytime activities challenge possibly impaired aculties, the user may display irrita-
bility and temper.
Rarely, ex oliative dermatitis may be caused by phenobarbital and can prove atal;
the skin eruption may be associated with ever, delirium, and marked degenerative
changes in the liver and other parenchymatous organs.
Barbiturates combine with other CNS depressants to cause severe depression; etha-
nol is the most requent o ender, and interactions with rst-generation antihista-
mines also are common.
Barbiturates competitively inhibit the metabolism o certain other drugs; however,
the greatest number o drug interactions results rom induction o hepatic CYPs
and the accelerated disappearance o many drugs and endogenous substances (see
answer to Case 9-4d above).
Because barbiturates enhance porphyrin synthesis, they are absolutely contraindi-
cated in patients with acute intermittent porphyria or porphyria variegata.
182
Hypnotics, Sedatives, and Ethanol CHAPTER 9
(20-30 g ethanol per day) is 1 o the actors con erring a cardioprotective e ect,
with 1 to 3 drinks per day resulting in a 10 to 40% decreased risk o coronary heart
disease compared with abstainers. One possible mechanism by which alcohol could
reduce the risk o CHD is through its e ects on blood lipids. Changes in plasma
lipoprotein levels, particularly increases in high-density lipoprotein (HDL; see
Chapter 20), have been associated with the protective e ects o ethanol.
b. Should abstainers rom alcohol be advised to consume ethanol in moderate
amounts?
T e answer is no. T ere have been no randomized clinical trials to test the e cacy
o daily alcohol use in reducing rates o coronary heart disease and mortality, and
it is inappropriate or physicians to advocate alcohol ingestion solely to prevent
heart disease.
c. What are the e ects o ethanol on various physiological systems?
able 9-2 lists the e ects o ethanol on various physiological systems. Most
notable are the CNS where ethanol is a general CNS depressant and perturbs
the balance between excitatory and inhibitory inf uences in the brain, result-
ing in anxiolysis, ataxia, and sedation; the cardiovascular system where ethanol
can result in cardiomyopathy; skeletal muscle where ethanol results in decreased
strength, and the gastrointestinal system where ethanol can produce signi cant
pathology in the pancreas and liver.
Neurochemical Pathways Alcohol perturbs the balance between excitatory and inhibitory inf uences in the brain, resulting in anxiolysis,
ataxia, and sedation. This is accomplished by either enhancing inhibitory or antagonizing excitatory
neurotransmission. Ethanol likely produces its e ects by simultaneously altering the unctioning o a number o
proteins that can a ect neuronal excitability (see Table 9-3). Many o the prominent e ects are on ligand-gated
and voltage-gated ion channels and GPCR systems.
While no de nitive data on the mechanisms or alcohol-induced psychiatric conditions are available, it is logical
to assume that alcohol-related changes in CNS pathways (NE and 5-HT levels, the balance between GABAA and
NMDA receptor activity, dopaminergic activity) may operate in a manner similar to those seen in depression,
anxiety, and schizophrenic disorders.
Ion Channels Substantial data implicate the GABAA receptor as an important target or the in vivo actions o ethanol.
Stimulation o this multisubunit, ligand-gated Cl– channel system contributes to eelings o sleepiness, muscle
relaxation, and the acute anticonvulsant properties associated with all GABA-boosting drugs.
The nicotinic ACh receptor is also sensitive to the e ects o ethanol. Drinking acutely increases ACh in the
ventral tegmental area, with a subsequent increase in DA in the nucleus accumbens.
Ethanol inhibits the unction o the NMDA and kainate receptor subtypes; AMPA receptors are largely resistant
to alcohol.
Ethanol enhances the activity o large-conductance, Ca2+-activated K+ channels in neurohypophyseal terminals,
perhaps contributing to the reduced release o oxytocin and vasopressin a ter ethanol consumption.
(Continued)
183
SECTION II Neuropharmacology
Protein Kinases and Intracellular signal-transduction cascades, such as MAPK, tyrosine kinases, and neurotrophic actor receptors,
Intracellular Signaling also are thought to be a ected by ethanol. Ethanol enhances the activities o several iso orms o adenylyl
Enzymes cyclase, with AC7 being the most sensitive. This promotes increased production o cyclic AMP and thus
increased activity o PKA. Ethanol’s actions appear to be mediated by activation o Gs and promotion o the
interaction between Gs and adenylyl cyclase.
Cardiovascular System Ethanol intake greater than 3 standard drinks per day elevates the risk or heart attacks and bleeding-related
strokes. Indeed, vascular-related diseases are among the leading causes o early death in alcohol-dependent
individuals. The risk includes a six old increased risk or coronary artery disease, a heightened risk or cardiac
arrhythmias, and an elevated risk o congestive heart ailure.
Serum Lipoproteins and Cardiovascular E ects
In France, there is relatively low mortality rom coronary heart disease (CHD) despite the consumption o
high quantities o saturated ats (the “French paradox”). Epidemiological studies suggest that widespread
wine consumption (20-30 g ethanol per day) is one o the actors con erring a cardioprotective e ect, with
1-3 drinks per day resulting in a 10-40% decreased risk o coronary heart disease compared with abstainers.
In contrast, daily consumption o greater amounts o alcohol leads to an increased incidence o noncoronary
causes o cardiovascular ailure, such as arrhythmias, cardiomyopathy, and hemorrhagic stroke, o setting the
bene cial e ects o alcohol on coronary arteries; that is, alcohol has a J-shaped dose-mortality curve. One
possible mechanism by which alcohol could reduce the risk o CHD is through its e ects on blood lipids.
Changes in plasma lipoprotein levels, particularly increases in high-density lipoprotein (HLD) (see Chapter 20),
have been associated with the protective e ects o ethanol.
Hypertension
Heavy alcohol use can raise diastolic and systolic blood pressure. The prevalence o hypertension attributable
to excess alcohol consumption is not known, but studies suggest a range o 5-11%.
Cardiac Arrhythmias
Alcohol has a number o pharmacological e ects on cardiac conduction, including prolongation o the QT
interval, prolongation o ventricular repolarization, and sympathetic stimulation. Atrial arrhythmias associated
with chronic alcohol use include supraventricular tachycardia, atrial brillation, and atrial f utter.
Cardiomyopathy
Ethanol is known to have dose-related toxic e ects on both skeletal and cardiac muscle. Numerous studies
have shown that alcohol can depress cardiac contractility and lead to cardiomyopathy.
Stroke
Clinical studies indicate an increased incidence o hemorrhagic and ischemic stroke in persons who drink
more than 40-60 g alcohol per day.
Skeletal Muscle Chronic, heavy, daily alcohol consumption is associated with decreased muscle strength, even when
adjusted or other actors such as age, nicotine use, and chronic illness. Heavy doses o alcohol also
can cause irreversible damage to muscle, re lected by a marked increase in the activity o creatine
kinase in plasma.
Body Temperature Ingestion o ethanol causes a eeling o warmth because alcohol enhances cutaneous and gastric blood f ow.
Increased sweating also may occur. Heat, there ore, is lost more rapidly, and the internal body temperature
alls. A ter consumption o large amounts o ethanol, the central temperature-regulating mechanism becomes
depressed, and the all in body temperature may become pronounced.
Diuresis Alcohol inhibits the release o vasopressin (antidiuretic hormone) rom the posterior pituitary gland, resulting in
enhanced diuresis. The volume loading that accompanies imbibing complements the diuresis that occurs as a
result o reduced vasopressin secretion.
(Continued)
184
Hypnotics, Sedatives, and Ethanol CHAPTER 9
Sexual Function Despite the widespread belie that alcohol can enhance sexual activities, the opposite e ect is generally noted.
Both acute and chronic alcohol use can lead to impotence in men. Increased blood alcohol concentrations
lead to decreased sexual arousal, increased ejaculatory latency, and decreased orgasmic pleasure. Many emale
alcoholics complain o decreased libido, decreased vaginal lubrication, and menstrual cycle abnormalities.
Hematological and Chronic alcohol use is associated with anemia. Microcytic anemia can occur because o chronic blood loss and
Immunological E ects iron de ciency. Macrocytic anemia and increases in mean corpuscular volume are common and may occur in
the absence o vitamin de ciencies. Normochromic anemia also can occur owing to e ects o chronic illness on
hematopoiesis.
Alcohol also a ects granulocytes and lymphocytes. E ects include leukopenia, alteration o lymphocyte subsets,
decreased T-cell mitogenesis, and changes in immunoglobulin production.
185
SECTION II Neuropharmacology
CASE 9-6
A 43-year-old man has been chronically abusing alcohol (up to one- h o whisky per
day) over the past 10 years. He is recently incarcerated and has had no access to alcohol
or the past 3 days.
a. What is this man at risk o ?
Physical dependence to ethanol is demonstrated by the elicitation o a withdrawal
syndrome when alcohol consumption is terminated. T e symptoms and severity are
determined by the amount and duration o alcohol consumption and include sleep
disruption, autonomic nervous system (sympathetic) activation, tremors, and in
severe cases, seizures. In addition, 2 or more days a er withdrawal, some individu-
als experience delirium tremens, characterized by hallucinations, delirium, ever,
and tachycardia. Delirium tremens can be atal.
b. How should alcohol withdrawal be treated?
Alcohol withdrawal syndrome should be treated with sedatives such as a long-
acting benzodiazepine, and general supportive care such as intravenous f uids and
seizure precautions.
CASE 9-7
A 40-year-old man has been consuming 4 to 5 alcoholic drinks each night a er work
and an additional 2 to 3 drinks each night at home. Recently, he has been consuming
alcohol prior to leaving or work in the morning. He is seeking help or his drinking
behavior.
a. What are the goals o any alcohol treatment program?
T e core o care is a process o interventions and sessions that help enhance
changes in how the person views their problem, along with e orts to help
them alter the problematic behaviors. With cognitive-behavioral approaches
serving as the core o treatment, and a 20% or greater rate o spontaneous
remission in alcohol use disorders, the role o medications can be di cult to
evaluate. T us, only those pharmacological approaches that have been shown
to be superior to placebo through double-blind control trials are worth consid-
ering in clinical practice.
b. What is the role o pharmacotherapy o alcoholism?
Currently, 3 drugs are approved in the United States or treatment o alcoholism:
disul ram, naltrexone, and acamprosate (see able 9-4). Disul ram has a long
history o use but has allen into dis avor because o its side e ects and problems
with patient adherence to therapy. Naltrexone and acamprosate were introduced
more recently. T e goal o these medications is to assist the patient in maintain-
ing abstinence.
(Continued)
Naltrexone 50 mg/day µ Opioid receptor antagonist; elt to ↓ drinking through ↓ eelings o reward
with alcohol and/or ↓ craving.
Acamprosate 666 mg three times daily Weak antagonist o NMDA receptors, activator o GABAA receptors; may ↓ mild
protracted abstinence syndromes with ↓ eelings o a “need” or alcohol.
186
Hypnotics, Sedatives, and Ethanol CHAPTER 9
CASE 9-8
A 22-year-old pregnant woman continues to drink 4 to 5 beers and 2 to 3 glasses
o wine each day despite being cautioned against the use o alcohol while she is
pregnant
a. What are possible teratogenic e ects o ethanol?
Children born to alcoholic mothers display a common pattern o distinct dysmor-
phology known as etal alcohol syndrome (FAS). T e diagnosis o FAS typically is
based on the observance o a triad o abnormalities shown in the Side Bar DIS IN-
GUISHING FEA URES OF FE AL ALCOHOL SYNDROME.
b. What is the likelihood that the child o this woman will have FAS?
T e incidence o FAS is believed to be in the range o 0.5 to 1 per 1000 live births
in the general US population, with rates as high as 2 to 3 per 1000 in A rican
American and Native American populations. A lower socioeconomic status o the
mother rather than racial background per se appears to be primarily responsible or
the higher incidence o FAS observed in those groups. Children who do not meet
all the criteria or a diagnosis o FAS still may show physical and mental de cits
consistent with a partial phenotype, termed etal alcohol e ects (FAEs) or alcohol-
related neurodevelopmental disorders.
T e incidence o FAEs is likely higher than that o FAS, making alcohol consump-
tion during pregnancy a major public health problem.
187
SECTION II Neuropharmacology
KEY CONCEPTS
Benzodiazepine can be categorized based on their elimination t 1/ 2 (see
Side Bar CA EGORIES OF BENZODIAZEPINES BASED ON HEIR
ELIMINA ION t 1/2).
Benzodiazepines are pharmacologically interchangeable.
Benzodiazepines act by modulating the e ects o GABA at the GABAA receptor.
Most benzodiazepines are metabolized extensively by hepatic CYPs; oxazepam
and lorazepam are conjugated directly (see able 9-5).
Flumazenil is a benzodiazepine antagonist used to reverse e ects o
benzodiazepines.
T e novel benzodiazepine agonists zolpidem, zaleplon, and zopiclone have
largely replaced benzodiazepines in the treatment o insomnia.
Ethanol is metabolized by sequential hepatic oxidation rst to acetaldehyde by
ADH, and then to acetic acid by ALDH (see Figure 9-2).
Ethanol has serious and long-lasting e ects on many physiological systems
(see able 9-2).
a
Compounds enclosed in boxes are marketed in the United States. The approximate hal -lives o the various compounds are denoted in
parentheses; S (shortacting), t1/2 <6 hours; I (intermediate-acting), t1/2 = 6-24 hours; L (long-acting), t1/2 = >24 hours. All compounds except
clorazepate are biologically active; the activity o 3-hydroxydesalkylf urazepam has not been determined. Clonazepam (not shown) is an
N-desalkyl compound, and it is metabolized primarily by reduction o the 7-NO2 group to the corresponding amine (inactive), ollowed by
acetylation; its t1/2 is 20-40 hours.
188
Hypnotics, Sedatives, and Ethanol CHAPTER 9
QUESTION 9-1 A 43-year-old man with severe hepatic cirrhosis requires a sedative or
insomnia. Which o the ollowing sedatives would be the best choice or this patient?
a. Phenobarbital
b. Diazepam
c. Lorazepam
d. Secobarbital
e. Flurazepam
QUESTION 9-5 A 53-year-old man with 15 years o alcohol abuse has developed weak-
ness in his legs and the onset o heart ailure. T e primary treatment is
a. digoxin.
b. metoprolol.
c. creatine.
d. abstinence rom alcohol.
e. thiamine.
189
SECTION II Neuropharmacology
190
Hypnotics, Sedatives, and Ethanol CHAPTER 9
TABLE 9-6 Trade Names, Routes o Administration, and Therapeutic Uses o Benzodiazepines
USUAL SEDATIVE-
COMPOUND (TRADE ROUTES OF EXAMPLES OF HYPNOTIC DOSAGE,
NAME) ADMINISTRATIONa THERAPEUTIC USESb COMMENTS t 1/2, Hoursc mg d
Chlordiazepoxide Oral, IM, IV Anxiety disorders, Long-acting and sel - 10±3.4 50-100, qd–qid e
(LIBRIUM, others) management o alcohol tapering because o
withdrawal, anesthetic active metabolites
premedication
Clorazepate Oral Anxiety disorders, Prodrug; activity due to 2.0±0.9 3.75-20, bid–qid e
(TRANXENE, others) seizure disorders ormation o nordazepam
during absorption
Diazepam (VALIUM, Oral, IM, IV, rectal Anxiety disorders, Prototypical 43±13 5-10, tid–qid e
others) status epilepticus, benzodiazepine
skeletal muscle
relaxation, anesthetic
premedication
Lorazepam (ATIVAN) Oral, IM, IV Anxiety disorders, Metabolized solely by 14±5 2-4
preanesthetic Conjugation
medication
Oxazepam (SERAX) Oral Anxiety disorders Metabolized solely by 8.0±2.4 15-30, tid–qid e
Conjugation
191
SECTION II Neuropharmacology
Novel Benzodiazepine Zolpidem Approved or the short- May produce daytime Hypnotic doses increase the
Receptor Agonists term treatment o sedation or amnesia hypoxia and hypercarbia o
insomnia patients with obstructive sleep
apnea
Benzodiazepine Flumazenil Available only or IVuse Duration o clinical e ect Flumazenil will precipitate
Receptor Antagonist to treat benzodiazepine usually only 30 to 60 withdrawal in patients who have
overdose (see Chapter minutes been using benzodiazepines
3) and to reverse A series o small injections chronically
the sedative e ects is pre erred to a single
o benzodiazepines large injection; additional
administered during courses o treatment
surgery or diagnostic may be required should
procedures sedation reappear
Melatonin Congeners Ramelteon Approved or the Dizziness, nausea, atigue No tolerance to its reduction in
treatment o insomnia sleep onset
Not a controlled
substance
Barbiturates Amobarbital All are used as sedatives, Residual CNS Pharmacodynamic and
Butabarbital mephobarbital and depression the day a ter pharmacokinetic tolerance to
Mephobarbital phenobarbital are also administration barbiturates can occur
Methohexital used to treat seizures Residual e ects may also Depression o respiratory drive
Pentobarbital See Table 9-1 or details o include vertigo, nausea, Induction o liver microsomal drug-
Phenobarbital di erences in plasma t1/2 vomiting, or diarrhea metabolizing enzymes
Secobarbital and uses Barbiturates may produce Ex oliative dermatitis caused by
Thiopental excitement rather than phenobarbital
depression in some Severe CNS depression especially
patients and may worsen when combined with other CNS
a patient’s perception o depressants such as ethanol
pain Because barbiturates cause
enhanced porphyrin synthesis they
are contraindicated in patients
with acute intermittent porphyria
or porphyria variegata
192
Hypnotics, Sedatives, and Ethanol CHAPTER 9
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE: CLINICALLY IMPORTANT
Miscellaneous Paraldehyde General CNS depressant Irritating to throat and Intravenous use is associated with
Sedative-Hypnotic no longer used in the stomach a ter oral use injuries to tissues
Drugs United States
Meprobamate Used as a sedative anti- Drowsiness and ataxia Abuse potential is high
anxiety agent Impairment o motor coordination
and prolongation o reaction time
Withdrawal syndrome on abruptly
stopping
Carisoprodol Muscle relaxant Drowsiness and ataxia Has abuse potential as a popular
Major metabolite is street drug
meprobamate Impairment o motor coordination
and prolongation o reaction time
Withdrawal syndrome on abruptly
stopping
Drugs Used to Treat Naltrexone Approved or the Nausea, abdominal Excessive doses can cause liver
Alcoholism treatment o ethanol cramps damage
dependence Contraindicated in patients with
liver ailure or acute hepatitis
Disul ram Used to promote By itsel disul ram may Severe reaction when ethanol,
abstinence rom ethanol cause lassitude, urticarial even in small quantities, is
rash, restlessness, tremor, co-ingested
headache, dizziness, and Reactions may include nausea,
mild GI disturbances vomiting, f ushing, sweating, chest
pain, hypotension, blurred vision,
and con usion
193
CHAPTER
10 Opioid Pharmacology
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN THIS
Chapter 18, Opioids, Analgesia, and Pain Management in Goodman & Gilman’s T e
CHAPTER Pharmacological Basis of T erapeutics, 12th Edition. In addition to the material pre-
• Al entanil (ALFENTA) sented here, the 12th Edition includes:
• Benzonatate (TESSALON, others) • A history o analgesic use
• Buprenorphine; injection (BUPRENEX); oral • A detailed description o the endogenous opioid systems: ligands and receptors
(SUBUTEX); in combination with naloxone • A discussion o opioid receptor classes, distribution, binding/coupling requirements
(SUBOXONE) or opiate ligands, and the unctional consequences o acute and chronic opiate
• Butorphanol (STADOL, others) receptor activation
• Codeine • Figure 18-8 Structures o morphine-related opiate agonists and antagonists
• Dextromethorphan marketed or over-the- • Figure 18-9 Chemical structures o piperidine and phenylpiperidine analgesics
counter sales • Details o the cellular and molecular mechanisms o opioid tolerance, dependence,
• Di enoxin (MOTOFEN) available onlyin and withdrawal
combination with atropine • Nonanalgesic therapeutic uses o opioids
• Diphenoxylate (LOMOTIL, others) available • able 18-4 Resources or Pain Management
onlyin combination with atropine
• able 18-5 World Health Organization Analgesic Ladder
• Fentanyl citrate (SUBLIMAZE, others);
transdermal patch (DURAGESIC, oth- LEARNING OBJECTIVES
ers); entanyl buccal tablets, buccal lm, Understand the mechanisms o action, adverse e ects, and therapeutic uses o
lollipop-like lozenges (FENTORA, ONSOLIS, opiate receptor agonists.
ACTIQ,others)
Know the mechanisms o action and therapeutic uses o opiate receptor antagonists.
• Hydrocodone (LORTAB, VICODIN, others)
Know the role o opiate receptor agonists in the management o acute and
• Hydromorphone (DILAUDID,others)
chronic pain.
• Levorphanol (LEVO-DROMORAN)
Know the di erent methods o administration o opiate receptor agonists that
• Loperamide (IMODIUM, others) improve analgesic e cacy while reducing side e ects.
• Meperidine (pethidine, DEMEROL, others)
• Methadone (DOLOPHINE, others)
• Methylnaltrexone (RELISTOR) ACTIONS AND SELECTIVITIES OF SOME OPIOIDS AT µ, δ, κ RECEPTORS
• Morphine sul ate; liposomal ormulation OPIATE LIGANDS RECEPTOR TYPES
(DEPODUR); preservative- ree or spinal µ δ κ
delivery(DURAMORPH, DEPODUR, others)
• Nalbuphine (NUBAIN, others) Agonists
194
Opioid Pharmacology CHAPTER 1 0
MOR
MOR
Ca 2+
K+
S pina l cord
FIGURE 10-1 Mechanisms o opiate action in producing analgesia. Top le t: Schematic o orga-
nization o opiate action in the periaqueductal gray (PAG). Top right: Opiate-sensitive pathways
in PAG µ opiate actions block the release o GABA rom tonically active systems that otherwise
regulate the projections to the medulla (1) leading to an activation o PAG out ow resulting in
activation o orebrain (2) and spinal (3) monoamine receptors that regulate spinal cord projec-
tions (4) which provide sensory input to higher centers and mood.
Bottom le t: Schematic o primary a erent synapse with second order dorsal horn spinal neuron,
showing pre- and postsynaptic opiate receptors coupled to Ca2+ and K+ channels, respectively.
Opiate receptor binding is highly expressed in the super cial spinal dorsal horn (substantia gela-
tinosa). These receptors are located presynaptically on the terminals o small primary a erents
(C- bers) and postsynaptially on second-order neurons. Presynaptically, activation o MOR blocks
the opening o the voltage-sensitve Ca2+ channel, which otherwise initiates transmitter release.
Postsynaptically, MOR activation enhances opening o K+ channels, leading to hyperpolarization.
Thus, an opiate agonist acting at these sites jointly serves to attenuate the a erent-evoked exci-
tation o the second-order neuron.
196
Opioid Pharmacology CHAPTER 1 0
Injury
PAIN STATES
Tis s ue Injury
P G, BK, K
• Acute nociception
Acute activation o small high-threshold
Loca l re le a s e of a ctive S e ns itiza tion sensorya erents (Aδ and C bers)
fa ctors (P G, BK, K) generates transient input into the spinal
cord, which in turn leads to activation o
neurons that project contralateral to the
Pe rs is te nt a ctiva tion/ thalamus and thence to the somatosen-
s e ns itiza tion of Aδ/C fibe rs
sory cortex; examples include a hot
co ee cup, a needle stick, or an incision
Activity in a s ce nding pa thways • Tissue injury (Figure 10-2)
+ Following tissue injuryor local infam-
s pina l fa cilita tion
Fa cilita tion mation (eg, local skin burn, toothache,
rheumatoid joint), an ongoing pain
Exa gge ra te d output for
state arises that is characterized by
give n s timulus input burning, throbbing, or aching, and an
abnormal pain response (hyperalgesia);
such tissue injury-evoked pain is o ten
Ongoing pa in + Hype ra lge s ia re erred to as“nociceptive”pain
• Nerve injury (Figure 10-3)
FIGURE 10-2 Mechanistic ow diagram o tissue injury–evoked nociception. BK, bradykinin; K,
Injuryto a peripheral nerve yields complex
cytokines; PG, prostagladins. anatomical and biochemical changes in
the nerve and spinal cord that induce
spontaneous dysesthesias (shooting,
pain and Figures 10-2 and 10-3 show mechanistic diagrams o these types o pain.
burning pain) and allodynia (light
Although nociceptive pain (as in this patient) usually is responsive to opioid analge-
touch hurts); this pain state is said to
sics, neuropathic pain is typically considered to respond less well to opioid analgesics.
be neuropathic
b. What are the mechanisms o action or morphine and other opiate ligands to
produce analgesia?
T e analgesic actions o opiates a er systemic delivery are believed to represent
actions in the brain (supraspinal), spinal cord, and in some instances in the periphery.
T e supraspinal and spinal actions o opiates are shown schematically in Figure 10-1.
c. What are the mechanisms o action by which morphine and other opiate ligands
alter mood and have rewarding properties that may be important in addiction?
T e mechanisms by which opioids produce euphoria, tranquility, and other altera-
tions o mood (including rewarding properties) are complex and not entirely clear.
(Continued)
Ne uroma
S pina l
s e ns itiza tion
Ne rve Injury
Pe riphe ra l ne rve
de ge ne ra tion...Ne uroma
Neural systems thought to mediate opioid rein orcement overlap with, but are
distinct rom, those involved in physical dependence and analgesia. Behavioral and
pharmacological data point to a pivotal role o the mesocorticolimbic (MCL) dopa-
mine system, a basal orebrain circuit long implicated in reward and motivation
(see Figure 10-4).
CASE 10-2
Following surgery or a hip replacement, a 64-year-old woman is treated with a par-
enteral opiate or pain. Upon release rom hospital, she is given a prescription or oral
oxycodone or pain. T ree days a er discharge she is complaining o constipation.
a. What is the cause o her constipation?
Opiates have important e ects upon all aspects o GI unction (see Chapter 33). It
is estimated that 40 to 95% o patients treated with opioids develop constipation
and that changes in bowel unction can be demonstrated even with acute dos-
ing. Opiate agonists suppress local neurogenic networks that provide a rhythmic
(Continued)
Hippoca mpus
Pre fronta l
cortex
(P FC)
N. Accumbe ns
(NAc)
Amygda la Ve ntra l te gme nta l
a re a (VTA)
P FC
Glu
VTA
DA
GABA
MOR
NAc µ opia te
MOR
VP
Rewa rd
198
Opioid Pharmacology CHAPTER 1 0
inhibition o muscle tone leading to concurrent increases in basal tone in the cir-
cular muscle o the small and large intestine. T is results in enhanced high-ampli-
tude phasic contractions, which are nonpropulsatile. T e upper part o the small
intestine, particularly the duodenum, is a ected more than the ileum. A period
o relative atony may ollow the hypertonicity. T e reduced rate o passage o the
intestinal contents, along with reduced intestinal secretion, leads to increased water
absorption, increasing viscosity o the bowel contents, and constipation.
b. What are the options or treatment o this patient?
T e peripherally limited antagonists such as methylnaltrexone have a very impor-
tant role in the management o the constipation and the reduced GI motility
present in the patient undergoing chronic opioid therapy (as or chronic pain or
methadone maintenance) and have been approved by the FDA or that use. With
distribution restricted to the periphery, these agents do not alter central opioid ago-
nist actions. Worrisome reports o GI per oration in this setting are under review
by FDA. Other strategies or the management o opioid-induced constipation are
described in Chapter 33.
CASE 10-3
A 43-year-old markedly obese man with the history o sleep apnea is being treated with
hydrocodone or chronic back pain.
a. What considerations should be taken into account when treating chronic pain
with opiates?
Management o pain is an important element in any therapeutic intervention.
Failure to adequately manage pain can have important negative consequences
on physiological unction such as autonomic hyper-reactivity (increased blood
pressure, heart rate, suppression o gastrointestinal motility, reduced secretions),
reduced mobility leading to deconditioning, muscle wasting, joint sti ening, and
decalci cation, and can contribute to deleterious changes in the psychological state
(depression, helplessness syndromes, anxiety). By many hospital-accrediting orga-
nizations, and by law in many states, appropriate pain assessment and adequate
pain management are considered to be standard o care, with pain being considered
the “ h vital sign.”
able 10-1 shows dosing data or clinically employed opioid analgesics. T ese are
only guidelines, but they can give a place to start a patient’s treatment.
Numerous societies and agencies have published guidelines or the use o strong
opioids in treating pain, including the American Academy o Pain Medicine, the
American Pain Society, the Federation o State Medical Boards (FSMB), and the
Drug En orcement Agency. While slightly di erent in particulars, all guidelines to
date share the criteria established by the FSMB (see able 10-2).
b. Why is this patient at risk o respiratory depression while taking the
hydrocodone?
T is patient’s history o sleep apnea puts him at increased risk o respiratory
depression with opiate therapy (see Side Bar FAC ORS EXACERBA ING OPIA E-
INDUCED RESPIRA ORY DEPRESSION). Although e ects on respiration are
readily demonstrated, clinically signi cant respiratory depression rarely occurs
with standard analgesic doses in the absence o other contributing variables. It
should be stressed, however, that respiratory depression represents the primary
cause o morbidity secondary to opiate therapy.
c. What is a possible mechanism or respiratory depression in this patient?
Morphine-like opioids depress respiration through MOR and DOR receptors in part
by a direct depressant e ect on rhythm generation, with changes in respiratory pat-
tern and rate observed at lower doses than changes in tidal volume. A key property
(Continued)
199
2
TABLE 10-1 Dosing Data or Clinically Employed Opioid Analgesics
0
0
RECOMMENDED STARTTNG DOSE RECOMMENDED STARTING DOSE
APPROXIMATE
(ADULTS >50 KG) (CHILDREN AND ADULTS <50 KG)a
APPROXIMATE EQUI EQUI ANALGESIC
S
DRUG ANALGESIC ORAL DOSE PARENTERAL DOSE ORAL PARENTERAL ORAL PARENTERAL
E
C
Opioid Agonists
T
I
O
Morphine b 30 mg q3–4h (around-the-clock 10 mg q3–4h 15 mg q3–4h 5 mg q3–4h 0.3 mg/kg q3–4h 0.1 mg/kg q3–4h
N
dosing) 60 mg q3–4h (single
dose or intermittent dosing
I
I
Codeine c 130 mg q3–4h 75 mg q3–4h 30 mg q3–4h 30 mg q2h (IM/SC) 1 mg/kg q3–4h d Not recommended
Hydromophone (DILAUDID)b 7.5 mg q3–4h 1.5 mg q3–4h 4 mg q3–4h 1 mg q3–4h 0.06 mg/kg q3–4h 0.015 mg/kg q3–4h
Hydrocodone (in LORCET, LORTAB, VICODIN, 30 mg q3–4h Not available 5 mg q3–4h Not available 0.2 mg/kg q3–4h d Not available
others, typically with acetominophen)
N
Levorphanol 4 mg q6–8h 2 mg q6–8h 2 mg q6–8h 1 mg q6–8h 0.04 mg/kg q6–8h 0.02 mg/kg q6–8h
e
u
r
Meperidine (DEMEROL) 300 mg q2–3h 100 mg q3h Not recommended 50 mg q3h Not recommended 0.75 mg/kg q2–3h
o
p
h
Methadone (DOLOPHINE, others) 20 mg q6–8h 10 mg q6–8h 2.5 mg q12h 2.5 mg q12h 0.2 mg/kg q12h 0.1 mg/kg q6–8h
a
r
m
Oxycodone (REXICODONE, OXYCONTIN, also 30 mg q3–4h Not available 5 mg q3–4h Not available 0.2 mg/kg q3–4h d Not available
a
in PERCOCET, PERCODAN, TYLOX, others)g
c
o
l
Oxymorphone b (NUMORPHAN) Not available 1 mg q3–4h Not available 1 mg q3–4h Not recommended Not recommended
o
g
y
Propoxyphene (DARVON) 130 mg e Not available 65 mg q4–6h e Not available Not recommended Not recommended
Tramadol (ULTRAM) 100 mg e 100 mg 50–100 mg q6h e 50-100 mg q6h e Not recommended Not recommended
Opioid Agonist Antagonists or Partial Agonists
Buprenorphine (BUPRENEX) Not available 0.3–0.4 mg q6–8h Not available 0.4 mg q6–8h Not available 0.004 mg/kg q6–8h
Butorphanol (STADOL) Not available 2 mg q3–4h Not available 2 mg q3–4h Not available Not recommended
Nalbuphine (NUBAIN) Not available 10 mg q3–4h Not available 10 mg q3–4h Not available 0.1 mg/kg q3–4h
Published tables vary in the suggested doses that are equi-analgesic to morphine. Clinical response is the criterion that must be applied or each patient; titration to clinical response is necessary.
Because there is not complete cross-tolerance among these drugs, it is usually necessary to use a lower than equi-analgesic dose when changing drugs and to retitrate to response. Caution:
Recommended doses do not apply to patients with renal or hepatic insuf ciency or other conditions a ecting drug metabolism and kinetics.
a
Caution: Doses listed or patients with body weight less than 50 kg cannot be used as initial starting doses in babies less than 6 months o age. Consult the Clinical Practice Guideline for Acute
Pain Management: Operative or Medical Procedures and Trauma section on management o pain in neonates or recommendations. bFor morphine, hydromorphone, and oxymorphone, rectal
administration is an alternate route or patients unable to take oral medications, but equi-analgesic doses may di er rom oral and parenteral doses because o pharmacokinetic di erences.
c
Caution: Codeine doses above 65 mg o ten are not appropriate due to diminishing incremental analgesia with increasing doses but continually increasing constipation and other side e ects.
d
Caution: Doses o aspirin and acetaminophen in combination opi-oid/NSAID preparations must also be adjusted to the patient’s body weight. Maximum acetaminophen dose: 4 g/day in adults,
90 mg/kg/day in children.
e
Doses or moderate pain not necessarily equivalent to 30 mg oral or 10 mg parenteral morphine.
Risk o seizures: parenteral ormulation not available in the United States.
g
Oxycontin is an extended-release preparation containing up to 160 mg o oxycodone per tablet and recommended or use every 12 hours. It has been subject to substantial abuse. Modi ed rom
Agency or Healthcare Policy and Research, 1992.
Opioid Pharmacology CHAPTER 1 0
CASE 10-4
A 56-year-old woman with advanced breast cancer is being treated with methadone
or her pain.
a. Why is methadone a good choice or this patient?
T e outstanding properties o methadone are its analgesic activity, its ef cacy by
the oral route, its extended duration o action in suppressing withdrawal symptoms
in physically dependent individuals, and its tendency to show persistent e ects with
repeated administration.
b. What are the major considerations in using methadone to treat this patient’s pain?
Side e ects, toxicity, and conditions that alter sensitivity, as well as the treatment o
acute intoxication, are similar to those described or morphine. During long-term
administration, there may be excessive sweating, lymphocytosis, and increased
concentrations o prolactin, albumin, and globulins in the plasma. Ri ampin and
phenytoin accelerate the metabolism o methadone and can precipitate withdrawal
symptoms. Unlike other opioids, methadone is associated with long Q syndrome
and is additive with agents known to prolong the Q interval. Serious cardiac
arrhythmias, including torsades de pointes, have been observed during treatment
with methadone.
Care must be taken when escalating the dosage because o the prolonged t 1/2
o the drug and its tendency to accumulate over a period o several days with
repeated dosing. Iatrogenic overdoses have occurred during initiation o therapy
and dosing titration with methadone because o too-rapid titration or the con-
comitant use o depressant drugs. T e peak respiratory depressant e ects o
methadone typically occur later and persist longer than the peak analgesic e ects
so it is necessary to exercise vigilance and strongly caution patients against sel -
medicating with CNS depressants, particularly during treatment initiation and
dose titration.
(Continued)
201
SECTION II Neuropharmacology
101-300 5 : 1
301-600 10 : 1
601-800 12 : 1
801-1000 15 : 1
>1000 20 : 1
While not necessarily relevant to this patient, able 10-3 shows the oral morphine
to methadone guidelines.
he pain state (see Side Bar PAIN S A ES) in any given clinical condition is
not typically constant and will vary over time. In chronic pain states, the daily
course o the pain may luctuate, or example, being greater in the morning
hours or upon awakening. Arthritic states display lares that are associated with
an exacerbated pain condition. Changes in the magnitude o pain occur during
the daily routine resulting in “breakthrough pain” during episodic events such
as dressing changes (incident pain). hese examples emphasize the need or
individualized management o increased or decreased pain levels with baseline
analgesic dosing supplemented with the use o short-acting “rescue” medica-
tions as required. In the ace o ongoing severe pain, analgesics should be dosed
in continuous or “around-the-clock” ashion rather than on an as-needed
basis. his provides more consistent analgesic levels and avoids unnecessary
su ering.
c. What are other options or the treatment o this patient’s pain?
T ere are a variety o routes o administration o opiates or the treatment o
chronic pain.
Patient-controlled analgesia (PCA)
With this modality, the patient has limited control o the dosing o opioid rom an
in usion pump programmed within tightly mandated parameters. PCA can be used
or intravenous, epidural, or intrathecal administration o opioids. T is technique
avoids delays inherent in administration by a caregiver and generally permits better
alignment between pain control and individual di erences in pain perception and
responsiveness to opioids.
Spinal delivery
Administration o opioids into the epidural or intrathecal space provides more
direct access to the rst pain-processing synapse in the dorsal horn o the spinal
cord. T is permits the use o doses substantially lower than those required or oral
or parenteral administration
Local drug action
Opioid receptors on peripheral sensory nerves respond to locally applied opioids
during in ammation. Peripheral analgesia permits the use o lower doses, applied
locally, than those necessary to achieve a systemic e ect.
Rectal administration
T is route is an alternative or patients with dif culty swallowing or other oral
pathology and who pre er a less invasive route than parenteral administration.
(Continued)
202
Opioid Pharmacology CHAPTER 1 0
Inhalation
Opioids can be delivered by nebulizer. However, this delivery method is rarely used
due to erratic absorption rom the lung and highly variable therapeutic e ect.
Oral transmucosal administration
Opioids can be absorbed through the oral mucosa more rapidly than through the
stomach. Bioavailability is greater owing to avoidance o rst-pass metabolism, and
lipophilic opioids are absorbed better by this route than are hydrophilic compounds
such as morphine. A transmucosal delivery system that suspends entanyl in a dis-
solvable sugar-based lollipop or rapidly dissolving buccal tablet have been approved
or the treatment o cancer pain; in this setting, transmucosal entanyl relieves pain
within 15 minutes, and patients easily can titrate the appropriate dose.
Transnasal administration
Butorphanol, a(n) KOR agonist/MOR antagonist, has been employed intranasally.
A transnasal pectin-based entanyl spray is currently in clinical trials or the treat-
ment o cancer-related pain.
Transdermal and iontophoretic administration
ransdermal entanyl patches are approved or use in sustained pain. T e opioid
permeates the skin, and a “depot” is established in the stratum corneum layer.
Iontophoresis is the transport o soluble ions through the skin by using a mild elec-
tric current. T is technique has been employed with morphine. Unlike transdermal
opioids, a drug reservoir does not build up in the skin, thus limiting the duration
o both desired and undesired e ects. Patient-controlled iontophoretic transdermal
entanyl systems have been developed, but none is currently marketed.
CASE 10-5
A 19-year-old man is brought to the emergency room with a suspected heroin over-
dose. He is unresponsive and his respirations are depressed. He was discharged rom
30 days in a detoxi cation program earlier in the day. Naloxone is administered
intravenously.
a. What is naloxone and why is it ef ective in this patient?
A variety o agents bind competitively to 1 or more o the opioid receptors, display
little or no intrinsic activity, and robustly antagonize the e ects o opiate receptor
agonists. Opioid antagonists, particularly naloxone, have an established use in the
treatment o opioid-induced toxicity, especially respiratory depression. Its speci c-
ity is such that reversal by this agent is virtually diagnostic or the contribution o
an opiate to the respiratory depression. Naloxone acts rapidly to reverse the respira-
tory depression associated with high doses o opioids.
b. What precautions must be taken with the administration o naloxone?
It should be used cautiously because it also can precipitate withdrawal in dependent
subjects and cause undesirable cardiovascular side e ects. By care ully titrating the
dose o naloxone, it usually is possible to rapidly antagonize the respiratory-depres-
sant actions without eliciting a ully expressed withdrawal syndrome. T e duration
o action o naloxone is relatively short, and it o en must be given repeatedly or by
continuous in usion.
c. What are other therapeutic uses o opiate antagonists?
T ere is considerable interest in the use o opiate antagonists such as naltrexone as an
adjuvant in treating a variety o nonopioid dependency syndromes such as alcoholism
(see Chapters 9 and 14), where an opiate antagonist decreases the chance o relapse.
Buprenorphine in a xed-dose combination with naloxone is approved or the
treatment o opioid dependence.
(Continued)
203
SECTION II Neuropharmacology
CASE 10-6
A 17-year-old boy is brought to the emergency room ollowing an injury to his arm
while playing soccer. He is administered meperidine by intramuscular injection or pain.
a. What is meperidine and how does it act as an analgesic?
Meperidine is predominantly an MOR agonist that produces a pattern o e ects
similar but not identical to those already described or morphine. T e major use
o meperidine is or analgesia. Unlike morphine and its congeners, meperidine is
not used or the treatment o cough or diarrhea. T e analgesic e ects o meperidine
are detectable ~15 minutes a er oral administration, peak in 1 to 2 hours, and
subside gradually.
b. What cautions should be taken with the use o meperidine?
T e pattern and overall incidence o untoward e ects that ollow the use o meperi-
dine are similar to those observed a er equi-analgesic doses o morphine, except
that constipation and urinary retention may be less common.
Meperidine and its congeners are contraindicated in patients taking MAO inhibitors
or within 14 days a er discontinuation o an MAO inhibitor. Severe reactions may
ollow the administration o meperidine to patients being treated with MAO inhibi-
tors. wo basic types o interactions can be observed. T e most prominent is an
excitatory reaction (“serotonin syndrome”) with delirium, hyperthermia, headache,
hyper- or hypotension, rigidity, convulsions, coma, and death. T is reaction may
be due to the ability o meperidine to block neuronal reuptake o 5-H , resulting in
serotonergic overactivity. Conversely, the MAO inhibitor interaction with meperi-
dine may resemble acute narcotic overdose owing to the inhibition o hepatic CYPs.
Meperidine is N-demethylated to normeperidine, which then may be hydrolyzed
to normeperidinic acid and subsequently conjugated. In patients or addicts who
are tolerant to the depressant e ects o meperidine, large doses repeated at short
intervals may produce an excitatory syndrome including hallucinations, trem-
ors, muscle twitches, dilated pupils, hyperactive re exes, and convulsions. T ese
excitatory symptoms are due to the accumulation o normeperidine, which has a
t 1/2 o 15 to 20 hours, compared to 3 hours or meperidine. Since normeperidine
is eliminated by the kidney and the liver, decreased renal or hepatic unction
increases the likelihood o toxicity. As a result o these properties, meperidine
is not recommended or the treatment o chronic pain because o concerns over
metabolite toxicity. It should not be used or longer than 48 hours or in doses
more than 600 mg/d.
KEY CONCEPTS
Opioids are a mainstay o pain treatment, but rational therapy may involve,
depending on the pain state, 1 or more drug classes, such as NSAIDs,
anticonvulsants, and antidepressants (see able 10-4).
Opioid analgesics provide symptomatic relie o pain, but the underlying
disease remains.
Opioids activate µ, δ, and κ opiate receptors to produce their pharmacological
e ects.
Sustained administration o an opiate agonist leads to tolerance, physical
dependence, and a withdrawal syndrome upon abrupt discontinuation.
(Continued)
204
Opioid Pharmacology CHAPTER 1 0
TABLE 10-4 Summary o Drug Target and Site o Action o Common Drug Classes and Relative Ef cacy by Pain State
DRUG CLASS REPRESENTATIVE
AGENTS IN PARENTHESES DRUG ACTION SITE OF ACTIONa RELATIVE EFFICACY IN PAIN STATESb
NSAIDs (ibupro en, aspirin Nonspeci c COX inhibitors Peripheral and spinal Tissue injury >> acute stimuli = nerve injury = 0
acetominophen)
COX 2 inhibitor (celecoxib) COX2-selective inhibitor Peripheral and spinal Tissue injury >> acute stimuli = nerve injury = 0
Opioids (morphine) µ receptor agonist Supraspinal and spinal Tissue injury = acute stimuli ≥ nerve injury > 0 (see
this chapter)
Anticonvulsants (gabapentin) Na+ channel block, α2δ Supraspinal and spinal Nerve injury > tissue injury = acute stimuli = 0
subunit o Ca2+ channel
Tricyclic antidepressants Inhibit uptake o 5-HT/NE Supraspinal and spinal Nerve injury ≥ tissue injury >> acute stimuli = 0
(amitryptiline)
a
Studies based on local delivery in preclinical models, eg, intracranial microinjection or intraventricular injections, lumbar intrathecal delivery or
topical/subcutaneous application at injury site.
b
Pain states are de ned by preclinical models: acute: hot plate/tail ick/acute mechanical compression; tissue injury: intraplantar injections
o irritants, ocal thermal injury; nerve injury: compression/ligation o sciatic nerve or its branches or o nerve roots; systemic delivery o
chemotherapeutics.
SUMMARY QUIZ
QUESTION 10-2 A 42-year-old man with chronic pain is brought to the emergency
room because o over-sedation and respiratory depression while using entanyl patches.
He is given intravenous naloxone. He is not given oral naloxone because naloxone
a. is not absorbed rom the GI tract.
b. undergoes rst-pass metabolism in the liver.
c. is metabolized to an inactive metabolite in the GI lining.
d. is excreted unchanged in the urine.
e. is destroyed by stomach acid.
205
SECTION II Neuropharmacology
QUESTION 10-3 A 48-year-old man is being treated with a long-acting opiate or pain
associated with terminal cancer. He is also prescribed a transmucosal entanyl ormula-
tion (lollipop) or “breakthrough” pain. T e transmucosal ormulation is an e ective
analgesic because it
a. avoids rst pass metabolism o entanyl.
b. avoids nausea and vomiting that is associated with the systemic use o entanyl.
c. delivers entanyl directly to opiate receptors in the mouth.
d. avoids constipation.
e. avoids respiratory depression.
QUESTION 10-4 A 50-year-old woman with back pain is administered an opiate ago-
nist. A er 2 weeks o therapy, she notices that she needs to increase the dose to get the
same analgesic e ect. She is experiencing
a. physical dependence.
b. addiction.
c. tolerance.
d. withdrawal.
e. drug-seeking behavior.
QUESTION 10-7 A 20-year-old man is given codeine to relieve the pain o a sprained
ankle. A er two days the man returns to his doctor saying that the codeine is not e ec-
tive. A likely cause is due to
a. poor absorption.
b. rapid urinary excretion.
c. poor metabolism.
d. high protein binding.
e. poor brain penetration.
QUESTION 10-8 A 53-year-old man is requesting meperidine or his chronic back pain.
His physician is reluctant to use meperidine or the treatment o chronic pain because o
a. metabolite toxicity.
b. poor oral absorption.
c. increased addiction potential.
d. patient noncompliance.
e. likelihood that meperidine will be diverted or sale on the street.
206
Opioid Pharmacology CHAPTER 1 0
o morphine’s analgesic actions. Indeed, with chronic oral dosing, the blood levels o
morphine-6-glucuronide typically exceed those o morphine. Given its greater MOR
potency and its higher concentration, morphine-6-glucuronide may be responsible or
most o morphine’s analgesic activity in patients receiving chronic oral morphine.
QUESTION 10-7 Answer is c. Codeine has an exceptionally low a nity or opioid
receptors, and the analgesic e ect o codeine is due to its conversion to morphine.
CYP2D6 catalyzes the conversion o codeine to morphine. Well-characterized genetic
polymorphisms in CYP2D6 lead to the inability to convert codeine to morphine thus
making codeine ine ective as an analgesic or ~10% o the Caucasian population.
QUESTION 10-8 Answer is a. Meperidine is N-demethylated to normeperidine,
which then may be hydrolyzed to normeperidinic acid and subsequently conjugated. In
patients or addicts who are tolerant to the depressant e ects o meperidine large doses
repeated at short intervals may produce an excitatory syndrome, including hallucina-
tions, tremors, muscle twitches, dilated pupils, hyperactive ref exes, and convulsions.
T ese excitatory symptoms are due to the accumulation o normeperidine, which has
a t1/2 o 15 to 20 hours, compared to 3 hours or meperidine. As a result o these prop-
erties, meperidine is not recommended or the treatment o chronic pain because o
concerns over metabolite toxicity. It should not be used or longer than 48 hours or in
doses more than 600 mg/d.
QUESTION 10-9 Answer is e. Doses o acetaminophen greater than 4 g/day may
result in hepatotoxicity (see Chapters 2 and 22). T is amount o acetaminophen is
easily reached in patients who are taking an acetaminophen-opiate combination
product, and who escalate their dose o the opiate-acetaminophen analgesic when
tolerance occurs. Recently the FDA has lowered the amount o acetaminophen that
can be ormulated in combination with opiate analgesics. Patients will still have
access to over-the-counter products that contain acetaminophen, which they may
use to supplement their pain therapy.
Opioid Morphine Treatment o acute and chronic pain Nausea, vomiting, Respiratory depression (see Side
Receptor Codeine dizziness, constipation, Bar FACTORS EXACERBATING
Agonist Hydromorphone pruritus, tolerance, and OPIOID-INDUCED RESPIRATORY
Hydrocodone physical dependence DEPRESSION)
Oxycodone Mental clouding, urinary retention,
Oxymorphone hypotension
Meperidine Propoxyphene has been associated
with cardiac toxicity
208
Opioid Pharmacology CHAPTER 1 0
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Tramadol Synthetic codeine analogues that are Nausea, vomiting, Less respiratory depression than
Tapentadol weak MOR agonists dizziness, dry mouth, equi-analgesic doses o morphine
Used to treat mild to moderate pain sedation and headache Abrupt discontinuation may
Possess monoamine reuptake inhibitor Less constipating than precipitate withdrawal syndrome
activity equivalent doses o
morphine
Di enoxin
Antitussives Dextromethorphan Over-the-counter treatment or Produces ewer subjective Should not be used to suppress
cough o ten in combination with or GI side e ects than a productive cough
antihistamines, decongestants, codeine
expectorants, and bronchodilators
Benzonatate Used in the treatment o cough Drowsiness, dizziness, and Should not be used to suppress
dysphagia a productive cough
209
CHAPTER
11 AnestheticAgents and
TherapeuticGases
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN
Chapter 19, General Anesthetics and T erapeutic Gases and Chapter 20, Local Anes-
THIS CHAPTER thetics in Goodman & Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition.
Articaine (SEPTOCAINE) In addition to the material presented here, the chapters in the 12th Edition include:
Benzocaine (large number o preparations • Details o the general principles o surgical anesthesia
or topical application) • A detailed discussion o the mechanisms o anesthesia
Bupivicane (MARCAINE, SENSORCAINE, • T e chemical structures o parenteral, inhalational, and local anesthetics
others)
• A detailed discussion o therapeutic gases
Carbon dioxide
• Figure 20-3 which is a depiction o the local anesthetic receptor site
Chloroprocaine (NESACAINE)
• able 20-1 Susceptibility to Block ypes o Nerve Fibers
Cocaine
• A detailed discussion o the mechanisms o action o local anesthetics
Des urane (SUPRANE)
• A detailed discussion o the various ways that local anesthetics are administered
Dexmedetomidine (PRECEDEX)
Dibucaine (NUPERCAINAL, others) LEARNING OBJECTIVES
Dyclonine (over-the-counter products Learn the mechanisms o action o parenteral, inhalational, and local
such as SUCRETS, ORAJELand OVERNIGHT anesthetics.
COLDSOREPATCH, and SKINSHIELD Understand the ways that anesthetics (parenteral, inhalational, and local) are
LIQUIDBANDAGE) used to acilitate surgical and other pain ul medical procedures.
En urane (ETHRANE)
Know the major pharmacological properties and toxicities o anesthetic drugs.
Etomidate (AMIDATE)
Fospropo ol (LUSEDRA)
Halothane (FLUOTHANE) MECHANISMS OF ACTION OF ANESTHETIC AGENTS
Helium DRUG CLASS DRUG MECHSM OF ACTION
Iso urane (FORANE, others) Parenteral Anesthetics Sodium thiopental Barbiturates act on GABAA
Ketamine (KETALAR) Methohexital receptors (see Chapter 9)
Lidocaine (XYLOCAINE, others); transdermal Propo ol Sedative and hypnotic
patch (LIDODERM); oral patch (DENTI- Fospropo ol The action o propo ol is
PATCH); combination with prilocaine in an mediated by its action on
occlusive dressing (EMLA); combination GABAA receptors to increase
with tetracaine (PLIAGIS) chloride conduction and
hyperpolarize neurons;
Mepivacaine (CARBAOCAINE, POLOCAINE, ospropo ol is a prodrug o
others) propo ol and has a similar
Methohexital (BREVITAL) mechanism o action
Nitricoxide Etomidate Modulator o GABAA receptors
Nitrous oxide Ketamine Inhibits NMDA receptors (see
Oxygen Chapter 5)
Pramoxine (various preparations including Inhalational Anesthetics Halothane See Side Bar MECHANISMS OF
creams, lotions, sprays, gel, wipes, and Iso urane GENERAL ANESTHESIA
oams available or topical application) En urane
Prilocaine (CITANEST) Des urane
Sevo urane
Procaine (NOVOCAINE)
Proparacaine (ALCAINE, OPHTHAINE, others) Nitrous oxide Potent and selective inhibitor
o NMDA-activated currents
Propo ol (DIPRIVAN)
(continues) (Continued)
210
Anesthetic Agents and Therapeutic Gases CHAPTER 1 1
L
m
indirect e ects o anestheticagents and
/
g
µ
AL
techniques t12 α = 6.8 –+ 2.8 10
)
L
m
min
• Sustain physiologichomeostasis, includ-
/
g
10 1 5 10 15
µ
(
ing preventing excessive blood loss, tissue Minute s
l
a
t
ischemia, reper usion o ischemictissues,
n
e
t12 β = 719 +
p
uid shi ts, exposure to cold environment, – 329 min
o
i
h
and impaired coagulation
t
1.0
m
u
• Improve postoperative outcomes bychoos-
r
e
S
ing techniques that blockor treat compo-
nents o the surgical stress response
0.1
a
Details canbe foundinChapter 19ofGoodman 0 4 8 12 16 20 24
andGilman’sThePharmacologicalBasisof Hours
Therapeutics, 12thEdition. FIGURE 11-1 Thiopental serum levels a ter a single intravenous induction dose. Thiopental
serum levels a ter a bolus can be described by 2 time constants, t1/2 α and t1/2 β. The initial all
is rapid (t1/2α<10 minutes) and is due to redistribution o drug rom the plasma and the highly
per used brain and spinal cord into less well-per used tissues such as muscle and at. During this
redistribution phase, serum thiopental concentration alls to levels at which patients awaken
(AL, awakening level; see inset—the average thiopental serum concentration in 12 patients a ter
a 6 mg/kg intravenous bolus o thiopental). Subsequent metabolism and elimination is much
slower and is characterized by a hal -li e (t1/2 β) o more than 10 hours. (Adapted with permission
from Burch PG, and Stanski DR, The role of metabolism and protein binding in thiopental anesthesia.
Anesthesiology, 1983;58:146-152. Copyright Lippincott Williams &Wilkins. http://lww.com.)
212
Anesthetic Agents and Therapeutic Gases CHAPTER 1 1
CASE 11-2
T e patient in Case 11-1 will be given a parenteral anesthetic as an inducing agent.
a. Why give an inducing agent?
Inhalational anesthetics are of en irritating and onset o anesthesia can be variable.
Consequently, anesthesia is usually begun with a parenteral agent that has a rapid
and predictable onset. T e commonly used parenteral anesthetics and their phar-
macological properties are shown in able 11-1.
b. What are actors that control onset and termination o ef ect o a parenteral
anesthetic?
Hydrophobicity is the key actor governing the pharmacokinetics o parenteral
anesthetics. Af er a single intravenous bolus, these drugs pre erentially partition
into the highly per used and lipophilic tissues o the brain and spinal cord where
they produce anesthesia within a single circulation time. Subsequently blood levels
all rapidly, resulting in drug redistribution out o the CNS back into the blood.
T e anesthetic then di uses into less per used tissues such as muscle and viscera,
and at a slower rate into the poorly per used but very hydrophobic adipose tissue.
ermination o anesthesia af er single boluses o parenteral anesthetics primarily
re ects redistribution out o the CNS rather than metabolism (see Figure 11-1).
Af er redistribution, anesthetic blood levels all according to a complex interaction
between the metabolic rate and the amount and lipophilicity o the drug stored in
(Continued)
Etomidate 2 mg/mL in 35% PG; 0.2-0.4 0.3 4-8 2.9 17.9 76 2.5
pH = 6.9
Ketamine 10, 50, or 100 mg/mL 0.5-1.5 1 10-15 3.0 19.1 27 3.1
in aqueous solution;
pH = 3.5-5.5
t1/2β, β phase hal -li e; CL, clearance; Vss, volume o distribution at steady state; EDTA, ethylenediaminetetraacetic acid; Na-MBS, Na-metabisul te;
PG, propylene glycol; PL, phospholipid.
213
SECTION II Neuropharmacology
150
Dia ze pa m
)
n
i
Thiope nta l
m
(
100
2
1
t
e
v
i
t
i
s
n
Mida zola m
e
S
-
50
xt
Ke ta mine
e
t
n
o
C
Propofol
Etomida te
0
0 1 2 3 4 5 6 7 8
Infus ion Dura tion (hours )
FIGURE 11-2 Context-sensitive hal -time o general anesthetics. The duration o action o
single intravenous doses o anesthetic/hypnotic drugs is similarly short or all and is determined
by redistribution o the drugs away rom their active sites (see Figure 11-1). However, a ter pro-
longed in usions, drug hal -lives and durations o action are dependent on a complex interaction
between the rate o redistribution o the drug, the amount o drug accumulated in at, and the
drug’s metabolic rate. This phenomenon has been termed the context-sensitive hal -time; that
is, the t1/2 o a drug can be estimated only i one knows the context—the total dose and over
what time period it has been given. Note that the hal -times o some drugs such as etomidate,
propo ol, and ketamine increase only modestly with prolonged in usions; others (eg, diazepam
and thiopental) increase dramatically. (Reproduced with permission from Reves JG, Glass PSA, Lubar-
sky DA, et al: Intravenous anesthetics, in Miller RD et al, (eds): Miller’s Anesthesia, 7th ed. Philadelphia:
Churchill Livingstone, 2010, p 718. Copyright © Elsevier.)
the peripheral compartments. T us, parenteral anesthetic hal -lives are “context-
sensitive,” and the degree to which a t1/2 is contextual varies greatly rom drug to
drug, as might be predicted based on their di ering hydrophobicities and meta-
bolic clearances (see able 11-1 and Figure 11-2). For example, af er a single bolus
o thiopental, patients usually emerge rom anesthesia within 10 minutes; however,
a patient may require more than a day to awaken rom a prolonged thiopental
in usion.
c. What are the dif erences between the parenteral anesthetic agents?
Each o these drugs will produce anesthesia and the choice o which agent to use
is usually based on its pharmacological properties. able 11-1 lists the pharmaco-
logical properties o the parenteral anesthetic agents. Most individual variability
in sensitivity to parenteral anesthetics can be accounted or by pharmacokinetic
actors. For example, in patients with lower cardiac output, the relative per usion
o the brain and the raction o anesthetic dose delivered to the brain are higher;
thus, patients in septic shock or with cardiomyopathy usually require lower doses
o anesthetic. T e elderly also typically require a smaller anesthetic dose, primarily
because o a smaller initial volume o distribution.
CASE 11-3
For the patient in Case 11-1, a er induction o her anesthesia with a parenteral agent
she is to be maintained with an inhalational anesthetic.
a. What are the choices o inhalational anesthetic agents to maintain anesthesia?
able 11-2 lists the widely varying physical properties o the inhalational agents in
clinical use. T ese properties are important because they govern the pharmaco-
kinetics o the inhalational agents. Ideally, an inhalational agent would produce a
rapid induction o anesthesia and a rapid recovery ollowing discontinuation.
(Continued)
214
Anesthetic Agents and Therapeutic Gases CHAPTER 1 1
Nitrous oxide 105 60.0 52.5 Gas 0.47 1.1 2.3 0.004
1 Nitrous 1
Oxide De s flura ne
S evoflura ne
Is oflura ne
I
Ha lotha ne
F
0.5 0.5
/
A
F
0 0
0 10 20 30
Minute s
FIGURE 11-3 Uptake o inhalational general anesthetics. The rise in end-tidal alveolar (FA)
anesthetic concentration toward the inspired (FI) concentration is most rapid with the least
soluble anesthetics, nitrous oxide and des urane, and slowest with the most soluble anesthetic,
halothane. All data are rom human studies. (Reproduced with permission from Eger EI, II: Inhaled
anesthetics: Uptake and distribution, in Miller RD et al, (eds): Miller’s Anesthesia, 7th ed. Philadelphia:
Churchill Livingstone, 2010, p 540. Copyright © Elsevier.)
the partial pressure o the anesthetic may be equal in all tissues, the concentration
o anesthetic in each tissue will be di erent. Indeed, anesthetic partition coe -
cients are de ned as the ratio o anesthetic concentration in 2 tissues when the
partial pressures o anesthetic are equal in the 2 tissues. Blood:gas, brain:blood,
and at:blood partition coe cients or the various inhalational agents are listed in
able 11-2. T ese partition coe cients show that inhalational anesthetics are more
soluble in some tissues (eg, at) than they are in others (eg, blood), and that there is
signi cant range in the solubility o the various inhalational agents in such tissues.
For example, des urane has a very low blood:gas partition coe cient (0.42) and
also is not very soluble in at or other peripheral tissues (see able 11-2). For this
reason, the alveolar (and blood) concentration rapidly rises to the level o inspired
concentration (see Figure 11-3). Indeed, within 5 minutes o administration, the
alveolar concentration reaches 80% o the inspired concentration. T is provides or
a very rapid induction o anesthesia and or rapid changes in depth o anesthesia
ollowing changes in the inspired concentration. Emergence rom anesthesia also is
very rapid with des urane. T e time to awakening ollowing des urane is shorter
than with halothane or sevo urane and usually does not exceed 5 to 10 minutes in
the absence o other sedative agents.
CASE 11-4
During anesthesia or the patient in Case 11-1, she will require endotracheal intubation.
a. What drugs are chosen or this?
Endotracheal intubation requently requires the administration o a neuromuscular
blocking drug to relax the muscles o the jaw. T e pharmacology o these drugs is
discussed in Chapter 6.
b. Why was the patient in Case 11-1 administered a benzodiazepine sedative prior
to her surgery?
As adjuncts, benzodiazepines are used or anxiolysis, amnesia, and sedation prior
to induction o anesthesia or or sedation during procedures not requiring general
anesthesia. T e benzodiazepine most requently used in the perioperative period is
midazolam ollowed distantly by diazepam, and lorazepam. T e pharmacology o
these drugs is discussed in Chapter 9.
(Continued)
216
Anesthetic Agents and Therapeutic Gases CHAPTER 1 1
c. Why will this patient require an analgesic prior to surgery, during the surgery,
USES OF LOCAL
and during the immediate postoperative period?
ANESTHETICSa
With the exception o ketamine, neither parenteral nor currently available inha-
lational anesthetics are e ective analgesics. T us, analgesics typically are admin- • Topical
istered with general anesthetics to reduce anesthetic requirement and minimize • Local infltration
hemodynamic changes produced by pain ul stimuli. Opioids are the primary • Field block
analgesics used during the perioperative period because o the rapid and pro ound
• Nerve block
analgesia they produce. During the perioperative period, opioids of en are given
at induction to preempt responses to predictable pain ul stimuli (eg, endotracheal • Intravenous regional anesthesia
intubation and surgical incision). Subsequent doses either by bolus or by in usion • Spinal anesthesia
are titrated to the surgical stimulus and the patient’s hemodynamic response. • Epidural anesthesia
a
Details ofeachcanbe foundinChapter 20of
CASE 11-5 GoodmanandGilman’sThePharmacologicalBasis
A 33-year-old man is about to undergo a dental procedure. His dentist says that the ofTherapeutics, 12thEdition.
local anesthetic he will be using contains epinephrine and asks i there is any history
o a heart condition or high blood pressure.
a. What is the mechanism o action o local anesthetics?
Local anesthetics act at the cell membrane to prevent the generation and the conduction
o nerve impulses. Local anesthetics block conduction by decreasing or preventing the
large transient increase in the permeability o excitable membranes to Na+ that normally
is produced by a slight depolarization o the membrane. T is action o local anesthetics is
due to their direct interaction with voltage-gated Na+ channels (see Figure 11-4). As the
anesthetic action progressively develops in a nerve, the threshold or electrical excitability
gradually increases, the rate o rise o the action potential declines, impulse conduction
slows, and the sa ety actor or conduction decreases. T ese actors decrease the prob-
ability o propagation o the action potential, and nerve conduction eventually ails.
b. Why would the local anesthetic contain epinephrine?
T e duration o action o a local anesthetic is proportional to the time o contact
with nerve. Consequently, maneuvers that keep the drug at the nerve prolong the
period o anesthesia. In clinical practice, a vasoconstrictor, usually epinephrine, is
of en added to local anesthetics. T e vasoconstrictor per orms a dual service. By
decreasing the rate o absorption, it not only localizes the anesthetic at the desired
site, but also allows the rate at which it is destroyed in the body to keep pace with the
rate at which it is absorbed into the circulation. T is reduces its systemic toxicity.
c. Are their any concerns about the use o epinephrine with local anesthetics?
Some o the vasoconstrictor agents used with local anesthetics may be absorbed system-
ically, occasionally to an extent su cient to cause untoward reactions. T ere also may
be delayed wound healing, tissue edema, or necrosis af er local anesthesia. T ese e ects
seem to occur partly because sympathomimetic amines increase the oxygen consump-
tion o the tissue; this, together with the vasoconstriction, leads to hypoxia and local tis-
sue damage. T e use o vasoconstrictors in local anesthetic preparations or anatomical
regions with limited collateral circulation could produce irreversible hypoxic damage,
tissue necrosis, and gangrene, and there ore are contraindicated. It should be stressed
that untoward cardiovascular e ects o local anesthetic agents may result rom their
inadvertent intravascular administration, especially i epinephrine also is present.
CASE 11-6
A 54-year-old man is having a procedure or which he has been told he will receive
spinal anesthesia.
a. What is spinal anesthesia?
Spinal anesthesia occurs ollowing the injection o local anesthetic into the cere-
brospinal uid (CSF) in the lumbar space. For a number o reasons, including the
(Continued)
217
SECTION II Neuropharmacology
A β 1 s ubunit α s ubunit
N I II III IV N
outs id e
me mb ra ne
ins id e
C C
Volta ge C
s e ns ing
S 4 tra ns me mbra ne ina ctiva tion
s e gme nt re gion –
+
N
ne utra l
P KA s ite
P KC s ite
FIGURE 11-4 Structure and unction o voltage-gated Na+ channels. A. A two-dimensional representation o the α (center), β 1 (le t), and β 2
(right) subunits o the voltage-gated Na+ channel rom mammalian brain. The polypeptide chains are represented by continuous lines with
length approximately proportional to the actual length o each segment o the channel protein. Cylinders represent regions o transmembrane
α helices. Ψ indicates sites o demonstrated N-linked glycosylation. Note the repeated structure o the 4 homologous domains (I-IV) o the
α subunit. Voltage Sensing. The S4 transmembrane segments in each homologous domain o the α subunit serve as voltage sensors. (+)
represents the positively charged amino acid residues at every third position within these segments. Electrical eld (negative inside) exerts a
orce on these charged amino acid residues, pulling them toward the intracellular side o the membrane; depolarization allows them to move
outward. Pore. The S5 and S6 transmembrane segments and the short membrane-associated loop between them (P loop) orm the walls o the
pore in the center o an approximately symmetrical square array o the 4 homologous domains (see panel B). The amino acid residues indicated
by circles in the P loop are critical or determining the conductance and ion selectivity o the Na+ channel and its ability to bind the extracellular
pore-blocking toxins tetrodotoxin and saxitoxin. Inactivation. The short intracellular loop connecting homologous domains III and IVserves as
the inactivation gate o the Na+ channel. It is thought to old into the intracellular mouth o the pore and occlude it within a ew milliseconds
a ter the channel opens. Three hydrophobic residues (isoleucine–phenylalanine–methionine; IFM) at the position marked h appear to serve as
an inactivation particle, entering the intracellular mouth o the pore and binding to an inactivation gate receptor there. Modulation. The gating
o the Na+ channel can be modulated by protein phosphorylation. Phosphorylation o the inactivation gate between homologous domains III
and IVby PKC slows inactivation. Phosphorylation o sites in the intracellular loop between homologous domains I and II by either PKC or PKA
reduces Na+ channel activation. (Adapted with permission from Catterall W, From ionic currents to molecular mechanisms: the structure and function
of voltage-gated sodium channels. Neuron, 2000;26:13-25. Copyright © Elsevier.) B. The 4 homologous domains o the Na+ channel α subunit
are illustrated as a square array, as viewed looking down on the membrane. The sequence o con ormational changes that the Na+ channel
undergoes during activation and inactivation is diagrammed. Upon depolarization, each o the 4 homologous domains sequentially undergoes
a con ormational change to an activated state. A ter all 4 domains have activated, the Na+ channel can open. Within a ew milliseconds a ter
opening, the inactivation gate between domains III and IVcloses over the intracellular mouth o the channel and occludes it, preventing urther
ion conductance.
KEY CONCEPTS
General anesthetics have low therapeutic indices and thus require administra-
tion by specially trained personnel.
All general anesthetics produce a relatively similar anesthetic state, but they are
quite dissimilar in their secondary actions (side e ects) on other organ systems.
A er a single intravenous bolus, a parenteral anesthetic partitions into the
highly per used and lipophilic tissues o the brain and spinal cord where it
produces anesthesia within a single circulation time.
ermination o a parenteral anesthetic a er a single bolus primarily re ects
redistribution out o the CNS (see Figure 11-1).
Parenteral anesthetics ultimately accumulate in atty tissue prolonging recovery
i multiple doses are given.
Inhalation anesthetics have a low sa ety margin.
A general anesthetic is rarely given as the sole agent; anesthetic adjuncts such
as sedatives, analgesics, or neuromuscular blocking agents are used to aug-
ment speci c components o anesthesia (Side Bar COMPONEN S OF ANES-
HE IC S A E).
Local anesthetics bind reversibly to a speci c receptor site within the pore o
Na+ channels in nerves and block ion movement through the pore.
T e duration o action o a local anesthetic is proportional to the time o con-
tact with the nerve; consequently, maneuvers (the addition o a vasoconstrictor
agent such as epinephrine) that keep the drug at the nerve prolong the period
o anesthesia.
Local anesthetics are administered clinically in various ways including topical,
in ltration, eld blocks, nerve blocks, intravenous regional, spinal, and epidural.
SUMMARY QUIZ
QUESTION 11-1 Current evidence supports the view that most intravenous general
anesthetics act predominantly through
a. 5-H receptors.
b. D2 dopamine receptors.
c. GABAA receptors.
219
SECTION II Neuropharmacology
d. α2-adrenergic receptors.
e. β1-adrenergic receptors.
220
Anesthetic Agents and Therapeutic Gases CHAPTER 1 1
d. gangrene.
e. necrosis o the optic nerve.
QUESTION 11-8 While eating mussels, a 36-year-old woman develops numbness and
tingling o her lips and tongue. She begins to have dif culty breathing and rapidly
becomes unconscious. Her apparent respiratory paralysis is the result o
a. the block o Na+ channels.
b. serotonin syndrome.
c. malignant hyperthermia.
d. depletion o norepinephrine.
e. inhibition o monoamine oxidase (MAO).
QUESTION 11-1 Answer is c. Current evidence supports the view that most intrave-
nous general anesthetics act predominantly through GABAA receptors and perhaps
through some interactions with other ligand-gated ion channels such as NMDA recep-
tors and two-pore K+ channels.
QUESTION 11-3 Answer is e. Propo ol is the most commonly used parenteral anes-
thetic in the United States. Propo ol is advantageous or procedures where rapid return
to a preoperative mental status is desirable.
QUESTION 11-4 Answer is e. Des urane has a very low blood:gas partition coef cient
(0.42) and also is not very soluble in at or other peripheral tissues (see able 11-2). For
this reason, the alveolar (and blood) concentration rapidly rises to the level o inspired
concentration. Indeed, within 5 minutes o administration, the alveolar concentration
reaches 80% o the inspired concentration (see Figure 11-3). T is provides or a very
rapid induction o anesthesia and or rapid changes in depth o anesthesia ollowing
changes in the inspired concentration. Emergence rom anesthesia also is very rapid
with des urane or the same reasons.
QUESTION 11-5 Answer is c. Inhaled anesthetics are administered via a circle sys-
tem circuit that permits unidirectional ow o gas. T is system permits rebreathing
o exhaled gases that contain CO2. o prevent rebreathing o CO2 (which can lead to
hypercarbia), CO2 absorbers are incorporated into the anesthesia delivery circuits. T ese
CO2 absorbers contained either Ca(OH)2 or Ba(OH)2 and smaller quantities o more
potent alkalis, NaOH and KOH. Interaction o inhaled anesthetics with these strong
alkalis results in the ormation o CO. T e amount o CO produced is insigni cant as
long as the CO2 absorbent is suf ciently hydrated. With almost complete desiccation o
the CO2 absorbents, substantial quantities o CO can be produced. T is e ect is greatest
with des urane and can be prevented by the use o well-hydrated, resh CO2 absorbent.
QUESTION 11-6 Answer is b. Although allergic responses to agents o the amide type
are uncommon, solutions o such agents may contain preservatives such as methylpara-
ben that may provoke an allergic reaction. Local anesthetic preparations containing a
vasoconstrictor, such as epinephrine, also may elicit allergic responses due to the sul te
added as an antioxidant or the catecholamine/vasoconstrictor.
Etomidate Induction o anesthesia in Pain at injection site Respiratory depression is less than
patients at risk or hypotension Myoclonic movements with thiopental
Nausea and vomiting
(Continued)
222
Anesthetic Agents and Therapeutic Gases CHAPTER 1 1
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE: CLINICALLY IMPORTANT
Inhalational En urane Dose-dependent decrease Concentration-dependent
Anesthetics in blood pressure depression o ventilation
(Cont.) Increased intracranial pressure
Therapeutic Oxygen Treatment o tissue hypoxia See Chapter 20 o See Chapter 20 o Goodman and
Gases Goodman and Gilman’s The Gilman’s The Pharmacological Basis
Pharmacological Basis of of Therapeutics, 12th Edition
Therapeutics, 12th Edition
Carbon dioxide Used or insuf ation during See Chapter 20 o See Chapter 20 o Goodman and
endoscopic procedures Goodman and Gilman’s The Gilman’s The Pharmacological Basis
Used to ood surgical eld Pharmacological Basis of of Therapeutics, 12th Edition
during cardiac surgery, and Therapeutics, 12th Edition
to adjust pH during cardiac
bypass surgery
223
SECTION II Neuropharmacology
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE: CLINICALLY IMPORTANT
Helium Used or pulmonary unction
testing, the treatment o
respiratory obstruction, laser
airway surgery, as a label in
imaging studies, and or gas
mixtures used or diving at depth
Local Lidocaine Used to provide local anesthesia Drowsiness, tinnitus, Respiratory depression and arrest,
Anesthetics Also used as an antiarrhythmic dysgeusia, dizziness, seizures, coma
agent (see Chapter 18) twitching
Ropivacaine
Dibucaine
Dyclonine
Pramoxine
224
CHAPTER
• Limit the sustained, repetitive ring o Topiramate Enhances ast inactivation o voltage-gated Na+
voltage-activated Na+ channels (see channel (see Figure 12-1)
Figure 12-1) GABAA receptor allosteric modulator (see Figure 12-2)
AMPA/kainate receptor antagonist
• Enhanced γ-aminobutyricacid (GABA)- Inhibitor o brain carbonic anhydrase
mediated synapticinhibition either bya
presynapticor postsynapticaction (see Felbamate Enhances ast inactivation o voltage-gated Na+
Figure 12-2) channel (see Figure 12-1)
GABAA receptor allosteric modulator (see Figure 12-2)
• Inhibition o voltage-activated Ca2+ NMDA receptor antagonist
channels responsible or T-type Ca2+
currents (see Figure 12-3) Zonisamide Inhibitor o T-type Ca2+ channel current (see
Figure 12-3)
Inhibitor o brain carbonic anhydrase
GABA
s uccinic
va lproa te s e mia lde hyde
s uccinic
s e mia lde hyde
de hydroge na s e
me ta bolite s
tia ga bine
GAT-1
GAT-1
GABA
Na + Na +
A A
ca rba ma ze pine I
la motrigine
I phe nytoin Na + va lproa te
Na + topira ma te zonis a mide Cl–
FIGURE 12-1 Antiseizure drug-enhanced Na+ channel FIGURE 12-2 Enhanced GABA synaptic transmission. In the presence
inactivation. Some antiseizure drugs (shown in blue text) o GABA, the GABAA receptor (structure on le t) is opened, allowing an
prolong the inactivation o the Na+ channels, thereby in ux o C1–, which in turn increases membrane polarization. Some anti-
reducing the ability o neurons to ire at high requen- seizure drugs (show in larger blue text) act by reducing the metabolism o
cies. Note that the inactivated channel itsel appears to GABA. Others act at the GABAA receptor, enhancing C1– in ux in response
remain open, but is blocked by the inactivation gate (I). to GABA. Gabapentin acts presynaptically to promote GABA release; its
A, activation gate. molecular target is currently under investigation. GABA molecules, GABA-T,
GABA transaminase; GAT-1, GABA transporter.
226
Pharmacotherapy o the Epilepsies CHAPTER 1 2
Tiagabine No No No No 3A4 No
Topiramate No No 2C19 No
Vigabatrin No No No No No No
227
SECTION II Neuropharmacology
CASE 12-1
A 12-year-old girl has her rst tonic-clonic seizure while at school. Her seizure was pre-
ceded by lip smacking and lasted about 1 minute during which she lost consciousness.
a. During subsequent neurological tests, her parents ask or a classi cation o epi-
leptic seizures so that they might understand where their child alls in the spec-
trum o epilepsies. What is a use ul classi cation o epilepsies?
able 12-2 classi es epileptic seizures into partial seizures and generalized seizures.
T e type o epileptic seizure is one determinant o the drug selected or therapy.
Apart rom this epileptic seizure classi cation, an additional classi cation speci-
es epileptic syndromes, which re er to a cluster o symptoms requently occurring
together and include seizure types, etiology, age o onset, and other actors. More than
50 distinct epileptic syndromes have been identi ed and categorized into partial versus
generalized epilepsies. T e partial epilepsies may consist o any o the partial seizure
types (see able 12-2) and account or roughly 60% o all epilepsies. T e etiology com-
monly consists o a lesion in some part o the cortex, such as a tumor, developmental
mal ormation, or damage due to trauma or stroke. Such lesions o en are evident on
brain magnetic resonance imaging (MRI). Alternatively, the etiology may be genetic.
T e generalized epilepsies are characterized most commonly by one or more o the
generalized seizure types listed in able 12-2 and account or ~40% o all epilepsies.
T e etiology is usually genetic. T e most common generalized epilepsy is re erred
to as juvenile myoclonic epilepsy, accounting or ~10% o all epileptic syndromes.
T e age o onset is in the early teens, and the condition is characterized by myo-
clonic, tonic-clonic, and o en absence seizures. Like most o the generalized-onset
epilepsies, juvenile myoclonic epilepsy is a complex genetic disorder that is prob-
ably due to inheritance o multiple susceptibility genes; there is a amilial cluster-
ing o cases, but the pattern o inheritance is not mendelian. T e classi cation o
epileptic syndromes guides clinical assessment and management, and in some
instances, selection o antiseizure drugs.
b. What seizure type is this patient exhibiting?
Although it is di cult to make an absolute diagnosis without all o the clinical data,
it would seem that this patient has had a complex partial seizure with a secondarily
generalized tonic-clonic seizure.
c. Should antiseizure medication be started immediately in this patient?
Early diagnosis and treatment o seizure disorders with a single appropriate agent
o ers the best prospect o achieving prolonged seizure- ree periods with the lowest
risk o toxicity. An attempt should be made to determine the cause o the epilepsy
with the hope o discovering a correctable lesion, either structural or metabolic.
T e e cacy combined with the unwanted e ects o a given drug determines which
particular drug is optimal or a given patient.
T e rst decision to make is whether and when to initiate treatment. For example,
it may not be necessary to initiate antiseizure therapy a er an isolated tonic-clonic
seizure in a healthy young adult who lacks a amily history o epilepsy and who has a
normal neurological examination, a normal EEG, and a normal brain MRI scan. T e
odds o seizure recurrence in the next year (15%) are similar to the risk o a drug reac-
tion su ciently severe to warrant discontinuation o medication. On the other hand, a
similar seizure occurring in an individual with a positive amily history o epilepsy, an
abnormal neurological examination, an abnormal EEG, and an abnormal MRI carries
a risk o recurrence approximating 60%, odds that avor initiation o therapy.
d. What other general principles o the treatment o seizure disorders should be
ollowed in this patient?
T e general principles o therapy o the epilepsies are outlined in the Side Bar
GENERAL PRINCIPLES AND CHOICE OF DRUGS FOR HE HERAPY OF
HE EPILEPSIES.
228
Pharmacotherapy o the Epilepsies CHAPTER 1 2
Generalized Seizures
Absence seizure Abrupt onset o impaired consciousness associated Ethosuximide, valproate, Lamotrigine
with staring and cessation o ongoing activities clonazepam
typically lasting less than 30 seconds.
Myoclonic seizure A brie (perhaps a second), shocklike contraction Valproate, clonazepam Levetiracetam
o muscles that may be restricted to part o one
extremity or may be generalized.
Tonic-clonic seizure As described earlier in table or partial with Carbamazepine, Lamotrigine, levetiracetam,
secondarily generalized tonic-clonic seizures phenobarbital, phenytoin, topiramate
except that it is not preceded by a partial seizure. primidone, valproate
Modi ed with permission rom Leppik IE, Kelly KM, deToledo-Morrell L et al. Basic research in epilepsy and aging. Epilepsy Res, 2006, 68 (Suppl 1): 21.
Copyright© Elsevier.
CASE 12-2
T e patient in Case 12-1 had a second tonic-clonic seizure and it was decided that she
should be treated with phenytoin.
a. What is the mechanism o action o phenytoin?
T e mechanisms o action o antiseizure drugs are listed in the able MECHANISMS
OF AC ION OF AN ISEIZURE DRUGS. Phenytoin limits the repetitive ring o
action potentials evoked by a sustained depolarization o mouse spinal cord neurons
maintained in vitro. T is e ect is mediated by a slowing o the rate o recovery o
voltage-activated Na+ channels rom inactivation, an action that is both voltage-
(greater e ect i membrane is depolarized) and use-dependent (see Figure 12-1).
b. What is unique about the elimination o phenytoin?
Phenytoin is one o the ew drugs or which the rate o elimination varies as a
unction o its concentration (ie, the rate is nonlinear). T e plasma t1/2 o phe-
nytoin ranges between 6 and 24 hours at plasma concentrations below 10 µg/mL
but increases with higher concentrations; as a result, plasma drug concentration
increases disproportionately as dosage is increased, even with small adjustments or
levels near the therapeutic range.
c. How should phenytoin treatment be monitored?
A good correlation usually is observed between the total concentration o phenyt-
oin in plasma and its clinical e ect. T us, control o seizures generally is obtained
(Continued)
229
SECTION II Neuropharmacology
with total concentrations above 10 µg/mL, while toxic e ects such as nystagmus
develop at total concentrations around 20 µg/mL.
d. What untoward ef ects might this patient expect rom long-term phenytoin
treatment?
oxic e ects associated with chronic phenytoin treatment are primarily dose-
related cerebellar-vestibular e ects but also include other CNS e ects, behavioral
changes, increased requency o seizures, GI symptoms, gingival hyperplasia, osteo-
malacia, and megaloblastic anemia. Hirsutism is an annoying untoward e ect in
young emales. Usually, these phenomena can be diminished by proper adjustment
o dosage. Serious adverse e ects, including those on the skin, bone marrow, and
liver, probably are mani estations o drug allergy. Although rare, they necessitate
withdrawal o the drug.
Gingival hyperplasia occurs in ~20% o all patients during chronic therapy and is
probably the most common mani estation o phenytoin toxicity in children and
young adolescents. It may be more requent in those individuals who also develop
coarsened acial eatures. T e overgrowth o gingival tissue appears to involve
altered collagen metabolism. oothless portions o the gums are not a ected.
T e condition does not necessarily require withdrawal o medication and can be
minimized by good oral hygiene.
A variety o endocrine e ects have been reported. Inhibition o release o antidi-
uretic hormone (ADH) has been observed in patients with inappropriate ADH
secretion. Hyperglycemia and glycosuria appear to be due to inhibition o insulin
secretion. Osteomalacia, with hypocalcemia and elevated alkaline phosphatase
activity, has been attributed to both altered metabolism o vitamin D and the
attendant inhibition o intestinal absorption o Ca2+.
Hypersensitivity reactions include morbilli orm rash in 2 to 5% o patients and
occasionally more serious skin reactions, including Stevens-Johnson syndrome and
toxic epidermal necrolysis.
CASE 12-3
A 7-year-old boy is diagnosed with absence seizures. T is patient has an older brother
who also has absence seizures that progressed to tonic-clonic seizures within 1 year.
a. What is an absence seizure and what is thought to be the mechanism o seizure
activity in this type o seizure?
In contrast to partial seizures, which arise rom localized regions o the cerebral
cortex, generalized-onset seizures arise rom the reciprocal ring o the thalamus
and cerebral cortex. T e EEG hallmark o an absence seizure is generalized spike-
and-wave discharges at a requency o 3 per second (3 Hz).
T ese reverberatory, low- requency rhythms are made possible by a combination o
actors, including reciprocal excitatory synaptic connections between the neocortex
and thalamus as well as intrinsic properties o neurons in the thalamus. One intrin-
sic property o thalamic neurons that is pivotally involved in the generation o the
3-Hz spike-and-wave discharges is a particular type o Ca2+ current, the low thresh-
old (“ -type”) current. -type Ca2+ channels are activated at a much more negative
membrane potential (hence “low threshold”) than most other voltage-gated Ca2+
channels expressed in the brain.
b. What are the mechanisms o action o valproic acid?
T e principal mechanism by which anti–absence-seizure drugs (ethosuximide,
valproic acid) are thought to act is by inhibition o the -type Ca2+ channels (see
Figure 12-3). T us, inhibiting voltage-gated ion channels is a common mechanism
o action among antiseizure drugs, with anti–partial-seizure drugs inhibiting
voltage-activated Na+ channels and anti–absence-seizure drugs inhibiting voltage-
activated Ca2+ channels (see Figures 12-1 and 12-3).
(Continued)
230
Pharmacotherapy o the Epilepsies CHAPTER 1 2
CASE 12-4
In the patient in Case 12-3, there was initial consideration o treatment with ethosuximide.
a. Why is valproate a better choice or this patient than ethosuximide?
Ethosuximide and valproate are considered equally e ective in the treatment o
absence seizures. Between 50 and 75% o newly diagnosed patients are ree o seizures
ollowing therapy with either drug. I tonic-clonic seizures are present (as with the
sibling o this patient) or emerge during therapy, valproate is the agent o rst choice.
b. What is the mechanism o action o ethosuximide?
Ethosuximide reduces low threshold Ca2+ currents ( -type currents) in thalamic
neurons (see Figure 12-3). T e thalamus plays an important role in generation o
3-Hz spike-and-wave rhythms typical o absence seizures. Neurons in the thalamus
exhibit large-amplitude -type currents that underlie bursts o action potentials
and likely play an important role in thalamic oscillatory activity such as 3-Hz spike-
and-wave activity. At clinically relevant concentrations, ethosuximide inhibits the
-type current, as is evident in voltage-clamp recordings o acutely isolated, ventro-
basal thalamic neurons rom rats and guinea pigs.
c. What side ef ects might have been expected i this patient were treated with
ethosuximide?
T e most common dose-related side e ects o ethosuximide are gastrointestinal
complaints (nausea, vomiting, and anorexia) and CNS e ects (drowsiness, lethargy,
euphoria, dizziness, headache, and hiccough). Some tolerance to these e ects devel-
ops. Parkinson-like symptoms and photophobia also have been reported. Restlessness,
agitation, anxiety, aggressiveness, inability to concentrate, and other behavioral e ects
have occurred primarily in patients with a prior history o psychiatric disturbance.
Urticaria and other skin reactions, including Stevens-Johnson syndrome, as well
as systemic lupus erythematosus, eosinophilia, leukopenia, thrombocytopenia,
pancytopenia, and aplastic anemia also have been attributed to ethosuximide. T e
leukopenia may be transient despite continuation o the drug, but several deaths
have resulted rom bone marrow depression. Renal or hepatic toxicity has not
been reported.
231
SECTION II Neuropharmacology
CASE 12-5
A 3-year-old boy with the diagnosis o Lennox-Gastaut syndrome has been treated
or 6 months with phenytoin. T e phenytoin has been reducing the seizure requency,
but the decision is made to add lamotrigine to the regimen to urther reduce seizure
requency.
a. What is Lennox-Gastaut syndrome?
Lennox-Gastaut syndrome is a disorder o childhood characterized by multiple
seizure types, mental retardation, and re ractoriness to antiseizure medication.
b. What is the mechanism o action o lamotrigine?
Lamotrigine blocks sustained repetitive ring o mouse spinal cord neurons and
delays the recovery rom inactivation o recombinant Na+ channels, mechanisms
similar to those o phenytoin and carbamazepine (see Figure 12-1). T is may
well explain lamotrigine’s actions on partial and secondarily generalized seizures.
Lamotrigine is e ective against a broader spectrum o seizures than phenytoin and
carbamazepine, suggesting that lamotrigine may have actions in addition to regu-
lating recovery rom inactivation o Na+ channels. T e mechanisms underlying its
broad spectrum o actions are incompletely understood. One possibility involves
lamotrigine’s inhibition o glutamate release in rat cortical slices treated with
veratridine, a Na+ channel activator, raising the possibility that lamotrigine inhibits
synaptic release o glutamate by acting at Na+ channels themselves.
c. What precaution with the dose o lamotrigine should be taken with this patient?
Patients who are already taking a hepatic enzyme–inducing antiseizure drug (such
as carbamazepine, phenytoin, phenobarbital, or primidone, but not valproate)
should be given lamotrigine initially at 50 mg/d or 2 weeks. T e dose is increased
to 50 mg twice per day or 2 weeks and then increased in increments o 100 mg/d
each week up to a maintenance dose o 300 to 500 mg/d divided into 2 doses.
d. What untoward ef ects might be expected rom lamotrigine?
T e most common adverse e ects are dizziness, ataxia, blurred or double vision,
nausea, vomiting, and rash when lamotrigine was added to another antiseizure
drug. A ew cases o Stevens-Johnson syndrome and disseminated intravascular
coagulation have been reported. T e incidence o serious rash in pediatric patients
(~0.8%) is higher than in the adult population (0.3%).
CASE 12-6
A 23-year-old woman is diagnosed with simple partial seizures. reatment with carba-
mazepine is initiated.
a. What is the mechanism o action o carbamazepine?
Like phenytoin, carbamazepine limits the repetitive ring o action potentials
evoked by a sustained depolarization o mouse spinal cord or cortical neurons
maintained in vitro. T is appears to be mediated by a slowing o the rate o recov-
ery o voltage-activated Na+ channels rom inactivation (see Figure 12-1).
T e predominant pathway o metabolism in humans involves conversion to the
10,11-epoxide. T is metabolite is as active as the parent compound in various ani-
mal models, and its concentrations in plasma and brain may reach 50% o those o
carbamazepine, especially during the concurrent administration o phenytoin or
phenobarbital. T e 10,11-epoxide is metabolized urther to inactive compounds,
which are excreted in the urine principally as glucuronides.
b. How should the therapy with carbamazepine be monitored?
T ere is no simple relationship between the dose o carbamazepine and concen-
trations o the drug in plasma. T erapeutic concentrations are reported to be 6 to
(Continued)
232
Pharmacotherapy o the Epilepsies CHAPTER 1 2
12 µg/mL, although considerable variation occurs. Side e ects re erable to the CNS
are requent at concentrations more than 9 µg/mL.
c. What toxicity might be expected in this patient?
During long-term therapy, the more requent untoward e ects o the drug include
drowsiness, vertigo, ataxia, diplopia, and blurred vision. T e requency o seizures
may increase, especially with overdosage. Other adverse e ects include nausea,
vomiting, serious hematological toxicity (aplastic anemia, agranulocytosis), and
hypersensitivity reactions (dangerous skin reactions, eosinophilia, lymphadenopa-
thy, splenomegaly). A late complication o therapy with carbamazepine is retention
o water, with decreased osmolality and concentration o Na+ in plasma, especially
in elderly patients with cardiac disease.
A transient, mild leukopenia occurs in ~10% o patients during initiation o ther-
apy and usually resolves within the rst 4 months o continued treatment; transient
thrombocytopenia also has been noted. In ~2% o patients, a persistent leukopenia
may develop that requires withdrawal o the drug.
d. Is carbamazepine used or other disorders?
Carbamazepine is the primary agent or treatment o trigeminal and glossopha-
ryngeal neuralgias. It is also e ective or lightning-type (“tabetic”) pain associ-
ated with bodily wasting. Most patients with neuralgia bene t initially, but only
70% obtain continuing relie . Adverse e ects require discontinuation o medica-
tion in 5 to 20% o patients. T e therapeutic range o plasma concentrations or
antiseizure therapy serves as a guideline or its use in neuralgia. Carbamazepine
is also used in the treatment o bipolar a ective disorders, as discussed urther in
Chapter 8.
KEY CONCEPTS
T erapy o epilepsies is symptomatic in that available drugs inhibit seizures, but
neither e ective prophylaxis nor cure is available.
Reducing the rate o recovery o Na+ channels rom inactivation would limit the
ability o a neuron to re at high requencies, an e ect that likely underlies the
e ects o carbamazepine, lamotrigine, phenytoin, topiramate, valproic acid, and
zonisamide against partial seizures.
T e principal mechanism by which anti-absence-seizure drugs (ethosuximide,
valproic acid) are thought to act is by inhibition o the -type Ca2+ channel.
Activation o the GABAA receptor inhibits the postsynaptic cell by increasing
the ow o Cl- ions into the cell, which tends to hyperpolarize the neuron.
T e antiseizure drug tiagabine inhibits the GABA transporter, GA -1, and
reduces neuronal and glial uptake o GABA.
T e goal o treating patients with epilepsy is to select the appropriate drug or
combination o drugs that best controls seizures at an acceptable level o untow-
ard e ects.
Measurement o drug concentrations in plasma acilitates optimizing antisei-
zure medication, especially when therapy is initiated, a er dosage adjustments,
in the event o therapeutic ailure, when toxic e ects occur, or when multiple-
drug therapy is instituted.
When initiating combination antiseizure therapy, it is wise to select 2 drugs that
act by distinct mechanisms (eg, one that promotes Na+ channel inactivation and
another that enhances GABA-mediated synaptic inhibition).
T e goal o treating status epilepticus is rapid termination o behavioral and
electrical seizure activity; the longer the episode is untreated, the more dif cult
it is to control and the greater the risk o permanent brain damage.
233
SECTION II Neuropharmacology
SUMMARY QUIZ
QUESTION 12-1 A 28-year-old man is being treated with phenytoin or tonic-clonic sei-
zures. His drug plasma concentration is in the low therapeutic range and he is still having
occasional seizures. His dose is increased slightly. Within 2 weeks he is ataxic, lethargic,
and has nystagmus. A repeat o his plasma concentration shows that he is now slightly
above the upper limit o the therapeutic range. T e reason or the dramatic rise in his
plasma concentration ollowing a modest increase in his dose is most likely because o
a. renal ailure.
b. liver ailure.
c. nonlinear elimination.
d. metabolic acidosis.
e. poor GI absorption o Ca2+.
QUESTION 12-3 A 19-year-old woman is being treated with ethosuximide, most likely
or which type o seizure?
a. Simple partial
b. Complex partial
c. onic-clonic
d. Absence
e. Status epilepticus
QUESTION 12-4 A 29-year-old woman is being treated with valproic acid or simple
partial seizures. She is at risk or developing a rise in her plasma
a. calcium.
b. hepatic transaminases.
c. blood urea nitrogen (BUN).
d. potassium.
e. glucose.
QUESTION 12-6 A 44-year-old man has levetiracetam added to his therapy because he
is re ractory to his current antiseizure regimen. Levetiracetam acts by
a. inactivation o voltage-gated Na+ channels.
b. enhanced GABA synaptic transmission.
(Continued)
234
Pharmacotherapy o the Epilepsies CHAPTER 1 2
c. an unknown mechanism.
d. reducing current through -type Ca2+ channels.
e. antagonizing D2 dopaminergic receptors.
QUESTION 12-8 A 32-year-old woman is being treated with vigabatrin because her
complex seizures have been re ractory to all other therapies. Vigabatrin is reserved or
use in patients such as this although its availability is restricted due to
a. renal ailure.
b. liver ailure.
c. heart ailure.
d. vision loss.
e. hearing loss.
QUESTION 12-1 Answer is c. Phenytoin is one o the ew drugs or which the rate
o elimination varies as a unction o its concentration (ie, the rate is nonlinear). T e
plasma t1/2 o phenytoin ranges between 6 and 24 hours at plasma concentrations below
10 µg/mL but increases with higher concentrations; as a result, plasma drug concentra-
tion increases disproportionately as dosage is increased, even with small adjustments
or levels near the therapeutic range.
235
SECTION II Neuropharmacology
QUESTION 12-8 Answer is d. Due to progressive and permanent bilateral vision loss,
vigabatrin must be reserved or patients who have ailed several alternative therapies;
its availability is restricted under the conditions o the SHARE special distribution
program.
Barbiturates Phenobarbital Used to treat generalized tonic- See Chapter 9 See Chapter 9
clonic and partial seizures
Imminostilbenes Carbamazepine Used to treat generalized tonic- Drowsiness, ataxia, vertigo, Acute intoxication results in
clonic and both simple and diplopia, blurred vision, stupor or coma, hyperirritability,
complex partial seizures nausea, and vomiting convulsions, and respiratory
Transient leukopenia and depression
thrombocytopenia Aplastic anemia
Transient elevation o hepatic
transaminases
May reduce plasma concentrations
o oral contraceptives
Succinimides Ethosuximide Ef ective against absence seizures, Nausea, vomiting, anorexia Parkinson-like symptoms,
but not tonic-clonic seizures Drowsiness, lethargy, photophobia, anxiety, aggression,
euphoria, dizziness, and inability to concentrate
headache, hiccough Hypersensitivity skin reactions
including Stevens-Johnson
syndrome
Transient leukopenia
Death rom bone marrow
depression has been reported
Valproic Acid Valproic acid Broad-spectrum antiseizure Anorexia, nausea, and Inhibits drugs that are substrates
drug ef ective against absence, vomiting or CYP2C9, including phenytoin
myoclonic, partial, and tonic-clonic Sedation, ataxia, and and phenobarbital
seizures tremor Inhibits UGT and thus the
metabolism o lamotrigine and
lorazepam
Elevation o hepatic transaminases
Rarely may cause ulminant
hepatitis
236
Pharmacotherapy o the Epilepsies CHAPTER 1 2
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE: CLINICALLY IMPORTANT
Benzodiazepines Clonazepam Used to treat absence seizures and See Chapter 9 Tolerance to antiseizure ef ects
myoclonic seizures in children develops a ter 1-6 months
Other Antiseizure Gabapentin Ef ective, when used with other Somnolence, dizziness, Pregnancy Category C
Drugs Pregabalin drugs, against partial seizures ataxia, and atigue
Lamotrigine Used as monotherapy and add-on Dizziness, ataxia, blurred o Stevens-Johnson syndrome
therapy o partial and secondarily double vision, nausea, and and disseminated intravascular
generalized tonic-clonic seizures vomiting coagulation have been reported
in adults and Lennox-Gastaut
syndrome in children and adults
Topiramate Used as initial monotherapy (in Somnolence, atigue, Renal calculi due to inhibition o
patients at least 10 years old) weight loss, and carbonic anhydrase
and as adjunctive therapy ( or nervousness Cognitive impairment
patients as young as 2 years o
age) or partial onset or primary
generalized tonic-clonic seizures,
or Lennox-Gastaut syndrome in
patients 2 years o age or older,
and or migraine prophylaxis in
adults
Zonisamide Add-on therapy or patients with Somnolence, ataxia, Renal calculi due to inhibition o
re ractory partial seizures anorexia, nervousness, and carbonic anhydrase
atigue Metabolic acidosis—more
requent and severe in younger
patients
237
CHAPTER
13 Drug Therapyof
Neurodegenerative Diseases
T is chapter wi be most use u a er having a basic understanding o the materia
DRUGS INCLUDED IN THIS
in Chapter 22, reatment o Centra Nervous System Degenerative Disorders in
CHAPTER Goodman & Gilman’s T e Pharmacological Basis o T erapeutics, 12th Edition. In addition
• Amantadine (SYMMETREL) to the materia presented here, the 12th Edition inc udes:
• Apomorphine (APOKYN) • A discussion o the se ective vu nerabi ities o speci c CNS neurons
• Baclo en (LIORESAL) • A detai ed discussion o the ro o genetics and environment in neurodegenerative
• Carbidopa (LODOSYN) disorders
• Carbidopa/levodopa (SINEMET,ATAMET, • T e common ce u ar mechanisms o neurodegeneration
others; orallydisintegratingtablet, PARCOPA) • A detai ed discussion o the neura mechanisms and neuroprotective mechanisms o
• Dantrolene (DANTRIUM) parkinsonism
• Donepezil (ARICEPT) • A comp ete discussion o the genetics o Huntington’s disease
• Entacapone (COMTAN; fxed combination • Chemica structures o the drugs used to treat and manage neurodegenerative disorders
with carbidopa/levodopa, STAVELO) • Figure 22-8 Monosynaptic muscle stretch ref ex with descending control via inhibitory
• Galantamine (NIVALIN, others) interneurons
• Levodopa (L-DOPA, LARODOPA)
LEARNING OBJECTIVES
• Memantine (NAMENDA)
Understand the pathophysio ogy o neurodegenerative diseases, inc uding
• Pramipexole (MIRAPEX) Parkinson’s disease (PD), A zheimer’s disease (AD), Huntington’s disease (HD),
• Rasagiline (AZILECT) and amyotrophic atera sc erosis (ALS).
• Riluzole (RILUTEK) Understand the ro e o drugs in the treatment and management o the symp-
• Rivastigmine (EXELON) toms o neurodegenerative diseases.
• Ropinirole (REQUIP) Know the mechanisms o action and the adverse ef ects o drugs that are used
• Selegiline (ELDEPRYL; oral disintegrating to treat and manage neurodegenerative diseases.
tablet, EMSAM;transdermal patch, ZELAPAR)
• Tacrine (COGNEX)—discontinued in the MECHANISMS OF ACTION OF DRUGS USED TO TREAT AND MANAGE
United States NEURODENERATIVE DISORDERS
• Tetrabenazine (XENAZINENITOMAN)
DRUG CLASS DRUG MECHANISM OF ACTION
• Tizanidine (ZANAFLEX)
Drugs Used to Treat Levodopa Decarboxylated in the brain to dopamine (DA)
• Tolcapone (TASMAR) Parkinson’s Disease
(Continued)
238
Drug Therapy of Neurodegenerative Diseases CHAPTER 1 3
CASE 13 1
A 68-year-o d man is diagnosed with Parkinson’s disease (PD).
a. What is the pathophysiology o Parkinson’s disease?
T e dopaminergic de cit in PD arises rom a oss o the neurons in the substantia
nigra pars compacta that provide innervation to the striatum (caudate and puta-
men). T e current understanding o the pathophysio ogy o PD is based on the
nding that the striata DA content is reduced in excess o 80%. T is para e ed the
oss o neurons rom the substantia nigra, suggesting that rep acement o DA cou d
restore unction.
CARDINAL FEATURES OF
b. How is dopamine synthesized in neurons? PARKINSON DISEASE (PD)
DA, a catecho amine, is synthesized in the termina s o dopaminergic neurons rom
• Bradykinesia (slowness and povertyo
tyrosine and stored, re eased, and metabo ized by processes described in Chapter
movement)
5 and summarized in Figure 13-1. T e actions o DA in the brain are mediated by
a ami y o DA receptor proteins. wo types o DA receptors are identi ed in the • Muscular rigidity
mamma ian brain using pharmaco ogica techniques: D1 receptors, which stimu ate • Resting tremor (which usuallyabates
the synthesis o the intrace u ar second messenger cyc ic AMP; and D2 receptors, during voluntarymovement)
which inhibit cyc ic AMP synthesis as we as suppress Ca2+ currents and activate • Impairment o postural balance leading to
receptor-operated K+ currents. disturbances o gait and alling
(Continued)
239
SECTION II Neuropharmacology
DA
D2
Ne uro nal re uptake a utore ce ptor
(DAT, NET), the n s tora ge
(VMAT2), or me ta bolis m
Syna ptic DA
Po s ts ynaptic uptake
D1/D2 fa mily [(OCT1, OCT2,
of re ce ptors ENT (OCT3)]
DA
Effe ctor
re s pons e COMT
ALDH
HVA HVA 3MT
MAO
FIGURE 13-1 Dopaminergic nerve terminal. Dopamine (DA) is synthesized rom tyrosine in
the nerve terminal by the sequential actions o tyrosine hydrolase (TH) and aromatic amino
acid decarboxylase (AADC). DA is sequestered by VMAT2 in storage granules and released
by exocytosis. Synaptic DA activates presynaptic autoreceptors and postsynaptic D1 and D2
receptors. Synaptic DA may be taken up into the neuron via the DA and NE transporters (DAT,
NET), or removed by postsynaptic uptake via OCT3 transporters. Cytosolic DA is subject to
degradation by monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH) in the
neuron, and by catechol-O-methyltrans erase (COMT) and MAO/ALDH in non-neuronal cells;
the nal metabolic product is homovanillic acid (HVA). See structures in Figure 13-4. PH,
phenylalanine hydroxylase.
T e key eature o this mode o basa gang ia unction, which accounts or the
symptoms observed in PD as a resu t o oss o dopaminergic neurons, is the di -
erentia e ect o DA on the direct and indirect pathways (see Figure 13-3). T e
dopaminergic neurons o the substantia nigra pars compacta (SNpc) innervate a
parts o the striatum; however, the target striata neurons express distinct types o
DA receptors. T e striata neurons giving rise to the direct pathway express pri-
mari y the excitatory D1 dopamine receptor protein, whereas the striata neurons
orming the indirect pathway express primari y the inhibitory D2 type. T us, DA
re eased in the striatum tends to increase the activity o the direct pathway and
reduce the activity o the indirect pathway, whereas the dep etion that occurs in
PD has the opposite e ect. T e net e ect o the reduced dopaminergic input in PD
is to increase marked y the inhibitory out ow rom the SNpc and g obus pa idus
interna (GPi) to the tha amus and reduce excitation o the motor cortex.
d. What is the prognosis or this patient?
Progressive oss o dopamine (DA)-containing neurons is a eature o norma aging;
however, most peop e do not ose the 70 to 80% o dopaminergic neurons required
to cause symptomatic PD. Without treatment, PD progresses over 5 to 10 years
to a rigid, akinetic state in which patients are incapab e o caring or themse ves.
Death requent y resu ts rom comp ications o immobi ity, inc uding aspiration
pneumonia or pu monary embo ism. T e avai abi ity o e ective pharmaco ogica
treatment has radica y a tered the prognosis o PD; in most cases, good unctiona
mobi ity can be maintained or many years. Li e expectancy o adequate y treated
patients is increased substantia y, but overa morta ity remains higher than that o
the genera popu ation. Common y used medications or the treatment o PD are
summarized in ab e 13-1.
+
Ce re bra l corte x
Glu
+ Glu + Glu
+
S tria tum Ce re bra l corte x
VA/VL Glu
DA
ACh tha la mus + Glu + Glu
D1 D2
(s timula tory) (inhibitory)
– S tria tum VA/VL
GABA
DA tha la mus
– GABA ACh
Glu +
– D1 D2
GPe STN – GABA
S Npc GABA
– GABA Glu + – GABA
Glu +
GP i/S Npr –
Glu To s p ina l c ord GPe STN
S Npc GABA
+ – GABA
a nd b ra ins te m Glu +
GP i/S Npr
FIGURE 13-2 Schematic wiring diagram o the basal ganglia. Glu
The striatum is the principal input structure o the basalganglia and + To s p ina l c ord
a nd b ra ins te m
receives excitatory glutamatergic input rom many areas o cerebral
cortex. The striatum contains projection neurons expressing predom- FIGURE 13-3 The basal ganglia in Parkinson’s disease. The pri-
inantly D1 or D2 dopamine receptors, as well as interneurons that use mary de ect is destruction o the dopaminergic neurons o the
acetylcholine (ACh) as a neurotransmitter. Out ow rom the striatum SNpc. The striatal neurons that orm the direct pathway rom the
proceeds along two routes. The direct pathway, rom the striatum to striatum to the SNpr and GPi express primarily the excitatory D1
the substantianigra pars reticulata (SNpr) and globus pallidus interna dopamine receptor, whereas the striatal neurons that project to the
(GPi), uses the inhibitory transmitter GABA. The indirect pathway, GPe and orm the indirect pathway express the inhibitory D2 dopa-
rom the striatum through the globus pallidus externa (GPe) and mine receptor. Thus, loss o the dopaminergic input to the striatum
the subthalamic nucleus (STN) to the SNpr and GPi consists o two has a dif erential ef ect on the two out ow pathways; the direct
inhibitory GABAergic links and one excitatory glutamatergic pro- pathway to the SNpr and GPi is less active (structures in light blue),
jection (Glu). The substantia nigra pars compacta (SNpc) provides whereas the activity in the indirect pathway is increased (structures
dopaminergic innervation to the striatal neurons, giving rise to both in dark blue). The net ef ect is that neurons in the SNpr and GPi
the direct and indirect pathways, and regulates the relative activity become more active. This leads to increased inhibition o the VA/VL
o these two paths. The SNpr and GPi are the output structures o the thalamus and reduced excitatory input to the cortex. (See legend
basal ganglia and provide eedback to the cerebral cortex through to Figure 13–2 or de nitions o anatomical abbreviations.)
the ventroanterior and ventrolateralnuclei o the thalamus (VA/VL).
241
SECTION II Neuropharmacology
CASE 13 2
T e patient in Case 13-1 is ear y in the course o his Parkinson’s disease
a. What are the treatment options at this stage o his disease?
Common y used medications or the treatment o PD are summarized in ab e 13-1.
Pharmaco ogica treatment o PD shou d be tai ored to the individua patient. Drug
therapy is not ob igatory in ear y PD; many patients can be managed or a time
with exercise and i esty e interventions. For patients with mi d symptoms, MAO-B
inhibitors, amantadine, or (in younger patients) anticho inergics are reasonab e
choices. In most patients, treatment with a dopaminergic drug, either evodopa
(Continued)
TABLE 13-1 Commonly Used Medications for the Treatment of Parkinson’s Disease
AGENT TYPICAL INITIAL DOSE DAILY DOSE RANGE COMMENTS
Levodopa Formulations
COMT Inhibitors
DA Agonists
MAO Inhibitors
Other Medications
242
Drug Therapy of Neurodegenerative Diseases CHAPTER 1 3
CASE 13 3
As this (the patient rom Case 13-1) patient’s disease progresses, it is recommended
that he be treated with evodopa.
a. What is levodopa, and how is it used in the treatment o Parkinson’s disease?
Levodopa, the metabo ic precursor o DA, is the sing e most e ective agent in the
treatment o PD. Levodopa is itse arge y inert; both its therapeutic and adverse
e ects resu t rom the decarboxy ation o evodopa to DA. T e metabo ism o
evodopa is shown in Figure 13-4.
Entry o evodopa into the CNS across the b ood-brain barrier is mediated by a
membrane transporter or aromatic amino acids, and competition between dietary
protein and evodopa may occur at this eve . In the brain, evodopa is converted to
DA by decarboxy ation primari y within the presynaptic termina s o dopaminer-
gic neurons in the stratium (see Figure 13-5). T e DA produced in the presynaptic
termina s is responsib e or the therapeutic e ectiveness o evodopa in PD; a er
re ease, it is either transported back into dopaminergic termina s by the presynaptic
uptake mechanism or metabo ized by the actions o MAO and catecho -O-methy -
trans erase (COM ) (see Figure 13-4).
b. What other drugs should be administered with levodopa?
In c inica practice, evodopa is a most a ways administered in combination with
a periphera y acting inhibitor o aromatic l -amino acid decarboxy ase, such as
carbidopa or benserazide (avai ab e outside the United States), drugs that do not
penetrate we into the CNS. I evodopa is administered a one, the drug is arge y
decarboxy ated by enzymes in the intestina mucosa and other periphera sites so
that re ative y itt e unchanged drug reaches the cerebra circu ation and probab y
(Continued)
COOH COOH
HO HO
AADC
DA 3MT
FIGURE 13-5 Pharmacological preservation o L-DOPA and striatal dopamine. The principal site
o action o inhibitors o catechol-O-methyltrans erase (COMT) (such as tolcapone and entaca-
pone) is in the peripheral circulation. They block the O-methylation o levodopa (L-DOPA) and
increase the raction o the drug available or delivery to the brain. Tolcapone also has ef ects
in the CNS. Inhibitors o MAO-B, such as low-dose selegiline and rasagiline, will act within the
CNS to reduce oxidative deamination o DA, thereby enhancing vesicular stores. AADC, aromatic
l -amino acid decarboxylase; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; MAO, mono-
amine oxidase; 3MT, 3-methoxyltyramine; 3-O-MD, 3-O-methyl DOPA.
ess than 1% penetrates the CNS. In addition, DA re ease into the circu ation by
periphera conversion o evodopa produces undesirab e e ects, particu ar y nau-
sea. Inhibition o periphera decarboxy ase, with carbidopa, marked y increases
the raction o administered evodopa that remains unmetabo ized and avai ab e
to cross the b ood-brain barrier (see Figure 13-5) and reduces the incidence o GI
side e ects.
Drugs or the treatment o PD inc ude inhibitors o the enzyme COM , which,
together with MAO, metabo izes evodopa and DA. COM trans ers a methy group
rom the donor S-adenosy -l -methionine, producing the pharmaco ogica y inactive
compounds 3-O-methy DOPA ( rom evodopa) and 3-methoxytyramine ( rom DA;
see Figure 13-4). T e principa therapeutic action o the COM inhibitors is to b ock
this periphera conversion o evodopa to 3-O-methy DOPA, increasing both the
p asma t1/2 o evodopa as we as the raction o each dose that reaches the CNS.
wo COM inhibitors present y are avai ab e or this use in the United States, to ca-
pone and entacapone. T e action o entacapone is attributab e principa y to periph-
era inhibition o COM . T e common adverse e ects o these agents are simi ar
to those o evodopa/carbidopa a one and inc ude nausea, orthostatic hypotension,
vivid dreams, con usion, and ha ucinations. An important adverse e ect associ-
ated with to capone is hepatotoxicity. Up to 2% o the patients treated with to capone
have increased serum a anine aminotrans erase and aspartate transaminase; and at
east 3 ata cases o u minant hepatic ai ure in patients taking to capone have been
observed, eading to the addition o a b ack box warning to the abe .
c. What are the adverse ef ects o levodopa that might be expected in this patient?
A common prob em is the deve opment o the “wearing o ” phenomenon: each
dose o evodopa e ective y improves mobi ity or a period o time, perhaps 1 to
2 hours, but rigidity and akinesia return rapid y at the end o the dosing interva .
Increasing the dose and requency o administration can improve this situation,
but this o en is imited by the deve opment o dyskinesias, excessive and abnorma
invo untary movements. Dyskinesias are observed most o en when the p asma
evodopa concentration is high, a though in some individua s dyskinesias or dysto-
nia may be triggered when the eve is rising or a ing. T ese movements can be as
uncom ortab e and disab ing as the rigidity and akinesia o PD. In the ater stages o
PD, patients may uctuate rapid y between being “o ,” having no bene cia e ects
rom their medications, and being “on” but with disab ing dyskinesias, a situation
ca ed the on/o phenomenon.
(Continued)
244
Drug Therapy of Neurodegenerative Diseases CHAPTER 1 3
In addition to motor comp ications and nausea, severa other adverse e ects may
be observed with evodopa treatment. A requent and troub ing adverse e ect is
the induction o ha ucinations and con usion, especia y in e der y patients or in
patients with preexisting cognitive dys unction. T is adverse e ect o en imits the
abi ity to treat parkinsonian symptoms adequate y.
Periphera decarboxy ation o evodopa and re ease o DA into the circu ation
may activate vascu ar DA receptors and produce orthostatic hypotension. Admin-
istration o evodopa with nonspeci c inhibitors o MAO, such as phene zine and
trany cypromine, marked y accentuate the actions o evodopa and may precipitate
i e-threatening hypertensive crisis and hyperpyrexia; nonspeci c MAO inhibi-
tors shou d a ways be discontinued at east 14 days be ore evodopa is administered
(note that this prohibition does not inc ude the MAO-B subtype-speci c inhibitors
se egi ine and rasagi ine, which are o en administered sa e y in combination with
evodopa). Abrupt withdrawa o evodopa or other dopaminergic medications may
precipitate the neuro eptic ma ignant syndrome o con usion, rigidity, and hyper-
thermia, a potentia y etha adverse e ect.
d. What other drugs can be used or the treatment o PD?
An a ternative to evodopa is the use o drugs that are direct agonists o striata
DA receptors, an approach that o ers severa potentia advantages. Since enzymatic
conversion o these drugs is not required or their activity, they do not depend
on the unctiona capacities o the nigrostriata neurons. T e direct DA receptor
agonists in c inica use have durations o action substantia y onger than that o
evodopa; they are o en used in the management o dose-re ated uctuations in
motor state, and may be he p u in preventing motor comp ications. Fina y, it has
been suggested that DA receptor agonists may have the potentia to modi y the
course o PD by reducing endogenous re ease o DA as we as the need or exogenous
evodopa, thereby reducing ree radica ormation.
wo ora y administered DA receptor agonists common y used or treatment o
PD are ropiniro e and pramipexo e.
wo isoenzymes o MAO oxidize monoamines. Whi e both isoenzymes (MAO-A
and MAO-B) are present in the periphery and inactivate monoamines o intesti-
na origin, the isoenzyme MAO-B is the predominant orm in the striatum and is
responsib e or most o the oxidative metabo ism o DA in the brain. wo se ective
MAO-B inhibitors are used or the treatment o PD: se egi ine and rasagi ine. Both
agents exert modest bene cia e ects on the symptoms o PD.
Se egi ine has been used or many years as a symptomatic treatment or PD and
is genera y we to erated in younger patients with ear y or mi d PD. In patients
with more advanced PD or under ying cognitive impairment, se egi ine may
accentuate the adverse motor and cognitive e ects o evodopa therapy. Metabo ites
o se egi ine inc ude amphetamine and methamphetamine, which may cause anxiety,
insomnia, and other adverse symptoms.
Un ike se egi ine, rasagi ine does not give rise to undesirab e amphetamine metabo-
ites. In randomized contro ed c inica tria s, rasagi ine monotherapy was e ective
in ear y PD.
Amantadine, an antivira agent used or the prophy axis and treatment o in uenza A
(see Chapter 44), has antiparkinsonian activity. Amantadine appears to a ter DA re ease
in the striatum, has anticho inergic properties, and b ocks NMDA g utamate receptors.
CASE 13 4
A 72-year-o d woman is diagnosed with A zheimer’s disease (AD).
a. What is the pathophysiology o AD?
T e patho ogica ha marks o AD are amy oid p aques, which are extrace u ar
accumu ations o amy oid-β peptides (Aβ), and intrace u ar neuro bri ary tang es
(Continued)
245
SECTION II Neuropharmacology
Ne uron
Mitochondrion Aβ
Apo E4
Trunca te d
Apo E4 Oligome rs
S igna ling
Nucle us mole cule s
Impa ire d
syna ps e Microglia l
Ta u ce ll Ne urite
Ne urofibrilla ry
ta ngle s
Amyloid
pla que
composed o the microtubu e-associated protein tau (see Figure 13-6). Whi e the
deve opment o amy oid p aques is an ear y and invariant eature o AD, tang e bur-
den accrues over time in a manner that corre ates more c ose y with the deve op-
ment o cognitive impairment. T e current consensus is that Aβ accumu ation is an
upstream event that triggers tau patho ogy, resu ting in impaired neurona unction
and ce oss.
T e most striking neurochemica disturbance in AD is a de ciency o acety cho ine
(ACh). T e anatomica basis o the cho inergic de cit is atrophy and degenera-
tion o subcortica cho inergic neurons, particu ar y those in the basa orebrain
(nuc eus basa is o Meynert) that provide cho inergic innervation to the cerebra
cortex. T e se ective de ciency o ACh in AD, as we as the observation that cen-
tra cho inergic antagonists such as atropine can induce a con usiona state that
bears some resemb ance to the dementia o AD, has given rise to the “cho inergic
hypothesis,” which proposes that a de ciency o ACh is critica in the genesis o the
AD symptoms. A though viewing AD as a “cho inergic de ciency syndrome” akin
to the “dopaminergic de ciency syndrome” o PD provides a use u ramework, it is
important to note that the de cit in AD is ar more comp ex. AD invo ves mu tip e
neurotransmitter systems, inc uding g utamate, 5-H , and neuropeptides, and there
is destruction o not on y cho inergic neurons but a so the cortica and hippocam-
pa targets that receive cho inergic input.
b. What treatment is available or the cognitive symptoms o AD?
Augmentation o the cho inergic transmission is current y the mainstay o AD
treatment. T ree drugs—donepezi , rivastigmine, and ga antamine—are wide y
used or this purpose; a ourth drug, tacrine, was the rst drug approved to treat
AD but is rare y used now because it has much more extensive side e ects com-
pared to the newer agents (see ab e 13-2).
A 4 agents are reversib e antagonists o cho inesterases, enzymes that act to imit
cho inergic neurotransmission by cata yzing the c eavage o acety cho ine in the
synaptic c e into cho ine and acetate (see Chapter 6).
Memantine is used either as an adjunct or as an a ternative to cho inesterase inhibi-
tors in AD and is a so common y used to treat other neurodegenerative dementias.
Memantine is a noncompetitive antagonist o the NMDA-type g utamate receptor.
(Continued)
246
Drug Therapy of Neurodegenerative Diseases CHAPTER 1 3
TABLE 13-2 Cholinesterase Inhibitors Used for the Treatment of Alzheimer’s Disease
DONEPEZIL RIVASTIGMINE GALANTAMINE TACRINEa
Brand name ARICEPT EXELON, generic RAZADYNE, generic COGNEX
Typical maintenance dose c 10 mg once daily 9.5 mg/24h (transdermal) 8-12 mg twice daily 20 mg, our times daily
3-6 mg twice daily (oral) (immediate-release)
16-24 mg/day (extended-release)
It interacts with the Mg2+ binding site o the channe to prevent excessive activation
whi e sparing norma unction. Memantine signi cant y reduces the rate o c inica
deterioration in patients with moderate to severe AD.
c. What treatment is available or the behavioral symptoms o AD?
In addition to cognitive dec ine, behaviora and psychiatric symptoms in dementia
(BPSD) are common, particu ar y in midd e stages o the disease. T ese symptoms,
inc uding irritabi ity and agitation, paranoia and de usiona thinking, wandering,
anxiety, and depression, are a major source o caregiver distress and o en precipi-
tate nursing home p acement.
Atypica antipsychotics, such as respiridone, o anzepine, and quetiapin (see Chapter 8),
are the most ef cacious therapy or agitation and psychosis in AD. Risperidone and
o anzapine are e ective, but their use is o en imited by adverse e ects, inc uding
parkinsonism, sedation, and a s. In addition, the use o atypica antipsychotics in
e der y patients with dementia-re ated psychosis has been associated with a higher
risk o stroke and overa morta ity, eading the FDA to order inc usion o a boxed
warning in the prescribing in ormation or a drugs in this c ass. Un ortunate y,
there are ew e ective a ternatives.
Antidepressants (see Chapter 8) can be use u or BPSD, particu ar y when depres-
sion or anxiety contribute. Because o the adverse anticho inergic e ects o tricyc ic
agents, serotonergic antidepressants are avored. T ese agents are genera y we
to erated. razodone has modest bene ts, but or the most part, se ective serotonin
reuptake inhibitors (SSRIs) are the pre erred c ass o drugs.
T e typica AD patient presenting in ear y stages o disease shou d probab y be
treated with a cho inesterase inhibitor. Patients and ami ies shou d be counse ed
that a rea istic goa o therapy is to induce a temporary reprieve rom progres-
sion, or at east a reduction in the rate o dec ine, rather than ong-term recovery
o cognition. As the disease progresses, memantine can be added to the regimen.
Behaviora symptoms are o en treated with a serotonergic antidepressant or, i
they are severe enough to warrant the risk o higher morta ity, an atypica antipsy-
chotic. E iminating drugs ike y to aggravate cognitive impairments, particu ar y
(Continued)
247
SECTION II Neuropharmacology
CASE 13 5
A 39-year-o d man is diagnosed with Huntington’s disease (HD).
a. What is the pathophysiology o Huntington’s disease?
HD is characterized by prominent neurona oss in the striatum (caudate/putamen)
o the brain. Atrophy o these structures proceeds in an order y ashion, rst a ecting
the tai o the caudate nuc eus and then proceeding anterior y rom mediodorsa
to ventro atera .
Se ective vu nerabi ity a so appears to under ie the most conspicuous c inica ea-
ture o HD, the deve opment o chorea. In most adu t-onset cases, the medium
spiny neurons that project to the GPi and SNpr (the indirect pathway) appear to be
a ected ear ier than those projecting to the g obus pa idus externa (GPe; the direct
pathway; see Figure 13-5). T e disproportionate impairment o the indirect path-
way increases excitatory drive to the neocortex, producing invo untary chorei orm
movements (see Figure 13-7).
b. What drugs are available or the treatment o patients with Huntington disease?
reatment or symptomatic HD emphasizes the se ective use o medications. None
o the current y avai ab e medications s ows the progression o the disease.
reatment is needed or patients who are depressed, irritab e, paranoid, exces-
sive y anxious, or psychotic. Depression can be treated e ective y with standard
antidepressant drugs with the caveat that drugs with substantia anticho inergic
pro es can exacerbate chorea. F uoxetine (see Chapter 8) is e ective treatment or
both the depression and the irritabi ity mani est in symptomatic HD. Carbamaze-
pine (see Chapter 12) a so has been ound to be e ective or depression. Paranoia,
de usiona states, and psychosis are treated with antipsychotic drugs, but usua y
at ower doses than those used in primary psychiatric disorders (see Chapter 8).
T ese agents a so reduce cognitive unction and impair mobi ity and thus shou d
be used in the owest doses possib e and shou d be discontinued when the psychi-
atric symptoms reso ve.
(Continued)
+
Ce re bra l corte x
Glu
+ Glu + Glu
S tria tum VA/VL
DA tha la mus
ACh
D1 D2
– GABA
– GABA
Glu + –
GPe STN
S Npc GABA
– GABA Glu +
GP i/S Npr
Glu
+ To s p ina l c ord
a nd b ra ins te m
FIGURE 13-7 The basal ganglia in Huntington’s disease. HD is characterized by loss o neurons
rom the striatum. The neurons that project rom the striatum to the GPe and orm the indirect
pathway are af ected earlier in the course o the disease than those which project to the GPi. This
leads to a loss o inhibition o the GPe. The increased activity in this structure, in turn, inhibits the
STN, SNpr, and GPi, resulting in a loss o inhibition to the VA/VL thalamus and increased thalamo-
cortical excitatorydrive. Structures in light blue have reduced activity in HD, whereas structures
in dark blue have increased activity. (See legend to Figure 13-2 or de nitions o anatomical
abbreviations.)
248
Drug Therapy of Neurodegenerative Diseases CHAPTER 1 3
CASE 13 6
A 53-year-o d man is diagnosed with amyotrophic atera sc erosis (ALS).
a. What is ALS?
ALS (or Lou Gehrig disease) is a disorder o the motor neurons o the ventra horn
o the spina cord ( ower motor neurons) and the cortica neurons that provide
their a erent input (upper motor neurons). T e disorder is characterized by rapid y
progressive weakness, musc e atrophy and ascicu ations, spasticity, dysarthria, dys-
phagia, and respiratory compromise. Sensory, autonomic, and ocu omotor unction
is genera y spared.
T e patho ogy o ALS corresponds c ose y to the c inica eatures: T ere is promi-
nent oss o the spina and brainstem motor neurons that project to striated musc es
(a though the ocu omotor neurons are spared), as we as oss o the arge pyramida
motor neurons in ayer V o the motor cortex, which are the origin o the descend-
ing corticospina tracts.
ALS usua y is progressive and ata . Most patients die o respiratory compromise
and pneumonia a er 2 to 3 years, a though some individua s have a more indo ent
course and survive or many years.
b. What treatment options are available or patients with ALS?
Ri uzo e is an agent with comp ex actions in the nervous system. It inhibits g uta-
mate re ease, but it a so b ocks postsynaptic NMDA- and kainate-type g utamate
receptors and inhibits vo tage-dependent Na+ channe s.
In c inica tria s ri uzo e has modest but genuine e ects on the surviva o patients
with ALS. Meta-ana yses o the avai ab e tria s indicate that ri uzo e extends surviva
by 2 to 3 months.
Spasticity is an important component o the c inica eatures o ALS and the eature
most amenab e to present orms o treatment. Spasticity o en eads to considerab e
pain and discom ort and urther reduces mobi ity, which a ready is compromised
by weakness. Spasticity is de ned as an increase in musc e tone characterized by an
initia resistance to passive disp acement o a imb at a joint, o owed by a sudden
re axation (the so-ca ed c asped-kni e phenomenon).
T e best agent or the symptomatic treatment o spasticity in ALS is bac o en, a
GABAB receptor agonist.
izanidine is an agonist o α2 adrenergic receptors in the CNS. It reduces musc e
spasticity and is assumed to act by increasing presynaptic inhibition o motor
neurons.
Benzodiazepines (see Chapter 9) such as c onazepam are e ective antispastic-
ity agents, but they are sedating and may contribute to respiratory depression in
patients with advanced ALS.
Dantro ene a so is approved in the United States or the treatment o musc e spasm.
In contrast to the other agents discussed, dantro ene acts direct y on ske eta
musc e bers, impairing Ca2+ re ease rom the sarcop asmic reticu um. Because it
can exacerbate muscu ar weakness, it is not used in ALS but is e ective in treating
spasticity associated with stroke or spina cord injury and in treating ma ignant
hyperthermia.
249
SECTION II Neuropharmacology
KEY CONCEPTS
Neurodegenerative disorders are characterized by progressive and irreversib e
oss o neurons rom speci c regions o the brain.
Current y avai ab e therapies or neurodegenerative disorders a eviate the dis-
ease symptoms but do not a ter the under ying neurodegenerative processes.
T e dopaminergic de cit in Parkinson’s disease arises rom a oss o the neurons
in the substantia nigra pars compacta that provide innervation to the striatum.
Drug therapy is not ob igatory in ear y Parkinson’s disease; pharmaco ogica
treatment o Parkinson’s disease shou d be tai ored to the individua patient.
A rea istic goa or the treatment o a patient with A zheimer’s disease is to
induce a temporary reprieve rom progression, or at east a reduction in the rate
o dec ine, rather than ong-term recovery o cognition.
Huntington’s disease is a dominant y inherited disorder characterized by
prominent neurona oss in the striatum o the brain and by the gradua onset
o motor incoordination and cognitive dec ine in mid i e.
At present there is no ef ective treatment or Huntington’s disease; therapy is
aimed toward contro o the motor and behaviora eatures o the disorder.
Amyotrophic atera sc erosis is a progressive degenerative disease o spina
motor neurons eading to weakness and eventua y para ysis.
T e drug ri uzo e is the on y treatment estab ished to a ter the course o amyotrophic
atera sc erosis; its ef ect is modest, pro onging surviva by on y a ew months.
SUMMARY QUIZ
QUESTION 13-1 A 72-year-o d man with Parkinson’s disease is being treated with se e-
gi ine. Over the past 2 weeks he has noticed an increase in insomnia and anxiety. It is
ike y these symptoms are due to
a. dopamine.
b. ephedrine.
c. amphetamine.
d. serotonin.
e. caf eine.
QUESTION 13-2 A 75-year-o d woman with Parkinson’s disease is being treated with
the combination o evodopa/carbidopa. Entacapone is added. T is patient is treated
with this combination o drugs to increase the amount o which o the o owing sub-
stance to reach the CNS?
a. Carbidopa
b. Levodopa
c. Entacapone
d. Acety cho ine
e. Dopamine
QUESTION 13-3 A 66-year-o d woman with A zheimer’s disease is being treated with
the cho inesterase inhibitor donepezi . T e patient’s ami y earns that donepezi is
re ated to pesticides. When the ami y expresses concern they are to d that donepezi
may decrease the rate o cognition dec ine by increasing the concentration o which
substance in the brain?
a. Acety cho ine
b. Serotonin
(Continued)
250
Drug Therapy of Neurodegenerative Diseases CHAPTER 1 3
c. Dopamine
d. Epinephrine
e. G utamate
QUESTION 13-4 A 73-year-o d man with A zheimer’s disease is being treated with
donepezi . Because his cognition is deteriorating, memantine is added. Memantine is
a noncompetitive antagonist o the
a. dopamine D2 receptor.
b. NMDA-type g utamate receptor.
c. β adrenergic receptor.
d. α adrenergic receptor.
e. 5-H 2 serotonergic receptor.
QUESTION 13-5 A 57-year-o d man with amyotrophic atera sc erosis is treated with
ri uzo e. T e patient’s ami y is to d that the drug may extend surviva by
a. 2 to 3 days.
b. 2 to 3 months.
c. 2 to 3 years.
d. an inde nite period o time.
e. none o the above; because it is not thought to extend surviva .
QUESTION 13-6 A 65-year-o d man with Parkinson’s disease is treated with pramipex-
o e. T is drug acts as an agonist at striata
a. 5-H serotonergic receptors.
b. D1 dopaminergic receptors.
c. norepinephrine adrenergic receptors.
d. D2 dopaminergic receptors.
e. opiate µ receptors.
QUESTION 13-1 Answer is c. Metabo ites o se egi ine inc ude amphetamine and
methamphetamine, which may cause anxiety, insomnia, and other adverse symptoms.
Un ike se egi ine, rasagi ine does not give rise to undesirab e amphetamine metabo ites.
QUESTION 13-5 Answer is b. Ri uzo e is an agent with comp ex actions in the nervous
system. It inhibits g utamate re ease, but it a so b ocks postsynaptic NMDA- and
kainate-type g utamate receptors and inhibits vo tage-dependent Na+ channe s. In
c inica tria s ri uzo e has modest but genuine ef ects on the surviva o patients with
ALS. Meta-ana yses o the avai ab e tria s indicate that ri uzo e extends surviva by
2 to 3 months.
252
Drug Therapy of Neurodegenerative Diseases CHAPTER 1 3
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE: CLINICALLY IMPORTANT
Selegiline Selective inhibitor o Anxiety and May exacerbate the adverse motor and
MAO-B used to treat insomnia due to its cognitive ef ects o levodopa
Parkinson’s disease amphetamine and Contraindicated or use with meperidine
meth-amphetamine Used with caution in patients taking SSRIs
metabolites
Apomorphine Intermittent therapy o Severe nausea and Hallucinations, dyskinesia, and abnormal
Parkinson’s disease vomiting requiring behavior
pretreatment with an
antiemetic not o the
5-HT3 antagonist class
Drugs Used to Treat Donepezil Used to treat Alzheimer’s GI distress, muscle See Chapter 6
Alzheimer’s Disease disease cramping, abnormal Used with caution in patients with
dreams bradycardia or syncope
Drugs Used to Riluzole Treatment o amyotrophic Nausea and diarrhea Associated with hepatic injury
Treat ALS lateral sclerosis (ALS)
May prolong survival by
2-3 months
253
CHAPTER
14 Drug Addiction
T is chapter will be most use ul a er having a basic understanding o the material
in Chapter 24, Drug Addiction in Goodman & Gilman’s T e Pharmacological Basis of
T erapeutics, 12th Edition. T e speci c pharmacology (including the mechanisms o
action) o drugs mentioned in Chapter 14 is discussed in previous or subsequent chap-
ters. T e drugs presented in Chapter 14 are discussed in relation to their ability to pro-
duce tolerance, physical dependence, and addiction. No Mechanisms o Action Table
nor Clinical Summary Table are included as a part o Chapter 14 because new drugs
are not introduced. T e ew drugs that are used therapeutically to treat speci c drug
addictions are discussed in the narratives o the clinical cases. In addition to the mate-
rial presented here, the 12th Edition includes:
• able 24-2 Dependence among Users 1990 to 1992
• Figure 24-2 Cocaine-induced changes in CNS dopamine release
• Figure 24-3 Nicotine concentrations in blood resulting rom ve di erent nicotine
delivery systems
• A detailed discussion o the variables a ecting the onset and continuation o drug
abuse and addiction
• A detailed discussion o the di erent types o tolerance
LEARNING OBJECTIVES
Understand the pharmacological principles o tolerance, physical dependence,
and withdrawal.
Describe the characteristic withdrawal syndromes or the commonly abused
drugs.
Know the patterns o abuse behavior and the toxicity o the commonly abused drugs.
Know the available pharmacological interventions or the acute treatment and
long-term management o the commonly abused drugs.
CASE 14-1
A 56-year-old obese woman is being treated with immediate-release oxycodone or
chronic back pain. She is also taking a muscle relaxant, cyclobenzaprine, and a short-
acting benzodiazepine or sleep.
a. What concerns are there with the use o an opiate-like immediate-release oxyco-
done or the treatment o chronic pain?
Rapi -onset, short- uration opioi s are excellent or acute short-term use, such as
uring the postoperative perio . As tolerance an physical epen ence evelop,
however, the patient may experience the early symptoms o with rawal between
oses, an uring with rawal, the threshol or pain ecreases. T e iversion o
prescription opioi s such as oxyco one an hy roco one to illegal markets has
become an important source o opiate abuse in the Unite States (see answer to
Case 14-1c below).
T e risk or a iction is highest in patients complaining o pain with no clear phys-
ical explanation or in patients with evi ence o a chronic, non-li e-threatening is-
or er. Examples are chronic hea aches, backaches, ab ominal pain, or peripheral
neuropathy. Even in these cases, an opioi may be consi ere as a brie emergency
treatment, but long-term treatment with opioi s shoul be use only a er other
alternatives have been exhauste .
(Continued)
254
Drug Addiction CHAPTER 1 4
b. Over the past year this patient has doubled her dose o oxycodone. Why has she
increased the dose o oxycodone?
While abuse an a iction are complex con itions combining many variables
(see able 14-1), there are a number o relevant pharmacological phenomena that
occur in epen ent o social an psychological imensions. First are the changes in
the way the bo y respon s to a rug with repeate use. olerance, the most com-
mon response to repetitive use o the same rug, can be e ne as the re uction in
response to the rug a er repeate a ministrations. Figure 14-1 shows an i ealize
ose-response curve or an a ministere rug. As the ose o the rug increases, the
observe e ect o the rug increases. With repeate use o the rug, however, the
curve shi s to the right (tolerance). T us, a higher ose is require to pro uce the
same e ect that was once obtaine at a lower ose. As outline in able 14-2, there
are many orms o tolerance, likely arising through multiple mechanisms.
olerance to some rug e ects evelops much more rapi ly than to other e ects o
the same rug. For example, tolerance evelops rapi ly to the euphoria pro uce
by opioi s such as heroin, an a icts ten to increase their ose in or er to reex-
perience that elusive “high.” In contrast, tolerance to the gastrointestinal e ects o
opioi s evelops more slowly. T e iscrepancy between tolerance to euphorigenic
e ects (rapi ) an tolerance to e ects on vital unctions (slow), such as respiration
an bloo pressure, can lea to potentially atal over oses in se ative abusers trying
to reexperience the euphoria they recall rom earlier use (see Case 14-5).
(Continued)
Host (user)
Heredity
Innate tolerance
Speed o developing acquired tolerance
Likelihood o experiencing intoxication as pleasure
Metabolism o the drug (nicotine and alcohol data already available)
Psychiatric symptoms
Prior experiences/expectations
Propensity or risk-taking behavior
Environment
Social setting
Community attitudes
Peer in uence, role models
Availability o other rein orcers (sources o pleasure or recreation)
Employment or educational opportunities
Conditioned stimuli: environmental cues become associated with drugs a ter repeated use in
the same environment
255
SECTION II Neuropharmacology
t
c
Acquired
e
f
f
e
Pharmacokinetic (dispositional or
ve
metabolic)
i
t
a
l
Pharmacodynamic
e
R
Learned tolerance
Tole ra nce
Behavioral
Conditioned
Acute tolerance
Reverse tolerance (sensitization)
Cross-tolerance Dos e
FIGURE 14-1 Shi ts in a dose-response curve with tolerance and sensitization. With tolerance,
there is a shi t o the curve to the right such that doses higher than initial doses are required to
achieve the same e ects. With sensitization, there is a le tward shi t o the curve such that or a
given dose, there is a greater e ect than seen a ter the initial dose.
CASE 14-2
A 43-year-old man is admitted to the hospital because o a ractured hip. He has a long
history o alcohol consumption. Recently he has begun taking a drink o alcohol in the
morning.
a. Is it appropriate to assume that he has developed tolerance and physical depen-
dence to alcohol?
Heavy consumers o alcohol not only acquire tolerance but also inevitably evelop a
state o physical epen ence. T is o en lea s to rinking in the morning to restore
TABLE 14-3 Alcohol Withdrawal bloo alcohol levels iminishe uring the night. Eventually, they may awaken uring
Syndrome the night an take a rink to avoi the restlessness pro uce by alling alcohol levels.
Alcohol craving b. What are the major signs and symptoms o alcohol withdrawal?
Tremor, irritability T e alcohol-with rawal syn rome (see able 14-3) generally epen s on the size o
Nausea the average aily ose an usually is “treate ” by resumption o alcohol ingestion.
Sleep disturbance
With rawal symptoms are experience requently but usually are not severe or li e-
Tachycardia
Hypertension threatening until they occur in conjunction with other problems, such as in ection,
Sweating trauma, malnutrition, or electrolyte imbalance. In the setting o such complica-
Perceptual distortion tions, the syn rome o elirium tremens becomes likely.
Seizures (6-48 hours a ter last drink)
Visual (and occasionally auditory or c. What is the appropriate treatment to prevent and treat alcohol withdrawal?
tactile) hallucinations (12-48 hours a ter A patient who presents in a me ical setting with an alcohol-with rawal syn rome
last drink) shoul be consi ere to have a potentially lethal con ition. Although most mil cases
Delirium tremens (48-96 hours a ter last o alcohol with rawal never come to me ical attention, severe cases require general
drink; rare in uncomplicated withdrawal)
evaluation; attention to hy ration an electrolytes; vitamins, especially high- ose
Severe agitation
Con usion thiamine (see Chapter 9); an a se ating me ication that has cross-tolerance with
Fever, pro use sweating alcohol. o block or iminish the symptoms escribe in able 14-3, a short-acting
Tachycardia benzo iazepine such as oxazepam can be use at a ose o 15 to 30 mg every 6 to 8
Nausea, diarrhea hours accor ing to the stage an severity o with rawal; some authorities recommen
Dilated pupils
(Continued)
256
Drug Addiction CHAPTER 1 4
CASE 14-3
A 75-year-old woman with early dementia has been taking alprazolam as a sleep aid or
the past 10 years. She has consistently taken the same prescribed dose, but when her
prescription expired she orgot to renew it.
a. Is she likely to have developed tolerance or physical dependence to the
benzodiazepine?
When a benzo iazepine is taken or up to several weeks, there is little tolerance or
physical epen ence an no i culty in stopping the me ication when the con i-
tion no longer warrants its use. A er several months, the proportion o patients TABLE 14-4 Benzodiazepine
who emonstrate physical epen ence increases, an re ucing the ose or stopping Withdrawal Symptoms
the me ication abruptly pro uces with rawal symptoms (see able 14-4).
Following moderate dose usage
b. What symptoms might she experience as a result o abruptly stopping the Anxiety, agitation
benzodiazepine? Increased sensitivity to light and sound
Paresthesias, strange sensations
It can be i cult to istinguish with rawal symptoms (see able 14-4) rom the
Muscle cramps
reappearance o the anxiety symptoms or which the benzo iazepine was prescribe Myoclonic jerks
initially. Some patients may increase their ose over time because tolerance e nitely Sleep disturbance
evelops to the se ative e ects. Many patients an their physicians, however, con- Dizziness
ten that antianxiety bene ts continue to occur long a er tolerance evelops to the Following high-dose usage
se ating e ects. Moreover, these patients continue to take the me ication or years Seizures
Delirium
(Continued)
257
SECTION II Neuropharmacology
accor ing to me ical irections without increasing their ose an are able to unction
very e ectively as long as they take the benzo iazepine. T e egree to which toler-
ance evelops to the anxiolytic e ects o benzo iazepines is a subject o controversy.
c. How might this patient’s withdrawal syndrome be treated?
I patients receiving long-term benzo iazepine treatment by prescription wish to
stop their me ication, the process may take months o gra ual ose re uction.
With rawal symptoms (see able 14-4) may occur uring this outpatient etoxi-
cation, but in most cases the symptoms are mil . I anxiety symptoms return, a
nonbenzo iazepine such as buspirone may be prescribe , but this agent usually is
less e ective than benzo iazepines or treatment o anxiety in these patients. Some
authorities recommen trans erring the patient to a long t 1/2 benzo iazepine uring
etoxi cation; others recommen an anticonvulsant, carbamazepine or phenobar-
bital. Controlle stu ies comparing i erent treatment regimens are lacking. Since
patients who have been on low oses o benzo iazepines or years usually have no
a verse e ects, the physician an patient shoul eci e jointly whether etoxi ca-
tion an possible trans er to a new anxiolytic are worth the e ort.
A er etoxi cation, the prevention o relapse requires a long-term outpatient
rehabilitation program similar to the treatment o alcoholism. No speci c me ica-
tions have been oun to be use ul in the rehabilitation o se ative abusers; but, o
course, speci c psychiatric isor ers such as epression or schizophrenia, i pres-
ent, require appropriate me ications.
CASE 14-4
A 53-year-old man has been smoking since he was a teenager. He now desires to
quit smoking.
a. What are the issues o nicotine addiction that should be considered in this patient?
T e basic pharmacology o nicotine an agents or smoking cessation are iscusse
in Chapter 6. Because nicotine provi es the rein orcement or cigarette smoking,
the most common cause o preventable eath an isease in the Unite States,
it is arguably the most angerous epen ence-pro ucing rug. T e epen ence
pro uce by nicotine can be extremely urable, as exempli e by the high ailure
rate among smokers who try to quit. Although more than 80% o smokers express
a esire to quit, only 35% try to stop each year, an ewer than 5% are success ul in
unai e attempts to quit.
Cigarette a iction is inf uence by multiple variables. Nicotine itsel pro uces rein-
orcement; users compare nicotine to stimulants such as cocaine or amphetamine,
although its e ects are o lower magnitu e. While there are many casual users o alco-
hol an cocaine, ew in ivi uals who smoke cigarettes smoke a small enough quan-
tity (≤5 cigarettes per ay) to avoi epen ence. Nicotine is absorbe rea ily through
the skin, mucous membranes, an lungs. T e pulmonary route pro uces iscernible
CNS e ects in as little as 7 secon s. T us, each pu pro uces some iscrete rein orce-
ment. With 10 pu s per cigarette, the 1-pack-per- ay smoker rein orces the habit
200 times aily. T e timing, setting, situation, an preparation all become associate
repetitively with the e ects o nicotine.
T ere is evi ence or tolerance to the subjective e ects o nicotine. Smokers typically
report that the rst cigarette o the ay a er a night o abstinence gives the “best”
eeling. Smokers who return to cigarettes a er a perio o abstinence may experi-
ence nausea i they return imme iately to their previous ose. Persons naive to the
e ects o nicotine will experience nausea at low nicotine bloo levels, an smokers will
experience nausea i nicotine levels are raise above their accustome levels.
Negative rein orcement re ers to the bene ts obtaine rom the termination o an
unpleasant state. In epen ent smokers, the urge to smoke correlates with a low
bloo nicotine level, as though smoking were a means to achieve a certain nicotine
(Continued)
258
Drug Addiction CHAPTER 1 4
level an thus avoi with rawal symptoms. Some smokers even awaken uring the
TABLE 14-5 Nicotine Withdrawal
night to have a cigarette, which ameliorates the e ect o low nicotine bloo levels
Symptoms
that coul isrupt sleep. T us, smokers may be smoking to achieve the rewar o
nicotine e ects, to avoi the pain o nicotine with rawal, or most likely a combina- Irritability, impatience, hostility
tion o the two. Nicotine with rawal symptoms are liste in able 14-5. Anxiety
Dysphoric or depressed mood
b. What options are available to help him with his desire to quit smoking? Dif culty concentrating
T e nicotine with rawal syn rome (see able 14-5) can be alleviate by nicotine- Restlessness
replacement therapy, available with a prescription (eg, NICO ROL inhaler an Decreased heart rate
nasal spray) or without (eg, NICORE E gum an others; COMMI lozenges an Increased appetite or weight gain
others; an NICODERM CQ trans ermal patch an others). Figure 24-3 in Good-
man and Gilman’s T e Pharmacological Basis of T erapeutics, 12th E ition shows the
bloo nicotine concentrations achieve by i erent metho s o nicotine elivery.
Because nicotine gum an a nicotine patch o not achieve the peak levels seen with
cigarettes, they o not pro uce the same magnitu e o subjective e ects as smok-
ing. T ese metho s o, however, suppress the symptoms o nicotine with rawal.
T us, smokers shoul be able to trans er their epen ence to the alternative eliv-
ery system an gra ually re uce the aily nicotine ose with minimal symptoms.
Although this results in more smokers achieving abstinence, most resume smoking
over the ensuing weeks or months. Comparisons with placebo treatment show large
bene ts o nicotine replacement at 6 weeks, but the e ect iminishes with time.
T e nicotine patch pro uces a stea y bloo level an seems to have better patient
compliance than that observe with nicotine gum. Veri e abstinence rates at
12 months are reporte to be in the range o 20%. T e necessary goal o complete
abstinence contributes to the poor success rate; when ex-smokers “slip” an begin
smoking a little, they usually relapse quickly to their prior level o epen ence.
T e search or better me ications to treat nicotine a iction has become an impor-
tant goal o the pharmaceutical in ustry, an other types o me ication have been
teste in clinical trials. A sustaine -release preparation o the anti epressant bupro-
pion (ZYBAN; see Chapter 8) improves abstinence rates among smokers an remains
a use ul option. T e cannabinoi CB1 receptor inverse agonist rimonabant improves
abstinence rates an re uces the weight gain seen requently in ex-smokers. Un ortu-
nately, the CB1 inverse agonist mechanism le to a high requency o epressive an
neurologic symptoms, en ing its evelopment in the Unite States. Varenicline, a
partial agonist at the α4β2 subtype o the nicotinic acetylcholine receptor, improves
abstinence rates but has also been linke to risk o eveloping suici al i eation.
Varenicline partially stimulates nicotinic receptors, thereby re ucing craving an
preventing most with rawal symptoms. It has high receptor a nity, thus blocking
access to nicotine, so i the treate smoker relapses, there is little rewar an absti-
nence is more likely to be maintaine .
CASE 14-5
A 16-year-old woman is brought to the emergency room with a heroin overdose. T is
has occurred 8 hours a er she was discharged rom a detoxi cation center.
a. Why is heroin so addictive?
Injection o a heroin solution pro uces a variety o sensations escribe as warmth,
taste, or high an intense pleasure (“rush”) o en compare with sexual orgasm.
T ere are some i erences among the opioi s in their acute e ects, with morphine
pro ucing more o a histamine-releasing e ect an meperi ine pro ucing more
excitation or con usion.
T us, the popularity o heroin may be ue to its availability on the illicit mar-
ket an its rapi onset. A er intravenous injection, the euphoric e ects begin
in less than a minute. Heroin has high lipi solubility, crosses the bloo -brain
barrier quickly, an is eacetylate to the active metabolites 6-monoacetyl mor-
phine an morphine. A er the intense euphoria, which lasts rom 45 secon s
(Continued)
259
SECTION II Neuropharmacology
Me thado ne
h
g
i
H
l
a
m
r
o
N
k
c
i
S
He ro in
0 6 12 18 24
Time (hours )
FIGURE 14-2 Di erences in responses to heroin and methadone. A person who injects heroin
(↑ ) several times per day oscillates (gray line) between being sick and being high. In contrast,
the typical methadone patient (blue line) remains in the “normal”range (indicated in shaded
blue) with little uctuation a ter dosing once per day. The ordinate values represent the subject’s
mental and physical state, not plasma levels o the drug.
260
Drug Addiction CHAPTER 1 4
Protracted withdrawal
change in the treatment o opiate a iction. T is rug pro uces minimal with-
rawal symptoms when iscontinue an has a low potential or over ose, a long
uration o action, an the ability to block heroin e ects. reatment can take place
in a quali e physician’s private o ce rather than in a special center, as require
or metha one. When taken sublingually, buprenorphine (SUBU EX) is active,
but it also has the potential to be issolve an injecte (abuse ). A buprenor-
phine-naloxone combination (SUBOXONE) is also available. When taken orally
(sublingually), the naloxone moiety is not e ective, but i the patient abuses the
me ication by injecting, the naloxone will block or iminish the subjective high
that coul be pro uce by buprenorphine alone.
Another pharmacological option is opioi antagonist treatment. Naltrexone
(REVIA, others; see Chapter 10) is an antagonist with a high a nity or the µ-opioi
receptor (MOR); it will competitively block the e ects o heroin or other MOR ago-
nists. Naltrexone has almost no agonist e ects o its own an will not satis y craving
or relieve protracte with rawal symptoms. For these reasons, naltrexone treatment
oes not appeal to the average heroin a ict, but it can be use a er etoxi cation
or patients with high motivation to remain opioi - ree. Physicians, nurses, an
pharmacists who have requent access to opioi rugs make excellent can i ates or
this treatment approach. A epot ormulation o naltrexone that provi es 30 ays o
me ication a er a single injection (VIVI ROL) has been approve or the treatment
o alcoholism. T is ormulation eliminates the necessity o aily me ication an pre-
vents relapse when the recently etoxi e patient leaves a protecte environment.
CASE 14-6
A 26-year-old man is brought to the emergency room as the result o a motor vehicle
accident. A urine drug screen is positive or benzoylecgonine. A blood alcohol concen-
tration is just below the legal limit or driving.
a. What does the urine drug screen indicate?
T e major route or cocaine metabolism involves hy rolysis o each o its 2 ester
groups. Benzoylecgonine, pro uce on loss o the methyl group, represents the
major urinary metabolite an can be oun in the urine or 2 to 5 ays a er a binge.
As a result, the benzoylecgonine test is a vali metho or etecting cocaine use; the
metabolite remains etectable in the urine o heavy users or up to 10 ays.
b. What are the e ects o cocaine that may have led to the accident?
T e general pharmacology an me icinal use o cocaine as a local anesthetic are
iscusse in Chapter 11. Cocaine pro uces a ose- epen ent increase in heart
rate an bloo pressure accompanie by increase arousal, improve per ormance
on tasks o vigilance an alertness, an a sense o sel -con ence an well-being.
Higher oses pro uce euphoria, which has a brie uration an o en is ollowe
by a esire or more rug. Repeate oses may lea to involuntary motor activity,
stereotype behavior, an paranoia. Irritability an increase risk o violence are
oun among heavy chronic users. O particular concern in rivers who are taking
cocaine is increase risk-taking an a sense o invincibility.
c. Why is cocaine addiction so dif cult to treat?
A orm o mala aptive memory begins with the a ministration o substances (eg,
cocaine) or behaviors (eg, the thrill o gambling) that irectly an intensely activate
brain rewar circuits. Activation o these circuits motivates normal behavior an
most humans simply enjoy the experience without being compelle to repeat it. For
some (~16% o those who try cocaine) the experience pro uces strong con itione
associations to environmental cues that signal the availability o the rug or the
behavior. T us, ref exive activation o rewar circuits becomes involuntary an with
a very rapi onset. T e cues acquire strong salience that overwhelms other behav-
iors. T e in ivi ual becomes rawn into compulsive repetition o the experience
(Continued)
262
Drug Addiction CHAPTER 1 4
CASE 14-7
A 35-year-old woman is an occasional user o cannabis.
a. What is the mechanism o action o cannabis?
T e cannabis plant has been cultivate or centuries both or the pro uction o
hemp ber an or its presume me icinal an psychoactive properties. T e smoke
rom burning cannabis contains many chemicals, inclu ing 61 i erent cannabi-
noi s that have been i enti e . One o these, Δ-9-tetrahy rocannabinol (Δ-9- HC),
pro uces most o the characteristic pharmacological e ects o smoke marijuana.
Cannabinoi receptors CB1 (mainly CNS) an CB2 (peripheral) have been i enti-
e an clone . An arachi onic aci erivative, anan ami e, has been propose as
an en ogenous ligan or CB receptors. While the physiological unction o these
receptors an their en ogenous ligan s are incompletely un erstoo , they are likely
to have important unctions because they are isperse wi ely with high ensities
in the cerebral cortex, hippocampus, striatum, an cerebellum.
b. What are the pharmacological e ects o marijuana?
T e pharmacological e ects o Δ-9- HC vary with the ose, route o a ministra-
tion, experience o the user, vulnerability to psychoactive e ects, an setting o use.
Intoxication with marijuana pro uces changes in moo , perception, an motiva-
tion, but the e ect most requently sought is the “high” an “mellowing out.” T is
e ect is escribe as i erent rom the high pro uce by a stimulant or opiate.
E ects vary with ose, but typically last ~2 hours. During the high, cognitive unc-
tions, perception, reaction time, learning, an memory are impaire . Coor ination
an tracking behavior may be impaire or several hours beyon the perception o
the high, with obvious implications or the operation o a motor vehicle an per or-
mance in the workplace or at school.
Marijuana also pro uces complex behavioral changes such as gi iness an
increase hunger. T ere are unsubstantiate claims o increase pleasure rom sex
an increase insight uring a marijuana high. Unpleasant reactions such as panic
or hallucinations an even acute psychosis may occur; several surveys in icate that
50 to 60% o marijuana users have reporte at least one anxiety experience. T ese
TABLE 14-8 Marijuana Withdrawal
reactions are seen commonly with higher oses an with oral ingestion rather than
Syndrome
smoke marijuana, because smoking permits the titration o ose accor ing to the
e ects. While there is no convincing evi ence that marijuana can pro uce a last- Restlessness
ing schizophrenia-like syn rome, association stu ies suggest a correlation o early Irritability
marijuana use with an increase risk o later eveloping schizophrenia. Numerous Mild agitation
clinical reports suggest that marijuana use may precipitate a recurrence o psycho- Insomnia
Sleep EEG disturbance
sis in people with a history o schizophrenia.
Nausea, cramping
263
SECTION II Neuropharmacology
KEY CONCEPTS
olerance to a drug is the reduction in response to the drug with repeated use.
Physical dependence is a state that develops as a result o tolerance to a drug
produced by a resetting o homeostatic mechanisms in response to repeated
drug use.
Withdrawal symptoms are characteristic or a given category o drugs and tend
to be opposite to the original e ects produced by the drug be ore tolerance
developed.
Addiction is usually characterized by compulsive drug-taking.
olerance, physical dependence, and withdrawal are biological phenomena and
in themselves do not imply that the individual is involved in misuse or addic-
tive behavior.
Fear o producing a medical addict o en results in needless su ering among
patients with pain due to limited use o appropriate medications.
Opioids should never be withheld rom patients with cancer out o ear o pro-
ducing addiction.
Abuse o combinations o drugs is common; alcohol is so widely available that
it is o en combined with all categories o abused drugs.
Patients with a history o alcohol- or other drug-abuse problems have an increased
risk or the development o benzodiazepine abuse and should rarely, i ever, be
treated with benzodiazepines on a chronic basis.
Smokers may be smoking to achieve the reward o nicotine e ects, to avoid the
pain o nicotine withdrawal, or most likely a combination o the two.
T e management o drug abuse and addiction must be individualized accord-
ing to the drugs involved and the associated psychosocial problems o the indi-
vidual patient.
SUMMARY QUIZ
QUESTION 14-2 A 28-year-old man has been taking the same dose o oxycodone or
several weeks as the result o a knee injury. He has not needed to increase his dose
o oxycodone to achieve analgesia. He develops irritability and muscle aches upon
abruptly stopping his oxycodone. T is is a demonstration o
a. physical dependence.
b. rst-pass metabolism.
c. tolerance.
d. an adverse e ect.
e. addiction.
alcohol concentration o 275 mg/dL. Within minutes o his blood being drawn he
develops a respiratory arrest and is intubated success ully. Because o tolerance to
alcohol’s sedative e ect the therapeutic index o alcohol in this patient is
a. increased.
b. decreased.
c. unchanged.
d. irrelevant.
e. negative rein orcement.
QUESTION 14-4 A 33-year-old woman who smokes 1 pack o cigarettes per day has
recently begun getting up at 3 AM to smoke a cigarette. T is is a demonstration o
a. positive rein orcement.
b. negative rein orcement.
c. insomnia.
d. depression.
e. increased therapeutic index o nicotine.
265
SECTION II Neuropharmacology
266
SECTION
Modulation of Cardiovascular
Function III
15. Drug T erapy o Hypertension, Edema,
and Disorders o Sodium and Water Balance 268
267
CHAPTER
Drug Therapyof Hypertension,
15 Edema, and Disorders of Sodium
and Water Balance
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN THIS
the section on hypertension in Chapter 27 Drug T erapy o Myocardial Ischemia and
CHAPTER Hypertension in Goodman & Gilman’s T e Pharmacological Basis of T erapeutics, 12th
• Acetazolamide (DIAMOX,others) Edition (pp 765-785), as well as material in Chapter 25 Regulation o Renal Volume
• β Adrenergicreceptor antagonists (many; and Vascular Volume and Chapter 26 Renin and Angiotensin In addition to the mate-
Table 15-1; see Chapter 7) rial presented here, the 12th Edition contains:
• Aliskiren (TEKTURNA) • T e molecular structures o drugs used to treat hypertension, edema, and other
• Amiloride (MIDAMOR, others) disorders o Na+ and water balance
• Amiloride/hydrochlorothiazide (generic) • Figure 25-1 T e anatomy and nomenclature o the nephron
• Amlodipine (NORVASC) • Figure 25-5 Changes in the extracellular uid volume and weight with diuretic therapy
• Bendro umethiazide (NATURETIN) • An extensive discussion o the unctions and e ects o the renin-angiotensin system
in Chapter 26
• Benzapril (LOTENSIN, others)
• Bumetanide (BUMEX,others) LEARNING OBJECTIVES
• Candesartan cilexetil (ATACAND) Understand the mechanisms o action o drugs used to treat hypertension,
• Captopril (CAPOTEN, others) edema, and other disorders o Na+ and water balance
• Chlorothiazide (DIURIL) Know the untoward e ects o drugs used to treat hypertension, edema, and
• Chlorthalidone (HYGROTON) other disorders o Na+ and water balance
• Clevidipine (CLEVIPREX) Know which patients should be treated and when treatment should be initiated
• Clonidine (CATAPRES, others) Know which drugs are most e ective in treating individual hypertensive
• Conivaptan (VAPRISOL) patients with speci c comorbidities, including diabetes mellitus, congestive
• Desmopressin acetate (1-deamino-8-d- heart ailure, and renal disease
arginine vasopressin, DDAVP, others) Know which drugs can be used in combination
• Diazoxide Know how to set treatment goals based on target blood pressures and other
• Dichlorphenamide (DARAMIDE) clinical measures
• Diltiazem(CARDIZEM)
• Doxazosin (CARDURA, others)
• Enalapril (VASOTEC, others) MECHANISMS OF ACTION OF DIURETICS
• Enalaprilat (VASOTECINJECTION, others) DRUG CLASS DRUG MECHANISM OF ACTION
• Eplerenone (INSPRA, others) Inhibitors o Carbonic Acetazolamide Inhibit carbonic anhydrase
• Ethacrynicacid (EDECRIN, others) Anhydrase Dichlorphenamide (CA) in the proximal tubule
Methazolamide resulting in abolition o
• Felodipine (PLENDIL) NaHCO3 reabsorption
• Fenoldopam(CORLOPAM) Inhibition o CA in the
collecting duct is a secondary
• Fosinopril (MONOPRIL, others)
site o action
• Furosemide (LASIX,others)
Osmotic Diuretics Glycerin Isosorbide Act at the loop o Henle
• Glycerin (OSMOGLYN) Mannitol (primary site o action) to
• Guanabenz(WYTENSIN) Urea diminish passive reabsorption
• Guanadrel o NaCl by reducing medullary
tonicity
• Guan acine (INTUNIV,TENEX) Act in the proximal tubule
• Human recombinant ANP(carperitide, (secondary site) by increasing
available onlyin Japan) the osmolality o tubular uid
thereby reducing luminal
• Human recombinant BNP(nesiritide, Na+ concentration and Na+
NATRECOR) reabsorption
(continues)
(Continued)
268
Drug Therapy of Hypertension and Na + Balance Disorders CHAPTER 1 5
• Normally~65%o ltered Na+ is reab- recommend diuretics as pre erred initial therapy or most patients with uncompli-
sorbed in the proximal tubule; this part o cated stage 1 hypertension who are unresponsive to nonpharmacological measures.
the tubule is highlypermeable to water. Patients also are commonly treated with other drugs (see able 15-2): β receptor
• Approximately25%o ltered Na+ is reab- antagonists, ACE inhibitors/A 1-receptor antagonists, and Ca2+ channel blockers.
sorbed in the loop o Henle. (Continued)
• The distal convoluted tubule activelytrans-
ports NaCl and is impermeable to water. TABLE 15-2 Classi cation o Antihypertensive Drugs by Their Primary Site or
Mechanism o Action
• The ine control o ultra iltrate
composition and volume takes place Diuretics
in the collecting duct. 1. Thiazides and related agents (hydrochlorothiazide, chlorthalidone, chlorothiazide,
indapamide, methylclothiazide, metolazone)
• The transport that occurs in a speci c 2. Loop diuretics ( urosemide, bumetanide, torsemide, ethacrynic acid)
segment o the nephron is primarily 3. K+-sparing diuretics (amiloride, triamterene, spironolactone)
determined bythe transporters present in
Sympatholytic drugs (see Chapter 7)
the epithelial cells and the whether they
1. β receptor antagonists (metoprolol, atenolol, betaxolol, bisoprolol, carteolol, esmolol,
are located on the luminal or basolateral nadolol, nebivolol, penbutolol, pindolol, propranolol, timolol)
membrane. 2. α receptor antagonists (prazosin, terazosin, doxazosin, phenoxybenzamine, phentolamine)
3. Mixed α-β receptor antagonists (labetalol, carvedilol)
4. Centrally acting adrenergic agents (methyldopa, clonidine, guanabenz, guan acine)
5. Adrenergic neuron blocking agents (guanadrel, reserpine)
Ca 2+ channel blockers (verapamil, diltiazem, nisoldipine, elodipine, nicardipine, isradipine,
amlodipine, clevidipine, ni edipine a)
PRINCIPLES OF DIURETIC
Angiotensin-converting enzyme inhibitors (captopril, enalapril, lisinopril, quinapril, ramipril,
ACTION benazepril, osinopril, moexipril, perindopril, trandolapril)
• Diuretics increase the rate o urine ow. AngII receptor antagonists (losartan, candesartan, irbesartan, valsartan, telmisartan,
• Clinicallyuse ul diuretics also increase the eprosartan, olmesartan)
rate o Na+ excretion (natriuresis), as well
Direct renin inhibitor (aliskiren)
as an anion such as Cl–.
• Most diuretics are used to reduce extracel- Vasodila tors
1. Arterial (hydralazine, minoxidil, diazoxide, enoldopam)
lular luid volume by decreasing total
2. Arterial and venous (nitroprusside)
NaCl content.
a
Extended-release ni edipine is approved or hypertension.
270
Drug Therapy of Hypertension and Na + Balance Disorders CHAPTER 1 5
Osmotic diuretics ++ + I + ++ + + + + I + NC - I
(loop o Henle)
Antagonists o + - - I - + (+) I I - NC NC NC NC
mineralocorticoid receptors
(late distal tubule, collecting
duct)
a
Except or uric acid, changes are or acute ef ects o diuretics in the absence o signi cant volume depletion, which would trigger complex
physiological adjustments.
H , titratable acid and NH4+.
b +
c
In general, these ef ects are restricted to those individual agents that inhibit carbonic anhydrase. However, there are notable exceptions in which
symport inhibitors increase bicarbonate and phosphate (eg, metolazone, bumetanide).
++, +, (+), -, NC, V, V(+), V(-), and I indicate marked increase, mild to moderate increase, slight increase, decrease, no change, variable ef ect,
variable increase, variable decrease, and insu cient data, respectively. For cations and anions, the indicated ef ects re er to absolute changes in
ractional excretion.
RBF, renal blood ow; GFR, glomerular ltration rate; FF, ltration raction; TGF, tubuloglomerular eedback; CA, carbonic anhydrase.
271
SECTION III Modulation o Cardiovascular Function
CO 2
Blood
out Colle cting Thiazide
CA duct
inhibito rs diure tic s
Thick sys te m
a s ce nding
limb
K+-s pa ring diure tic
Na +–K+–2Cl– symport inhibitors
Lo o p MR-MRA
(ina ctive ) MRA MRA
K+
diure tic s Nucle us
K +
MR-Aldo MR
K+ + Aldo Aldo
ATPa s e Na + mRNA
Na
Na + 2Cl – Symporte r 2Cl– (+)
Aldo-induce d prote ins
Cl– Cl–
K+
(+)
+ Na + Na +
K+ K
K+ Na + Na +
ATPa s e
2+ Re na l pa pilla
Ca K+ K+ K+
K+
Mg 2+
Na + c hanne l
inhibito rs
FIGURE 15-1 Summary o the site and mechanism o action o diuretics. Three important eatures o this summary gure are
worth special note. 1. Transport o solute across epithelial cells in all nephron segments involves highly specialized proteins,
which or the most part are apical and basolateral membrane integral proteins. 2. Diuretics target and block the action o epi-
thelial proteins involved in solute transport. 3. The site and mechanism o action o a given class o diuretics are determined by
the speci c protein inhibited by the diuretic. Aldo, aldosterone; CA, carbonic anhydrase; MR, mineralocorticoid receptor; MRA,
mineralocorticoid receptor antagonist.
FIGURE 15-2 Schematic portrayal o the 3 major physiological pathways regulating renin release. ACE, angiotensin-converting
enzyme; AngII, angiotensin II; AT1 R, angiotensin subtype 1 receptor; JGCs, juxtaglomerular cells; MD, macula densa; NE/Epi,
norepinephrine/epinephrine; NSAIDs, nonsteroidal anti-in ammatory drugs; PGI2/PGE2, prostaglandins I2 and E2.
272
Drug Therapy of Hypertension and Na + Balance Disorders CHAPTER 1 5
MECHANISMS OF ACTION OF INHIBITORS OF THE RENIN-ANGIOTENSIN SYSTEM (RAS; see Table 15-4)
DRUG CLASS DRUG MECHANISM OF ACTION
Angiotensin Converting Enzyme Captopril Prevent the conversion o AngI to active AngII by inhibiting angiotensin
Inhibitors (ACEIs) Enalapril converting enzyme (ACE), thus blocking AngII’s pressor responses and
Enalaprilat cardiovascular structural ef ects (see Figures 15-2, 15-3, and 15-4)
Lisinopril Note: Many o the drugs are ester-containing prodrugs that have better
Benzapril bioavailability than the active molecules (see Figure 26-9 rom Goodman &
Fosinopril Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition or
Trandolapril structures o drugs and prodrugs)
Quinapril
Ramipril
Moexipril
Perindopril
Angiotensin Receptor Blockers (ARBs) Candesartan cilexetil Competitive (but insurmountable) inhibitors o angiotensin AT1 receptors
Irbesartan (see Figures 15-2 and 15-4) that block AngII’s pressor responses and
Losartan cardiovascular structural ef ects (see Figure 15-3)
Olmesartan medoxomil Note: Some o the drugs are prodrugs that have better bioavailability
Telmisartan than the active molecules (see Figure 26-10 rom Goodman &Gilman’s The
Valsartan Pharmacological Basis of Therapeutics, 12th Edition or structures o drugs
and prodrugs)
Direct Renin Inhibitors (DRIs) Aliskiren Competitive inhibitor o renin preventing the conversion o
angiotensinogen to AngI (see Figures 15-2 and 15-4)
CASE 15 2
A 68-year-old woman is being treated with 25 mg o hydrochlorothiazide or her
hypertension During her most recent checkup, her blood pressure was 161/93 and
she was also diagnosed with type 2 diabetes
a. What changes should be made in her treatment?
T is patient has stage 2 hypertension (see able 15-1) and an important comorbid-
ity, type 2 diabetes mellitus. T e risk o cardiovascular disease, disability, and death
in hypertensive patients is increased markedly by concomitant cigarette smoking,
diabetes, or elevated low-density lipoprotein; the coexistence o hypertension with
(Continued)
PRC ↑ ↑ ↑ ↑ ↔ ↓
PRA ↓ ↑ ↑ ↑ ↔ ↓
AngI ↓ ↑ ↑ ↑ ↔ ↓
AngII ↓ ↓ ↑ ↑ ↔ ↓
ACE ↔ ↓ ↔
Bradykinin ↔ ↑ ↔
PRC, plasma renin concentration; PRA, plasma renin activity; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker.
273
SECTION III Modulation o Cardiovascular Function
DIURETIC THERAPY
Ang io te ns in II
• Diuretics are used to treat hypertension
(see Table 15-2), edema, or volume over-
load associated with various disease states
(see Figure 15-5). Alte re d Alte re d Alte re d
Pe riphe ral Re nal Cardiovas c ular
• Restriction o dietaryNa+ intake is also Re s is tanc e Func tio n S truc ture
important in reducing hypertension
and edema, but compliance can be
MECHANIS MS MECHANIS MS MECHANIS MS
problematic.
I. Dire ct e ffe ct to incre a s e Na +
• The pathophysiological mechanisms o I. Dire ct va s ocons triction
re a bs orption in proxima l
I. Non-he modyna mica lly-
me dia te d e ffe cts :
edema ormation and the e ects o diuret- II. Enha nce me nt of tubule . A. Incre a s e d expre s s ion of
proto-oncoge ne s
ics and dietaryNa+ restriction are shown in pe riphe ra l nora dre ne rgic II. Re le a s e of a ldos te rone
B. Incre a s e d production of
ne urotra ns mis s ion: from a dre na l cortex
Figure 15-5. A. Incre a s e d NE re le a s e (incre a s e d Na + re a bs orption
growth fa ctors
B. De cre a s e d NE re upta ke C. Incre a s e d synthe s is of
• An algorithm or treating edema in patients a nd incre a s e d K+ excre tion extra ce llula r ma trix
C. Incre a s e d va s cula r in dis ta l ne phron) prote ins
caused byrenal, hepatic, or cardiacdisor- re s pons ive ne s s
III. Alte re d re na l he modyna mics :
ders is shown in Figure 15-6. III. Incre a s e d sympa the tic A. Dire ct re na l va s ocons triction II. He modyna mica lly
B. Enha nce d nora dre ne rgic me dia te d e ffe cts :
dis cha rge (CNS )
• Diureticresistance to a less e ective ne urotra ns mis s ion in A. Incre a s e d a fte rloa d
(ca rdia c)
diureticsuch as a thiazide mayrequire sub- IV. Re le a s e of ca te chola mine s kidney
B. Incre a s e d wa ll te ns ion
from a dre na l me dulla C. Incre a s e d re na l sympa the tic
stituting with a more ef cacious drug such tone (CNS ) (va s cula r)
• NSAIDcoadministration, which reduces the Ra pid Pre s s or Re s pons e S low Pre s s or Re s pons e
Va s cula r a nd Ca rdia c
production o prostaglandins (especially Hypertrophy and Remodeling
PGE2), is a common cause o diureticresis-
FIGURE 15-3 Summary o the 3 major ef ects o AngII and the mechanisms that mediate them.
tance that can be prevented. NE, norepinephrine.
• There are several options available to over-
come resistance to loop diuretics:
» Bed rest to increase renal circulation
» Increasing dose o the diureticto the
ceiling dose these risk actors increases cardiovascular morbidity and mortality to a degree
» Administering smaller doses more that is compounded by each additional risk actor. Because the purpose o treating
requently hypertension is to decrease cardiovascular risk, other dietary and pharmacological
interventions may be required to treat these comorbid conditions. ACE inhibitors/
» Continuous intravenous in usion
A 1-receptor antagonists should be rst-line drugs in the treatment o diabetics
» Combination therapywith 2 diuretics with hypertension in view o these drugs’ well-established bene ts in slowing the
with di erent sites o action (eg, a development and progression o diabetic glomerulopathy.
thiazide and loop diuretic), although
patients should be monitored to b. How would this patient’s treatment di er i she did not have diabetes?
avoid serious complications such as Patients with uncomplicated stage 2 hypertension will likely require a diuretic and
hyponatremia, hypokalemia, and another drug rom a di erent class. Subsequently, doses can be titrated upward and
volume depletion additional drugs added to achieve goal blood pressures (blood pressure <140/90 mm
» Reducing salt intake Hg in uncomplicated patients). Some o these patients may require our di erent
drugs to reach the goal.
» Administering diuretics shortly
be ore ood intake to ensure e ective c. T is patient is prescribed enalapril in addition to her hydrochlorothiazide. What
concentrations o diureticin the tubule adverse e ects are possible that the patient should be counseled to be aware o ?
lumen when salt load is highest T ere are several cautions in the use o ACE inhibitors such as enalapril in patients
with hypertension. Following the initial dose o an ACE inhibitor, there may be a
considerable all in blood pressure in some patients; this response to the initial dose
is a unction o plasma renin activity prior to treatment. T e potential or a large
initial drop in blood pressure is the reason or using a low dose to initiate therapy,
especially in patients who may have a very active RAS supporting blood pressure,
such as patients with diuretic-induced volume contraction or congestive heart ailure.
(Continued)
274
Drug Therapy of Hypertension and Na + Balance Disorders CHAPTER 1 5
Ang io te ns ino g e n
PHYSIOLOGICAL FACTORS
AND PHARMACOLOGICAL
DRI Re nin
AGENTS REGULATING
RENIN RELEASE
Ang io te ns in I (1-10) se e Figure 15-2)
As p-Arg-Va l-Tyr-Ile -His -Pro-P he -His -Le u • Physiological actors
Bra dykinin 1 2 3 4 5 6 7 8 9 10
» Arterial blood pressure (intrarenal
chyma s e baroreceptor pathway)
ACE ACE-I ACE
» Dietarysalt intake (macula densa
pathway)
Ina ctive
pe ptide s Ang io te ns in II (1-8) » Activation o the sympatheticnervous
system(β adrenergicreceptor pathway)
ARB
» Prostaglandins (PGI2/PGE2)
» Activation o juxtaglomerular
AT1 angiotensin AT1 receptors
• Pharmacological agents
FIGURE 15-4 Inhibitors o the RAS. ACE-I, angiotensin-converting enzyme inhibitor; ARB, » Loop diuretics
angiotensin receptor blocker; DRI, direct renin inhibitor. » Nonsteroidal anti-in ammatoryagents
(NSAIDs)
» ACEinhibitors, ARBs, and renin
inhibitors
» Centrallyacting sympatholyticdrugs
1
» β Adrenergicblockers
DIURETICS
n
o
i
e
+
t
t
MABP MABP
e
a
a
r
N
R
c
x
E
MABP “S e ns e d” ECFV
ECFV
te a h )
)
st n
(=
n
e o
rs c e e r
c o rc u n o
io
g ti
p de
tit
e m
(= c Ve
ia
l
2 5
i
Ne t ∆ Na + = Na + inta ke
l
die ta ry 6
c
Othe r
o
y
Na + – Na + excre tion
r
m
los s e s
a
4 Tota l
)
p
O
n
a
s
– othe r los s e s
a
inta ke
o
g
t
m
(e g , swe a t,
h
r
m
ECFV
n
t
e
e
m
u
l
fe ce s, e tc.)
d
r
u
L
e
e
p
n
=
t
s
3
(
H2 O inta ke
(=
Na + Th irs
t
Psc a
cae
ivrte
re s triction Ne t ∆ Na +
iitotsy
∆ ECFV
n)
ADH
e
a
me ch
l
a n is m H2 O excre tion
FIGURE 15-5 Interrelationships among renal unction, Na+ intake, water homeostasis, distribu-
tion o extracellular uid volume, and mean arterial blood pressure. Pathophysiological mecha-
nisms o edema ormation. 1. Rightward shi t o renal pressure natriuresis curve. 2. Excessive
dietary Na+ intake. 3. Increased distribution o extracellular uid volume (ECFV) to peritoneal cavity
(eg, liver cirrhosis with increased hepatic sinusoidal hydrostatic pressure) leading to ascites orma-
tion. 4. Increased distribution o ECFVto lungs (eg, le t-sided heart ailure with increased pulmonary
capillary hydrostatic pressure) leading to pulmonary edema. 5. Increased distribution o ECFVto
venous circulation (eg, right-sided heart ailure) leading to venous congestion. 6. Peripheral edema
caused by altered Starling orces causing increased distribution o ECFVto interstitial space (eg,
diminished plasma proteins in nephrotic syndrome, severe burns, and liver disease).
275
SECTION III Modulation o Cardiovascular Function
C r
C
> l
< 50
0
5
50
a dd a dd
A
d
d
K+-s pa ring diure tic: Thia zide diure tic:
If CrCl > 75 & urina ry [Na ]:[K] ra tio is < 1 CrCl >50, us e 25 to 50 mg/d HCTZ
(Note : May a dd K+-s pa ring diure tic to loop CrCl 20 to 50, us e 50 to 100 mg/d HCTZ
a nd/or thia zide diure tic a t a ny point in a lgorithm CrCl <20, us e 100 to 200 mg/d HCTZ
for K+ home os ta s is.)
While ma inta ining othe r diure tics, switch loop a ge nt to continuous infus ion
FIGURE 15-6 “Brater’s algorithm” or diuretic therapy o chronic renal ailure, nephrotic syndrome,
congestive heart ailure, and cirrhosis. Follow algorithm until adequate response is achieved. I
adequate response is not obtained, advance to the next step. For illustrative purposes, the thi-
azide diuretic used in Brater’s algorithm is hydrochlorothiazide (HCTZ). An alternative thiazide-type
diuretic may be substituted with appropriate dosage adjustment so as to be pharmacologically
equivalent to the recommended dose o HCTZ. Do not combine two K+-sparing diuretics because of
the risk of hyperkalemia. CrCl indicates creatinine clearance in mL/min, and ceiling dose re ers to the
smallest dose o diuretic that produces a near-maximal ef ect. Ceiling doses o loop diuretics and
dosing regimens or continuous intravenous in usions o loop diuretics are disease-state-speci c.
Doses are or adults only.
With continuing treatment, there usually is a progressive all in blood pressure that in
most patients does not reach a maximum or several weeks.
ACE inhibitors not only prevent conversion o angiotensin I (AngI) to AngII, but
also block degradation o bradykinin and substance P. T e increase in bradykinin
and substance P can give rise to a common (5-20% o patients) adverse e ect, dry
cough, and may also contribute to the less requent (0.1-0.5%) occurrence o angio-
edema. Angioedema is a rare but serious and potentially atal adverse e ect o the
ACE inhibitors. Patients starting treatment with these drugs should be explicitly
warned to discontinue their use with the advent o any signs o angioedema; once
ACE inhibitors are stopped, angioedema disappears within hours. AngII receptor
antagonists have a reduced risk o dry cough and angioedema and can be used as
alternative RAS inhibitors in patients who cannot tolerate the dry cough or who
develop angioedema.
T e attenuation o aldosterone production by ACE inhibitors also in uences K+
homeostasis. T ere is only a very small and clinically unimportant rise in serum K+
when these agents are used alone in patients with normal renal unction. However,
substantial retention o K+ can occur in some patients with renal insu ciency or
diabetes. Furthermore, the potential or developing hyperkalemia should be con-
sidered when ACE inhibitors are used with other drugs that can cause K+ retention,
including the K+-sparing diuretics (amiloride, triamterene, and spironolactone),
NSAIDs, K+ supplements, and β receptor antagonists. Some patients with diabetic
nephropathy may be at greater risk o hyperkalemia.
276
Drug Therapy of Hypertension and Na + Balance Disorders CHAPTER 1 5
α1 Adrenergic Receptor Prazosin Block α2 adrenergic receptors in arteriolar and venous vascular smooth muscle
Antagonists Terazosin reduces arteriolar resistance and increases venous capacitance, respectively
Doxazosin
Centrally Acting Adrenergic Methyldopa Converted to α-methylnorepinephrine and stored in central adrenergic
Agents—Methyldopa neurons; it inhibits adrenergic neuronal out ow rom the brainstem to the
peripheral sympathetic nervous system
Centrally Acting Adrenergic Clonidine Stimulate the α2A subtype o α2 adrenergic receptors in the brainstem,
Agents—α2 Adrenergic Guanabenz reducing sympathetic out ow rom the CNS
Receptor Antagonists Guan acine
Adrenergic Neuron Blocking Guanadrel Guanadrel acts as a alse (inactive) neurotransmitter in postganglionic
Agents Reserpine adrenergic neurons
Reserpine acts at central and peripheral adrenergic neurons to delete
catecholamines
Nondihydropyridines Verapamil Inhibit L-type voltage-gated Ca2+ channels in arteriolar vascular smooth
Diltiazem resulting in smooth muscle relaxation
The nondihydropyridine calcium channel blockers also inhibit L-type Ca2+
channels in heart, thereby lowering cardiac output by ef ects on SA node
(bradycardia) and reduced contractility
CASE 15 3
A 31-year-old woman is being treated or mild hypertension with valsartan and hydro-
chlorothiazide She is in good health and becomes pregnant
a. Are the drugs she is taking or her hypertension sa e in pregnancy?
All o the thiazide-like drugs cross the placenta, but they have not been shown to
have direct adverse e ects on the etus. However, ACE inhibitors, A 1-receptor
antagonists, and the direct renin inhibitor, aliskiren, are teratogenic and should be
discontinued as soon as pregnancy is detected.
b. What changes in her drug therapy should be made?
T is woman had chronic hypertension prior to her pregnancy, but is considered
low risk because she had mild hypertension with no evidence o organ damage. o
minimize risk to the etus, she should not receive an antihypertensive drug unless
(Continued)
277
SECTION III Modulation o Cardiovascular Function
No a ntihype rte ns ive drugs Hos pita liza tion a t initia l vis it
Ultra s ound e xa mina tion a t 16-20 wk, Antihype rte ns ive drugs a re ne e de d to ke e p s ys tolic be low
re pe a t a t 30-32 wk, a nd 140 a nd dis a tolic be low 90 mm Hg
monthly a fte r tha t until te rm
Ultra s ound e xa mina tion a t 16-20 wk, re pe a t a t
28 wk a nd the n e ve ry 3 wk until de live ry
2. If pre e cla mps ia de ve lops , if a nti- 1. Hos pita liza tion if the re is e xa ce rba tion to s e ve re
hype rte ns ive drugs a re us e d, or if hype rte ns ion, if the re is pre e cla mps ia , or if the re is
the re is a bnorma l fe ta l growth, e vide nce of a bnorma l fe ta l growth
the n be gin imme dia te fe ta l te s ting
with nons tre s s te s t or biophys ica l 2. Fre que nt e va lua tion of ma te rna l a nd fe ta l we ll-be ing
profile . Continue s e ria l te s ting
until de live ry 3. Cons ide r de live ry a t 36-37 wk
FIGURE 15-7 Algorithm or the management o pregnant women with chronic hypertension.
(Reproduced with permission from Sibai BM. Chronic hypertension in pregnancy. Obstet Gynecol.
2002;100:369-377.)
her systolic blood pressure exceeds 160 mm Hg or her diastolic pressure exceeds
110 mm Hg (see Figure 15-7). I her blood pressure exceeds these values, methyl-
dopa is the drug o choice because o its record o sa ety and e cacy. Hydralazine
and a β-adrenergic blocker such as labetalol can also be used. Patients at high risk
or who develop hypertension during pregnancy should be managed according to
the algorithm shown in Figure 15-7.
CASE 15 4
A 68-year-old man has taken diltiazem or his hypertension and his chronic angina
or more than 5 years He su ers a mild myocardial in arction and during his stay in
the hospital, he is taken o diltiazem and placed on a regimen that includes captopril,
carvedilol, and aspirin
a. What is the rationale or taking this patient o diltiazem?
Diltiazem is a calcium channel blocker that is e ective in treating hypertension
and stable angina because o its e ects on relaxing vascular smooth muscle, thus
reducing arterial blood pressure and dilating coronary arteries. Its calcium chan-
nel blocking activity also reduces cardiac output by slowing heart rate and lowering
cardiac contractility. Because o its negative inotropic e ects, it can impair cardiac
output during and af er a myocardial in arction.
(Continued)
278
Drug Therapy of Hypertension and Na + Balance Disorders CHAPTER 1 5
b. What is the rationale or placing this patient on captopril during his stay in
the hospital?
T e bene cial e ects o ACE inhibitors in acute myocardial in arction are particu-
larly large in hypertensive and diabetic patients. Unless contraindicated (eg, cardio-
genic shock or severe hypotension), ACE inhibitors should be started immediately
during the acute phase o myocardial in arction and can be administered along
with thrombolytics, aspirin, and β adrenergic receptor antagonists. In high-risk
patients (eg, large in arct, systolic ventricular dys unction), ACE inhibition should
be continued long term. One o the bene ts o long-term ACE inhibitor therapy is
to inhibit AngII-stimulated remodeling o the cardiovascular system, which causes
hypertrophy o vascular and cardiac cells and increased synthesis and deposition o
collagen by cardiac broblasts (see Figure 15-3). T is remodeling process is thought
to be an important eature in the development o chronic heart ailure. Current rec-
ommendations are to use ACE inhibitors as rst-line agents or the treatment o heart
ailure and to reserve ARBs or treatment o heart ailure in patients who cannot tol-
erate or have an unsatis actory response to ACE inhibitors.
c. Within an hour o starting the patient on captopril, he begins to notice swelling
in his nose, throat, mouth, glottis, larynx, lips, and tongue. What is likely to be
causing this adverse e ect and how can it be reversed?
T e patient is experiencing angioedema, which is caused by an increase in circu-
lating bradykinin. A small number o patients receiving ACE inhibitors experi-
ence angioedema that results rom inhibition o ACE, the enzyme that degrades
bradykinin and substance P. o reverse the drug’s e ect, the ACE inhibitor should
be stopped, and the angioedema will disappear within hours. While the e ects o
the angioedema are diminishing, the patient’s airway should be protected, and i
necessary, epinephrine, an antihistamine, and/or a glucocorticoid should be admin-
istered. A rican Americans have a 4.5 times greater risk o ACE inhibitor–induced
angioedema than Caucasians. Although rare, angioedema o the intestine (visceral
angioedema) characterized by emesis, watery diarrhea, and abdominal pain also
has been reported. As an alternative to an ACE inhibitor in this patient, an ARB
such as valsartan can be substituted. T e incidence o angioedema with ARBs is
much lower than with ACE inhibitors. Valsartan is approved or heart ailure and
to reduce cardiovascular mortality in clinically stable patients with lef ventricular
ailure or lef ventricular dys unction ollowing myocardial in arction.
d. What is the rationale or starting this patient on carvedilol?
β Adrenergic receptor antagonists that do not have intrinsic sympathomimetic
activity (ie, partial agonists) improve mortality in myocardial in arction patients.
T ey should be started early and continued inde nitely in patients who can toler-
ate them. Carvedilol is a mixed α–β receptor antagonist that is approved or use in
patients with lef ventricular dys unction.
MECHANISMS OF ACTION OF VASOPRESSIN RECEPTOR AGONISTS AND ANTAGONISTS (see Figure 15-8)
DRUG CLASS DRUG MECHANISM OF ACTION
Vasopressin Agonist—V1 Receptor Agonists Vasopressin Activate V1 receptors in GI and vascular smooth muscle to cause contraction
Terlipressin
Vasopressin Agonist—V2 Receptor Agonist Desmopressin Activate V2 receptors in collecting duct to increase water permeability (antidiuresis)
Activate extrarenal V2 receptors on vascular endothelium to release procoagulant
actor VIII and von Willebrand actor
Vasopressin Antagonists—Selective V2 Tolvaptan Inhibit V2 receptors in collecting duct to increase ree water excretion without
Receptor (V2R) Antagonists (“Aquaretics”) excretion o electrolytes
Vasopressin Antagonists—Nonselective V1aR/ Conivaptan Inhibit V2 receptors in collecting duct to increase ree water excretion without
V2R Antagonist (“Aquaretics”) excretion o electrolytes
Inhibition o V1a receptors in mesangial cells and vascular smooth muscle cells
o vasa recta and ef erent arteriole acts to increase inner medullary blood ow
279
SECTION III Modulation o Cardiovascular Function
Ra pid de cre a s e
in inne r V1a Re ce ptor Vas o pre s s in
me dulla ry
blood flow
V2 Re c e pto r
Ra pid a ctiva tion
of VRUT in a pica l
me mbra ne of IMCD
FIGURE 15-8 Mechanisms by which vasopressin increases the renal conservation o water. Gray
and black arrows denote major and minor pathways, respectively. IMCD, inner medullary collect-
ing duct; TAL, thick ascending limb; VRUT, vasopressin-regulated urea transporter.
CASE 15 5
A 74-year-old male patient with heart ailure is hospitalized because o signi cant pul-
monary edema that is impairing his breathing He is receiving valsartan and urosemide
a. What are the mechanisms o action o these agents?
Valsartan is an angiotensin receptor blocker (ARB) that lowers blood pressure and
prevents vascular and cardiac remodeling by blocking the e ects o AngII on A 1
receptors (see Figure 15-3). It has been shown to reduce morbidity and mortality in
patients with heart ailure. Furosemide is a highly e cacious diuretic that inhibits
the Na+-K+-2Cl– symporter in the thick ascending limb o the loop o Henle; hence,
it is termed a loop diuretic.
b. What additional agent(s) might be added to improve natriuresis and improve
hemodynamics?
An agent that might be use ul in this patient is nesiritide which is recombinant
human B-type natriuretic peptide (BNP). BNP is an endogenous peptide released
by cardiac ventricular muscle when it is stretched. BNP activates natriuretic peptide
receptors on the sur ace o epithelial cells in the inner medullary collecting duct
which stimulates the ormation o cyclic GMP that subsequently inhibits the cyclic
nucleotide-gated nonspeci c cation channel (CNGC); the CNGC is the primary
channel or Na+ entry in these cells. BNP also relaxes vascular smooth muscle and
lowers vascular resistance.
Eplerenone might also be use ul in this patient. It is a diuretic that acts on the
mineralocorticoid receptor to blocks the synthesis o aldosterone-induced proteins
(AIPs) in epithelial cells in the late distal tubule and collecting duct. It has been
(Continued)
280
Drug Therapy of Hypertension and Na + Balance Disorders CHAPTER 1 5
shown to reduce morbidity and mortality in patients when added to other agents in
patients with moderate to severe heart ailure. However, because it is a K+-sparing
diuretic, it could cause hyperkalemia when used in combination with valsartan.
c. A er several days in the hospital, the patient still has signif cant edema, but
he has become hyponatremic. What agent might be use ul in causing diuresis
without loss o Na+?
A vasopressin receptor antagonist such as tolvaptan or conivaptan might be used
to induce diuresis without signi cant loss o Na+. T ese agents are re erred to as
aquaretics because they can increase renal- ree water excretion without corresponding
loss o Na+ as with diuretics such as urosemide.
olvaptan is a selective oral V2R antagonist that is approved or clinically sig-
ni cant hypervolemic and euvolemic hyponatremia. T e drug is labeled with a
black box warning against too rapid correction o hyponatremia (can have serious
and atal consequences) and the recommendation to initiate therapy in a hospital
setting capable o close monitoring o serum Na+. olvaptan is contraindicated in
patients receiving drugs that inhibit CYP3A4.
Conivaptan is a nonselective V1aR/V2R antagonist that is FDA approved or the
treatment o hospitalized patients with euvolemic hyponatremia and hypervol-
emic hyponatremia. T e drug is available only or intravenous in usion. In CHF
patients, conivaptan increases renal ree water excretion without a change in
systemic vascular resistance.
KEY CONCEPTS
Nonpharmacological approaches to treat moderately elevated blood pressure
may be suf cient in many patients and can augment the e ects o antihyperten-
sive drugs
Choice o antihypertensive drugs or individual patients may be complex and
should be driven by the likely bene t to patient, taking into consideration the
patient’s concomitant diseases, adverse e ects o speci c drugs, and cost
Diuretics are pre erred as initial therapy or most patients with uncomplicated
stage 1 hypertension who are unresponsive to nonpharmacological approaches,
although patients are also commonly treated with other drugs: β receptor
antagonists, ACE inhibitors/A 1 receptor antagonists, and Ca2+ channel
blockers
Patients with congestive heart ailure should ideally be treated with a diuretic,
β receptor antagonist, ACE inhibitor/A 1 receptor antagonist, and (in selected
patients) spironolactone
ACE inhibitors or A 1 receptor antagonists should be rst-line drugs in the
treatment o diabetics with hypertension
o achieve stringent control o hypertension, many patients require 2, 3, or 4
appropriately selected drugs used at optimal doses
SUMMARY QUIZ
QUESTION 15-2 A 55-year-old woman who begins taking amlodipine to lower her
blood pressure develops edema in her ankles a er several weeks o taking the drug
What is causing the edema?
a T e reduced blood pressure is causing reduced water excretion by the kidneys
b Amlodipine has direct e ects on the kidney to reduce water excretion
c Amlodipine increases capillary hydrostatic pressure by dilating precapillary arteri-
oles without dilating postcapillary vessels
d T e edema is unrelated to the pharmacological e ects o the drug
QUESTION 15-3 An elderly man with stage 2 hypertension is taking valsartan and
hydrochlorothiazide He also takes ibupro en or his arthritis He monitors his blood
pressure daily, and tells you that his blood pressure is o en greater than 140/90 What
is likely causing these high blood pressure readings?
a T e valsartan-hydrochlorothiazide combination is known to be ine ective
b T e ibupro en is reducing the e ectiveness o the antihypertensives
c He is probably not using the blood pressure cu correctly
d He is probably not taking his antihypertensive drugs as prescribed
QUESTION 15-5 A 71-year-old man with chronic renal ailure with edema has been
titrated up to the maximal single daily dose o bumetanide, but he still has signi cant
edema What option should initially be considered to reduce the edema?
a Increase the single dose o bumetanide above the ceiling dose
b Increase the requency o dosing o bumetanide
c Add a K+-sparing diuretic
d Add a thiazide diuretic
e Begin IV in usion o bumetanide
282
Drug Therapy of Hypertension and Na + Balance Disorders CHAPTER 1 5
QUESTION 15-3 Answer is b. It is most likely that ibupro en is opposing the actions
o the antihypertensive drugs NSAIDs are known to reduce the e ectiveness o many
antihypertensive drugs, especially those that inhibit the renin-angiotensin system (see
Figure 15-2) It is also possible that the patient is not adherent to his antihypertensive
medications, or his salt intake is excessive Another possibility is that other drugs,
including over-the-counter drugs or herbal preparations, are the cause For example,
NSAIDs, sympathomimetic decongestants, cyclosporine, erythropoietin, ephedra (ma
huang), and licorice are known to reduce the e ectiveness o many antihypertensive
drugs Be ore changing medications or altering dosing it is important to identi y and
eliminate, i possible, causes o the resistant hypertension
QUESTION 15-4 Answer is a. Both aliskiren, a direct renin inhibitor, and triamterene,
a K+-sparing diuretic, can increase plasma K+ concentrations When used in combina-
tion they can be additive in their e ects and can cause hyperkalemia
QUESTION 15-5 Answer is b. Patients with chronic renal ailure and other disease
states o en require aggressive diuretic therapies to control edema Figure 15-6
illustrates “Brater’s algorithm” or diuretic therapy in various disease states including
chronic renal ailure According to the algorithm, the next step a er titrating the single
daily dose o a loop diuretic up to the ceiling dose is to increase the requency o
dosing In the case o bumetanide, the algorithm recommends increasing the requency
o the ceiling dose to 4X daily Nothing is gained by increasing a single dose above
the ceiling dose (the dose that gives near maximal e ect or a given disease state) A
K+-sparing diuretic can be added to the loop diuretic to maintain K+ homeostasis and
may improve therapeutic response T e next step in the algorithm is to add a thiazide
diuretic which may result in a synergistic interaction T e last step in the algorithm
is to switch to continuous in usion o the loop diuretic while maintaining the
other diuretics
SUMMARYTABLE: DRUGS USED IN THE TREATMENT OF HYPERTENSION, EDEMA, AND DISORDERS OF NA+ AND
WATER BALANCE
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Diuretics—Inhibitors o Acetazolamide Edema when used in combination Most adverse ef ects, Sul onamide-related
Carbonic Anhydrase with other diuretics contraindications, and toxicities, including bone
Prophylaxis and treatment o drug interactions are marrow suppression, skin
high-altitude sickness secondary to urinary toxicities, renal lesions, and
Familial periodic paralysis alkalinization or metabolic allergic reactions
Correcting metabolic alkalosis, acidosis At high doses, drowsiness
especially diuretic-induced H+ and paresthesias
excretion
283
SECTION III Modulation o Cardiovascular Function
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Diuretics—Inhibitors Furosemide Hypertension (although short t1/2 Overzealous use o loop Ototoxicity (including
o Na+-K+-2Cl– Symport Bumetanide limits use) diuretics can cause hearing loss and vertigo) is
(Loop Diuretics, High- Ethacrynic acid Chronic congestive heart ailure serious depletion o usually reversible
Ceiling Diuretics) Torsemide to reduce venous and pulmonary total-body Na+ Irreversible ototoxicity can
congestion I dietary K+ intake is not occur at high doses, with
Acute pulmonary edema su cient, hypokalemia rapid IVadministration,
Edema o nephrotic syndrome, may develop increasing and during concomitant
chronic kidney disease, and liver the risk o arrhythmias therapy with other drugs
cirrhosis known to be ototoxic
Hyperuricemia,
hyperglycemia, and
dyslipidemia
Contraindicated in severe
hyponatremia and volume
depletion, hypersensitivity
to sul onamides (only the
sul onamide-based agents)
Diuretics—Inhibitors Bendro umethiazide Widely used or the treatment I dietary K+ intake is not Most serious adverse
o Na+-Cl– Symport Chlorothiazide o hypertension either alone su cient, hypokalemia ef ects o thiazides are
(Thiazide and Thiazide- Hydrochlorothiazide or in combination with other may develop increasing related to abnormalities
Like Diuretics) Hydro umethiazide antihypertensive drugs (can have the risk o arrhythmias o uid and electrolyte
Methyclothiazide additive or synergistic ef ects Hypokalemia can balance (extracellular
Polythiazide when used in combination with increase risk o atal volume depletion,
Trichlormethiazide other classes) arrhythmias when used hypotension, hypokalemia,
Chlorthalidone Best initial therapy or in combination with hyponatremia,
Indapamide uncomplicated hypertension quinidine (see Chapter 18) hypochloremia, metabolic
Metolazone Edema associated with heart alkalosis, hypomagnesemia,
Quinethazone ailure, hepatic cirrhosis, and hypercalcemia, and
renal disease (except when GFR hyperuricemia)
is <30-40 mL/min) Thiazide diuretics have
Ca2+ nephrolithiasis caused atal or near- atal
Treatment o nephrogenic hyponatremia
diabetes insipidus by increasing Impaired glucose
proximal tubular water tolerance, dyslipidemias
reabsorption (secondary to Contraindicated in
volume contraction) and by patients with sul onamide
blocking the ability o the hypersensitivity
distal convoluted tubule to
orm dilute urine
Diuretics—Inhibitors Triamterene and xed Used in combination with thiazide Nausea, vomiting, Li e-threatening
o Renal Epithelial Na+ dose combination and loop diuretics to augment diarrhea, and headache hyperkalemia, thus
Channels (K+-sparing triamterene/ diuresis and antihypertensive contraindicated in patients
Diuretics) hydrochloro-thiazide ef ects and of set the kaliuretic with hyperkalemia or those
ef ects o the thiazide and loop at risk o hyperkalemia
diuretics
Amiloride and xed Used in combination with thiazide Nausea, vomiting, leg Li e-threatening
dose combination and loop diuretics to augment cramps, and dizziness hyperkalemia, thus
amiloride/ diuresis and antihypertensive contraindicated in patients
hydrochlorothiazide ef ects, and of set the kaliuretic with hyperkalemia or those
ef ects o the thiazide and loop at risk o hyperkalemia
diuretics
284
Drug Therapy of Hypertension and Na + Balance Disorders CHAPTER 1 5
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Diuretics—Mineralo- Spironolactone Similar to other K+-sparing Can bind to other steroid Li e-threatening
corticoid Receptor Eplerenone diuretics, spironolactone is o ten receptors and may hyperkalemia, thus
Antagonists (Aldosterone co-administered with thiazide or cause gynecomastia, contraindicated in patients
Antagonists, K+-Sparing loop diuretics to treat edema and impotence, decreased with hyperkalemia or those
Diuretics) hypertension libido, hirsutism, and at risk o hyperkalemia
Spironolactone is the diuretic o menstrual irregularities Contraindicated in patients
choice in patients with hepatic Can induce diarrhea and with peptic ulcers
cirrhosis other gastric disturbances
When added to standard therapy, Can cause CNS ef ects
morbidity and mortality are such drowsiness, ataxia,
reduced in patients with heart and headache
ailure (see Chapter 17)
Angiotensin Converting Captopril Treatment o hypertension as Hypotension, especially May cause hyperkalemia in
Enzyme Inhibitors (ACEIs) Enalapril monotherapy or in combination in patients with elevated patients taking K+-sparing
Enalaprilat with a Ca2+ channel blocker, plasma renin activity diuretics, K+ supplements,
Lisinopril β adrenergic blocker, or diuretic Dry cough (5-20% β receptor blockers, or
Benzapril Prevention or delay o heart o patients) due to NSAIDs
Fosinopril ailure in patients with systolic accumulation o Acute renal ailure in
Trandolapril dys unction bradykinin, substance P patients with reduced renal
Quinapril Prevention o cardiovascular and/or prostaglandins in per usion
Ramipril events in patients with acute the lungs Patients who are pregnant
Moexipril myocardial in arction and in should discontinue
Perindopril patients who are high risk o ACEIs due to teratogenic
cardiovascular events potential
Prevention or delay o renal Angioedema (0.1-0.5% o
disease in patients with type 1 patients)
diabetes mellitus
Angiotensin Receptor Candesartan cilexetil Treatment o hypertension as Hypotension in patients Hyperkalemia in patients
Blockers (ARBs) Irbesartan monotherapy or in combination whose blood pressure is with renal disease or those
Losartan with a Ca2+ channel blocker, β highly dependent on the taking K+-sparing diuretics
Olmesartan medoxomil adrenergic blocker, or diuretic RAS or with combination or K+ supplements
Telmisartan Irbesartan and losartan therapy with other Acute renal ailure in
Valsartan are approved or diabetic antihypertensive drugs patients with reduced renal
nephropathy Incidence o cough is per usion
Losartan is approved or stroke lower than ACEIs Incidence o angioedema is
prophylaxis lower than ACEIs
Valsartan is approved or Patients who are pregnant
heart ailure and to reduce should discontinue
cardiovascular events in patients ARBs due to teratogenic
with le t ventricular dys unction potential
ollowing myocardial in arction
285
SECTION III Modulation o Cardiovascular Function
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Direct Renin Aliskiren Treatment o hypertension as Mild GI symptoms at Not recommended in
Inhibitors (DRIs) monotherapy or in combination high doses pregnant patients
with other antihypertensive Incidence o cough and
agents, particularly with ACE angioedema less than
inhibitors or ARBs (which increase with ACE inhibitors
plasma renin activity; see Table 15-2)
Cardioprotective and
renoprotective in combination
therapy
Recommended in patients
intolerant to other antihypertensive
drugs or or urther blood pressure
control
β Adrenergic Receptor Many (see Table 15-2 Ef ective therapy or all grades o Should be avoided in Risk o hypoglycemic
Antagonists and Chapter 7) hypertension as monotherapy or patients with reactive reactions may be increased
in combination with other agents airway disease (asthma) in diabetics taking insulin
Highly pre erred or hypertensive or with SA or AVnodal Sudden discontinuation
patients with conditions such dys unction or in can cause rebound
as MI, ischemic heart disease, or combination with other hypertension; dosage
congestive heart ailure drugs that inhibit AV should be tapered
conduction, such as gradually over 10-14 days
verapamil prior to discontinuation
α1 Adrenergic Receptor Prazosin Not recommended as First-dose phenomenon Patients with pheo-
Antagonists Terazosin monotherapy or hypertensive (in up to 50% o patients) chromocytoma can have a
Doxazosin patients in which symptomatic vasoconstrictor response to
Used primarily in conjunction with orthostatic hypotension epinephrine resulting rom
diuretics, β blockers, and other occurs within 30-90 activation o unblocked
antihypertensive agents minutes (or longer) o the vascular α2 adrenergic
Use ul or hypertensive patients initial dose o the drug or receptors
with benign prostatic a ter a dosage increase
hyperplasia because they also
improve urinary symptoms
Centrally Acting Methyldopa Current use largely limited to Transient sedation May precipitate severe
Adrenergic treatment o hypertension in Diminution in psychic bradycardia and sinus arrest
Agents—Methyldopa pregnancy, where it has a record energy may persist, Hepatotoxicity, sometimes
or sa ety depression occurs associated with ever
occasionally >20% o patients who
Dryness o the mouth receive methyldopa or
Diminished libido a year develop a positive
Parkinsonian signs Coombs test and 1-5% o
Hyper-prolactinemia that these patients will develop
may cause gynecomastia a hemolytic anemia
and galactorrhea that requires prompt
discontinuation o the drug
Centrally Acting Clonidine No xed place or these drugs in Sedation and xerostomia Symptomatic bradycardia
Adrenergic Agents—α2 Guanabenz the treatment o hypertension are prominent and sinus arrest in patients
Adrenergic Receptor Guan acine because o CNS ef ects and Postural hypotension and with dys unction o the
Antagonists lack o evidence demonstrating erectile dys unction may SA node and AVblock
reduction in risk o adverse be prominent in patients with AV
cardiovascular events nodal disease; sudden
discontinuation may cause
a withdrawal syndrome
consisting o headache,
apprehension, tremors,
abdominal pain, sweating,
tachycardia, rebound
hypertension
286
Drug Therapy of Hypertension and Na + Balance Disorders CHAPTER 1 5
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Adrenergic Neuron Guanadrel (not Rarely used because o Undesirable ef ects that Occasional psychotic
Blocking Agents marketed in the adverse ef ects are related to sympathetic depression that can lead
United States) blockade, including to suicide with reserpine
Reserpine hypotension during Reserpine must be
standing and exercise, discontinued at rst
general eeling o atigue sign o depression;
and lassitude reserpine-induced
CNS ef ects with reserpine depression may last
include sedation and several months a ter drug
inability to per orm is discontinued
complex tasks
L–type Ca2+ Verapamil Used alone or in combination Direct negative May worsen symptoms in
Channel Blockers— Diltiazem with other antihypertensive drugs chrontropic and patients with heart ailure
Nondihydropyridines May be more e ciacious than inotropic ef ects due to direct negative
other agents as monotherapy in Concurrent use o a inotropic ef ects
elderly subjects and in A rican β receptor antagonist
Americans, population groups in may magni y
which the low renin status is more negative chronotropic
prevalent ef ects o these drugs
May be a pre erred treatment or cause heart block in
in patients with isolated systolic susceptible patients
hypertension
Arterial Vasodilators Hydralazine Hydralazine no longer a rst-line Hydralazine causes Hydralazine can cause
Minoxidil drug; may have utility in the symptoms o severe autoimmune reactions,
Diazoxide treatment o severe hypertension, vasodilation, including including drug-induced
Fenoldopam in some patients with CHF, and headache, nausea, lupus syndrome, serum
in hypertensive emergencies ushing, hypotension, sickness, hemolytic
in pregnant women (especially palpitations, tachycardia, anemia, vasculitis, and
preeclampsia) dizziness, and angina rapidly progressive
Systemic minoxidil best reserved pectoris glomerulonephritis
or severe hypertension that Minoxidil has strong
responds poorly to other antinatriuretic ef ects,
antihypertensive medications, causes re ex increases
especially in male patients with in sympathetic cardiac
renal insu ciency ef ects, and hypertrichosis
Arterial and Venous Nitroprusside Used primarily to treat Excessive vasodilation At high doses, conversion
Vasodilators hypertensive emergencies, also to cyanide can be
in situations when short-term toxic but prevented by
reduction o cardiac preload coadministration o sodium
and/or a terload is desired thiosul ate
287
SECTION III Modulation o Cardiovascular Function
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Vasopressin Agonist—V1 Vasopressin Used to induce GI smooth muscle V1-mediated ef ects Vasoconstriction o
Receptor Agonists Terlipressin contraction to treat postoperative include cutaneous coronary and peripheral
ileus, abdominal distension, vasoconstriction, nausea, arteries
and dispel intestinal gas prior to belching, cramps, and an Vasopressin should be
abdominal x-ray imaging urge to de ecate administered only at low
Used to vasoconstrict splachnic Major V2 receptor- doses and with extreme
and portal arteries to reduce mediated adverse ef ect caution in individuals
bleeding associated with o vasopressin is water suf ering rom vascular
various abdominal procedures, intoxication; must not disease, especially coronary
hemorrhagic disorders such be administered to artery disease
as esophogeal varices, and patients with primary or Arrhythmia and decreased
surgeries in patients with portal psychogenic polydipsia cardiac output
hypertension Peripheral vasoconstriction
Terlipressin is pre erred or and gangrene with large
bleeding esophageal varices doses o vasopressin
because o increased sa ety, and is
ef ective in treating patients with
hepatorenal syndrome
Vasopressin Agonist—V2 Desmopressin Drug o choice or treatment Mild acial ushing and May cause transient
Receptor Agonist (DDAVP) o central diabetes insipidus to headache thrombo-cytopenia in
control polyuria and polydypsia Major adverse ef ect individuals with type IIb
Reduces bleeding time by is water intoxication; vWD and is contraindicated
increasing release o vWF and patients receiving in such patients
actor VIII in patients with certain desmopressin to maintain
bleeding disorders hemostasis should be
Primary nocturnal enuresis advised to reduce uid
Relieves post-lumbar puncture intake
headache Must not be administered
to patients with primary
or psychogenic polydipsia
Tachyphylaxis to
desmopressin’s
procoagulant ef ects
usually occurs a ter several
days owing to depletion
o actor VIII and vWF
Vasopressin Antagonists— Tolvaptan Used in disease states with water GI ef ects, hyperglycemia, Metabolized by CYP3A4
Selective V2 Receptor (V2R) excess and hyponatremia (chronic and pyrexia (drug-drug interactions)
Antagonists (“Aquaretics”) heart ailure, cirrhosis, nephrosis) Less common adverse
to increase renal ree water ef ects: li e-threatening
without changing electrolyte thrombosis, ventricular
excretion brillation, urethral and
Used in patients with euvolemic vaginal hemorrhage,
or hypervolemic hyponatremia respiratory ailure, diabetic
associated with SIADH ketoacidosis, ischemic colitis,
increase in prothrombin
time, rhabdomyolysis
Vasopressin Antagonists— Conivaptan Treatment o hospitalized patients In usion site reaction Metabolized by CYP3A4
Nonselective V1aR/V2R with euvolemic hyponatremia and (drug should only (drug-drug interactions)
Antagonist (“Aquaretics”) hypervolemic hyponatremia be in used into large
veins and in usion sites
changed daily)
Headache, hypertension,
hypotension,
hypokalemia, and pyrexia
288
CHAPTER
289
SECTION III Modulation of Cardiovascular Function
Unstable angina and non-ST- Acute or subacute worsening Therapies directed at decreasing myocardial oxygen demand (nitrates and
segment-elevation myocardial o anginal symptoms caused β adrenergic antagonists) have limited e cacy
in arction (acute coronary by decreased coronary ow Additional therapies are directed at the atherosclerotic plaque and
syndrome) due to thrombosis at the site consequences or prevention o its rupture including:
o ruptured coronary plaque • antiplatelet agents
with partial or total occlusion • antithrombin agents
o the vessel • thrombolytic agents
• angioplasty and mechanotherapy with intracoronary stents (see Side Bar
DRUG-ELUTING INTRACORONARYSTENTS)
• coronary bypass surgery in selected patients
Reduce coronary vasospasm with IVnitroglycerin, and possibly a Ca2+ channel
blocker to increase O2 supply (see Figure 16-1)
Acute myocardial in arction Ischemia with loss o Therapy is directed at reducing the size o the in arct, preserving viable tissue
myocardial tissue caused by reducing O2 demand o the myocardium, and preventing ventricular
by blockage o one or more remodeling
coronary vessels Nitroglycerin to relieve ischemic pain but should not be used i hypotension
limits the administration o β blockers
Reper usion therapies are critical with angioplasty and stents having better
outcomes than thrombolytic therapy
Variant or Prinzmetal angina Intermittent decrease in ow Increase myocardial O2 supply with coronary vasodilators (see Figure 16-1);
due to localized coronary Ca2+ channel blockers reduce mortality and the incidence o MI
vasospasm Long-acting nitrates can occasionally be e ective alone but additional Ca2+
channel blocker therapy is usually required
290
Drug Therapy o Myocardial Ischemia CHAPTER 1 6
FIGURE 16-1 Pharmacological modif cation o the major determinants o myocardial O2 supply. When myocardial O2 requirements exceed O2
supply, an ischemic episode results. This f gure shows the primary hemodynamic sites o actions o pharmacological agents that can reduce O2
demand (le t side) or enhance O2 supply (right side). Some classes o agents have multiple e ects. Stents, angioplasty, and coronary bypass
surgery are mechanical interventions that increase O2 supply. Both pharmacotherapy and mechanotherapy attempt to restore a dynamic
balance between O2 demand and O2 supply.
INTERACTIONS OF
NITRATES WITH
CASE 16-1 PHOSPHODIESTERASE 5
A 52-year-old man who su ers rom angina when he climbs stairs or participates in simi- (PDE5) INHIBITORS
lar activities receives a prescription or nitroglycerin (glyceryl trinitrate). He is instructed • Erectile dys unction is common in
to take a tablet 1 or 2 minutes be ore he expects to climb stairs to prevent the angina. patients with coronary artery dis-
a. What is the mechanism o action o nitroglycerin that prevents angina rom ease; thus many men desiring ther-
developing in this patient? apy or erectile dys unction may be
Nitroglycerin and the other organic nitrates used to treat angina are prodrugs receiving antianginal therapy.
that are sources o nitric oxide (NO). NO activates the soluble iso orm o guanylyl • T e PDE5 inhibitors (sildena l,
cyclase, thereby increasing intracellular levels o cyclic GMP and leading to the tadala l, and vardena l) block the
relaxation o smooth muscle cells in a broad range o tissues. T e NO-dependent cyclic GMP-speci c PDE5 am-
relaxation o vascular smooth muscle leads to vasodilation. Low concentrations ily o phosphodiesterases which
o nitroglycerin pre erentially dilate veins more than arterioles. T is venodilation are widely expressed in vascular
decreases venous return, leading to a all in le and right ventricular chamber size smooth muscle, including the
and end-diastolic pressures, but usually results in little change in systemic vascular smooth muscle o the corpus cav-
resistance. Systemic arterial pressure may all slightly, and heart rate is unchanged or ernosum and penile arteries.
may increase slightly in response to a decrease in blood pressure. Nitroglycerin can • T e accumulation o cyclic GMP
dilate epicardial stenoses and reduce the resistance to ow through such areas result- in vascular smooth muscle that
ing in an increase in blood ow that would be distributed pre erentially to ischemic occurs with NO stimulation o
myocardial regions as a consequence o vasodilation induced by autoregulation. guanylyl cyclase can be enhanced
By their e ects on the systemic circulation, the organic nitrates also can reduce by inhibiting PDE5 activity.
myocardial O2 demand (see Figure 16-1). T e major determinants o myocardial • Given alone, the PDE5 inhibi-
O2 consumption include le ventricular wall tension, heart rate, and myocardial tors cause modest drops in blood
contractility. Ventricular wall tension is a ected by a number o actors that may be pressure, but in men who are
considered under the categories o preload and a erload. Organic nitrates decrease taking organic nitrate vasodila-
both preload and a erload as a result o respective dilation o venous capacitance tors, a all in blood pressure o
and arteriolar resistance vessels. T e ability o nitrates to dilate epicardial coronary more than 25 mm Hg can occur.
arteries, even in areas o atherosclerotic stenosis, is modest, and the preponderance • Because o the possibility o
o evidence continues to avor a reduction in myocardial work, and thus in myocar- extreme hypotension, PDE5
dial O2 demand, as their primary e ect in chronic stable angina. inhibitors are contraindicated
b. How and when should the nitroglycerin be administered to prevent anginal pain? or patients receiving any orm
Anginal pain may be prevented when the drug is used prophylactically immedi- o nitrate and should not be
ately prior to exercise or stress. T e smallest e ective dose should be prescribed. prescribed to such patients.
Sublingual organic nitrates should be taken at the time o an anginal attack or in • Patients should be questioned
anticipation o exercise or stress. Such intermittent treatment provides reproduc- about the use o PDE5 inhibitors
ible cardiovascular e ects. Peak concentrations o nitroglycerin are ound in plasma within the past 24 hours be ore
within 4 minutes o sublingual administration; the drug has a t1/2 o 1 to 3 minutes nitrates are administered; a
because o rapid and complete rst-pass metabolism by the liver. T e onset o action period longer than 24 hours may
o nitroglycerin may be even more rapid i it is delivered as a sublingual spray rather be needed to avoid drug interac-
than as a sublingual tablet. tions, especially with tadala l
which has the longest hal -li e.
(Continued)
291
SECTION III Modulation of Cardiovascular Function
CASE 16-2
A 67-year-old woman with mild heart ailure (LVEF = 45%) has anginal pain with
exercise and is prescribed a β adrenergic blocker.
a. How does therapy with a β adrenergic blocker prevent anginal pain?
T e e ectiveness o β adrenergic receptor antagonists in the treatment o exertional
angina is attributable primarily to a all in myocardial O2 consumption at rest and
during exertion, although there also is some tendency or increased ow toward
ischemic regions. T e decrease in myocardial O2 consumption is due to a negative
chronotropic e ect (particularly during exercise), a negative inotropic e ect, and a
reduction in arterial blood pressure (particularly systolic pressure) during exercise
(see Figure 16-1). T e reduction in arterial blood pressure is secondary to a drop in
cardiac output due to the negative chronotropic and inotropic e ects o β blockers.
(Continued)
292
Drug Therapy o Myocardial Ischemia CHAPTER 1 6
TABLE 16-1 Recommended Drug Therapy or Angina in Patients with Other Medical Conditions
RECOMMENDED TREATMENT AND
CONDITION ALTERNATIVES FOR ANGINA DRUGS TO AVOID
Medical Conditions
Severe peripheral vascular disease with rest ischemia Ca2+ channel antagonists β receptor antagonists
Sinus bradycardia Dihydropyridine Ca2+ channel antagonists β receptor antagonists, diltiazem, verapamil
Atrioventricular block Dihydropyridine Ca2+ channel antagonists β receptor antagonists, diltiazem, verapamil
293
SECTION III Modulation of Cardiovascular Function
Reproduced with permission rom Gibbons RJ, Chatterjee K, Daley J et al. ACC/AHA/ACP-ASIM Guidelines or the management o patients
with chronic stable angina: A report o the American College o Cardiology / American Heart Association Task Force on Practice Guidelines
(Committee on Management o Patients With Chronic Stable Angina). J Am Coll Cardiol 1999;33:2092-197. Copyright © 1999 by the American
College o Cardiology Foundation.
CASE 16-3
A man with hypertension and occasional symptoms o angina with exercise is prescribed
amlodipine.
a. What is the mechanism o action o amlodipine that is benef cial in treating
hypertension and angina?
Amlodipine inhibits L-type voltage-sensitive Ca2+ channels in vascular smooth
muscle, especially in arterial beds. T e basis or the use o Ca2+ channel antagonists
in hypertension comes rom the understanding that hypertension generally is the
result o increased peripheral vascular resistance. All o the Ca2+ channel block-
ers lower blood pressure by relaxing arteriolar smooth muscle and decreasing
(Continued)
294
Drug Therapy o Myocardial Ischemia CHAPTER 1 6
peripheral vascular resistance. Ca2+ channel blockers are e ective when used alone
TREATMENT OF
or in combination with other drugs or the treatment o hypertension.
CLAUDICATION AND
T e utility o Ca2+ channel antagonists in the treatment o exertional, or exercise- PERIPHERAL VASCULAR
induced, angina results rom an increase in coronary blood ow owing to coronary
DISEASE
arterial dilation, rom a decrease in myocardial O2 demand (secondary to a decrease
in arterial blood pressure, heart rate, or contractility), or both (see Figure 16-1). • Most patients with peripheral artery
Amlodipine, as with other dihydropyridine Ca2+ channel blockers, has potent vaso- disease also have coronaryarterydisease
dilator activity but minimal e ects on cardiac contractility, SA nodal activity, or AV and the therapeuticapproaches overlap.
nodal activity at concentrations that cause vasodilation ( able 16-2). In contrast to • Reductions in cardiovascular morbidityand
the dihydropyridines, verapamil and diltiazem have direct negative inotropic and mortalityin patients with peripheral
chronotropic e ects (see able 16-2). arterial disease have been documented
b. What are the potential side e ects o the Ca2+ channel antagonists? with antiplatelet therapy, ACEinhibitors,
and treatment o hyperlipidemia.
T e pro le o adverse reactions to the Ca2+ channel blockers varies among the
drugs in this class. Patients receiving immediate-release short-acting ormulations • Risk actor and li estyle modi cations
o ni edipine develop headache, ushing, dizziness, and peripheral edema; these (physical exercise, rehabilitation, and
preparations are not appropriate in the long-term treatment o angina or hyperten- smoking cessation) remain cornerstones o
sion. Dizziness and ushing are much less o a problem with sustained-release or- therapy or patients with claudication.
mulations and with the dihydropyridines having a long t1/2 and relatively constant • Pentoxi ylline and cilostazol are drugs used
concentrations o drug in plasma. Peripheral edema may occur in some patients speci cally or lower extremityclaudication.
with Ca2+ channel blockers and most likely results rom increased hydrostatic pres- » Pentoxi ylline is a rheological modi er
sure in the lower extremities owing to precapillary dilation and re ex postcapillary that increases the de ormabilityo red
constriction. Some other adverse e ects o these drugs are due to actions in non- blood cells.
vascular smooth muscle such as the lower esophageal sphincter (which can cause » Cilostazol is PDE3 inhibitor that inhibits
or aggravate gastroesophageal re ux), constipation (a common side e ect o vera-
platelet aggregation and vasodilation
pamil, but less requent with other Ca2+ channel blockers), and urinary retention
byincreasing intracellular cyclicAMPin
(a rare adverse e ect).
manycells, including platelets.
c. What are the important contraindications or the use o Ca2+ channel blockers?
T e use o intravenous verapamil with an intravenous β adrenergic receptor antag-
onist is contraindicated because o the increased propensity or AV block and/or
severe depression o ventricular unction. Patients with ventricular dys unction, SA
or AV nodal conduction disturbances, and systolic blood pressures below 90 mm
Hg should not be treated with verapamil or diltiazem, particularly intravenously
(see able 16-1).
TABLE 16-2 Ca 2+ Channel Blockers: Chemical Structures and Some Relative Cardiovascular Ef ectsa
CHEMICAL STRUCTURE VASODILATION SUPPRESSION OF SUPPRESSION OF SUPPRESSION OF
GENERIC NAME (TRADE NAME) CORONARY FLOW CARDIAC CONTRACTILITY AUTOMATICITY SA NODE CONDUCTION AV NODE
5 1 1 0
5 1 1 0
295
SECTION III Modulation of Cardiovascular Function
NR NR NR NR
5 0 1 0
5 1 1 0
3 2 5 4
4 4 5 5
a
Relative e ects are ranked rom no ef ect (0) to prominent (5). NR, not ranked.
CASE 16-4
A 58-year-old man with a long history o exertional angina begins to develop more re-
quent episodes o anginal pain that are also more intense. His cardiologist tells him he
has unstable angina.
a. What is the medical therapy or patients with unstable angina?
T e term unstable angina pectoris has been used to describe a broad spectrum o
clinical entities characterized by an acute or subacute worsening in a patient’s angi-
nal symptoms. More recently, e orts have been directed toward identi ying patients
with unstable angina on the basis o their risks or subsequent adverse outcomes
such as MI or death. T e term acute coronary syndrome has been use ul in this
context. Common to most clinical presentations o acute coronary syndrome is dis-
ruption o a coronary plaque, leading to local platelet aggregation and thrombosis
at the arterial wall, with subsequent partial or total occlusion o the vessel.
T e principal therapeutic goal in unstable angina is to increase myocardial blood
ow. Medical therapy or unstable angina involves the administration o aspirin,
(Continued)
296
Drug Therapy o Myocardial Ischemia CHAPTER 1 6
which reduces mortality, nitrates, β adrenergic receptor blocking agents, and hepa-
DRUG-ELUTING
rin, which are e ective in controlling ischemic episodes and angina. Because vaso-
INTRACORONARY STENTS
spasm occurs in some patients with unstable angina, Ca2+ channel blockers may
o er an additional approach to the treatment o unstable angina. However, there is • Intracoronarystents can ameliorate angina
insuf cient evidence to assess whether such treatment decreases mortality except and reduce adverse events in patients with
when the underlying mechanism is vasospasm. In contrast, therapy directed toward acute coronarysyndromes.
reduction o platelet unction and thrombotic episodes clearly decreases morbidity • Luminal subacute restenosis caused by
and mortality in patients with unstable angina (see Chapters 34 and 30 in Goodman smooth muscle proli eration within the
& Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition), and adminis- lumen o the stented arteryreduces the
tration o statins to treat dyslipidemias (see Chapter 20) also can reduce the risk o long-termef cacyo stents in a substantial
adverse cardiac events. minorityo patients.
b. What other therapies might be considered to relieve angina symptoms in • Drug-eluting stents containing either
this patient? paclitaxel or sirolimus can reduce the rate o
Percutaneous coronary interventions (PCI) such as angioplasty and coronary artery restenosis compared to“bare metal”stents.
stent deployment, or (less commonly) emergency coronary bypass surgery, can • Long-term(6 months) therapywith clopi-
complement pharmacological treatment. In some subsets o patients, percutaneous dogrel and li elong therapywith aspirin
or surgical revascularization may have a survival advantage over medical treatment maybe needed to prevent stent throm-
alone. Intracoronary stents can ameliorate angina and reduce adverse events in bosis in patients receiving drug-eluting
patients with acute coronary syndromes. However, the long-term ef cacy o intra- stents, but these long-termantiplatelet
coronary stents is limited by subacute luminal restenosis within the stent, which therapies can increase the risko bleeding
occurs in a substantial minority o patients. T e development o drug-eluting stents (see Chapter 19).
to prevent the smooth muscle proli eration that is responsible or restenosis has
had an important impact on clinical practice. wo drugs are currently being used
in intravascular stents: paclitaxel and sirolimus (see Side Bar DRUG-ELU ING
IN RACORONARY S EN S).
Stent-induced damage to the vascular endothelial cell layer can lead to thrombosis;
patients typically are treated with antiplatelet agents, including clopidogrel ( or
up to 6 months) and aspirin (inde nitely), sometimes in conjunction with intra-
venous heparin and/or GPIIb/IIIa inhibitors (see Chapter 19) administered at the
time o the revascularization procedure. T e inhibition o cellular proli eration by
paclitaxel and sirolimus not only a ects vascular smooth muscle cell proli eration
but also attenuates the ormation o an intact endothelial layer within the stented
artery. T ere ore, antiplatelet therapy (typically with clopidogrel) is continued or
several months a er intracoronary stenting with drug-eluting stents.
CASE 16-5
A 42-year-old woman develops symptoms o angina at rest. She has not had angina
be ore and has no history o cardiovascular disease. A er an exercise stress test and
other tests, she is diagnosed as having variant angina.
a. What is variant angina and what is the main therapeutic goal in treating it?
In variant angina, ocal or di use coronary vasospasm episodically reduces coro-
nary ow. Patients also may display a mixed pattern o angina with the addition
o altered vessel tone on a background o atherosclerotic narrowing. T e principal
therapeutic aim in variant or Prinzmetal angina is to prevent coronary vasospasm
and improve O2 delivery to ischemic myocardium.
b. What are the treatment options to relieve this patient’s symptoms o angina?
Whereas long-acting nitrates alone are occasionally ef cacious in abolishing epi-
sodes o variant angina, additional therapy with Ca2+ channel blockers usually is
required. Ca2+ channel blockers, but not nitrates, have been shown to in uence
mortality and the incidence o MI avorably in variant angina; they should gener-
ally be included in therapy. β Receptor antagonists should be used with caution i
the underlying pathophysiology is coronary vasospasm.
297
SECTION III Modulation of Cardiovascular Function
KEY CONCEPTS
In typical stable angina, the primary therapeutic goal is to reduce myocardial
O2 demand, typically with an organic nitrate, a β receptor antagonist, a Ca2+
channel blocker, or a combination o these 3 classes o drugs.
T e therapeutic goal in treating vasospastic angina is to prevent coronary
vasospasm and maintain myocardial O2 supply using a Ca2+ channel blocker, an
organic nitrate, or a combination o these 2 classes o drugs.
Acute coronary syndromes are caused by disruption o an atherosclerotic
coronary plaque causing local platelet aggregation and thrombosis that partially
or totally occludes the coronary vessel.
T e primary therapeutic goal in treating acute coronary syndromes is to prevent
the disruption o coronary blood ow by inhibiting platelet aggregation and
thrombosis, and secondarily reducing myocardial O2 demand.
In addition to pharmacological therapy, long-term prevention o angina in
patients with acute coronary syndrome may require angioplasty, intracoronary
stents, or in some patients, coronary bypass surgery.
SUMMARY QUIZ
299
SECTION III Modulation of Cardiovascular Function
Phosphodiesterase Sildenaf l Treatment o erectile Headache, ushing, rhinitis, Extreme hypotension when
5 Inhibitors (PDE5 Tadalaf l dys unction dyspepsia owing to relaxation administered in combination with
Inhibitors) Vardenaf l Less commonly used to o smooth muscle (all o these organic nitrates
treat pulmonary artery are predictable based on their PDE5 inhibitors should not
hypertension e ects on PDE5) be prescribed to patients
Sildenaf l and vardenaf l can receiving nitrates
produce visual disturbances Nitrates should not be
and one-sided hearing loss administered within 24 hours (or
longer) a ter use o a PDE5 inhibitor
β Adrenergic Propranolol Treatment o angina See Chapter 7 See Table 16-1 and Chapter 7
Receptor Timolol (slow heart rate, decrease
Antagonists Metoprolol contractility)
Atenolol Other indications are
Many others (see described in Chapter 7
Chapter 7)
Ca2+ Channel Verapamil Treatment o angina Constipation, headache, IVadministration with IVβ blocker
Antagonists (Ca2+ (reduce a terload, relax ushing, dizziness, and is contraindicated because o risk o
Entry blockers)— coronary vessels, slow heart peripheral edema AVblock and/or severe depression
Phenylalkylamine rate, decrease contractility) o ventricular unction
Treatment o hypertension Avoid in patients with ventricular
(see Chapter 15) dys unction, SA or AVnodal
conduction disturbances, or systolic
blood pressures below 90 mm Hg
See Table 16-1
Blocks the P-glycoprotein
transporter
Ca2+ Channel Diltiazem Treatment o angina Headache, ushing, dizziness, Avoid in patients with ventricular
Antagonists (Ca2+ (reduce a terload, relax and peripheral edema dys unction, SA or AVnodal
Entry Blockers)— coronary vessels, slow heart conduction disturbances,
Benzothiazepine rate, decrease contractility) or systolic blood pressures
Treatment o hypertension <90 mm Hg
(see Chapter 15) See Table 16-1
Ca2+ Channel Amlodipine Treatment o angina Headache, ushing, dizziness, May aggravate anginal symptoms
Antagonists (Ca2+ Clevidipine (reduce a terload, relax and peripheral edema in some patients when used
Entry Blockers)— Felodipine Isradipine coronary vessels) without a β blocker because o
Dihydropyridines Nicardipine Treatment o hypertension re ex tachycardia
Ni edipine Nimodipine (see Chapter 15) See Table 16-1
Nisoldipine
Na+ Channel Ranolazine Treatment o angina Prolongs QTc interval Avoid using with other drugs that
Blocker (Late Inward (reduces ventricular prolong QT interval
Na+ Current Blocker) diastolic wall tension, Contraindicated in patients with
reducing O2 demand); used hepatic cirrhosis
in patients re ractory to
other antianginal therapy
300
CHAPTER
COMORBIDITIES COMMON FIGURE 17-1 Pathophysiologic mechanisms o heart ailure and major sites o drug action.
Congestive heart ailure is accompanied by compensatory neurohormonal responses, including
IN HEART FAILURE activation o the sympathetic nervous and renin–angiotensin–aldosterone axis. Increased ven-
• Coronaryarterydisease (CAD) tricular a terload, due to systemic vasoconstriction and chamber dilation, causes depression in
systolic unction. In addition, increased a terload and the direct e ects o angiotensin and norepi-
• Atrial brillation (AF) nephrine on the ventricular myocardium cause pathologic remodeling characterized by progres-
• Myocardial in arction (MI) sive chamber dilation and loss o contractile unction. Key congestive heart ailure medications
and their targets o action are presented. ACE, angiotensin-converting enzyme; AT1 receptor, type
• Sudden cardiacdeath 1 angiotensin receptor.
302
Pharmacotherapy of Heart Failure CHAPTER 1 7
Ca 2+-
ATPa s e
P KA
PL
2+
Ca RyR2
SR P KA
S ERCA2 Ca 2+ Ca 2+
P KA L-type cha nne l
Ca 2+ Ca 2+
NCX NCX
(de pola rize d) (pola rize d)
3Na +
3 Na + 3 Na +
Na +, K+
ATPa s e
Na + cha nne l
Na + 2K+
FIGURE 17-2 Sarcolemmal exchange o Na+ and Ca2+ during cell depolarization and repolarization. Na+ and Ca2+ enter the cardiac myocyte
via the Na+ channel and the L-type Ca2+ channel during each cycle o membrane depolarization, triggering the release, through the ryanodine
receptor (RyR), o larger amounts o Ca2+ rom internal stores in the sarcoplasmic reticulum (SR). The resulting increase in intracellular Ca2+ inter-
acts with troponin C and activates interactions between actin and myosin that result in sarcomere shortening. The electrochemical gradient
or Na+ across the sarcolemma is maintained by active transport o Na+ out o the cell by the sarcolemmal Na+,K+-ATPase. The bulk o cytosolic
Ca2+ is pumped back into the SR by a Ca2+-ATPase, SERCA2. The remainder is removed rom the cell by either a sarcolemmal Ca2+-ATPase or a
high-capacity Na+-Ca2+ exchanger, NCX. NCX exchanges 3 Na+ or every Ca2+, using the electrochemical potential o Na+ to drive Ca2+ extrusion.
The direction o Na+-Ca2+ exchange may reverse brie y during depolarization, when the electrical gradient across the sarcolemma is transiently
reversed. β Adrenergic agonists and PDE inhibitors, by increasing intracellular cyclic AMP levels, activate PKA, which phosphorylates phosphol-
amban (PL), the α subunit o the L-type Ca2+ channel, and regulatory components o the RyR, as well as TnI, the inhibitory subunit o troponin
(not shown). As a result, the probabilities o opening o the L-type Ca2+ channel and the RyR2 Ca2+ channel are doubled; SERCA2 is uninhibited
and accumulates Ca2+ into the SR aster, more avidly, and to a higher concentration; and relaxation occurs at slightly higher [Ca2+]i due to slightly
reduced sensitivity o the troponin complex to Ca2+. The net e ect o these phosphorylations is a positive inotropic e ect: a aster rate o ten-
sion development to a higher level o tension, ollowed by a aster rate o relaxation. m indicates site o cardiac glycoside binding. See the text in
Chapter 28, Pharmacotherapy o Heart Failure in Goodman &Gilman’s The Pharmacological Basis o Therapeutics, 12th Edition or the mechanism o
positive inotropic e ect o cardiac glycosides.
RATIONALE FOR
CASE 17-1 PHARMACOLOGICAL
A 64-year-old man who su ered a myocardial in arction at the age o 56 complains THERAPY OF HEART
o di culty sleeping because he wakes up eeling out o breath. Chest sounds reveal FAILURE (Se e Fig u re 17 3)
crackles and rales. He has di culty walking more than 150 eet be ore having to stop to • The goal o therapy or patients who are at
catch his breath. He is taking a β adrenergic blocker (metoprolol) and an ACE inhibitor risko developing heart ailure (Stages A
(captopril). He also takes ibupro en every day to relieve pain in his knees. and B) is to slowor stop the progression o
a. What Stage o heart ailure is this patient in? the disease, decrease morbidityand mor-
tality, and improve qualityo li e through
T s pat e t s Sta e C (structural sease w th curre t symptoms, see F ure 17-3). the use o inhibitors o the renin-angioten-
H s pr or myocar al arct o cause structural ama e to h s heart wh ch s ow sin-aldosterone system(ACEinhibitors and
mpa r le ve tr cular u ct o e ou h to cause symptoms o heart a lure. ARBs) and β adrenergicreceptor blockers.
b. What is causing this patient’s symptoms? • ACEinhibitors, ARBs, and β blockers are
T s pat e t has evelope pulmo ary e ema (co est o ) ecause he s reta - also used in patients who have structural
Na+ a water ue to act vat o o the re -a ote s -al ostero e ax s. T e disease with symptoms o heart ailure
pat e t has culty reath at ht whe ly ow ecause the pulmo ary (Stages Cand D), but additional therapies
e ema worse s a mpa rs ve t lat o a as excha e. Heart a lure pat e ts are added to treat symptoms o edema
w th pulmo ary co est o o e sleep more com orta ly the r hea a upper (diuretics), improve hemodynamics (ino-
o y are elevate w th a couple o p llows. T e symptoms o exerc se tolera ce tropes and vasodilators), and acilitate
a short ess o reath are also the result o the pat e t’s heart a lure. natriuresis (dopamine and nesiritide).
(Continued)
303
SECTION III Modulation of Cardiovascular Function
AngII, angiotensin II; AT1, type 1 angiotensin II receptor; NO, nitric oxide; ACE, angiotensin converting enzyme; PDE, cyclic nucleotide
phosphodiesterase; BK, bradykinin.
CASE 17-2
You are counseling a 34-year-old woman who is moderately overweight, and has mild
hypertension and type II diabetes. Her ather had his rst myocardial in arction when
he was 45 and died o a subsequent myocardial in arction when he was 52.
a. Is this patient at risk to develop heart ailure and what can she do to lower her risks?
T s woma has several r sk actors or evelop heart a lure, clu o es ty,
hyperte s o , a etes, a her am ly h story o car ovascular sease. She may also
have ysl p em a. She s Sta e A o heart a lure (h h r sk o evelop heart
a lure ut o symptoms). She has o co trol over her e et cs, ut she ca re uce her
r sk o evelop heart a lure y co troll her we ht, loo pressure, a a etes.
b. What medications are recommended or this patient?
T s pat e t may e a le to re uce all o her co trolla le r sks y a opt a
health er l e-style ( e, re ular exerc se a a opt a health er et). I l estyle
(Continued)
304
Pharmacotherapy of Heart Failure CHAPTER 1 7
S ta ge C S ta ge D
S truc tural he art dis e as e Re frac to ry HF
with prio r o r c urre nt
S ta ge B s ympto ms o f HF
S truc tural he art dis e as e P a tie nts with:
S ta ge A but witho ut s ig ns o r -ma rke d HF
At hig h ris k fo r HF but s ympto ms o f HF s ymptoms a t re s t
witho ut s truc tural P a tie nts with: -re curre nt
he art dis e as e o r -known s tructura l hos pita liza tions
s ympto ms o f HF he a rt dis e a s e de s pite a tte mpts to
P a tie nts with: -HF s igns a nd optimize the ra py
-pre vious MI s ymptoms including diure tics
-LV re mode ling a nd guide line -
P a tie nts with: THERAPY
including LV dire cte d me dica l
-hype rte ns ion Go als
hype rtrophy a nd low the ra py
-a the ros cle rotic dis e a s e -Control s ymptoms
e je ction fra ction-
-dia be te s -P re ve nt hos pita liza tion
a s ymptoma tic THERAPY
me llitus -P re ve nt morta lity
va lvula r dis e a s e Go als
-obe s ity
-me ta bolic s yndrome Drug s fo r us e in patie nts -Control s ymptoms
THERAPY -Improve HRQOL
with pre s e rve d EF (EF ≥50)
or Go als -Re duce hos pita l
P a tie nts : -Diure tics for fluid re te ntion
-P re ve nt HF s ymptoms re a dmis s ions
-us ing ca rdiotoxic drugs -Tre a t comorbiditie s (HTN,
-P re ve nt furthe r ca rdia c -Es ta blis h e nd-of-life goa ls
-with fa mily his tory of AF, CAD, DM)
re mode ling
ca rdiomyopa thy Optio ns
Drug s fo r ro utine us e in
Drug s patie nts with re duc e d EF -Adva nce d ca re me a s ure s
THERAPY -ACE inhibitor or ARB in -He a rt tra ns pla nt
Go als -Diure tics for fluid re te ntion -Chronic inotrope s
a ppropria te pa tie nts -ACE inhibitor or ARB
-He a rt he a lthy life s tyle -Be ta blocke r in -Te mpora ry or pe rma ne nt
-Be ta blocke r me cha nica l s upport
-P re ve nt va s cula r, a ppropria te pa tie nts -Aldos te rone a nta gonis t -Expe rime nta l s urge ry or
corona ry dis e a s e
-P re ve nt LV s tructura l In s e le c te d patie nts Drug s fo r us e in s e le c te d drugs
a bnorma litie s -Impla nta ble patie nts with re duc e d EF -P a llia tive ca re a nd
ca rdiove rte r- -Hydra la zine /IS DN hos pice
Drug s de fibrilla tor (ICD) -ACE inhibitor a nd ARB -ICD de a ctiva tion
-ACE inhibitor or ARB -Re va s cula riza tion or -Digita lis
in a ppropria te pa tie nts va lvula r s urge ry a s
for va s cula r dis e a s e or In s e le c te d patie nts
a ppropria te
DM -CRT
-S ta tins a s a ppropria te -ICD
-Re va s cula riza tion or
va lvula r s urge ry a s
a ppropria te
FIGURE 17-3 Stages in the development o HF and recommended therapy by stage. ACE indi-
cates angiotensin-converting enzyme; AF, atrial brillation; ARB, angiotensin-receptor blocker;
CAD, coronary artery disease; CRT, cardiac resynchronization therapy; DM, diabetes mellitus; EF,
ejection raction; GDMT, guideline-directed medical therapy; HF, heart ailure; HRQOL, health-
related quality o li e; HTN, hypertension; ICD, implantable cardioverter-de brillator; LV, le t
ventricular; and MI, myocardial in arction. Preserved EF is de ned as an EF ≥ 50%. Reduced EF is
de ned as an EF ≤ 40%. (Modif ed rom Yancy CW et al. Circulation. 2013;128:e240-e327.)
CASE 17-3
You are reviewing the medications o a 67-year-old man who has recently developed
mild pulmonary congestion and peripheral edema. He has a history o mild heart ail-
ure, hypertension, and he occasionally su ers rom angina. T e drugs he is prescribed
to take on a daily basis are aspirin, urosemide, lisinopril, lovastatin, metoprolol, and
verapamil. He is also on a low-salt diet.
a. What are the possible reasons or the pulmonary congestion and peripheral edema?
Desp te e o a ACE h tor (l s opr l), a β locker (metoprolol), a a loop
uret c ( urosem e), th s pat e t s ecompe sat a reta u . It’s pos-
s le the pat e t’s heart a lure s worse , or the pat e t s ot a her to the
low-salt et or s ot tak h s uret c as prescr e .
(Continued)
305
SECTION III Modulation of Cardiovascular Function
CASE 17-5
A 72-year-old man with atrial brillation is hospitalized because o severe pulmonary
and peripheral edema that is not adequately treated by his current medications that
include losartan, carvedilol, and urosemide. During his stay in the hospital, his edema
is controlled by aggressive intravenous (IV) urosemide administration and a strict
low-salt diet. He is also started on digoxin and spironolactone.
a. What is the rationale or adding digoxin?
D ox s a m l otrope that was o ce use most pat e ts w th co est ve
heart a lure. Cl cal tr als have show that t oes ot re uce mortal ty ut oes
re uce hosp tal zat o rates o pat e ts w th mo erate to severe heart a lure whe
a e to sta ar therapy. By creas the otrop c state o the ve tr cles, t w ll
mprove k ey u ct o a re uce the r sk o rehosp tal zat o ue to e ema.
T s pat e t w ll also e ef t rom ox ecause he has atr al f r llat o , wh ch
ca lea to ve tr cular tachycar a. D ox w ll crease va al to e to the heart
a there y slow or lock co uct o o mpulses pass throu h the AV o e
a protect the ve tr cles rom atr al- uce tachycar a.
b. What are the risks o digoxin therapy in this patient?
D ox has a arrow therapeut c ex, w th tox c ty poss le at therapeut c oses.
L e-threate tox c t es clu e ve tr cular arrhythm as a s us ra ycar a.
c. What are the symptoms o digoxin toxicity?
T e symptoms o ox tox c ty clu e car ac rhythm stur a ces, eurolo cal
e ects, clu var ous v sual stur a ces, a astro test al symptoms. Severe
tox c ty ca e treate w th a eutral z a t ox a t sera Fa ra me t (digibind).
(Continued)
306
Pharmacotherapy of Heart Failure CHAPTER 1 7
CASE 17-6
A 72-year-old woman who had a coronary artery bypass gra when she was 60, and
has had symptoms o heart ailure or the past 6 years is hospitalized with decompen-
sated heart ailure. Her medications prior to hospitalization included losartan, meto-
prolol, aldosterone, urosemide, and digoxin.
a. What medications should be considered to restore lef ventricular unction?
A pare teral otrope such as o utam e, opam e, or a type 3 phospho ester-
ase (PDE3) h tor s o e ee e or pat e ts Sta e D heart a lure to ma -
ta LVF. T ese a e ts are much more power ul otropes tha ox . T e cho ce
o a a e t epe s o whether the pat e t s hypote s ve, has s s o re al su -
f c e cy, or has ecome re ractory to a other otrope.
b. What are the mechanisms by which inotropic agents exert their e ects on the heart?
All otrop c a e ts act y creas Ca2+ el very to the co tract le apparatus
ve tr cular myocytes, ut throu h ere t mecha sms.
D ox (a car ac lycos e) s a weak orally a m stere otrope that acts y
h t myocar al Na+, K+-A Pase. I h t o o th s pump re uces the a l ty
o the myocyte to remove Ca2+ throu h the Na+-Ca2+ excha er (NCX). T s results
more tracellular Ca2+, more Ca2+ e take up y the sarcoplasm c ret culum
(SR), a more Ca2+ release rom the SR ur su seque t exc tat o -co tract o
cycles (see F ure 28-5 Goodman & Gilman’s T e Pharmacological Basis of T era-
peutics, 12th E t o ).
Do utam e a opam e are β a re er c a o sts that are a m stere par-
e terally a are reserve or pat e ts Sta e D heart a lure. At the oses use
cl cally to ma ta car ac output pat e ts w th heart a lure, the r pr mary
mecha sm s throu h st mulat o o myocar al β a re er c receptors. Act va-
t o o β a re er c receptors causes a crease cAMP, wh ch act vates prote
k ase A (PKA). Act vat o o PKA results phosphorylat o o the L-type Ca2+
cha el wh ch creases Ca2+ e try to car ac myocytes. PKA also phosphorylates
prote s o the sarcoplasm c ret culum (SR) mem ra e that crease SR uptake o
Ca2+ a su seque t release o Ca2+ rom the SR.
Do utam e s a m stere as a co t uous IV us o (t1/2 o ~2 m utes) to
pat e ts e -sta e systol c ys u ct o (Sta e D) to ma ta car ac output. It
s a stro pos t ve otrope ecause o ts myocar al β1 receptor a o sm . It also
re uces loa o the heart ecause o ts β2 a re er c vaso lat e ects skeletal
muscle loo vessels. achyphylax s ue to β a re er c receptor ese s t zat o
e s to evelop at 2 hours a ecomes s f ca t a er 72 hours wh ch may
requ re a or sw tch to a PDE3 h tor to ma ta car ac output. Some
pat e ts Sta e D heart a lure may e ef t rom co curre t a m strat o o a
β locker, ut th s ca re uce the e cacy o o utam e.
Dopam e s pre erre over o utam e pat e ts w th car o e c shock or com-
prom se re al u ct o ecause o ts a l ty to crease mea arter al pressure a
(Continued)
307
SECTION III Modulation of Cardiovascular Function
AFib: atrial brillation; CO: cardiac output; MAP: Mean arterial pressure; PCWP: Pulmonary
capillary wedge pressure; SVR: Systemic vascular resistance
KEY CONCEPTS
Contemporary approaches to treating heart ailure recognize that it is a pro-
gressive disorder that can be “staged.”
ACE inhibitors and ARBs are rst-line drugs used at all stages to prevent and
slow the progression o heart ailure by inhibiting the renin-angiotensin-aldo-
sterone system.
β Blockers are rst-line drugs used a er structural heart disease occurs to pre-
vent the cardiotoxic and arrhythmogenic e ects o high catecholamine levels.
Diuretics are used symptomatically to reduce edema and f uid volume.
Diuretics do not reduce mortality.
(Continued)
308
Pharmacotherapy of Heart Failure CHAPTER 1 7
Vasodilators are used in selected patients in combination with the rst-line drugs
to reduce the load on the heart.
Inotropic agents are used at late stages o heart ailure to improve symptoms by
maintaining adequate cardiac output.
Inotropes do not reduce mortality or slow progression o heart ailure.
SUMMARY QUIZ
QUESTION 17-1 You are counseling a heart ailure patient who is receiving a new pre-
scription or digoxin to treat their atrial brillation. Which o the ollowing are common
side e ects that might indicate digoxin toxicity?
a. Blood in the urine
b. Muscle cramps and joint pain
c. GI disturbances and yellow-green vision changes
d. Photosensitivity and skin discoloration
QUESTION 17-2 A 32-year-old woman has chronic hypertension and a amily history o
cardiomyopathy. She has no history hersel o heart problems and no symptoms o heart
ailure. Which drug is most appropriate to prevent or slow the development o heart ailure
in this patient?
a. Lisinopril
b. Verapamil
c. Digoxin
d. Dobutamine
QUESTION 17-3 A 74-year-old man who sel -describes himsel as being A rican-
American is taking metoprolol, losartan, urosemide, and digoxin to treat his heart
ailure. However, he still has some symptoms o heart ailure. T e most appropriate
drug to add to this patient’s drugs is
a. captopril.
b. diltiazem.
c. nesiritide.
d. BiDil (a combination o hydralazine and isosorbide dinitrate).
QUESTION 17-4 You are reviewing the discharge instructions o a 52-year-old man
who was hospitalized with a mild myocardial in arction. He has recovered well and
will be able to return to work next week. Be ore his hospitalization, he was tak-
ing lovastatin, enalapril, and low-dose aspirin. T e ollowing drug should be added
to these drugs because clinical trials have demonstrated that it will help reduce his
risk o death:
a. diltiazem.
b. hydrochlorothiazide.
c. carvedilol.
d. digoxin.
QUESTION 17-5 A patient who has recently been hospitalized with severe heart ailure
and has been receiving IV dobutamine starts to have worsening symptoms. What drug
should be used to replace the dobutamine?
a. Norepinephrine
b. Epinephrine
c. Isoproteronol
d. Milrinone
309
SECTION III Modulation of Cardiovascular Function
Angiotensin Receptor Losartan Same as ACE inhibitors; Hypotension and renal Teratogenic
(AT1) Blockers (ARBs) Candesartan indicated in patients who insuf ciency
Valsartan cannot tolerate the side
Others (see Chapter 15) e ects o increased levels
o kinins associated with
ACE inhibitors
β Adrenergic Receptor Metoprolol First-line agents used in Bradycardia, hypotension Risk o hypoglycemic
Blockers Carvedilol Stages B, C, and D to slow Can impair LV unction and reactions may be increased
Bisoprolol disease progression and exacerbate heart ailure in diabetics taking insulin
reduce mortality symptoms
Should be avoided in patients
with reactive airway disease
(asthma) or with SA or AVnodal
dys unction or in combination
with other drugs that inhibit AV
conduction, such as verapamil
310
Pharmacotherapy of Heart Failure CHAPTER 1 7
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Na+, K+-ATPase Inhibitor Digoxin Indicated in patients with GI disturbances Can exacerbate
LVdys unction in atrial Neurological disturbances supraventricular arrhythmias
brillation, or patients (con usion, hallucinations, and lead to ventricular
who remain symptomatic other), visual (yellow-green) arrhythmias
despite maximal therapy disturbances Ventricular
with ACE inhibitors and bradycardia, AVblock,
β blockers supraventricular tachycardia
Aldosterone Receptor Spironolactone Indicated or patients with Hyperkalemia Gynecomastia (less requently
Antagonists Eplerenone low LVejection raction Can induce diarrhea and other with eplerenone)
When added to standard gastric disturbances Li e-threatening hyperkalemia,
therapy, morbidity and Can cause CNS e ects such thus contraindicated in
mortality are reduced in drowsiness, ataxia, and patients with hyperkalemia or
patients with heart ailure headache those at risk o hyperkalemia
Contraindicated in patients
with peptic ulcers
Diuretics (Many Many agents (see To reduce uid retention, Hypokalemia, hyponatremia, Depends on agent (see
Subclasses) Chapter 15) especially in patients with and other electrolyte e ects, Chapter 15)
peripheral and pulmonary depending on agent (see
edema Chapter 15)
311
CHAPTER
18 AntiarrhythmicDrugs
T is chapter wi be most use u a er having a basic understanding o the materia
DRUGS IN THIS CHAPTER
in Chapter 29, Anti-Arrhythmic Drugs in Goodman & Gilman’s T e Pharmacological
• Adenosine (ADENOCARD) Basis of T erapeutics, 12th Edition. In particu ar, the reader is directed to the o owing
• Amiodarone (CORDARONE) tab es, and to animations avai ab e in the on ine version o Goodman & Gilman’s T e
Pharmacological Basis of T erapeutics:
• Digoxin (LANOXIN; see Chapter 17)
• Diltiazem(CARDIZEM) • ab e 29-1 Drug-Induced Cardiac Arrhythmias, which shows drugs known to cause
arrhythmias (ie, proarrhythmias), the ike y arrhythmogenic mechanism, the treat-
• Disopyramide (NORPACE) ment, and the c inica eatures o the proarrhythmia
• Do etilide (TIKOSYN) • ab e 29-4 Patient-Speci c Anti-arrhythmic Drug Contraindications, which shows
• Dronedarone (MULTAQ) conditions and contraindicated drugs
• Esmolol (BREVIBLOC) • Severa animations in the on ine version o Goodman & Gilman’s T e Pharmaco-
• Flecainide (TAMBOCOR) logical Basis of T erapeutics i ustrate the e ectrophysio ogy o cardiac ce s and the
• Ibutilide (CORVERT) mechanism o action o antiarrhythmic drugs
• Lidocaine (XYLOCAINE) LEARNING OBJECTIVES
• Mexiletine (MEXITIL) Know the princip es o cardiac e ectrophysio ogy especia y the ion channe s,
• Procainamide (PRONESTYL) exchangers, and pumps that are targets o antiarrhythmic drugs.
• Propa enone (RYTHMOL) Understand the mechanisms that cause cardiac arrhythmias.
• Propranolol (INDERAL; see Chapter 7) Know the common and important tachyarrhythmias and their mechanisms.
• Quinidine (QUINIDEX) Understand the mechanisms and c assi cation o antiarrhythmic drugs.
• Sotalol (BETAPACE)
Know the princip es o antiarrhythmic drug pharmacotherapy.
• Verapamil (CALAN; see
Know the pharmaco ogica , pharmacokinetic, and adverse e ects o speci c
Chapter 16)
antiarrhythmic agents.
• In slow-conducting cells o the sinoatrial Class IB Lidocaine, mexiletine Na+ channel blocker, rapid
(SA) node and atrioventricular (AV) node, dissociation
which have relatively ewvoltage-gated
Class IC Flecainide, propa enone Na+ channel blocker, slow
Na+ channels, Phase 0 depolarization is dissociation
caused byopening o voltage-gated L-type
Ca2+ channels. Class II Propranolol, sotalol, esmolol β Adrenergic blocker
• Phase 3 repolarization is primarilycaused Class III Amiodarone, sotalol, ibutilide, Prolongs APD (primarily by K+
byK+ movement out o the cell through do etilide, dronedarone channel blockade)
voltage-gated K+ channels.
Class IV Verapamil, diltiazem Ca2+ channel blocker
• Figure 18-1 shows action potentials rom (nondihydropyridine)
di erent regions o the heart, the ion
currents that contribute to these action Miscellaneous Adenosine Adenosine receptor agonist
potentials, and the corresponding e ects
Miscellaneous Digoxin Na+, K+-ATPase inhibitor
o the ion currents on the electrocardio-
gram(ECG). *Note: Most antiarrhythmic drugs have multiple mechanisms o action (Table 18-1).
312
Antiarrhythmic Drugs CHAPTER 1 8
S inus
node Atria
Ve ntricle s
Conducting s ys te m Ve ntricula r
AV node P urkinje fibe r
myocyte
1
S A node Atria AV n o d e 2
Ac tio n 0
po te ntials P ha s e 4 3
Na + curre nt
Ca 2+ L-type
curre nt
T-type
tra ns ie nt ITO1
outwa rd (4-AP -s e ns itive ) (4-AP -s e ns itive ) (4-AP -s e ns itive ) (4-AP -s e ns itive ) (4-AP -s e ns itive )
curre nt ITO2
(Ca 2+-a ctiva te d) (Ca 2+-a ctiva te d) (Ca 2+-a c tiva te d ) (C a 2+-a ctiva te d) (Ca 2+-a ctiva te d)
Io n fluxe s IKs
de laye d
Inward re ctifie rs IKr
(IK)
Outward IKur
ICl
inwa rd re ctifie r, IK1
pa ce ma ke r curre nt, If
Na +-Ca 2+ excha nge
Na +, K+-ATPa s e
QRS
T
P R inte rva l corre s ponds P QT inte rva l corre s ponds to
ECG
to a tria l de pola riza tion/ ve ntricula r de pola riza tion/
re pola riza tion P R QT re pola riza tion
FIGURE 18-1 Action potentials that occur during normal impulse propagation and the time course o the ion currents that generate them.
MECHANISMS OF CARDIAC
TACHYARRHYTHMIAS
• Three arrhythmogenicmechanisms are
CASE 18-1 thought tounderlie most tachyarrhythmias:
A 53-year-o d woman visits the emergency department a er osing consciousness Enhanced automaticityresulting
»
whi e working in her garden. She says she has recent y had episodes o dizziness and romenhanced phase 4 spontaneous
ainting. Her ECG ooks unremarkab e except that the Q interva is pro onged. depolarization (see Figure 29-10,
Goodman &Gilman, 12th Edition)
a. What are the possible causes o her recent ainting spells?
Triggered automaticity, including
»
T e prolonged Q interval suggests that her ainting spells may be due to torsade
abnormal rhythms associated with
de pointes ( dP) (see Side Bar LONG Q AND ORSADE DE POIN ES).
delayed a terdepolarizations (DADs)
Because her syncope has started airly recently, it is likely that the dP might be
resulting romCa2+ overload, and those
due to a drug that prolongs action potential duration. Drugs that can prolong
associated with earlya terdepolarizations
Q include Class IA and Class III antiarrhythmic drugs (see MECHANISMS OF
(EADs) caused byprolongation o the
AC ION OF DRUGS USED O REA CARDIAC ARRHY HMIAS), as well as
action potential (see Figure 29-6,
many other drugs, including antibiotics (erythromycin, spar oxacin), antipsychot-
Goodman&Gilman, 12th Edition)
ics (chlorpromazine, haloperidol), and antiemetics (domperidone, droperidol).
Another possible cause is hypokalemia, especially i she has been taking diuretics Reentry, which involves the ormation
»
that cause loss o K+. She might also have a orm o hereditary long Q that has o a sel -perpetuating circuit caused
become mani ested due to a Q -prolonging drug or hypokalemia. It is important to byanisotropicconduction around an
determine the drugs that this patient is currently taking and whether any o them anatomicor unctional barrier (see
have been started recently. It would also be use ul to know whether there is a amily Figures 29-7 and 29-8, Goodman &
history o sudden cardiac death which might indicate she has a hereditary orm o Gilman’s The Pharmacological Basis of
long Q syndrome. Therapeutics, 12th Edition)
• Understanding the underlying arrhythmo-
(Continued)
genicmechanismcan acilitate the choice
o antiarrhythmicdrugs (see Table 18-1)
313
SECTION III Modulation of Cardiovascular Function
314
Antiarrhythmic Drugs CHAPTER 1 8
315
SECTION III Modulation of Cardiovascular Function
CASE 18-3
A 59-year-o d man sudden y oses consciousness in a shopping ma . A security guard
at the ma cannot detect a pu se and uses an automated externa de bri ator (AED) to
resuscitate the man. He regains consciousness and is taken by ambu ance to a nearby
hospita . In the emergency department waiting room, he oses consciousness again. His
ECG shows that he is in ventricu ar bri ation.
a. What treatment will this patient receive in the ED?
Ventricular brillation is a li e-threatening arrhythmia and must be treated aggres-
sively to restore normal sinus rhythm. T e patient should be de brillated and
should be administered an intravenous antiarrhythmic drug such as amiodarone,
lidocaine, or procainamide to prevent recurrence. O these 3 drugs, IV amiodarone
is the drug o choice or this indication (see able 18-1).
b. What is the mechanistic rationale or the drug(s) used or the acute treatment o
patients in ventricular bbrillation?
Ventricular brillation is characterized by disorganized reentry in the ventricular myo-
cardium. Amiodarone, lidocaine, and procainamide all block the voltage-gated Na+
channel and increase the threshold voltage required to open the channel. Moreover, all
3 agents exhibit state-dependent block o the Na+ channel ( able 18-2), with amioda-
rone binding the Inactive (I) state, procainamide binding the Open (O) state, and lido-
caine binding both the Inactive and Open states (I>O). By blocking the Na+ channel in
the Open and Inactive states, the drugs will pre erentially block rapidly depolarizing
myocytes, leaving those myocytes depolarizing at normal rates relatively una ected.
T us, any reentrant circuits ormed in the ventricles ollowing the electrical de bril-
lation will be selectively inhibited, thereby preventing recurrence o the tachyarrhyth-
mia. In addition to blocking the Na+ channel, amiodarone and procainamide also have
antiarrhythmic e ects through their actions on blocking outward K+ currents.
c. What treatments might be used in the long-term to prevent another episode o
ventricular brillation in this patient?
T e treatment o choice or long-term prevention o ventricular brillation is an
implantable cardioverter-de brillator (ICD; see able 18-1). Such a device can
be programmed to detect ventricular tachyarrhythmias and deliver a shock and/
or pacing to maintain normal sinus rhythm. As an alternative or in addition to an
ICD, drug therapy that includes a Na+ and/or K+ channel blocker could be used.
Amiodarone is a drug o choice or chronic therapy because it has both Na+ and K+
channel blocking activities and has minimal negative inotropic e ects.
CASE 18-4
A 38-year-o d man comp ains o not having the energy to participate in strenuous
sports that are part o his active i esty e. He had been a competitive amateur cyc ist but
now has di cu ty training. An ECG indicates he has atria bri ation.
a. What are the risks and bene ts o starting this patient on antiarrhythmic drug
therapy?
T e risks o therapy include proarrhythmias as well as extracardiac side e ects
associated with long-term drug therapy. Pharmacological therapy that alleviates the
patient’s atrial brillation may improve quality o li e and reduce the risk o stroke,
but may not reduce mortality.
b. What are the treatment options?
Because o the patient’s age and good health, nonpharmacological therapies should
be considered including ablation and DC cardioversion (see able 18-1). T ese
have the potential to provide permanent or long-term termination o the arrhyth-
mia. Antiarrhythmic drugs carry signi cant risks, and it might be sa er to avoid any
drug therapy, except or anticoagulant therapy, to reduce the risk o stroke.
316
Antiarrhythmic Drugs CHAPTER 1 8
Phenytoin 0.2 I
Mexiletine a 0.3
Disopyramide b 9 O Anticholinergic
Sotalolb β Blockade
Do etilide
Ibutilide
Verapamila
Diltiazem a
Indicates an e ect that is important in mediating the clinical action o a drug. (x)Indicates a demonstrable e ect whose relationship to drug action
in patients is less well established.
a
Indicates drugs prescribed as racemates, and the enantiomers are thought to exert similar electrophysiologic e ects.
b
Indicates racemates or which clinically relevant di erences in the electrophysiologic properties o individual enantiomers have been reported
(see text). One approach to classi ying drugs is: Class Major action
I Na+ channel block
II β blockade
III action potential prolongation (usually by K+ channel block)
IV Ca2+ channel block
Drugs are listed here according to this scheme. It is important to bear in mind, however, that many drugs exert multiple e ects that contribute
to their clinical actions. It is occasionally clinically use ul to subclassi y Na+ channel blockers by their rates o recovery rom drug-induced
block (τrecovery) under physiologic conditions. Because this is a continuous variable and can be modulated by actors such as depolarization o
the resting potential, these distinctions can become blurred: class Ib, τrecovery <1 s; class Ia, τrecovery 1–10 s; class Ic, τrecovery >10 s. These class and
subclass e ects are associated with distinctive ECG changes, characteristic “class”toxicities, and ef cacy in speci c arrhythmia syndromes.
1
These data are dependent on experimental conditions, including species and temperature. O, open-state blocker; I, inactivated-state blocker;
APD, action potential duration.
317
SECTION III Modulation of Cardiovascular Function
CASE 18-5
A 12-year-o d gir is brought to the ED with intermittent symptoms o dizziness and
syncope. Her ECG shows that she has paroxysma supraventricu ar tachycardia (PSV ).
a. What is the most likely arrhythmogenic mechanism causing the PSV ?
T e most common mechanism causing PSV is a reentrant circuit within or near
the AV node (see Figures 29-7 and 29-8, in Goodman & Gilman’s T e Pharmacologi-
cal Basis of T erapeutics, 12th Edition).
b. What is the drug o choice to rapidly terminate the PSV ?
Adenosine (IV) is the drug o choice to rapidly terminate PSV because o its abil-
ity to inhibit conduction through the AV node (see able 18-1). It acts through
purinergic receptors to hyperpolarize AV nodal cells and has a very short hal -li e
(<10 seconds). Other drugs that block AV nodal conduction include Ca2+ chan-
nel blockers (diltiazem and verapamil) and β adrenergic blockers, but adenosine
is the drug o rst choice because o its short hal -li e. Drugs that increase vagal
tone (digitalis, edrophonium, phenylephrine) are less commonly used AV nodal
blockers.
c. What can be done to prevent recurrence o PSV in this patient?
Oral AV nodal blocking agents are the drugs o choice to prevent recurrence o
PSV s (see able 18-1). Flecainide and propa enone are also use ul drugs because
o their ability to alter the electrophysiological properties o the ast-conducting
tissue in the reentrant circuit. Selective ablation o tissue that is critical to the main-
tenance o the reentrant circuit (eg, an accessory pathway) is a treatment o choice
because it can result in a permanent cure.
CASE 18-6
A 62-year-o d man who had a myocardia in arction 3 years ago now comp ains o epi-
sodes o ight-headedness. His cardio ogist determines that his symptoms are the resu t
o nonsustained ventricu ar tachycardia (V ), and that he has deve oped moderate
systo ic heart ai ure.
a. What is the likely cause o this patient’s ventricular tachycardia?
T is patient’s V is likely due to a reentrant circuit near the site o the healed
in arction (see able 18-1).
b. What are the treatment options or this patient?
T e treatment o choice or this patient is an ICD that can sense when the patient
has V or ventricular brillation and can pace or cardiovert the heart into normal
sinus rhythm (see able 18-1). Alternatively or in addition to the ICD, this patient
might receive an antiarrhythmic drug. Because this patient has heart ailure, anti-
arrhythmic drugs that decrease lef ventricular unction (eg, disopyramide and
ecainide) should be avoided. Drugs that would be appropriate are amiodarone,
dronedarone, and K+ channel blockers such as do etilide.
c. T e patient’s cardiologist prescribes amiodarone. What are the toxicities that
might be seen with long-term therapy?
As with most antiarrhythmic agents, there are risks o long-term therapy with
amiodarone that must be considered and mitigated, i possible. Although amio-
darone is e ective in treating a wide range o arrhythmias and is one o the ew
antiarrhythmic agents that has been shown to reduce mortality in clinical trials, it
is associated with a large number o extracardiac toxicities. Serious toxicities (some
o which are li e threatening) include pulmonary toxicity, hepatotoxicity, e ects on
thyroid unction, neuromuscular symptoms, dermatological reactions, and e ects
on vision. T e risk o these toxicities is increased because the mean elimination
hal -li e o amiodarone is more than 50 days.
318
Antiarrhythmic Drugs CHAPTER 1 8
319
SECTION III Modulation of Cardiovascular Function
320
Antiarrhythmic Drugs CHAPTER 1 8
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Disopyramide Chronic treatment o atrial Anticholinergic e ects Can worsen heart ailure
utter/AF Long QT (TdP)
Chronic treatment o ventricular
tachycardia and VF
Class IB Antiarrhythmics— Lidocaine Chronic treatment o ventricular CNS: seizures and tinnitus CNS: tremor, hallucinations,
Sodium Channel Blockers tachycardia and VF drowsiness, coma
(Little E ect on ECG; Fast Severe interactions with
Kinetics) other antiarrhythmics
Mexiletine Chronic treatment o ventricular Tremor and nausea Severe interactions with
tachycardia and VF other antiarrhythmics
Propa enone Chronic treatment o AVnodal β Adrenergic blocking Can increase requency
reentry (PSVTs) and AF e ects (worsening o heart or severity o ventricular
Chronic treatment o ventricular ailure and bronchospasm) tachycardias
arrhythmias (modest ef cacy)
Class II Antiarrhythmics—β Propranolol (and Chronic prevention o TdP β Adrenergic blocking See Chapter 7
Adrenergic Receptor others, see Chapter 7) Rate control in AF e ects (worsening o heart
Antagonists ailure and bronchospasm;
see Chapter 7)
Esmolol Rapid, short-term control o β Adrenergic blocking Because o short hal -li e (9
ventricular rate in patients e ects (dissipate rapidly min), should only be used
with AF or atrial utter in when drug is removed) or short-term use
perioperative and post-
operative settings
Class III Antiarrhythmics— Amiodarone Drug o choice or acute Hypotension and Pulmonary brosis with
Increase Re ractory Period treatment o VF (IV depressed ventricular chronic therapy which can
(Prolong QT) administration) unction with IV be atal (requires periodic
Acute and chronic treatment o monitoring o lung
ventricular tachycardia unction)
Chronic treatment o AF and VF Many other AEs:
corneal microdeposits,
hepatotoxicity,
neuropathies
photosensitivity, thyroid
dys unction
Note: Tissue half-life of
several months
321
SECTION III Modulation of Cardiovascular Function
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Do etilide Chronic treatment o AF Prolongs QT interval
increasing risk o TdP
Class IVAntiarrhythmics— Diltiazem Acute and chronic treatment o Hypotension Sinus bradycardia or AV
Ca2+ Channel Blockers AVnodal reentry (PSVTs) block in combination with
(Nondihydropyridine; Acute and chronic control β blockers
Inhibit SA and AVNodes; o ventricular rate in atrial
Prolong PR) utter/AF
Miscellaneous Adenosine Drug o choice or acute Asystole (<5 seconds) Short hal -li e (<5 seconds)
Antiarrhythmics— treatment o AVnodal reentry Dyspnea minimizes toxicities
Adenosine Receptor (IVadministration)
Agonist
Miscellaneous Digoxin Ventricular rate control in atrial GI, vision, cognitive Arrhythmias
Antiarrhythmics—Na+, brillation dys unction Sinus bradycardia and
K+-ATPase Inhibitor That Modest positive inotrope (see AVblock
Increases Vagal Tone Chapter 17) Severe toxicities can be
treated with antibody
(DIGIBIND)
322
CHAPTER
323
SECTION III Modulation of Cardiovascular Function
Plate le ts
+
COX-1
TxA2
GP IIb/IIIa
IIa
P 2Y1 /P 2Y12
PAR1/PAR4 COX-1 Fibrinoge n
GP IIb/IIIa P GI2
ADP
GP Ia /IIa GP Ib
Co llag e n vWF
FIGURE 19-1 Platelet adhesion and aggregation. GPIa/IIa and GPIb are platelet receptors that bind to collagen and
von Willebrand actor (vWF), causing platelets to adhere to the subendothelium o a damaged blood vessel. PAR1 and
PAR4 are protease-activated receptors that respond to thrombin (IIa); P2Y1 and P2Y12 are receptors or ADP; when stim-
ulated by agonists, these receptors activate the brinogen-binding protein GPIIb/IIIa and cyclooxygenase-1 (COX-1) to
promote platelet aggregation and secretion. Thromboxane A2 (TxA2) is the major product o COX-1 involved in platelet
activation. Prostaglandin I2 (prostacyclin, PGI2), synthesized by endothelial cells, inhibits platelet activation.
324
Drug Therapy of Thromboembolic Disorders CHAPTER 1 9
FIGURE 19-2 Sites o action o antiplatelet drugs. Aspirin inhibits thromboxane A2 (TxA2)
synthesis by irreversibly acetylating cyclooxygenase-1 (COX-1). Reduced TxA2 release attenuates
platelet activation and recruitment to the site o vascular injury. Ticlopidine, clopidogrel, and COMMON INDICATIONS
prasugrel irreversibly block P2Y12, a key ADP receptor on the platelet sur ace; cangrelor and FOR THE USE OF
ticagrelor are reversible inhibitors o P2Y12. Abciximab, epti batide, and tiro ban inhibit the nal ANTICOAGULANTS
common pathway o platelet aggregation by blocking brinogen and von Willebrand actor
(vWF) rom binding to activated glycoprotein (GP) IIb/IIIa. SCH530348 (now known as vorapaxar • Treatment o venous thrombosis and
[ZANTIVITY]) and E5555 (also known as atopaxar) inhibit thrombin-mediated platelet activation pulmonaryembolism
by targeting protease-activated receptor-1 (PAR-1), the major thrombin receptor on platelets.
• Prevention o thromboembolismin
epti batide, or tiro ban). o inhibit the ormation o brin clots, the patient would patients with unstable angina or acute
receive heparin or an LMWH. He would also be started on an oral anticoagulant myocardial in arction
(ie, war arin) be ore discharge but kept on the heparinoid until his INR (see Side • Prevention o thromboembolismin
Bar LABORA ORY MONI ORING OF AN ICOAGULAN HERAPY) is patients with atrial brillation
within the therapeutic range. • Prevention o postoperative deep vein
c. What drugs is this patient likely to receive a er being discharged rom the hospital? thrombosis in patients undergoing
abdominothoracicsurgery, and knee and
o prevent reocclusion o the stented coronary artery, he will need to take low-dose
hip replacements
aspirin, an ADP receptor antagonist (clopidogrel or prasugrel), and war arin. He will
also be started on a β adrenergic antagonist to reduce his risk o heart ailure and • Cardiopulmonarybypass surgerytoprevent
ventricular arrhythmias. clotting o the oxygenator
CASE 19-2
A 78-year-old man receives a total knee replacement. He lives by himsel about an hour’s
drive rom the nearest medical acility. Upon discharge, he is given a prescription
or lovenox.
a. What is the rationale or the use o this agent?
Patients having major orthopedic surgeries such as total knee replacement or hip
replacement are at risk o brin clot ormation because o the surgery which acti-
vates the clotting cascade (see Figure 19-3) and subsequent immobilization which
(Continued)
325
SECTION III Modulation of Cardiovascular Function
promotes blood stasis. o minimize the risk o brin clot ormation that could lead
to pulmonary embolism or stroke, such patients receive an LMWH such as lovenox.
Because this agent has very predictable pharmacokinetics, it does not require labo-
ratory monitoring, and it can be sel -administered by subcutaneous injection, and
is thus well suited or this patient who lives a considerable distance rom the nearest
medical acility.
b. What is the mechanism o action o lovenox?
Lovenox is one o several LMWH agents and has the same mechanism o action as
heparin and other heparinoids such as ondaparinux. Heparin and all o the hepari-
noids contain a pentasaccharide structure (see Figure 19-4) that binds and activates
antithrombin, an endogenous anticoagulant (see Figure 30-5 in Goodman & Gilman’s
T e Pharmacological Basis of T erapeutics, 12th Edition). Once activated, antithrom-
bin inhibits the clotting actors thrombin ( actor IIa) and actor Xa (see Figure 19-3).
Inhibition o thrombin blocks the conversion o brinogen to insoluble brin, whereas
inhibition o actor Xa inhibits conversion o the inactive prothrombin ( actor II)
zymogen to active thrombin ( actor IIa). Because o the smaller size o the LMWHs
compared to standard heparin, the LMWH-antithrombin complexes are more speci c
inhibitors o actor Xa than thrombin (see Figure 30-5 in Goodman & Gilman’s T e
Pharmacological Basis of T erapeutics, 12th Edition).
c. What are the important drug toxicities that this patient should be cautioned to
watch or?
As with all anticoagulants, bleeding is the most important and common toxicity.
Heparin-induced thrombocytopenia (HI ) is also possible with the LMWHs, but
this adverse e ect is much less common than with standard heparin.
CASE 19-3
A 32-year-old woman in good health is discovered to have atrial brillation during a
routine checkup. She does not recall having any symptoms o arrhythmia such as dizzi-
ness or ainting, although she is not able to exercise or as long as she could a ew years
ago. Her cardiologist prescribes war arin.
(Continued)
Plate le ts
X II
VIIIa
X IX IXa Xa Va Fibrino g e n
IIa
VIIa
TF
TF Fibrin TF
TF
TF TF
TF
TF
FIGURE 19-3 Major reactions o blood coagulation. Shown are interactions among proteins o the “extrinsic”(tissue actor
and actor VII), “intrinsic”( actors IX and VIII), and “common”( actors X, V, and II) coagulation pathways that are important
in vivo. Boxes enclose the coagulation actor zymogens (indicated by Roman numerals); the rounded boxes represent the
active proteases. TF, tissue actor. Activated coagulation actors are ollowed by the letter “a”: II, prothrombin; IIa, thrombin.
326
Drug Therapy of Thromboembolic Disorders CHAPTER 1 9
(or –H)
– – – –
H2 COS O 3 COO H2 COS O 3 H2 COS O 3
6
5
O O O –O O
COO
O 4
OH 1
OH O OS O 3 – OH O OH
3 2 O O –
O
–
NHCOCH3 OH NHS O 3 OS O 3 NHS O 3 –
(or –S O 3 – )
FIGURE 19-4 The antithrombin-binding pentasaccharide structure o heparin. Sul ate groups required or binding
to antithrombin are indicated in blue.
(Continued)
Non-functiona l Functiona l
prozymoge ns zygome ns
γ-gluta myl
ca rboxyla s e
OH O
CH3 CH3
oxidize d vita min K Vitamin K oxidize d vita min K O
cycle
R R
OH O
(VKORC1)
NAD vita min K NADH
re ducta s e
X
CPYs 1A1,
1A2, 3A4 R-wa rfa rin S -wa rfa rin CYP 2C9
FIGURE 19-5 The vitamin Kcycle and mechanism o action o war arin. In the racemic mixture o S- and R-enantiomers, S-war arin is more
active. By blocking vitamin Kepoxide reductase encoded by the VKORC1 gene, war arin inhibits the conversion o oxidized vitamin Kepoxide
into its reduced orm, vitamin Khydroquinone. This inhibits vitamin K-dependent γ-carboxylation o actors II, VII, IX, and Xbecause reduced
vitamin Kserves as a co actor or a γ-glutamyl carboxylase that catalyzes the γ-carboxylation process, thereby converting prozymogens to
zymogens capable o binding Ca2+ and interacting with anionic phospholipid sur aces. S-war arin is metabolized by CYP2C9. Common genetic
polymorphisms in this enzyme can in uence war arin metabolism. Polymorphisms in the C1 subunit o vitamin Kreductase (VKORC1) also can
a ect the susceptibility o the enzyme to war arin-induced inhibition, thereby in uencing war arin dosage requirements.
327
SECTION III Modulation of Cardiovascular Function
328
Drug Therapy of Thromboembolic Disorders CHAPTER 1 9
PAI-1
PAI-2
Plas mino g e n
t-PA α 2 -AP
Plas min
Fibrin
FIGURE 19-6 Fibrinolysis. Endothelial cells secrete tissue plasminogen activator (t-PA) at sites o injury. t-PA
binds to brin and converts plasminogen to plasmin, which digests brin. Plasminogen activator inhibitors-1
and -2 (PAI-1, PAI-2) inactivate t-PA; α2-antiplasmin (α2-AP) inactivates plasmin.
329
SECTION III Modulation of Cardiovascular Function
SUMMARY QUIZ
330
Drug Therapy of Thromboembolic Disorders CHAPTER 1 9
Prasugrel Same as clopidogrel; more Bleeding; increased risk Contraindicated in patients with a
ef cacious and predictable or bleeding i urgent history o cerebrovascular disease
antiplatelet e ects than surgery required due because o increased risk o li e-
clopidogrel because o high to irreversible inhibition threatening bleeding
degree o bioactivation o platelets Dose reduction in patients
weighing <60 kg, >75 years o age,
or renal impairment
332
Drug Therapy of Thromboembolic Disorders CHAPTER 1 9
TOXICITIES
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLYIMPORTANT
Fondaparinux Same as heparin; pre erred Bleeding Should not be used in renal
over heparin because o more patients because drug is excreted
predictable PK, no monitoring, in urine
much less risk o HIT than
heparin or LMWHs
Anticoagulant (oral)— War arin Prevent progression or Bleeding, with risk o Contraindicated during pregnancy
Vitamin KAntagonist recurrence o acute DVT or major bleeding <3% in due to birth de ects and abortion
pulmonary embolism ollowing patients with target (use a heparinoid anticoagulant
heparin therapy INR o 2-3; risk o instead)
Prevent venous intracranial bleeding Skin necrosis (rare)
thromboembolism in at-risk increases with INR >4 Purple toe syndrome
patients including those with Antidote to war arin overdose is
acute MI, prosthetic heart valve, vitamin K
atrial brillation, or undergoing
orthopedic or gynecological
surgery
Anticoagulant (oral)- Dabigatran Alternative to war arin or Bleeding (routine No currently available antidote (as
Direct Thrombin Inhibitor etexilate chronic anticoagulation in laboratory monitoring there is or war arin)
nonvalvular atrial brillation is unnecessary)
Prevention o venous
thromboembolism and stroke
a ter knee, hip surgery
Anticoagulant (oral)— Rivaroxaban, Alternative to war arin or Bleeding (routine No currently available antidote
Direct Factor Xa Inhibitor apixaban chronic anticoagulation in laboratory monitoring
nonvalvular atrial brillation is unnecessary)
Prevention o venous
thromboembolism and stroke
a ter knee, hip surgery
333
CHAPTER
Bile Acid–Binding Cholestyramine, colestipol, Highly positively charged bile acid sequestrants that bind bile acids in the GI
Resins (Bile Acid colesevelam system, thereby depleting the pool o bile acids and stimulating hepatic bile acid
Sequestrants) production which leads to reduced hepatic cholesterol content
(Continued)
334
Drug Therapy o Dyslipidemias CHAPTER 2 0
Fibric acid (Fibrates) Gem brozil, eno brate, Unclear, but likely involves activation o PPARα in liver and brown adipose tissue
cipro brate (not marketed in the which stimulates atty acid oxidation, increases lipoprotein lipase, and reduces
United States), beza brate (not expression o apoC-III
marketed in the United States),
clo brate (no longer available)
Cholesterol Ezetimibe Inhibits cholesterol absorption at the brush border o the small intestine by inhibiting
Absorption Inhibitors sterol transport protein Niemann-PickC1-Like1 (NPC1L1) in jejunal enterocytes
CASE 20-1
A 58-year-old man sees his physician or a routine checkup. He is in good health with
no symptoms or complaints. He does not have a amily history o premature heart dis-
ease, although his paternal grand ather su ered a non atal heart attack when he was 67.
Just prior to the checkup, he provides asting blood samples or lipid pro les. His
plasma cholesterols are: total cholesterol, 203 mg/dL; HDL cholesterol, 52 mg/dL; LDL
cholesterol, 130 mg/mL; VLDL cholesterol, 21 mg/dL. His triglycerides are 148 mg/dL.
His asting serum glucose is in the normal range and his blood pressure is 128/75. He is
not currently taking any medications, has never smoked, and usually has 1 or 2 glasses TRADITIONAL MAJOR RISK
o wine with dinner, but consumes no other alcoholic beverages. FACTORS FOR CORONARY
a. What is this patient’s 10-year risk o a CVD event? HEART DISEASE
able 31-6 in Goodman & Gilman’s T e Pharmacological Basis of T erapeutics, 12th • Elevated LDL-C(>160 mg/dL; see
Edition provides an algorithm or estimating the 10-risk o coronary vascular Tables 20-1 and 20-2)
disease (CVD) events based on data rom the Framingham Heart Study. T e risk • Reduced HDL-C(<40 mg/dL; see
prediction or a CVD event will exceed the risk o a coronary heart disease (CHD) Table 20-2)
event. For this patient, the risk actors and CVD points associated with each risk
• Cigarette smoking (within the preceding
(Continued)
30 days)
Die ta ry fa t + chole s te rol
• Hypertension (blood pressure ≥140/90 mm
Hg or use o antihypertensive medication,
LP L Chylomicron regardless o blood pressure)
Chylomicrons
re mna nts
INTESTINE FFA • Type 2 diabetes mellitus
Adipos e LP L
tis s ue • Advancing age (men >45 years o age or
HL
women >55 years o age)
• Familyhistoryo premature coronaryheart
Pe riphe ra l
Bile a cids FFA tis s ue s
disease (CHD) events (men <55 years;
(with LDL women <65years) in a frst-degree relative
re ce ptors )
FFA • Obesity(bodymass index[BMI] >25 kg/m2
LP L
and waist circum erence >40 in [men] or
VLDL IDL LDL >35 in [women])
LDL LP L HL
LIVER re ce ptors
ApoE me dia te d
Re mna nt
re ce ptors ApoB me dia te d
ApoE me dia te d
HIGH-RISK DYSLIPIDEMIAS
FIGURE 20-1 The major pathways involved in the metabolism o chylomicrons synthesized
by the intestine and VLDL synthesized by the liver. Chylomicrons are converted to chylomicron
(SEE TABLE 20-2)
remnants by the hydrolysis o their triglycerides by LPL. Chylomicron remnants are rapidly cleared • High total cholesterol (≥240 mg/dL)
rom the plasma by the liver. “Remnant receptors”include the LDL receptor–related protein (LRP),
LDL receptors, and perhaps other receptors. Free atty acid (FFA) released by LPL is used by mus- • High LDL-C(>160 mg/dL)
cle tissue as an energy source or taken up and stored by adipose tissue. HL, hepatic lipase; IDL, • LowHDL-C(<40 mg/dL)
intermediate-density lipoproteins; LDL, low-density lipoproteins; LPL, lipoprotein lipase; VLDL, • Severe hypertriglyceridemia (≥500 mg/dL)
very-low-density lipoproteins.
335
SECTION III Modulation of Cardiovascular Function
actor are: age (10 points); HDL (–1 point); total cholesterol (2 points); systolic
PRIMORDIAL PREVENTION
blood pressure (0 points); smoker (0 points), diabetic (0 points). T e total number
GUIDELINES (TO PREVENT
o CVD points is 11, placing his 10-year risk o a CVD event at 11.2%.
DEVELOPMENT OF CVD
RISK FACTORS) b. What, i anything, can be done to reduce this patient’s risk o a CVD event?
• 150 min/wko moderate intensityexercise T is patient’s largest CVD risk is his age, which is not a modi able risk actor.
(walking 20-30 min/d) Another risk actor which cannot be modi ed is his sex; a woman o the same age
with all the same lipid, blood pressure, and history would have a 10-year risk o a
• Reducing total calories rom at to less than CVD event o 6.3%. Based on able 31-6 in Goodman & Gilman’s T e Pharmacologi-
30%, with saturated and trans at toless cal Basis of T erapeutics, 12th Edition, the modi able risk actors or this patient are
than 7% his blood lipids and his systolic blood pressure. With optimal blood lipids and sys-
• Consuming less than 300 mg cholesterol/d tolic blood pressure, his CVD points would be reduced to 6 points and his 10-year
• Eat a varietyo oilyfsh at least twice a week risk o a CVD event would be reduced to 4.7%.
• Eat oils/ oods rich in α-linolenicacid c. What are the treatment options to maximally reduce this patient’s 10-year
• Restricting sugarybeverages to less than CVD risk?
36 oz/wk or a person consuming 2000 T e rst option is or the patient to adopt changes in exercise and diet (see Side
Kcal daily Bar PRIMORDIAL PREVEN ION GUIDELINES). Such li estyle changes can be
e ective in lowering blood pressure and improving blood lipid pro les. I li estyle
changes do not adequately improve blood lipid pro les, it may be prudent to start
the patient on drugs that lower serum cholesterol (based on able 20-1). o reach
optimal levels o total cholesterol and LDL-C in this patient (<200 mg/dL and <100
mg/dL, respectively; see able 20-2), the lowest dose o a statin drug should be su -
cient (see able 31-10 in Goodman & Gilman’s T e Pharmacological Basis of T era-
peutics, 12th Edition).
(Continued)
TABLE 20-1 Treatment Based on LDL-C Levels (2004 Revision o NCEP Adult Treatment Panel III Guidelines)
LDL C GOAL NON HDL C THERAPEUTIC THRESHOLD FOR
RISK CATEGORY mg/dL GOAL mg/dL LIFESTYLE CHANGE DRUG THERAPY mg/dL
Very high risk <70a <100 No threshold No threshold (initiate therapy)
Atherosclerosis-induced CHD plus (initiate change)
one o :
• multiple risk factors
• diabetes mellitus
• a poorly controlled single factor
• acute coronary syndrome
• metabolic syndrome
Moderately high risk <130 (optional <100) <160 No threshold ≥130 (100-129)b
2+ risk actors
10-year risk: <10–20%
336
Drug Therapy o Dyslipidemias CHAPTER 2 0
<200 Desirable
≥240 High
HDL-C
>60 High
LDL-C
<70 Optimal or very high risk (minimal goal or CHD equivalent patients)
<100 Optimal
160-189 High
Triglycerides
<150 Normal
200-499 High
337
SECTION III Modulation of Cardiovascular Function
CASE 20-2
A 52-year-old woman with a history o angina, hypertension (blood pressure o
140/80 mm Hg), and type 2 diabetes su ers an acute myocardial in arction and
receives angioplasty and a stent to open a blocked coronary artery. She has been taking
medications or her hypertension and diabetes, but no other medications. She smokes
a pack o cigarettes each day. Be ore she is discharged rom the hospital, her asting
blood lipids are measured: total cholesterol, 240 mg/dL; HDL-C, 30 mg/dL; LDL-C,
160 mg/dL; triglycerides, 220 mg/dL.
a. What is the 10-year risk this woman will have a CVD event?
Based on able 31-6 in Goodman & Gilman’s T e Pharmacological Basis of T era-
peutics, 12th Edition, this patient’s risk actors and CVD points are: age (7 points),
HDL-C (2 points), total cholesterol (4 points), SBP (5 points), smoker (3 points),
and diabetes (4 points). Her total number o CVD points is 25 placing her 10-year
risk o a CVD event at greater than 30%.
b. What are the recommended treatment options to reduce the risk o another
myocardial in arction or other CVD event in this patient?
Patients such as this woman who have had a CVD event are at the greatest risk o
another CVD event and need to be treated aggressively to reduce their risk (see
able 20-1). She should be counseled to adopt a healthy diet and to begin a moder-
ate exercise program (see Side Bar PRIMORDIAL PREVEN ION GUIDELINES).
Her hypertension and diabetes medications should also be reviewed and adjusted
to optimize systolic blood pressure and blood glucose.
Her dyslipidemias should be treated aggressively with goals o reducing her
LDL-C to less than 70 mg/dL (see able 20-1) and C:HDL-C ratio to less than
3.5 (see able 31-9 in Goodman & Gilman’s T e Pharmacological Basis of T era-
peutics, 12th Edition). o reach the goal o reducing her LDL-C to less than 70
mg/L (ie, 44%), she should be started on a statin dosage that achieves this goal
(see able 31-10 in Goodman & Gilman’s T e Pharmacological Basis of T erapeu-
tics, 12th Edition).
c. She is started on rosuvastatin 10 mg daily. When should she take this dose?
Rosuvastatin has a t1/2 o 20 to 30 hours and can be taken at any time o the day.
Statins with a short t1/2 (<4 hours) such as uvastatin, lovastatin, simvastatin, and
others (see text) should be taken in the evening since hepatic cholesterol synthesis
is maximal between midnight and 2:00 AM.
d. What are the common adverse ef ects o statins?
Myopathy and rhabdomyolysis are the major adverse e ects o statins and can
result in death (1 death per million 30-day prescriptions). T e risk o myopathy
is increased with dose and plasma concentrations. Concomitant use o drugs that
diminish statin catabolism or inter ere with hepatic uptake is associated with 50 to
60% o all cases o myopathy and rhabdomyolysis. T e most common statin inter-
actions are with some o the brates such as gem brozil. Gem brozil inter eres
with hepatocyte uptake o statins by OA P1B1 and its catabolism by glucuronida-
tion. Fibrates such as eno brate do not inter ere with statin glucuronidation, and
are not associated with myopathy when used concomitantly.
Hepatotoxicity has also been associated with statin use and is dose-related. Serious
hepatotoxicity occurs at a rate o 1 case per million person-years o use. Because
there is some risk o liver damage with statins, it is reasonable to measure serum ala-
nine aminotrans erase (AL ) at baseline and subsequently when clinically indicated.
CASE 20-3
A 64-year-old man with highly elevated total cholesterol and LDL-C is not responding
adequately to high-dose statin therapy.
(Continued)
338
Drug Therapy o Dyslipidemias CHAPTER 2 0
a. What additional drug therapies are available to lower this patient’s serum
cholesterol?
When used in combination with statins, other lipid-lowering drugs such as the bile
acid–binding resins, niacin, brate, and ezetimibe can produce greater reductions
in LDL-C than can be achieved with statins alone (see text: Statins in Combination
With Other Lipid-Lowering Drugs in Goodman & Gilman’s T e Pharmacological
Basis of T erapeutics, 12th Edition). riple therapy with resins, niacin, and statins
can reduce LDL-C by up to 70%. Vytorin, a xed combination o simvastatin and
ezetimibe, can reduce LDL-C levels by 60%.
b. What are the considerations in using multiple agents to treat dyslipidemias?
T ere can be adverse drug interactions that occur when statins are combined with
other lipid-lowering agents, as well adverse e ects due solely to each o the indi-
vidual agents. Cholestyramine and colestipol bind to many drugs and inter ere with
their absorption, including some o the statins. T us, it is wise to administer all
drugs either 1 hour be ore or 3 to 4 hours a er a dose o cholestyramine, colestipol,
or other bile acid–binding resins. Patients taking cholestyramine and colestipol
o en complain o bloating and dyspepsia.
T e occurrence o myopathy increases when statin doses o greater than 25% o the
maximal dose (eg, 20 mg o simvastatin or atorvastatin) are used with niacin.
T ere is also an increased risk o myopathy with combination therapy using a statin
and brate (gem brozil or eno brate), but this combination is usually sa e i the
brate is used at its usual maximal dose and a statin at no more than 25% o its
maximal dose. Feno brate is least likely to inter ere with statin metabolism and
appears to be the sa est drug to use with statins. Combined statin- brate therapy
should be avoided in patients with compromised renal unction.
CASE 20-4
A 30-year-old woman makes her rst visit to the doctor in 10 years. Her asting plasma
lipids are: total cholesterol, 210 mg/dL; LDL-C, 140 mg/dL; HDL-C, 40 mg/dL; and
triglycerides, 180 mg/dL. Her asting glucose is 110 mg/dL, her waist circum erence is
40 in, and her blood pressure is 125/80 mm Hg. T is patient has 3 or more risk actors
that identi y her as having metabolic syndrome.
a. What are this patient’s CHD risk actors that are part o the constellation known
as metabolic syndrome?
T e CHD risk actors that identi y this patient as having metabolic syndrome are
her abdominal obesity, high levels o triglycerides, low HDL-C, and high asting
glucose (see able 31-8 in Goodman & Gilman’s T e Pharmacological Basis of T era-
peutics, 12th Edition). T ere is an increased CHD risk associated with the insulin-
resistant, prediabetic state known as metabolic syndrome.
b. What should be the ocus o treatment in this patient?
reatment should ocus on weight loss and increased physical activity to reduce
obesity. In addition, reducing or eliminating alcohol intake and reducing as much
at as possible rom the diet can reduce triglyceride levels. Drug therapy should
ocus on reducing LDL-C, non–HDL-C, and triglycerides, and increasing HDL-C.
T e LDL-C therapy goal should be less than 70 mg/dL (see able 20-1).
c. What drug therapies are most ef ective in treating patients with high triglycer-
ides and low HDL-C levels associated with the metabolic syndrome?
T e brates play an important role in such patients. It is important to monitor LDL
levels when using brates in these patients as LDL levels may rise. I LDL levels rise,
it might be necessary to add a low-dose statin. Many such patients are treated rst
with a statin; then a brate is added. It is important to monitor or myopathy when
using a statin- brate combination (see answer to Case 20-3, question b).
(Continued)
339
SECTION III Modulation of Cardiovascular Function
CASE 20-5
A male patient’s LDL-C levels remain high even with maximal dosing (80 mg daily) o
simvastatin. He is changed to a combination tablet (VY ORIN) containing 80 mg sim-
vastatin and 10 mg ezetimibe.
a. What is the rational or this drug combination?
Statins, which inhibit cholesterol biosynthesis, increase intestinal cholesterol
absorption. Ezetimibe, which inhibits intestinal cholesterol absorption, enhances
cholesterol biosynthesis. Dual therapy with these 2 classes o drugs prevents both
the enhanced cholesterol synthesis induced by ezetimibe and the increase in choles-
terol absorption induced by statins. T is combination provides additive reductions
in LDL-C levels irrespective o the statin employed.
b. What is the molecular target o ezetimibe?
Ezetimibe inhibits luminal cholesterol uptake by jejunal enterocytes, by inhibit-
ing the transport protein NPC1L. Ezetimibe does not a ect intestinal triglyceride
absorption. In human subjects, ezetimibe reduced cholesterol absorption by 54%,
precipitating a compensatory increase in cholesterol synthesis that can be inhibited
with a cholesterol synthesis inhibitor such as a statin.
c. How does ezetimibe reduce plasma LDL-C?
Inhibiting intestinal cholesterol absorption causes a reduction in the incorporation
o cholesterol into chylomicrons. T e reduced cholesterol content o chylomicrons
diminishes the delivery o cholesterol to the liver by chylomicron remnants. Reduced
delivery o intestinal cholesterol to the liver by chylomicron remnants stimulates
expression o the hepatic genes regulating LDL receptor expression and cholesterol
biosynthesis. T e greater expression o hepatic LDL receptors enhances LDL-C clear-
ance rom the plasma. Indeed, ezetimibe reduces LDL-C levels by 15 to 20%.
d. Why not use ezetimibe or monotherapy?
T e maximal ef cacy o ezetimibe or lowering LDL-C is 15 to 20% when used as
monotherapy. T is reduction is equivalent to, or less than, that attained with 10- to
20-mg doses o most statins. Consequently, the role o ezetimibe as monotherapy
in patients with elevated LDL-C levels appears to be limited to the small group o
statin-intolerant patients.
340
Drug Therapy o Dyslipidemias CHAPTER 2 0
KEY CONCEPTS
Patients with any type o dyslipidemia are at increased risk o CHD and
CVD events.
In the absence o vascular disease, type 2 diabetes mellitus, or metabolic syn-
drome, the need or cholesterol-lowering drugs in many patients will be allevi-
ated by maintaining ideal body weight, eating a diet low in saturated at and
cholesterol, and regular exercise.
Li estyle changes are a cornerstone o managing dyslipidemias.
Dyslipidemic patients with a risk or a CVD should be treated to achieve target
lipid values.
Statins should be the rst-line choice when choosing a lipid-lowering drug.
Initiate treatment with statin doses adequate to reduce the patient’s lipid values
to target goals.
Patients should be counseled regarding the rare but serious side e ects o hepa-
totoxicity and rhabdomyolysis.
For patients with low HDL-C levels, treatment should be based on both LDL-C
levels and the ratio o total cholesterol:HDL-C (see able 31-9 in Goodman &
Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition).
SUMMARY QUIZ
QUESTION 20-1 A patient is prescribed eno brate as part o his therapy to raise his/
her HDL-C levels. Feno brate most likely acts by
a. inhibiting HMG-CoA reductase.
b. binding cell membrane receptors that leads to lowering o adipocyte hormone–
sensitive lipase activity.
c. sequestering bile acids in the small intestine.
d. binding PPARα receptors in liver and brown adipose tissue.
e. inhibiting cholesterol uptake rom the small intestine.
QUESTION 20-3 A patient is prescribed lovastatin to lower total cholesterol and LDL-C.
For maximal e ect, he should take his medication
a. be ore break ast.
b. with break ast.
c. an hour a er break ast.
d. with his evening meal.
e. at bedtime.
341
SECTION III Modulation of Cardiovascular Function
QUESTION 20-4 A patient taking digoxin or his heart ailure is started on lovastatin
and cholestyramine to lower his/her LDL-C levels. T e dose o digoxin
a. should be increased.
b. should be decreased.
c. should be taken 1 hour be ore or 3 to 4 hours a er a dose o cholestyramine.
d. should be eliminated to prevent serious drug interactions.
e. will not be a ected as there are no known drug interactions among these drugs.
QUESTION 20-5 A patient is being started on statin therapy. What should be consid-
ered in choosing which statin to use?
a. Ef cacy in reducing LDL-C
b. Cost
c. Sa ety
d. All o the above
e. None o the above
L-thyroxine, digoxin, war arin, and some o the statins. T e e ect o cholestyramine
and colestipol on the absorption o most drugs has not been studied. For this reason, it
is wise to administer all drugs either 1 hour be ore or 3 to 4 hours a er a dose o chole-
styramine or colestipol. Colesevelam does not appear to inter ere with the absorption
o at-soluble vitamins or o drugs such as digoxin, lovastatin, war arin, metoprolol,
quinidine, and valproic acid. T e e ect o colesevelam on the absorption o other drugs
has not been tested, but it seems prudent to recommend that patients take other medi-
cations 1 hour be ore or 3 to 4 hours a er a dose o colesevelam.
QUESTION 20-5 Answer is d. T e choice o statins should be based on ef cacy (reduction
o LDL-C), cost, and sa ety. T ree drugs (lovastatin, simvastatin, and pravastatin) have
been used sa ely in clinical trials involving thousands o subjects or 5 or more years. T e
documented sa ety records o these statins should be considered, especially when initiating
therapy in younger patients. Once drug treatment is initiated, it is almost always li elong.
Bile Acid–Binding Cholestyramine Probably the sa est Bloating and dyspepsia Rare instances o hyperchloremic
Resins (Bile Acid Colestipol lipid-lowering drugs Constipation acidosis because these are
Sequestrants) Colesevelam because they are not Colesevelam may be less administered as chloride salts
absorbed systemically likely to cause dyspepsia, Severe hypertriglyceridemia is
Recommended or bloating, and constipation a contraindication to the use o
patients 11-20 y o age Cholestyramine and colestipol cholestyramine and colestipol because
O ten used as second bind and inter ere with the these resins increase triglyceride levels
agents with statins absorption o many drugs; it
is wise to administer all drugs
either 1 h be ore or 3-4 h a ter
a dose o a bile acid resin
Nicotinic Acid Niacin Favorably af ects all lipid Flushing, pruritus, and Hepatotoxicity, mani ested as elevated
parameters, it is the best dyspepsia limit patient serum transaminases
agent or increasing compliance Hyperglycemia and niacin-induced
HDL-C, and also lowers Rarer episodes o nausea, insulin resistance; in patients with
triglycerides, and reduces vomiting, and diarrhea known or suspected diabetes, blood
LDL-C Should not be taken by glucose levels should be monitored at
pregnant women least weekly until proven to be stable
Concurrent use o niacin and a statin
can cause myopathy; the statin should
be administered at no more than 25%
o its maximal dose; patients should be
instructed to discontinue therapy i u-
like muscle aches occur
Patients with any history o peptic ulcer
disease should not take niacin
Gout is a relative contraindication
343
SECTION III Modulation of Cardiovascular Function
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Fibric Acid (Fibrates) Gem brozil Usually the drugs o Gastrointestinal side ef ects A myopathy syndrome occasionally
Clo brate (no choice or treating severe occur in up to 5% o patients occurs in subjects taking clo brate,
longer available) hypertriglyceridemia, Fibrates should not be used by gem brozil, or eno brate
Feno brate the chylomicronemia children or pregnant women Myopathy may occur in up to 5% o
Cipro brate (not syndrome, hyperlipidemic patients treated with a combination o
marketed in the subjects with type III gem brozil and higher doses o statins
United States) hyperlipoproteinemia Feno brate-statin combinations are
Beza brate (not as well as subjects less likely to cause myopathy than
marketed in the with severe combination therapy with gem brozil
United States) hypertriglyceridemia and statins
(triglycerides >1000 mg/ Renal ailure and hepatic dys unction
dL) who are at risk or are relative contraindications to the use
pancreatitis o brates
Fibrates appear to
have an important role
in subjects with high
triglycerides and low
HDL-C levels associated
with the metabolic
syndrome or type 2
diabetes mellitus
344
SECTION
Infammation, Immunomodulation,
and Hematopoiesis IV
21. Histamine, Bradykinin, and T eir Antagonists 346
345
CHAPTER
21 Histamine, Bradykinin,
and Their Antagonists
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED
Chapter 32, Histamine, Bradykinin, and T eir Antagonists in Goodman & Gilman’s
IN THIS CHAPTER T e Pharmacological Basis of T erapeutics, 12th Edition In addition to the material
• Acrivastine (SEMPREX-D*) presented here, the 12th Edition contains:
• Aprotinin (TRAYSYLOL) • able 32-1 Characteristics o Histamine Receptors, which shows the biochemical
• Azelastine (ASTELIN) properties, tissue distribution, and representative agonists and antagonists o the
4 histamine receptors (H 1, H 2, H 3, and H 4)
• Brompheniramine maleate
(BROMPHEN, others) • able 32-2 Preparations and Dosage o Representative H 1-Receptor Antagonists
• Carbinoxamine (RONDEC*, others) • T e molecular structures o histamine and drugs that are agonists and antagonists
o the various histamine receptors
• Cetirizine (ZYRTEC)
• Chlorpheniramine (CHLOR-TRIMETON, others)
• Clemastine umarate (TAVIST,others) LEARNING OBJECTIVES
• Cyclizine (MAREZINE) Understand the role o histamine and bradykinin in di erent physiological and
pathophysiological processes
• Cyproheptadine (PERIACTIN)
• Desloratadine (CLARINEX,AERIUS) Understand the mechanisms o action o drugs that act as antagonists o the
H 1 receptor
• Dimenhydrinate (combination o diphen-
hydramine and 8-chlorotheophylline; Know the therapeutic utility o H 1-receptor antagonists, alone and in combina-
DRAMAMINE, others) tion with other agents
• Diphenhydramine (BENADRYL, others) Know the important adverse e ects o H 1-receptor antagonists, and the di er-
ence between rst- and second-generation H 1 antihistamines with regard to
• Doxepin (SINEQUAN)
adverse e ects
• Ebastine (EBASTEL)
• Fexo enadine (ALLEGRA,TELFAST)
• Hydroxyzine (ATARAX,others) MECHANISMS OF ACTION OF HISTAMINE RECEPTOR AND BRADYKININ
ANTAGONISTS
• Hydroxyzine (VISTARIL)
• Icatibant (FIRAZYR) DRUG CLASS DRUG MECHANISM OF ACTION
346
Histamine, Bradykinin, and Their Antagonists CHAPTER 2 1
347
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
b. She nds the diphenhydramine causes her to be drowsy. Why does this agent
FIRST-GENERATION
cause drowsiness?
VERSUS SECOND-
GENERATION H1 T e rst-generation H 1 antagonists can cross the blood-brain barrier and can both
stimulate and depress the CNS. T e most requent side e ect in rst-generation H 1
ANTIHISTAMINES (Cont.)
antagonists is sedation and usually accompanies therapeutic doses o the older H 1
• ManyH1 antihistamines (both rst and sec- antagonists. Diminished alertness, slowed reaction times, and somnolence are com-
ond generation) are metabolized byCYPs; mon mani estations o the central CNS depression caused by these agents. Concur-
thus, inhibitors o CYPactivitycan increase rent ingestion o alcohol or other CNS depressants produces an additive e ect that
H1 antihistamine levels, leading to toxicity. impairs motor skills. Patients vary in their susceptibility and responses to individual
• Certain H1 antihistamines, especially rst- drugs. T e ethanolamines, which include diphenhydramine, are particularly prone
generation drugs, are possible teratogens to causing sedation. Because o the sedation that occurs with rst-generation anti-
or cause symptomatice ects in in ants histamines, these drugs cannot be tolerated or used sa ely by many patients except
resulting romsecretion o the drug into at bedtime. Even then, patients may experience an antihistamine “hangover” in
breast milk. the morning, resulting in sedation with or without psychomotor impairment. CNS
» Cetirizine and loratadine are pre erred stimulation occasionally is encountered in patients given conventional doses o
in pregnant women i H1 antihistamines rst-generation H 1 antagonists; they become restless, nervous, and unable to sleep.
are required, but i theyare not Central excitation also is a striking eature o overdose, which commonly results
e ective, diphenhydramine can be in convulsions, particularly in in ants. Other untoward central actions caused by
used sa elyin pregnant (but not breast- rst-generation H 1 antagonists include dizziness, tinnitus, lassitude, incoordination,
eeding) women. atigue, blurred vision, diplopia, euphoria, nervousness, insomnia, and tremors.
c. What alternatives does she have to treat her allergy symptoms without getting
drowsy?
T e second-generation H 1 antagonists (eg, levocetirizine, cetirizine, loratadine,
desloratadine, exo enadine) are largely devoid o these side e ects because they do
not penetrate the central nervous system (CNS). T us, they usually are the drugs o
choice or the treatment o allergic disorders.
d. She plans to get pregnant and is concerned about whether she can treat her
allergies when she is pregnant. What are her options?
Caution should be used in treating pregnant or lactating women with certain H 1
antihistamines, especially rst-generation drugs, because o their possible terato-
genic e ects or symptomatic e ects on in ants resulting rom secretion o the drug
into breast milk. Cetirizine and loratadine are pre erred i H 1 antihistamines are
required, but i they are not e ective, diphenhydramine can be used sa ely in preg-
nant (but not breast- eeding) women.
CASE 21-2
A 32-year-old man visits his dermatologist because he is very sensitive to mosquito bites
When bitten by a mosquito, he immediately experiences redness at the site o the bite
T e redness gradually grows to about the size o a dime and a small itchy bump orms
a. What is causing the progression in this patient’s symptoms ollowing a
mosquito bite?
T e mosquito bite is causing the release o histamine rom mast cells in the skin that
results in a classic “triple response” (see Side Bar RIPLE RESPONSE OF LEWIS)
o redness, are, and wheal characteristic o intradermal injection o histamine.
b. What can be done to treat this patient’s mosquito bites?
H 1 antihistamines can e ectively attenuate or block all o the reactions to the mos-
quito bite. opical preparations o H 1 antihistamines are available (see able 32-2 in
Goodman & Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition) that
can be applied to the mosquito bite to relieve itching and reduce the redness and
wheal. However, there is a possibility o producing allergic dermatitis due to the
development o drug allergy with topical application o H 1 antagonists. T e patient
may also bene t rom taking an oral antihistamine i he receives a number o bites,
although relie o symptoms may take 1 hour or longer.
(Continued)
348
Histamine, Bradykinin, and Their Antagonists CHAPTER 2 1
CASE 21-3
A 57-year-old woman with a history o allergies to sea ood suddenly develops swelling
o her lips and ace while dining in a restaurant She also begins to eel light-headed,
and her tongue and mouth begin to itch
a. What is likely causing this woman’s symptoms?
Her symptoms are consistent with an allergic (ie, immediate hypersensitivity) reac-
tion, perhaps due to the presence o sea ood in something she has just eaten at the
restaurant. T e principal target cells o immediate hypersensitivity reactions are
mast cells and basophils. As part o the allergic response to an antigen, immuno-
globulin E (IgE) antibodies are generated and bind to the sur aces o mast cells and
basophils via speci c high-a nity Fc receptors. Antigen bridges the IgE molecules
and via FcεRI activates signaling pathways in mast cells or basophils involving tyro-
sine kinases and subsequent phosphorylation o multiple protein substrates within
5 to 15 seconds o contact with antigen. T ese events trigger the exocytosis o the
contents o secretory granules, which contain histamine. A er its release rom
storage granules, histamine plays a central role in immediate hypersensitivity and
allergic responses. T e actions o histamine on bronchial smooth muscle and blood
vessels account or many, but not all, o the symptoms o the allergic response. A
broad spectrum o other in ammatory mediators is released on mast cell activation
including platelet-activating actor (PAF) and metabolites o arachidonic acid such
as leukotrienes C4 and D4, which contract the smooth muscles o the bronchial tree.
Kinins also are generated during some allergic responses.
T e e ects o histamine in an allergic reaction are largely mediated by its activation
o H 1 receptors which are distributed widely in the periphery. Histamine characteris-
tically dilates resistance vessels, increases capillary permeability, and lowers systemic
blood pressure. Vasodilation is the most important vascular e ect o histamine in
humans. Activation o either the H 1 or H 2 receptor can elicit maximal vasodilation,
but the responses di er. H 1 receptors have a higher a nity or histamine and cause
Ca2+-dependent activation o endothelial NOS (eNOS) in endothelial cells; NO
di uses to vascular smooth muscle, increasing cyclic guanosine monophosphate
(cyclic GMP) (see able 32–1 in Goodman & Gilman’s T e Pharmacological Basis of
T erapeutics, 12th Edition) and causes relaxation that results in a relatively rapid and
short-lived vasodilation. By contrast, activation o H 2 receptors on vascular smooth
muscle stimulates the cyclic AMP–PKA pathway, causing dilation that develops
more slowly and is more sustained. As a result, H 1 antagonists e ectively counter
small dilator responses to low concentrations o histamine but only blunt the initial
phase o larger responses to higher concentrations o the amine. Histamine’s e ect
on small vessels results in ef ux o plasma protein and uid into the extracellular
spaces and an increase lymph ow, causing edema. H 1 receptors on endothelial cells
are the major mediators o this response. Increased capillary permeability results
rom histamine activation o H 1 receptors on postcapillary venules, which causes
contraction o the endothelial cells, disrupts interendothelial junctions, and exposes
the basement membrane, which is reely permeable to plasma proteins and uid.
b. T e woman recognizes the symptoms o an allergic reaction and takes some
diphenhydramine, which she always carries with her (as well as an EPI-PEN
autoinjector). T e swelling in her throat continues and she begins having
di culty breathing so she sel -administers epinephrine using the EPI-PEN.
Why did she need epinephrine in addition to diphenhydramine?
During hypersensitivity reactions, histamine is one o the many potent autacoids
released, and its relative contribution to the ensuing symptoms varies widely.
Edema ormation and itch are e ectively suppressed by H 1 antagonists such as
diphenhydramine, but other e ects, such as hypotension, are less well antagonized.
T is may be explained by the participation o other types o H receptors and by
e ects o other mast cell mediators, chie y eicosanoids (see Chapter 22).
(Continued)
349
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
CASE 21-4
A patient who is prone to motion sickness will be taking a small erry to reach an
island destination on her vacation travels
a. She would like to take something to prevent the motion sickness on the erry
ride. What are her options?
Many o the rst-generation H 1 antagonists have antimuscarinic actions in the CNS
that can be used to treat motion sickness (see Chapter 9). Cyclizine and meclizine
are used primarily to prevent motion sickness and vertigo although promethazine
and diphenhydramine are more e ective. None o these agents are as e ective as the
antimuscarinic agent scopolamine, which is the most e ective drug or the prophy-
laxis and treatment o motion sickness. However, the H 1 antagonists are use ul or
milder cases o motion sickness and have ewer adverse e ects. Promethazine is the
most potent and e ective o the H 1 antagonists in preventing motion sickness, and
its additional antiemetic properties may be valuable in reducing vomiting.
b. When should she take the medication?
Whenever possible, the various drugs should be administered ~1 hour be ore the
anticipated motion. reatment a er the onset o nausea and vomiting rarely is
bene cial.
c. What side ef ects should she expect with the H1 antagonists used or motion
sickness?
Sedation is to be expected with all o these agents.
CASE 21-5
A 23-year old woman has a 2-year old son and both she and her son have symptoms
o a cold, including cough, runny nose, sneezing, and watery eyes She nds an O C
cough and cold medication at the grocery store that is advertised to be e ective in
relieving their symptoms
a. When she gets home rom the store she reads the label more care ully and sees
that promethazine is one o the active ingredients in the cough and cold medica-
tion she purchased. She also reads a warning “Do Not Use in Children 4 Years
and Younger.” What is the reason or this warning?
Use o O C cough and cold medicines (containing mixtures o antihistamines,
decongestants, antitussives, expectorants) in young children has been associated
with serious side e ects and deaths. In 2008, the Food and Drug Administration
(FDA) recommended that they not be used in children younger than 2 years, and
drug manu acturers a liated with the Consumer Healthcare Products Association
voluntarily relabeled products “do not use” or children younger than 4 years. T e
FDA is reviewing the sa ety o these medicines in children aged 2 to 11 years.
b. What value does promethazine have in this cold medication?
H 1 antagonists are without value in combating the causes o the common cold. T e
weak anticholinergic e ects o the older agents may tend to lessen rhinorrhea, but
this drying e ect may do more harm than good, as may their tendency to induce
somnolence.
350
Histamine, Bradykinin, and Their Antagonists CHAPTER 2 1
KEY CONCEPTS
H 1 antagonists are most use ul in acute types o allergy that present with
symptoms o rhinitis, urticaria, and conjunctivitis
T eir e ect is con ned to the suppression o symptoms attributable to the
histamine released by the antigen-antibody reaction
In the treatment o systemic anaphylaxis, where autacoids other than histamine
are important, the mainstay o therapy is epinephrine; histamine antagonists
have only a subordinate and adjuvant role
Histamine antagonists have limited ef cacy in treating bronchial asthma and
are not used as sole therapy
Because o their e ects on the CNS, the rst-generation H 1 antagonists also
have therapeutic value in suppressing motion sickness or or sedation
Second-generation drugs are usually the drugs o choice or the treatment o
allergic disorders as they are largely devoid o sedating side e ects because
they do not penetrate the CNS and do not have antimuscarinic properties
SUMMARY QUIZ
351
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
QUESTION 21-3 Answer is c. H 1 antagonists are most use ul in acute types o allergy
that present with symptoms o rhinitis, urticaria, and conjunctivitis T eir e ect is
con ned to the suppression o symptoms attributable to the histamine released by the
antigen-antibody reaction In bronchial asthma, histamine antagonists have limited
ef cacy and are not used as sole therapy In the treatment o systemic anaphylaxis,
where autacoids other than histamine are important, the mainstay o therapy is epi-
nephrine; histamine antagonists have only a subordinate and adjuvant role T e same is
true or severe angioedema, in which laryngeal swelling constitutes a threat to li e
352
Histamine, Bradykinin, and Their Antagonists CHAPTER 2 1
353
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
First-Generation H1- Chlorpheniramine Treatment o allergic disorders, Less prone to produce Not recommended or
Receptor Antagonists— Brompheniramine relieving the symptoms o seasonal drowsiness and are use in children because
Alkylamines maleate rhinitis and conjunctivitis more suitable or their sedative e ects can
Limited bene t in bronchial asthma daytime use, but a impair learning and school
Use ul adjuncts to epinephrine in the signi cant proportion per ormance
treatment o systemic anaphylaxis or o patients experience OTC cough and cold
severe angioedema sedation medicines (containing
Used to treat certain allergic Side e ects involving mixtures o antihistamines,
dermatoses CNS stimulation are and other drugs) have
more common than been associated with
rst-generation agents serious side e ects and
rom other chemical deaths in young children
structure groups Do not use in children <4
GI side e ects years o age
First-Generation H1- Hydroxyzine Treatment o allergic disorders, Considerable CNS- Not recommended or
Receptor Antagonists— Cyclizine relieving the symptoms o seasonal depressant activity and use in children because
Piperazines Meclizine rhinitis and conjunctivitis antimuscarinic e ects their sedative e ects can
Limited bene t in bronchial asthma Loss o appetite, impair learning and school
Use ul adjuncts to epinephrine in the nausea, vomiting, per ormance
treatment o systemic anaphylaxis or epigastric distress, and OTC cough and cold
severe angioedema constipation or diarrhea medicines (containing
Hydroxyzine is a long-acting (taking the drug with mixtures o antihistamines,
compound widely used or skin meals may reduce and other drugs) have
allergies; its considerable CNS- incidence o GI e ects) been associated with
depressant activity may contribute to serious side e ects and
its prominent antipruritic action deaths in young children
Cyclizine and meclizine are used Do not use in children
primarily to prevent motion sickness <4 years o age
and vertigo although promethazine
and diphenhydramine are more
e ective
First-generation H1- Promethazine Treatment o allergic disorders, Considerable CNS- Not recommended or
Receptor Antagonists— relieving the symptoms o seasonal depressant activity and use in children because
Phenothiazines rhinitis and conjunctivitis antimuscarinic e ects their sedative e ects can
Limited bene t in bronchial asthma Loss o appetite, impair learning and school
Use ul adjuncts to epinephrine in the nausea, vomiting, per ormance
treatment o systemic anaphylaxis or epigastric distress, and OTC cough and cold
severe angioedema constipation or diarrhea medicines (containing
Used to treat certain allergic (taking the drug with mixtures o antihistamines,
dermatoses meals may reduce and other drugs) have
Promethazine is the most e ective incidence o GI e ects) been associated with
H1 antagonist in combating motion serious side e ects and
sickness because o its antimuscarinic deaths in young children
e ects Do not use in children
<4 years o age
First-Generation H1- Cyproheptadine Treatment o allergic disorders, Cause drowsiness, Not recommended or
Receptor Antagonists— Phenindamine relieving the symptoms o seasonal have signi cant use in children because
Piperidines rhinitis and conjunctivitis anticholinergic e ects their sedative e ects can
Limited bene t in bronchial asthma Can increase appetite impair learning and school
Use ul adjuncts to epinephrine in the and cause weight gain per ormance
treatment o systemic anaphylaxis or OTC cough and cold
severe angioedema medicines (containing
Used to treat certain allergic mixtures o antihistamines,
dermatoses and other drugs) have
been associated with
serious side e ects and
deaths in young children
Do not use in children
<4 years o age
354
Histamine, Bradykinin, and Their Antagonists CHAPTER 2 1
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Second-Generation H1- Olopatadine Usually drugs o choice or treatment Somewhat higher
Receptor Antagonists— o allergic disorders, relieving the incidence o drowsiness
Tricyclic Dibenzoxepins symptoms o seasonal rhinitis and than the other
conjunctivitis second-generation H1
Limited bene t in bronchial asthma antagonists
Use ul adjuncts to epinephrine in the
treatment o systemic anaphylaxis or
severe angioedema
Used to treat certain allergic
dermatoses
Second-Generation H1- Acrivastine Usually drugs o choice or treatment Lack signi cant
Receptor Antagonists— o allergic disorders, relieving the anticholinergic actions;
Alkylamines symptoms o seasonal rhinitis and penetrate poorly
conjunctivitis into the CNS, and
Limited bene t in bronchial asthma low incidence o side
Use ul adjuncts to epinephrine in the e ects
treatment o systemic anaphylaxis or
severe angioedema
Used to treat certain allergic
dermatoses
Second-Generation H1- Cetirizine Usually drugs o choice or treatment Lack signi cant
Receptor Antagonists— Levocetirizine o allergic disorders, relieving the anticholinergic actions;
Piperazines symptoms o seasonal rhinitis and penetrate poorly
conjunctivitis into the CNS, and
Limited bene t in bronchial asthma low incidence o side
Use ul adjuncts to epinephrine in the e ects
treatment o systemic anaphylaxis or
severe angioedema
Used to treat certain allergic
dermatoses
Cetirizine is a pre erred drug in
pregnant or breast- eeding women i
H1 antihistamines are required
Second-Generation H1- Azelastine Usually drugs o choice or treatment Lack signi cant
Receptor Antagonists— o allergic disorders, relieving the anticholinergic actions;
Phthalazines symptoms o seasonal rhinitis and penetrate poorly
conjunctivitis into the CNS, and
Limited bene t in bronchial asthma low incidence o side
Use ul adjuncts to epinephrine in the e ects
treatment o systemic anaphylaxis or
severe angioedema
Used to treat certain allergic dermatoses
Second-Generation H1- Levocabastine Usually drugs o choice or treatment Lack signi cant
Receptor Antagonists— Ketoti en umarate o allergic disorders, relieving the anticholinergic actions;
Piperidines Loratadine symptoms o seasonal rhinitis and penetrate poorly
Desloratadine conjunctivitis into the CNS, and
Ebastine Limited bene t in bronchial asthma low incidence o side
Mizolastine Use ul adjuncts to epinephrine in the e ects
Fexo enadine treatment o systemic anaphylaxis or
severe angioedema
Used to treat certain allergic
dermatoses
Loratadine is a pre erred drug in
pregnant or breast- eeding women i
H1 antihistamines are required
H2-Receptor Antagonists See Chapter 32 Inhibit gastric secretion See Chapter 32 See Chapter 32
Kinin Receptor Icatibant Treatment o acute episodes o
Antagonists—B2 swelling in patients with hereditary
(Bradykinin) Antagonist angioedema
355
CHAPTER
356
Prostaglandins, NSAIDs, and Pharmacotherapy o Gout CHAPTER 2 2
357
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
COOH
Arac hido nic Ac id Endoca nna ba noids :
CYPs COOH
Ara chidonyle tha nola mide
O 11,12-EET 2-a ra chidonoylglyce rol
COOH c yclo -
LOXs oxyg e nas e ca nna ba noid
re ce ptors
O 14,15-EET
COX-2
O 5,6-EET
COOH
5-LOX/COX COX-1 As pirin Glyce ryl
Inhibitors COX-2 tNSAIDs pros ta gla ndins
O 8,9-EET e .g.:
COOH Lic ofe lone
s e le ctive ac e tylate d
COX-2 inhibitors COX-2
e .g.: c oxib s
Epi-lipoxins
Fre e radic al O (S e e Figure 22-2)
attac k COOH
O
HETEs PGG2
Le ukotrie ne s hydro - OOH
pe roxidas e COX-1
Lipoxins COX-2
Is opros ta ne s (S e e Figure 22-2)
O
COOH
O
TXA s ynthas e
OH PGH2
OH OH
HO
O
COOH COOH
O PGD2
HO OH PGE2 OH
HO
COOH COOH
TP α , β EP 1 EP 2 EP 3A-D EP 4 FP DP DP 2 IP
FIGURE 22-1 Metabolism o arachidonic acid (AA). The cyclooxygenase (COX) pathway is highlighted in gray. The lipoxygenase (LOX) path-
ways are expanded in Figure 22-2. Cyclic endoperoxides (PGG2 and PGH2) arise rom the sequential COX and hydroperoxidase actions o COX-1
or COX-2 on AA released rom membrane phospholipids. Subsequent products are generated by tissue-speci c synthases and transduce their
e ects via membrane-bound receptors (blue boxes). Dashed lines indicate putative ligand–receptor interactions. Epoxyeicosatrienoic acids (EETs;
shaded in blue) and isoprostanes are generated via CYP activity and nonenzymatic ree radical attack, respectively. COX-2 can use modi ed ara-
chidonoylglycerol, an endocannabinoid, to generate the glyceryl prostaglandins. Aspirin and tNSAIDs are nonselective inhibitors o COX-1 and
COX-2, but do not a ect LOX activity. Epi-lipoxins are generated by COX-2 ollowing its acetylation by aspirin (see Figure 22-2). Dual 5-LOX–COX
inhibitors inter ere with both pathways.
358
Prostaglandins, NSAIDs, and Pharmacotherapy o Gout CHAPTER 2 2
FIGURE 22-2 Lipoxygenase pathways o arachidonic acid metabolism. 5-LOX–activating protein (FLAP) presents arachidonic acid to 5-LOX,
leading to the generation o the LTs. CysLTs are shaded in gray. Lipoxins (shaded in blue) are products o cellular interaction via a 5-LOX–12-LOX
pathway or via a 15-LOX–5-LOX pathway. Biological e ects are transduced via membrane-bound receptors dark (blue boxes). The dashed line
indicates putative ligand–receptor interactions. Zileuton inhibits 5-LOX but not the COX pathways (expanded in Figure 22-1). Dual 5-LOX–COX
inhibitors inter ere with both pathways. CysLT antagonists prevent activation o the CysLT1 receptor.
P
L
A
A2
n
a
tr
O
R C O-
Lys o-P AF Lys o-P AF
H2C O R´ H2C O R´
HO CH O HO CH O
H2C O P Choline H2C O P Choline
O- O-
H3 C C O - H3 C C CoA
A
O O
c
e
e
ty
s
s F
ra
P yd
CoA
lh
n A
A r
fe
ra -P
F o
lt o
ty s
e Ly
la
s
H2C O R´
e
c
A
H3 C C O CH O
O H2C O P Choline
O-
P AF
FIGURE 22-3 Synthesis and degradation o platelet-activating actor (PAF). RCOO– is a mixture o atty
acids but is enriched in arachidonic acid that may be metabolized to eicosanoids. CoA, coenzyme A.
359
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
A Che mica l s imila rity (a rbitra ry s ca le ) B COX is oform s e le ctivity (log s ca le ) C P la s ma t1/2 (log s ca le )
FIGURE 22-4 Classi cation o NSAIDs by chemical similarity (panel A), cyclooxygenase (COX) iso orm selectivity (panel B), and plasma t1/2
(panel C). tNSAIDs, traditional nonsteroidal anti-in ammatory drugs.
Di unisal Peak Cp 2-3 hours 250-500 mg every Not metabolized to Analgesic and
(de uoro-phenyl) Protein binding 99% 8-12 hours salicylic acid anti-in ammatory
Metabolites Glucuronide Competitive COX e ects 4-5 times
t1/2 8-12 hours inhibitor more potent
Excreted into breast Antipyretic e ect
milk weaker
Fewer platelet
and GI side e ects
(Continued)
360
Prostaglandins, NSAIDs, and Pharmacotherapy o Gout CHAPTER 2 2
CLASS/DRUG COMPARED TO
SUBSTITUTION PHARMACOKINETICS D0SING d
COMMENTS ASPIRIN
Para aminophenol derivative
Acetaminophen Peak Cp 30-60 minutes 10-15 mg/kg Weak nonspeci c Analgesic and
Protein binding 20-50% every 4 hours COX inhibitor at antipyretic e ects
Metabolites Glucuronide (maximum o 5 common doses equivalent
conjugates (60%); doses/24 hours) Potency may be Anti-in ammatory,
sul uric acid modulated by GI, and platelet
conjugates (35%) peroxides e ects less than
t1/2 2 hours Overdose leads to aspirin at 1000
production o toxic mg/day
metabolite and liver
necrosis
Indomethacin Peak Cp 1-2 hours 25 mg 2-3 times/ Side e ects 10-40x more
(methylated Protein binding 90% day; 75-100 mg at (3-50% o patients): potent;
indole) Metabolites O-demethylation night rontal headache, intolerance limits
(50%); unchanged neutropenia, dose
(20%) thrombocytopenia;
t1/2 2.5 hours 20% discontinue
therapy
361
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
CLASS/DRUG COMPARED TO
SUBSTITUTION PHARMACOKINETICS D0SINGd
COMMENTS ASPIRIN
Diclo enac Peak Cp 2-3 hours 50 mg 3 times/day Available as topical More potent;
(phenylacetate Protein binding 99% or 75 mg twice/ gel, ophthalmic 20% develop
derivatives) Metabolites Glucuronide and day solution, and oral side e ects, 2%
sul de (renal 65%, tablets combined discontinue use,
bile 35%) with misoprostol 15% develop
t1/2 1-2 hours First-pass e ect; oral elevated liver
bioavailability, 50% enzymes
Fenamates (N phenyl anthranilates)
Me enamic acid Peak Cp 2-4 hours 500-mg load, then Isolated cases o Ef cacy similar; GI
Protein binding High 250 mg every 6 hemolytic anemia side e ects (25%)
Metabolites Conjugates hours May have some
o 3-hydroxy central action
and 3-carboxyl
metabolites (20%
recovered in eces)
t1/2 3-4 hours
Meclo enamate Peak Cp 0.5-2 hours 50-100 mg 4-6/ Ef cacy similar; GI
Protein binding 99% day (maximum o side e ects (25%)
Metabolites Hepatic 400 mg/day)
metabolism;
ecal and renal
excretion
t1/2 2-3 hours
Flu enamic acid Not available in
the U.S.
Propionic acid Intolerance o one Usually better
derivatives does not preclude use tolerated
o another propionate
derivative
Ibupro en Peak Cp 15-30 minutes Analgesia 200-400 mg every 10-15% discontinue Equipotent
Protein binding 99% Anti-in ammatory 4-6 hours due to adverse e ects
Metabolites Conjugates 300 mg/6-8 hours Children’s dosing
o hydroxyl or 400-800 mg Antipyretic: 5-10 mg/
and carboxyl 3-4 times/day kg every 6 hours
metabolites (max: 40 mg/kg/day)
t1/2 2-4 hours Anti-in ammatory:
20-40 mg/kg/day in
3-4 divided doses
Naproxen Peak Cp 1 hour 250 mg 4 times/ 5 mg/kg twice/ Peak anti- More potent
Protein binding 99% (less in day or 500 mg day in ammatory e ects in vitro; usually
Metabolites elderly) twice/day may not be seen until better tolerated;
6-demethyl and Children: 2-4 weeks o use variably
other metabolites anti-in ammatory Decreased protein prolonged t1/2
t1/2 14 hours binding and delayed may a ord
excretion increase risk cardioprotection
o toxicity in elderly in some
individuals
362
Prostaglandins, NSAIDs, and Pharmacotherapy o Gout CHAPTER 2 2
CLASS/DRUG COMPARED TO
SUBSTITUTION PHARMACOKINETICS D0SING d
COMMENTS ASPIRIN
Ketopro en Peak Cp 1-2 hours Analgesia 25 mg 3-4 30% develop side
Protein binding 98% Anti-in ammatory times/day e ects (usually GI,
Metabolites Glucuronide 50-75 mg usually mild)
conjugates 3-4 times/day
t1/2 2 hours
Nabumetone Peak Cp 3-6 hours 500-1000 mg 1-2 A prodrug, rapidly Shows some
(naphthyl Protein binding 99% times/day metabolized to COX-2 selectivity
alkanone) Major metabolites O-demethylation, 6-methoxy-2- (active metabolite
then conjugation naphthyl acetic acid; does not)
t1/2 24 hours pharmacokinetics Fewer GI side
re ect active e ects than many
compound NSAIDs
Celecoxib [diaryl Peak Cp 2-4 hours 100 mg Substrate or CYP2C9; See the text or
substituted Protein binding 97% 1-2 times/day inhibitor o CYP2D6 an overview o
pyrazone; Metabolites Carboxylic acid Coadministration COX-2 inhibitors
(sul onamide and glucuronide with inhibitors o
derivative)] conjugates CYP2C9 or substrates
t1/2 6-12 hours o CYP2D6 should be
done with caution
363
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
MAJOR THERAPEUTIC USES TABLE 22-2 Common and Shared Side Ef ects o NSAIDs
OF NSAIDs SYSTEM MANIFESTATIONS
• All NSAIDs, including COX-2 Inhibitors, are GI Abdominal pain
anti-in ammatory, analgesic, and anti- Nausea
pyretic, except or acetaminophen, which is Diarrhea
largelydevoid o anti-in ammatoryactivity. Anorexia
» Used as anti-in ammatoryagents in the Gastric erosions/ulcersa
Anemiaa
treatment o musculoskeletal disorders GI hemorrhage a
(the primaryclinical applicationo NSAIDs) Per oration/obstruction a
Rheumatoid arthritis
Platelets Inhibited platelet activation a
Osteoarthritis Propensity or bruising a
Ankylosing spondylitis Increased risk o hemorrhage a
Gout Renal Salt and water retention
» Used as analgesics to treat pain o low Edema, worsening o renal unction in renal/cardiac and cirrhotic patients
to moderate intensity Decreased e ectiveness o antihypertensive medications
Decreased e ectiveness o diuretic medications
NSAIDs lackthe unwanted adverse Decreased urate excretion (especially with aspirin)
CNSe ects o opiates (respiratory Hyperkalemia
depression and development o
physical dependence). Cardiovascular Closure o ductus arteriosus
Myocardial in arction b
Coadministration o NSAIDs with Stroke b
opioids can reduce the dose o opiate Thrombosisb
and the likelihood o adverse CNS
e ects. CNS Headache
Vertigo
NSAIDs are particularlye ective in Dizziness
treating dental pain, postoperative Con usion
pain, pain arising romin ammation, Hyperventilation (salicylates)
and menstrual cramps (the latter due
Uterus Prolongation o gestation
torelease o prostaglandins romthe Inhibition o labor
endometrium).
NSAIDs are commonlyused as rst- Hypersensitivity Vasomotor rhinitis
Angioneurotic edema
line agents in treating migraine
Asthma
attacks and can be combined with Urticaria
second-line agents such as the Flushing
triptans, or with antiemetics or Hypotension
relie o nausea. Shock
NSAIDs lackef cacyin treating a
Side e ects decreased with COX-2-selective NSAIDs.
neuropathicpain or pain arising b
With the exception o low-dose aspirin.
romthe hollowviscera.
» Can reduce ever in most situations,
but antipyretice ects mayobscure the CASE 22 1
course o illness
A 24-year-old woman experiences severe menstrual cramping each month. T e
Antipyretictherapyis reserved or cramping and pain are relieved when she takes ibupro en.
patients with deleterious ever and
those who experience relie when a. What is causing this patient’s menstrual cramping?
ever is lowered. T e release o PGs by the endometrium during menstruation may cause severe
• Used in neonates to close inappropriately cramps and other symptoms o primary dysmenorrhea.
patent ductus arteriosus, which is very
b. What is the mechanism o action o ibupro en in relieving this patient’s pain and
sensitive to the dilating e ects o PGE1.
cramping?
• Low-dose aspirin reduces the risko serious
Ibupro en and other NSAIDs are e ective in treating menstrual cramping because
cardiovascular events in high-riskpatients,
o their ability to inhibit synthesis o PGs by the endometrium through their
probablybyirreversiblyinhibiting throm-
inhibitory e ects on COX-1 and COX-2. T e selective COX-2 inhibitors also are
boxane A2 (TxA2) production byplatelets
e cacious in this condition.
(see Chapter 19).
(Continued)
364
Prostaglandins, NSAIDs, and Pharmacotherapy o Gout CHAPTER 2 2
c. I this patient becomes pregnant, are there any hazards to her or the etus in
MECHANISMS OF GASTRIC
using NSAIDs or relie o headaches and musculoskeletal pains?
DAMAGE BY NSAIDs
T e use o NSAIDs and aspirin late in pregnancy may increase the risk o post-
partum hemorrhage. T ere ore, pregnancy, especially close to term, is a relative • Inhibition o COX-1 in gastricepithelial
contraindication to the use o all NSAIDs. In addition, their use must be weighed cells depresses mucosal cytoprotective PGs,
against potential etal risk, even in cases o premature labor, and especially in cases especiallyPGE2 and PGI2.
o pregnancy-induced hypertension. NSAID use is associated with closure o the » COX-2 inhibition in gastricepithelial
ductus arteriosus and impaired etal circulation in utero, particularly in etuses cells mayalso contribute to some loss o
older than 32 weeks’ gestation. cytoprotective PGs.
• Local irritation o gastricmucosa byorally
CASE 22 2 administered NSAIDs.
A 64-year-old man who su ered a myocardial in arction 2 years earlier is taking 80 mg • Enhanced generation o lipoxygenase
o aspirin each day on the recommendation o his amily physician. His doctor has advised (LOX) products (eg, LTs; see Figure 22-2)
him that this will reduce his chances o another myocardial in arction or stroke. maycontribute to ulcerogenicityin
patients treated with NSAIDs.
a. What is the mechanism o aspirin’s cardioprotective e ect in this patient?
T is e ect is due to irreversible acetylation o platelet COX-1, which permanently
and completely suppresses platelet thromboxane A2 ( xA2) ormation, with the CARDIOVASCULAR
consequent inhibition o platelet unction (see Figure 19-1). Platelets, which being HAZARD WITH COX-2–
anucleate, have a markedly limited capacity or protein synthesis. T us, the conse- SELECTIVE NSAIDs
quences o inhibition o platelet COX-1 (COX-2 is not expressed in mature platelets)
• Inhibition o COX-2 in the vasculature
last or the li etime o the platelet. Inhibition o platelet COX-1–dependent xA2
reduces vascular PGI2 (prostacyclin)
ormation, there ore, is cumulative with repeated doses o aspirin (at least as low as
production which is antithromboticand
30 mg/d) and takes ~8 to 12 days—the platelet turnover time—to recover ully once
antiatherogenic.
therapy has been stopped. Low-dose aspirin therapy does not signi cantly impair
synthesis o PGI2 by vascular endothelium, in part because o the ability o endothe- • Inhibition o COX-2 in the kidneyreduces
lial cells to continuously express COX-1 and COX-2. T us, daily low-dose aspirin renal PGI2 and PGE2 production which
blocks the ormation o xA2, which promotes platelet aggregation, while leaving results in hypertension and edema due to
intact the synthesis o PGI2, which inhibits platelet unction (see Figure 19-1). the contribution o these PGs in maintain-
ing arterial pressure homeostasis.
Aspirin reduces the risk o serious vascular events in high-risk patients (eg, those
with previous myocardial in arction) by 20 to 25%. Low-dose (<100 mg/d) aspirin, • In addition to the COX-2-selective (“coxib”)
which is relatively (but not exclusively) selective or COX-1, is as e ective as higher drug celecoxib, several traditional NSAIDs
doses (eg, 325 mg/d). (tNSAIDs) exhibit relative selectivity or
COX-2 (eg, etodolac, diclo enac, meloxi-
b. What are the hazards o daily aspirin therapy? cam; see Figure 22-4) and are likelyto have
Because o impairment o platelet unction, the most serious hazard to daily aspirin similar cardiovascular risks as the coxibs.
therapy is an increased risk o hemorrhage. Placebo-controlled trials reveal that • The COX-2-selective NSAIDs (including the
aspirin increases the incidence o serious GI bleeds, re ecting suppression not just tNSAIDs with relative selectivity or COX-2)
o platelet thromboxane, but also reduction in gastroepithelial PGE2 and PGI2. It should not be used in patients with isch-
also increases the incidence o intracranial bleeds. Although bene t rom aspirin emicheart disease or stroke, and should
outweighs these risks in the case o secondary prevention o cardiovascular disease, be used with caution in patients with risk
the issue is much more nuanced in patients who have never had a serious athero- actors or heart disease.
thrombotic event (primary prevention); here, prevention o myocardial in arction » For all such COX-2-selective NSAIDs, it
by aspirin is numerically balanced by the serious GI bleeds it precipitates
is advisable to use the lowest possible
Daily aspirin therapy can also increase the risk o gastric ulcers. COX-1 is expressed dose or the shortest possible time.
as the dominant, constitutive iso orm in gastric epithelial cells and is thought to be
the major source o cytoprotective PG ormation. Inhibition o COX-1 at this site
is thought to account largely or the gastric adverse events that complicate therapy
with tNSAIDs.
c. What concomitantly administered drugs might impair the cardioprotective
e ects o aspirin?
Many patients combine either tNSAIDs or COX-2 inhibitors with cardioprotective,
low-dose aspirin. Epidemiological studies suggest that this combination therapy
increases signi cantly the likelihood o GI adverse events over either class o
NSAID alone.
(Continued)
365
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
Prior occupancy o the active site o platelet COX-1 by the commonly consumed
tNSAID ibupro en impedes access o aspirin to its target Ser 529 and prevents irre-
versible inhibition o platelet unction. Whether this interaction is clinically impor-
tant has yet to be de nitively answered.
CASE 22 3
A 23-year-old male college student su ering rom a cold started taking several di erent
over-the-counter (O C) cold/ u medications 2 days ago to relieve symptoms. He is
eeling better and decides to attend an end-o -term party with his classmates where
they will be celebrating with beer and other alcoholic beverages.
a. Is this student at risk o any serious drug interactions when taking multiple
O C cold/f u medications?
A large number o nonprescription multisymptom cold/ u medications contain
acetaminophen to reduce ever and relieve the muscle aches that are common symp-
toms o colds and the u. Severe liver damage can occur with more than 4000 mg
o acetaminophen in a 24-hour period. aking the maximum recommended daily
dose o a single multisymptom cold/ u medication will typically be 2400 mg or less
o acetaminophen, but taking maximal doses o multiple cold/ u medication, or a
cold/ u medication in combination with acetaminophen could result in a total dose
that is more than 4000 mg o acetaminophen. In 2009, a Food and Drug Administra-
tion (FDA) advisory panel recommended a lower maximum daily dose o acetamin-
ophen o 2600 mg and a decrease in the maximum single dose rom 1000 to 650 mg.
b. Are there any risks with consuming alcohol while taking O C cold/f u medications?
T e chances o severe liver damage are increased when alcohol is consumed while
taking acetaminophen. Conditions o cytochrome P450 (CYP) induction (eg, heavy
alcohol consumption) or glutathione (GSH) depletion (eg, asting or malnutrition)
increase the susceptibility to hepatic injury with acetaminophen, which has been
documented, albeit uncommonly, with doses in the therapeutic range. T e maxi-
mum daily dose o acetaminophen is 2000 mg/d or chronic alcoholics.
c. What are the symptoms o acetaminophen toxicity?
Symptoms that occur during the rst 2 days o acute poisoning by acetaminophen
re ect gastric distress (eg, nausea, abdominal pain, anorexia) and belie the potential
seriousness o the intoxication (see Case 3-5 in Chapter 3). Plasma transaminases
become elevated, sometimes markedly so, beginning ~12 to 36 hours af er ingestion.
Clinical indications o hepatic damage mani est within 2 to 4 days o ingestion o
toxic doses, with right subcostal pain, tender hepatomegaly, jaundice, and coagulopa-
thy. Renal impairment or rank renal ailure may occur. Liver enzyme abnormalities
typically peak 72 to 96 hours af er ingestion. T e onset o hepatic encephalopathy or
worsening coagulopathy beyond this time indicates a poor prognosis. Biopsy o the
liver reveals centrilobular necrosis with sparing o the periportal area. In non atal
cases, the hepatic lesions are reversible over a period o weeks or months.
CASE 22 4
A 72-year-old woman has developed arthritis in her hands and has dif culty opening
jars and other common tasks because o the pain. She asks her doctor to recommend
a drug to relieve the pain so she can complete her normal tasks.
a. What are the considerations in choosing a drug to relieve this patient’s symptoms?
NSAIDs are the drugs o choice or treating the symptoms o arthritis because o
their analgesic and anti-in ammatory e ects. Choice and dosing o an NSAID are
usually guided by multiple considerations, including patient age, coincident dis-
eases or allergies, the drug’s sa ety and interaction pro le, and cost considerations.
Drugs with a longer duration o action may be pre erable or management o
arthritic pain.
(Continued)
366
Prostaglandins, NSAIDs, and Pharmacotherapy o Gout CHAPTER 2 2
368
Prostaglandins, NSAIDs, and Pharmacotherapy o Gout CHAPTER 2 2
CASE 22 5
A 6-year-old girl catches a viral in ection that some o her classmates at kindergarten
have recently had. She develops a ever and headache. Her parents are concerned and
want to give her something to relieve her symptoms.
a. What are the considerations in choosing an NSAID or this patient?
T erapeutic indications or NSAID use in children include ever, mild pain, post-
operative pain, and in ammatory disorders, such as juvenile arthritis and Kawasaki
disease. T e choice o drugs or children is considerably restricted; only drugs that
have been extensively tested in children should be used (acetaminophen, ibupro en,
and naproxen).
b. Why is aspirin to be avoided in this patient?
Because o the possible association with Reye syndrome, aspirin and other salicy-
lates are contraindicated in children and young adults aged younger than 20 years
with viral illness–associated ever. Reye syndrome, a severe and of en atal disease,
is characterized by the acute onset o encephalopathy, liver dys unction, and atty
in ltration o the liver and other viscera. T e etiology and pathophysiology are not
clear, nor is it clear whether a causal relationship between aspirin and Reye syn-
drome exists. However, the epidemiologic evidence or an association between aspi-
rin use and Reye syndrome seemed su ciently compelling that labeling o aspirin
and aspirin-containing medications to indicate Reye syndrome as a risk in children
was rst mandated in 1986 and extended to bismuth subsalicylate in 2004. Since
then, the use o aspirin in children has declined dramatically, and Reye syndrome
has almost disappeared. Acetaminophen has not been implicated in Reye syndrome
and is the drug o choice or antipyresis in children, teens, and young adults.
(Continued)
Xanthine Oxidase Inhibitor Allopurinol Prevents the synthesis o urate rom hypoxanthine and
Febuxostat xanthine by inhibiting xanthine oxidase
Allopurinol is a substrate or xanthine oxidase and its
product, oxypurinol, is a noncompetitive inhibitor o the
reduced orm o the enzyme
Febuxostat orms a stable enzyme-inhibitor complex
with both the reduced and oxidized orm o the enzyme
Recombinant Urate Oxidase Rasburicase Catalyzes the enzymatic oxidation o uric acid into the
soluble and inactive metabolite, allantoin
Uricosuric Agents Probenecid Inhibits URAT-1, the primary organic anion transporter
involved in reabsorption o urate in the kidney, thus
increasing the rate o excretion o urate
369
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
CASE 22 6
A 50-year-old man has occasional episodes o gout that are pain ul and debilitating. He
requires drugs to treat the symptoms o acute gout attacks and to prevent recurrent attacks.
a. What causes this patient’s pain ul episodes o gout?
Gout results rom the precipitation o urate crystals in the tissues and the subse-
quent in ammatory response. Acute gout usually causes an exquisitely pain ul distal
monoarthritis, but it also can cause joint destruction, subcutaneous deposits (tophi),
and renal calculi and damage. Gout a ects ~0.5 to 1% o the population o Western
countries. It is the most common orm o in ammatory arthritis in the elderly.
T e pathophysiology o gout is not ully understood. Hyperuricemia, while a pre-
requisite, does not inevitably lead to gout. Uric acid, the end product o purine
metabolism, is relatively insoluble compared to its hypoxanthine and xanthine pre-
cursors, and normal serum urate levels (~5 mg/dL, or 0.3 mM) approach the limit
o solubility. In most patients with gout, hyperuricemia arises rom underexcretion
rather than overproduction o urate.
b. What is the therapeutic rationale or the drugs used to treat gout in this patient?
T e aims o treatment are to decrease the symptoms o an acute attack, decrease
the risk o recurrent attacks, and lower serum urate levels (see Side Bar PHAR-
MACO HERAPY OF GOU ). T e drugs that relieve the symptoms o an acute
attack (in ammation and pain) are NSAIDs, colchicine, and glucocorticoids (see
Chapter 29). T e drugs that decrease the risk o recurrent attacks by preventing
in ammatory responses to urate crystals are colchicine and NSAIDs. T e drugs
that inhibit urate crystal ormation by lowering serum urate levels act by reduc-
ing urate ormation (allopurinol, ebuxostat) or augmenting urate excretion
(probenecid).
c. T is patient is prescribed colchicine. What is the mechanism o action o
this drug?
Colchicine is thought to alleviate in ammation rapidly through multiple mecha-
nisms, including the inhibition o neutrophil chemotaxis and activation. Symptoms
usually resolve within 2 to 3 days, but adverse GI events are requent, and toxicity
may include bone marrow depression. T e therapeutic index o colchicine is
narrow—especially in the elderly.
d. How does probenecid increase the excretion o uric acid?
Probenecid and other uricosuric agents increase the rate o uric acid excretion by
inhibiting its tubular reabsorption. T ey compete with uric acid or organic acid
transporters, primarily URA -1, which mediate urate exchange in the proximal
tubule. Certain drugs, particularly thiazide diuretics (see Chapter 15), and immu-
nosuppressant agents (especially cyclosporine, see Chapter 23) may impair urate
excretion and thereby increase the risk o gout attacks. Probenecid generally is well
tolerated but causes mild GI irritation in some patients.
KEY CONCEPTS
NSAIDs are e ective in reducing in ammation (except or acetominophen,
which lacks appreciable anti-in ammatory activity), most orms o low to mod-
erate pain, and ever.
NSAIDs inhibit the ormation o prostaglandins by inhibiting COX-1 and/or
COX-2.
GI disturbances are the most common adverse e ects o NSAIDs, except
the COX-2-selective inhibitors which have reduced e ects on prostaglandin
production by gastric epithelium.
(Continued)
370
Prostaglandins, NSAIDs, and Pharmacotherapy o Gout CHAPTER 2 2
All NSAIDs except aspirin increase the risk o cardiovascular events (myocardial
in arction, stroke, and thrombosis).
Patients at risk o cardiovascular disease should not be treated with COX-2–
selective inhibitors.
For patients treated with COX-2–selective inhibitors, treatment should be with
the lowest dose possible or the shortest time possible.
Pharmacotherapy o gout includes treatment o pain and in ammation, and
reduction in tissue urate crystals.
SUMMARY QUIZ
QUESTION 22-1 Which NSAID has the least anti-in ammatory ef cacy?
a. Aspirin
b. Acetaminophen
c. Ibupro en
d. Naproxen
e. Celecoxib
QUESTION 22-5 Diclo enac has a t 1/2 in plasma o 1 to 2 hours, yet its therapeutic
e ects in treating rheumatoid arthritis last or much longer. T is prolongation o
therapeutic e ect is due to
a. irreversible inhibition o COX-1 and COX-2.
b. its relative selectivity or COX-2.
c. its accumulation in synovial uid.
d. the ormation o a long-lived active metabolite.
e. CNS e ects unrelated to inhibition o prostaglandin synthesis.
371
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
372
Prostaglandins, NSAIDs, and Pharmacotherapy o Gout CHAPTER 2 2
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
NSAID—Irreversible Aspirin (acetylsalicylic Antiplatelet (irreversible GI e ects (see Side Bar Increased risk o GI
COX-1 Inhibitor acid, ASA) COX-1 inhibition) MECHANISMS OF GASTRIC bleeding and intracranial
Pain/ ever DAMAGE BYNSAIDs) bleeding
Anti-in ammatory (See Side Increased bleeding time Associated with Reye
Bar MAJORTHERAPEUTIC Hypersensitivity (see syndrome (see Case
USES OF NSAIDs) Table 22-2) 22-5) (see Table 22-2 or
additional toxicities)
NSAID—Traditional Salsalate Pain (ef cacy depends on GI (see Side Bar Increased risk o
(tNSAID) Salicylate agent) MECHANISMS OF GASTRIC cardiovascular disease
Di unisal Fever (ef cacy depends on DAMAGE BYNSAIDs) (see Table 22-2 or
Mesalamine agent) (See Table 22-2 or additional additional toxicities)
Sul asalazine Anti-in ammatory (ef cacy toxicities)
Balsalazide depends on agent)
Olsalazine (See Table 22-1 and Side Bar
Acetaminophen MAJORTHERAPEUTIC USES
Indomethacin OF NSAIDs)
Sulindac
Etodolac
Tolmetin
Ketorolac
Diclo enac
Brom enac
Nepa enac
Me enamic acid
Meclo enamate
Ibupro en
Naproxen
Fenopro en
Ketopro en
Flurbipro en
Oxaprozin
Piroxicam
Meloxicam
Nabumetone
Microtubule Disruptor Colchicine Acute gout attacks GI (nausea, vomiting, Acute intoxication causes
Prevention o acute gout diarrhea, and abdominal hemorrhagic gastropathy
(o -label) pain) Li e-threatening (especially
in combination with P-gp
or CYP3A4 inhibitors):
myelosuppression,
leukopenia,
granulocytopenia,
thrombopenia,
aplastic anemia, and
rhabdomyolysis
373
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Febuxostat Hyperuricemia with gout Liver unction abnormalities, Increase in gout ares
attacks nausea, joint pain, rash with initiation o therapy
caused by mobilization o
urate rom tissue deposits
Possible increased
cardiovascular risk
Contraindicated in
patients on azathioprine,
mercaptopurine, or
theophylline (drugs
metabolized by xanthine
oxidase)
Recombinant Urate Rasburicase Initial management o Vomiting, ever, nausea, Hemolysis in G6PD-
Oxidase elevated plasma uric headache, abdominal pain, de cient patients,
acid levels in pediatric constipation, diarrhea, and methemoglobinemia,
patients with leukemia, mucositis acute renal ailure,
lymphoma, and solid anaphylaxis
tumor malignancies who Ef cacy may be
are receiving anticancer hampered by antibodies
therapy expected to result produced against the
in tumor lysis and signi cant drug
hyperuricemia
374
CHAPTER
ImmunotherapeuticAgents 23
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED
Chapter 35, Immunosuppressants, olerogens, and Immunostimulants in Goodman &
Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition. In addition to the IN THIS CHAPTER
material presented here, the 12th Edition contains: • Abatacept (ORENCIA)
• Figure 35-3 Generation o monoclonal antibodies that illustrates the method used to • Adalimumab (HUMIRA)
generate monoclonal antibodies • Aldesleukin (PROLEUKIN)
• T e molecular structures o immunotherapeutic drugs • Ale acept (AMEVIVE)
• A Case Study: Immunotherapy or Multiple Sclerosis that includes able 35-3 Phar- • Alemtuzumab (CAMPATH)
macotherapy o Multiple Sclerosis listing speci c pharmacotherapies or treating • Anakinra (KINERET)
multiple sclerosis (MS)
• Azathioprine (IMURAN, others)
LEARNING OBJECTIVES • Bacillus Calmette–Guerin (BCG; TICEBCG,
THERACYS)
Understand the mechanisms o action o drugs used to suppress the immune
response in organ transplantation and autoimmune diseases. • Basiliximab (SIMULECT)
• Belatacept (NULOJIX)
Understand the mechanisms o action o drugs used to stimulate the immune
system. • Canakinumab (ILARIS)
• Cyclosporine (NEORAL, SANDIMMUNE,
Know the untoward e ects o immunotherapeutic drugs.
GENGRAF, others)
Know the drugs used at each step in organ transplantation.
• Daclizumab (ZENAPAX)
Know the drugs used in treating di erent autoimmune disorders. • Ealizumab (RAPTIVA)
Know which immunotherapeutic drugs are used in combination with • Etanercept (ENBREL)
other drugs. • Everolimus
• Glatiramer acetate (GA; COPAXONE)
MECHANISMS OF ACTION OF DRUGS USED AS IMMUNOSUPPRESSANTS • Immune globulin preparations such as ATG
DRUG CLASS DRUG MECHANISM OF ACTION (see Table 23-1)
Glucocorticoids See Chapter 29 Regulate gene expression • In iximab (REMICADE)
in lymphocytes and other • Inter eron-α-2b (IFN-α-2b; INTRONA)
in ammatory cells by binding
• Inter eron-β-1a (IFN-β-1a; AVONEX,REBIF)
glucocorticoid response elements
in DNA • Inter eron-β-1b (IFN-β-1b; BETASERON)
• Inter eron-γ-1b (IFN-γ-1b; ACTIMMUNE)
Calcineurin Inhibitors Cyclosporine Inhibit the protein phosphatase
Tacrolimus activity o calcineurin, thus blocking • Lenalidomide (REVLIMID)
expression o NFAT-regulated • Mitoxantrone (NOVANTRONE, others)
cytokines (see Figure 23-1)
• MPA(MYFORTIC)
Antiproli erative/ Sirolimus (rapamycin) Sirolimus and everolimus inhibit • Muromonab-CD3 (OKT3, ORTHOCLONE
Antimetabolic Agents Everolimus mTOR kinase activity blocking cell- OKT3)
Azathioprine cycle progression o lymphocytes
Some cancer (see Figure 23-1) • Mycophenolate mo etil (MMF, CELL-CEPT)
chemotherapeutic agents (see Azathioprine is converted to • Natalizumab (TYSABRI)
Chapter 45) 6-mercaptopurine which is
• Rilonacept (IL-1TRAP)
Mycophenolate mo etil (MMF) incorporated into DNA as 6-thio-
MPA GTP impairing proli eration o • Sirolimus (rapamycin; RAPAMUNE)
lymphocytes • Some cancer chemotherapeuticagents
MMF is a prodrug that is converted (see Chapter 45)
to mycophenolic acid (MPA)
which in turn inhibits lymphocyte • Tacrolimus (PROGRAF, FK506)
guanine nucleotide synthesis • Tacrolimus (PROGRAF, PROTOPIC, others)
(Continued) • Thalidomide (THALOMID)
375
SECTION IV Immunomodulatory Agents
• The immune systemis composed o 2 Biological Immune globulin preparations Immune globulin preparations
complementarymechanisms, described as Immunosuppressants— such as antithymocyte (polyclonal antibodies raised
Polyclonal Antibodies globulin (ATG; see Table 23-1) in animals against human
innate and adaptive immunity, capable o
thymocytes) are cytotoxic
discriminating sel romnonsel (microbes to lymphocytes and impair
and tumors). lymphocyte unction by binding to
• Characterisiticso innate (natural) immunity: cell sur ace proteins
» Does not require priming Biological Muromonab-CD3 mAb that binds the CD3 cell
» Broadlyreactive immunosuppressants— sur ace protein on T lymphocytes
Anti-CD3 Monoclonal causing its internalization, thus
» Relativelylowa nity Antibody (mAb) preventing antigen recognition
» The most active component o and depleting T cells rom the
the immune systemearlyon in bloodstream
an immune response Biological Daclizumab Anti-IL-2 (anti-CD25) recombinant
» Major e ectors include complement, Immunosuppressants— Basiliximab mAbs that bind IL-2 receptors on
granulocytes, monocytes/macrophages, Anti–IL-2 receptor activated T cells
natural killer cells, mast cells, (anti-CD25) mAbs
and basophils Biological Alemtuzumab Humanized mAb that targets
• Characterisitics o adaptive Immunosuppressants— CD52 on lymphocytes, monocytes,
(learned) immunity: Anti-CD52 mAb macrophages, and natural killer
cells, causing apoptosis
» Antigen-specifc
» Depends on antigen priming Biological In iximab In iximab, adalimumab, and
Immunosuppressants— Etanercept golimumab are anti–TNF-α (anti–
» Can be veryhigh a nity Anti-TNF Reagents Adalimumab tumor necrosis actor-α) mAbs
» Becomes the more dominant component Golimumab that bind TNF-α, thus blocking this
o the immune response over time Certolizumab pegol cytokine binding to its receptor
Certolizumab is a Fab ragment o
» Important in normal immune response an anti–TNF-α mAb
to in ection and tumors Etanercept is a usion receptor
» Mediates transplant (allogra t) rejection protein containing the ligand-
binding portion o human
and autoimmunity
TNF-α receptor used to the Fc
» Majore ectorsincludeBandTlymphocytes portion o human IgG1; it binds
» Blymphocytes make antibodies TNF-α and prevents it rom
binding its receptor
(immunoglobulins)
» Tlymphocytes unction as Biological Anakinra Anakinra is a recombinant,
helper, cytolytic, and regulatory Immunosuppressants— Canakinumab nonglycosylated orm o the
(suppressor) cells IL-1 Inhibitors Rilonacept naturally occurring IL-1 receptor
antagonist (IL-IRA) that blocks IL-1
» Once activated byspecifcantigen in ammatory activity
recognition via cell sur ace receptors, Canakinumab is an anti–IL-1β mAb
BandTlymphocytes di erentiate and that blocks this proin ammatory
divide, leading to release o soluble cytokine
mediators (cytokines and lymphokines) Rilonacept is a usion protein that
blocks IL-1 activity by binding it
376
Immunotherapeutic Agents CHAPTER 2 3
TCR
IL-2
Re ce ptor
DG P IP 2
P LC δ1 P O4
X
P KC IP 3 Prote in Tyros ine
Kina s e s (S rc, Ick,
X-P O 4 fyn, Za p 70)
S irolimus
Ra s Vav or
GRB2/s os [Ca 2+]
FKBP mTOR Cdk 2 IL-2
Prote in
Ra f-1
Cyclophilin
or FKBP Ca lcine urin Prolife ra tion
MEK
Cyclos porine
or Ta crolimus Pi
Imme dia te
e a rly ge ne s
fos /jun NFATn NFATc
IL 2 Ge ne
FIGURE 23-1 Mechanisms o action o cyclosporine, tacrolimus, and sirolimus on T lymphocytes. Both cyclosporine and tacrolimus bind to
immunophilins (cyclophilin and FK506-binding protein [FKBP], respectively), orming a complex that binds the phosphatase calcineurin and
inhibits the calcineurin-catalyzed dephosphorylation essential to permit movement o the nuclear actor o activated T cells (NFAT) into the
nucleus. NFAT is required or transcription o interleukin-2 (IL-2) and other growth- and di erentiation-associated cytokines (lymphokines).
Sirolimus (rapamycin) works at a later stage in T-cell activation, downstream o the IL-2 receptor. Sirolimus also binds FKBP, but the FKBP-sirolimus
complex binds to and inhibits the mammalian target o rapamycin (mTOR), a kinase involved in cell-cycle progression (proli eration). TCR, T-cell
receptor. (Reproduced with permission from Pattison JM et al. Mechanisms of allograft rejection. In Neilson EG, Couser WG, eds. Immunologic Renal Dis-
eases. Philadelphia, PA: Lippincott-Raven; 1997. http://lww.com.)
377
SECTION IV Immunomodulatory Agents
ADVERSE EFFECTS OF
IMMUNOSUPPRESSANTS
CASE 23-1
• General suppression o the immune system
increases the risko opportunisticin ections A 38-year-old male patient requires a kidney transplant because his kidneys have ailed
and secondarytumors. as the result o congenital renal disease. His biological daughter has agreed to donate
one o her kidneys.
• Calcineurin inhibitors are nephrotoxic.
• Glucocorticoids are diabetogenicand have a. What is typically done prior to an organ transplant such as this?
manyother adverse e ects (see Chapter 29). Organ transplantation therapy is organized around 5 general principles (see Side
• Using drugs that have synergistice ects can Bar GENERAL PRINCIPLES OF ORGAN RANSPLAN HERAPY). T e rst
reduce the doses needed or therapeutic principle is care ul patient preparation and selection o the best available ABO
e cacyand limit specifctoxicities. blood type–compatible human leukocyte antigen (HLA) match or organ donation.
Because the organ donor in this case is the patient’s daughter, the match is likely to
be excellent. By having a good match, the possibility o acute immune rejection is
signi cantly reduced.
b. What drugs are used prophylactically to prevent organ transplant rejection?
Biological agents or induction therapy in the prophylaxis o rejection currently are
used in ~70% o de novo transplant patients and have been propelled by several ac-
tors, including the introduction o the relatively sa e anti–IL-2R antibodies and the
emergence o antithymocyte globulin (A G) as a sa er and more e ective alterna-
tive to lymphocyte immune globulin or muromonab-CD3. Induction therapy with
biological agents is used to delay the use o the nephrotoxic calcineurin inhibitors
or to intensi y the initial immunosuppressive therapy in patients at high risk o
rejection (ie, repeat transplants, broadly presensitized patients, A rican American
patients, or pediatric patients).
Biologicals or induction can be divided into 2 groups: the depleting agents and the
immune modulators. T e depleting agents consist o lymphocyte immune globulin,
A G, and muromonab-CD3 mAb (the latter also produces immune modulation);
their e cacy derives rom their ability to deplete the recipient’s CD3-positive cells
at the time o transplant and antigen presentation. A G is the most requently used
depleting agent. Lymphocyte immune globulin and OK 3 are rarely used because
o poorer e cacy and acute side e ects, respectively. Alemtuzumab, a humanized
anti-CD52 monoclonal antibody that produces prolonged lymphocyte depletion, is
increasingly used o -label as induction therapy in transplantation.
(Continued)
378
Immunotherapeutic Agents CHAPTER 2 3
T e second group o biological agents used or induction are the immune modula-
tors, speci cally the anti–IL-2R mAbs. T ese agents do not deplete lymphocytes,
with the possible exception o regulatory cells, but rather block IL-2–mediated
-cell activation by binding to the α chain o IL-2R. T ese agents include anakinra,
canakinumab, and rilonacept.
c. What is the approach to using immunosuppressants in organ transplants?
Immunosuppressive drugs are used to dampen the immune response in organ
transplantation. A multitiered approach to immunosuppressive drug therapy is
employed. Several agents, each o which is directed at a di erent molecular target
within the allogra response (see MECHANISMS OF AC ION OF DRUGS USED
AS IMMUNOSUPPRESSAN S), are used simultaneously. Synergistic e ects per-
mit use o the various agents at relatively low doses, thereby limiting speci c toxici-
ties while maximizing the immunosuppressive e ect. T erapy typically involves a
calcineurin inhibitor, glucocorticoids, and mycophenolate, each directed at a dis-
crete site in -cell activation. Glucocorticoids, azathioprine, cyclosporine, tacroli-
mus, mycophenolate, sirolimus, and various monoclonal and polyclonal antibodies
all are approved or use in transplantation.
Greater immunosuppression is required to gain early engra ment and/or to treat
established rejection than to maintain long-term immunosuppression. Maintenance
immunosuppression consists o a calcineurin inhibitor (cyclosporine or tacrolimus),
glucocorticoids, and an antimetabolite (azathioprine or mycophenolate). Mycophe-
nolate has largely replaced azathioprine as part o the standard immunosuppressive
regimen a er transplant.
d. What are the risks of immunosuppressant drugs?
Immunosuppressant therapies require li elong use and nonspeci cally suppress the
entire immune system, exposing patients to considerably higher risks o in ection
and cancer. T e calcineurin inhibitors and glucocorticoids, in particular, are neph-
rotoxic and diabetogenic, respectively, thus restricting their use ulness in a variety
o clinical settings. o minimize risks a er engra ment is achieved, lower-dose
maintenance drug protocols are employed. In addition, a drug should be reduced
or withdrawn i its toxicity exceeds its bene t.
e. What might cause organ transplant dysfunction?
T ere can be many causes o transplant dys unction, including rejection, drug toxicity,
and in ection. T ese various problems can and o en do coexist. Organ-speci c
problems (eg, obstruction in the case o kidney transplants) also must be considered.
A general principle o organ transplantation is to investigate each episode o trans-
plant dys unction to identi y the cause(s) and adjust therapy.
CASE 23-2
A 62-year-old woman su ers rom severe rheumatoid arthritis. Her pharmaco-
therapy includes several agents that are also commonly used or organ transplant
pharmacotherapy.
a. What is the therapeutic rationale in using immunosuppressant drugs to treat
this patient’s arthritis?
Rheumatoid arthritis is an autoimmune disease driven largely by activated cells,
giving rise to cell–derived cytokines, such as IL-1 and NF-α. Nonsteroidal anti-
inf ammatory drugs (NSAIDs) are widely used in patients with rheumatoid arthri-
tis to relieve symptoms o pain and reduce inf ammation (see Chapter 22), but they
have minimal e ect on disease progression and joint de ormity. DMARDs (disease-
modi ying antirheumatic drugs), on the other hand, reduce the disease activity
o rheumatoid arthritis and retard the progression o arthritic tissue destruction.
T ese include a diverse group o small molecule nonbiologicals and biological
agents (mainly antibodies or binding proteins), as summarized in able 22-3,
(Continued)
379
SECTION IV Immunomodulatory Agents
Disease-Modi ying Antirheumatic Drugs. Many o the agents listed in able 22-3
INDUCTION OF
include the immunosuppressants covered in this chapter, including cyclosporine,
IMMUNOLOGICAL
azathioprine, NF-α antagonists (in iximab, adalimumab, etanercept), IL-1 recep-
TOLERANCE BY tor antagonists (anakinra), and costimulatory blockers (abatacept).
COSTIMULATORY
Cyclosporine is used in severe cases o rheumatoid arthritis that have not
BLOCKADE responded to methotrexate. It can be combined with methotrexate, but the levels
• Immunological tolerance is the state o o both drugs must be monitored closely. Azathioprine is used in patients with
nonresponsiveness o the immune system severe rheumatoid arthritis. Lower initial doses o azathioprine are used or rheu-
to a specifcantigen or group o antigens. matoid arthritis than used to prevent organ rejection. Biological DMARDs remain
• Antigen-specifctolerance would theoreti- reserved or patients with persistent moderate or high disease activity and indica-
callyeliminate the risko opportunistic tors o poor prognosis such as unctional impairment, radiographic bony erosions,
in ections and secondarytumors that occur extra-articular disease, and rheumatoid actor positivity. T erapy is tailored to the
with immunosuppression. individual patient, and the use o these agents must be weighed against their poten-
tially serious adverse ef ects. In iximab is approved in the United States or treating
• Induction o antigen-specifcimmune
the symptoms o rheumatoid arthritis and is typically used in combination with
responses byTlymphocytes requires 2
methotrexate in patients who do not respond to methotrexate alone. Etanercept is
signals (re erred to as costimulation; see
approved or treatment o rheumatoid arthritis in patients who have not responded
Figure 23-2):
to other treatments and can be used in combination with methotrexate in patients
» An antigen-specifcsignal via the who have not responded adequately to methotrexate alone.
T-cell receptor
» Acostimulatorysignal provided by
the interaction o molecules such as
CD28 on the Tlymphocyte and CD80
and CD86 on the antigen-presenting
AP C
cell (APC) 1 MHC
AP C
1 MHC
CD28
FIGURE 23-2 T-Cell Activation. Two signals are required for T-cell activation. The upper left
panel shows Signal 1, stimulation via the T-cell receptor (TCR) by the MHC-antigen complex on
the antigen presenting cell (APC). The upper right panel depicts Signal 2, co-stimulatory interac-
tions between CD28 on the T cell (co-stimulatory receptor) and the co-stimulatory ligand on the
APC, CD80/CD86. Signal 1 in the absence of Signal 2 does not result in T-cell activation. The lower
left panel shows additional co-stimulatory interactions that occur after T-cell activation. CD152
interaction with CD40 on the APC enhances T-cell activation (+), whereas CD154 interaction with
CD80/86 attentuates (-) T-cell activation. The lower right panel shows the mechanism of action
of abatacept and belatacept, fusion proteins that contain the CTLA4 domain of CD154. These
agents block co-stimulation of T cells by binding CD80/CD86.
380
Immunotherapeutic Agents CHAPTER 2 3
CASE 23-3
A 24-year-old woman who has had symptoms o abdominal pain, diarrhea, and blood
in the stool is diagnosed with Crohn’s disease.
a. What is the pathophysiology of Crohn’s disease and what agents are typically
used to initiate therapy?
Crohn’s disease is an inf ammatory bowel disease that is associated with activation
o the immune system. Drugs used to treat mild to moderately active Crohn’s dis-
ease include sul asalazine (an intestinal anti-inf ammatory), budesonide (an enteric
glucocorticoid with local anti-inf ammatory e ects), and oral corticosteroids (see
Chapter 33).
b. What is the rationale for using TNF-α antagonists in the treatment of Crohn’s
disease?
Patients with Crohn’s disease have elevated levels o NF-α in their stools. As a
result, a number o anti- NF agents are used or the treatment o this disorder,
including inf iximab, adalimumab, and certolizumab pegol. Because these agents
are associated with signi cant risks, they are reserved or patients with moderate to
severe Crohn’s disease who have ailed to respond to conventional therapy. Also see
Case 33-6.
Selective T-Cell Costimulation Abatacept Contains a congener o the CD80- and CD86-binding region o CTLA4 (a CD28 homolog),
Blocker and competitively inhibits CD28 co-stimulatory interactions o T cells with APCs
Immunostimulant—BCG Bacillus Calmette– Attenuated, live culture o the BCG o Mycobacterium bovis that induces a granulomatous
Guerin (BCG) reaction at the site o administration; mechanisms o action as an immunostimulatory drug
are unclear
Immunostimulants— Inter eron-α-2b Bind to specif c cell-sur ace receptors that initiate a series o intracellular events: induction
Recombinant Cytokines, (IFN-α-2b) o certain enzymes, inhibition o cell proli eration, and enhancement o immune activities,
α and γ IFNs Inter eron-γ-1b including increased phagocytosis by macrophages and augmentation o specif c
(IFN-γ-1b) cytotoxicity by T lymphocytes
Immunostimulants— Aldesleukin Simulates the biological e ects o native IL-2: enhancement o lymphocyte proli eration
Recombinant Cytokines, and growth o IL-2–dependent cell lines, enhancement o lymphocyte-mediated
Interleukin-2 (IL-2) cytotoxicity and killer cell activity, and induction o IFN-γ activity
Immunostimulants—Passive See Table 23-1 Used to provide nonspecif c or highly specif c immunoglobulins to patients with
Immunization immunodef ciencies, when there is inadequate time or active immunization, or when an
existing disease can be ameliorated by passive antibodies
Immunomodulators— Inter eron-β-1a IFN-β-1a and IFN-β-1b have antiviral and immunomodulatory properties: suppress
Recombinant Cytokines, (IFN-β-1a) proli eration o T lymphocytes, inhibit their movement into the CNS rom the periphery,
β 1 IFNs Inter eron-β-1b and shi t the cytokine prof le rom pro- to anti-in ammatory types
(IFN-β-1b)
(Continued)
381
SECTION IV Immunomodulatory Agents
Immunomodulators— Glatiramer Induces T-helper type 2 cells that enter the CNS; mediates bystander suppression at sites o
Universal Altered Peptide acetate (GA) in ammation
Ligands (APLs)
Immunomodulators— Mitoxantrone Intercalates DNA and suppresses cellular and humoral immune response
Anthracenedione-Derivative
Immunomodulators—mAb Natalizumab mAb directed against the adhesion molecule α4 integrin, antagonizes interactions o α4-
containing integrin heterodimers on the sur ace o activated lymphocytes and monocytes,
thereby blocking their movement out o the bloodstream
CASE 23-4
A 31-year-old woman is diagnosed with relapsing-remitting multiple sclerosis (MS).
a. What is the pathophysiology of MS?
MS is a demyelinating inf ammatory disease o the CNS white matter that displays
a triad o pathogenic ndings: mononuclear cell in ltration, demyelination, and
scarring (gliosis). T e peripheral nervous system is uninvolved. T e disease, which
may be episodic or progressive, occurs in early to middle adulthood with prevalence
increasing rom late adolescence to 35 years o age and then declining. T e cause is
unknown, but there is a strong genetic component, with a number o immune-related
genetic variants, many o which are shared with di erent autoimmune diseases. In
addition, MS patients have activated cells that are reactive to di erent myelin anti-
gens, and autoantibodies to myelin proteins can be eluted rom CNS plaque tissue.
b. What is the rationale for using β-1 interferons in treating this patient’s
symptoms?
T e β-1 inter erons (IFN-β-1a, IFN-β-1b) are immunomodulatory and suppress the
proli eration and activation o lymphocytes by inter ering with costimulatory mole-
cules, inhibit -cell movement into the CNS rom the periphery, and shi the cytokine
pro le rom pro- to anti-inf ammatory types. T ese agents reduce the recurrence o
relapsing-remitting attacks by one-third and reduce disease progression.
KEY CONCEPTS
Immunosuppressant drugs are essential in preventing grant rejection in organ
transplantation.
Immunosuppressant drugs also have application in reducing symptoms and
disease progression in a variety o autoimmune diseases.
Immunosuppressant drugs with di erent mechanisms o action are typically
used in combination to achieve greater e cacy and reduce dosing to reduce
risk o drug-speci c toxicities.
General suppression o the immune system increases the risk o secondary
in ections and cancer.
Many immunosuppressants must be used chronically over the li e o the patient,
which increases the risk o adverse e ects.
SUMMARY QUIZ
QUESTION 23-3 Sirolimus is used in combination with other drugs in patients receiv-
ing organ transplants. T e mechanism o action o sirolimus is to
a. intercalate DNA in proli erating cells.
b. block guanine nucleotide synthesis in proli erating cells.
c. block CD52 on the sur ace o activated cells.
d. block the protein phosphatase activity o calcineurin.
e. block the protein kinase activity o m OR.
TOXICITIES
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Calcineurin Inhibitors Cyclosporine Indicated or the prophylaxis Nephrotoxicity (occurs in Because o its potential or
Tacrolimus o solid-organ allogra t the majority o patients), nephrotoxicity, tacrolimus blood
rejection neurotoxicity (eg, levels and renal unction should
Tacrolimus has become the tremor, headache, motor be monitored closely, especially
pre erred calcineurin inhibitor disturbances, seizures), GI when tacrolimus is used with other
in most transplant centers complaints, hypertension, potentially nephrotoxic drugs
Severe cases o rheumatoid hyperkalemia, Coadministration with
arthritis and psoriasis in which hyperglycemia, and cyclosporine results in additive
other therapies have ailed diabetes (combined use or synergistic nephrotoxicity;
o calcineurin inhibitors there ore, a delay o at least 24 h is
and glucocorticoids is required when switching a patient
particularly diabetogenic) rom cyclosporine to tacrolimus
Increased risk o Great care must be taken to
secondary tumors and di erentiate renal toxicity rom
opportunistic in ections rejection in kidney transplant
patients
Antiproli erative/ Sirolimus Sirolimus and everolimus are Sirolimus and I azathioprine and allopurinol
Antimetabolic Agents (rapamycin) indicated or prophylaxis o everolimus in renal are used concurrently, the
Everolimus organ transplant rejection transplant patients is azathioprine dose must be
Azathioprine usually in combination with a associated with a dose- decreased to 25-33% o the usual
Mycophenolate reduced dose o calcineurin dependent increase in dose; it is best not to use these 2
mo etil (MMF) inhibitor and glucocorticoids serum cholesterol and drugs together
MPA Sirolimus has been used triglycerides Coadministration o azathioprine
with glucocorticoids and Azathioprine is associated with other myelosuppressive
mycophenolate in patients with bone marrow agents or ACE inhibitors include
experiencing or at high risk suppression, including leukopenia, thrombocytopenia,
or calcineurin inhibitor– leukopenia (common), and anemia
associated nephrotoxicity thrombocytopenia MMF is teratogenic; women
Azathioprine is indicated as (less common), and/or o childbearing age must use
an adjunct or prevention o anemia (uncommon), e ective contraception
organ transplant rejection hepatotoxicity, alopecia,
(but not with MMF) and in GI toxicity, pancreatitis
severe rheumatoid arthritis MMF principal toxicities
are GI and hematologic
Increased risk o
neoplasms and in ections
Biological Immune globulin ATG is used or induction Polyclonal antibodies Serum sickness and
Immunosuppressants— preparations immunosuppression, although are xenogeneic proteins glomerulonephritis can occur;
Polyclonal Antibodies such as ATG (see the only approved indication that can elicit major anaphylaxis is a rare event
Table 23-1) is in the treatment o acute side e ects, including Hematologic complications
renal transplant rejection ever and chills with the include leukopenia and
in combination with other potential or hypotension thrombocytopenia
immunosuppressive agents Increased risk o in ection
and malignancy
Biological Muromonab-CD3 Indicated or treatment Major side e ect is the Potentially atal pulmonary
Immunosuppressants— o acute organ transplant “cytokine release syndrome” edema, acute respiratory distress
Anti-CD3 Monoclonal rejection caused by release o syndrome, cardiovascular collapse,
Antibody (mAb) Rarely used or induction and proin ammatory cytokines cardiac arrest, and arrhythmias
rejection therapy because o by activated Tcells Administration o glucocorticoids
toxicity and the availability o Clinical mani estations be ore the injection o
ATG and alemtuzumab include high ever, muromonab-CD3 prevents
chills/rigor, headache, the release o cytokines and is
tremor, nausea, vomiting, standard procedure
diarrhea, abdominal A ully competent resuscitation
pain, malaise, myalgias, acility must be immediately
arthralgias, and available or patients receiving
generalized weakness their f rst several doses o this
Increased risk o in ections therapy
and neoplasms
(Continued)
385
SECTION IV Immunomodulatory Agents
TOXICITIES
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Biological In iximab Used in treating several About 1 o 6 patients Increase the risk or serious
Immunosuppressants— Etanercept immune-mediated intestinal, receiving in iximab in ections, lymphomas, and other
Anti-TNF Reagents Adalimumab skin, and joint diseases experiences an in usion malignancies
Golimumab including rheumatoid arthritis, reaction characterized Patients should be closely
Certolizumab pegol Crohn’s disease, ankylosing by ever, urticaria, monitored or the signs and
spondylitis, juvenile idiopathic hypotension, and symptoms o in ection during
arthritis, plaque psoriasis, dyspnea within 1-2 h and a ter treatment including
psoriatic arthritis, and the possible development o
ulcerative colitis tuberculosis in patients who
tested negative prior to
initiating therapy
Fatal lymphomas and other
malignancies have been reported
in children, adolescent and
young adult patients treated
with TNF blockers
386
Immunotherapeutic Agents CHAPTER 2 3
TOXICITIES
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Selective T-Cell Belatacept Prevention o rejection in Increased risk o in ections Risk o PTLD is signif cantly
Costimulation Blocker renal transplantation (such as PML) and increased in patients without
malignancies (including immunity to Epstein-Barr virus
PTLD predominantly (EBV), thus contraindicated in
involving the CNS) patients who are EBVseronegative
Common adverse or unknown serostatus
e ects are anemia,
diarrhea, peripheral
edema, constipation,
hypertension, pyrexia,
gra t dys unction, cough,
nausea, vomiting,
headache, hypokalemia,
hyperkalemia, and
leukopenia
Selective T-Cell Abatacept Treatment o moderate to Increased risk o in ections Increased risk o serious adverse
Costimulation Blocker severe rheumatoid arthritis, (especially in combination events in patients with COPD
juvenile idiopathic arthritis with TNF antagonists) and
malignancies
Immunostimulant— Thalidomide Thalidomide is indicated Lenalidomide causes Teratogenic and should never
Thalidomide and Its Lenalidomide or treatment o erythema signif cant neutropenia be taken by women who are
Analogs nodosum leprosum (see and thrombocytopenia pregnant or who could become
Chapter 42) and multiple in almost all patients, pregnant while taking the drug
myeloma, and has orphan which requires weekly Lenalidomide is associated with
drug status or mycobacterial blood counts and dosing a signif cant risk or deep vein
in ections, Crohn’s disease, adjustments thrombosis
HIV-associated wasting,
Kaposi sarcoma, lupus,
myelof brosis, brain
malignancies, leprosy, gra t-
versus-host disease, and
aphthous ulcers
Lenalidomide is approved
or treating trans usion-
dependent anemia due
to low- or intermediate-
risk 5q minus cytogenetic
myelodysplastic syndromes
Immunostimulants— Inter eron-α-2b Indicated in the treatment o Flu-like symptoms, Risk o developing pulmonary
Recombinant Cytokines, (IFN-α-2b) a variety o tumors, including including ever, chills, and hypertension
α Inter erons hairy cell leukemia, malignant headache Risk o cardiovascular
melanoma, ollicular (hypotension, arrhythmias, and
lymphoma, and AIDS-related rarely, cardiomyopathy, myocardial
Kaposi sarcoma, and is also in arction) and CNS (depression,
indicated or in ectious con usion) e ects
diseases, chronic hepatitis B,
and condylomata acuminata
(Continued)
387
SECTION IV Immunomodulatory Agents
TOXICITIES
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Immunostimulants— Inter eron-γ-1b Indicated to reduce requency Fever, headache, rash, May increase mortality in patients
Recombinant Cytokines, (IFN-γ-1b) and severity o serious atigue, GI distress, with idiopathic pulmonary f brosis
γ Inter erons in ections associated with anorexia, weight loss,
chronic granulomatous myalgia, and depression
disease and to delay time
to progression in severe
malignant osteopetrosis
Immunostimulants— Aldesleukin Indicated or the treatment o Increased risk o Associated with serious
Recombinant Cytokines, adults with metastatic renal disseminated in ection cardiovascular toxicity resulting
Interleukin-2 cell carcinoma and melanoma due to impaired rom capillary leak syndrome
neutrophil unction (loss o vascular tone and leak o
plasma proteins and uid into the
extravascular space); hypotension,
reduced organ per usion, and
death may occur
Immunomodulators— Mitoxantrone Treatment o worsening Cardiac toxicity; generally FDA recommends that LVEF
Anthracenedione orms o RRMS and secondary can be tolerated only up be evaluated be ore initiating
Derivative progressive MS (SPMS) to to an accumulated dose therapy, prior to each dose, and
reduce requency o relapses o 100-140 mg/m 2 annually a ter patients have
and slow progression f nished treatment to detect
late-occurring cardiac toxicity
Immunomodulators- Natalizumab Treatment o RRMS to reduce Headache, joint pain, Increases the risk o developing
Monoclonal Antibody requency o episodes and injection site reaction, progressive multi ocal
(mAb) slow progression o disability edema, and in usion leukoencephalopathy (PML)
Treatment o moderate to reaction
severe Crohn’s disease
388
CHAPTER
PulmonaryPharmacology 24
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN THIS
Chapter 36, Pulmonary Pharmacology in Goodman & Gilman’s T e Pharmacological
Basis of T erapeutics, 12th Edition. In addition to the material presented here, the 12th CHAPTER
Edition contains: • Albuterol (salbutamol; VENTOLIN, PROVEN-
• A description o the pathogenesis o asthma, including Figure 36-1: Cellular mecha- TIL, ACCUNEB, others)
nisms o asthma • Ambrisentan (LETAIRIS)
• A description o the pathogenesis o chronic obstructive pulmonary disease (COPD), • Ar ormoterol (BROVENA)
including Figure 36-2: Cellular mechanisms in chronic obstructive pulmonary disease • Beclomethasone dipropionate (QVAR)
• A description o the various routes o drug delivery to the lungs, including Figure 36-3: • Benzonatate (TESSALON, others)
Schematic representation o the deposition o inhaled drugs
• Bosentan (TRACLEER)
• T e molecular structures o some o the drugs used to treat asthma, COPD, and
• Budesonide (PULMICORT,others)
other pulmonary diseases
• Budesonide/ ormoterol (SYMBICORT)
LEARNING OBJECTIVES • Ciclesonide (ALVESCO, OMNARIS)
Understand the mechanisms o action o bronchodilator drugs used to relax air- • Codeine
way smooth muscle and drugs used to prevent bronchoconstriction. • Dextromethorphan
Understand the anti-in ammatory mechanism o action o corticosteroids, and • DNAase (dornase al a, PULMOZYME)
the role o inhaled and oral corticosteroids in the pharmacotherapy o asthma. • Doxapram(DOPRAM, others)
Understand the mechanism o action o mucolytic agents. • Epoprostenol (prostacyclin, PGI2; FLOLAN,
Understand the mechanisms o action o antitussive drugs. others)
Understand the mechanisms o action o drugs used to treat pulmonary artery • Flunisolide (AEROBID)
hypertension (PAH). • Fluticasone (AEROSPAN, FLOVENT)
Know the untoward e ects o the various bronchodilator drugs, corticosteroids, • Fluticasone/salmeterol (ADVAIR)
antitussive drugs, and drugs used to treat PAH. • Formoterol (FORADIL, others)
Know which patients should be treated and when treatment should be initiated • Guai enesin
in patients with asthma, COPD, and PAH.
• Hydrocortisone
Know which drugs are most e ective in treating patients with asthma, COPD, • Iloprost (VENTAVIS)
and PAH.
• Indacaterol (ARCAPTANEOHALER)
Know which drugs can be used in combination to treat asthma, COPD,
• Ipratropiumbromide (ATROVENT,others)
and PAH.
• Ipratropium/albuterol (COMBIVENT,
DUONEB, others)
MECHANISMS OF ACTION OF DRUGS USED TO TREAT PULMONARY DISORDERS • Levalbuterol (XOPENEX)
DRUG CLASS DRUG MECHANISM OF ACTION • Metaproterenol (ALUPENT,METAPREL)
β2 Adrenergic Albuterol β2 Agonists produce bronchodilation by • Methylprednisolone
Agonists—Short- (salbutamol) directly stimulating β2 receptors in airway • Mometasone (ASMANEX)
Acting (3-6 h) Levalbuterol smooth muscle (see Figure 24-1), resulting
Metaproterenol in bronchodilation and a rapid decrease in • Montelukast (SINGULAIR)
Pirbuterol airways resistance • N-acetylcysteine (MUCOMYST,others)
Terbutaline In addition, β2 agonists act indirectly by
• Omalizumab
inhibiting the release o bronchoconstrictor
mediators rom in ammatory cells and • Pirbuterol (MAXAIR)
o bronchoconstrictor neurotransmitters • Prednisolone
rom airway nerves (see Side Bar INDIRECT
ACTIONS OF β2 AGONISTS TO CAUSE • Prednisone
BRONCHODILATION) • Salmeterol (SEREVENT)
(Continued) (continues)
389
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
390
Pulmonary Pharmacology CHAPTER 2 4
β 2 a gonis t
R1 C C NH
HO OH R2
K+
Ibe riotoxin
Ce ll AC β 2 AR
me mbra ne β γ Gs
αs
ATP
GTP Gs
Cyclic AMP
Ca 2 +-a ctiva te d K+ cha nne l a ctiva tion
Me thylxa nthine s
P DE P LC-IP 3 -Ca 2 + pa thway a ctivity
MLCK
FIGURE 24-1 Molecular actions o β 2 agonists to induce relaxation o airway smooth muscle cells.
Activation o β 2 receptors (β 2AR) results in activation o adenylyl cyclase (AC) via a stimulatory G protein
intracellular cyclic adenosine monophosphate (cAMP) and activation o protein kinase A (PKA). PKA
phosphorylates a variety o target substrates, resulting in opening o Ca2+-activated K+ channels (KCa),
thereby acilitating hyperpolarization, decreased phosphoinositide (PI) hydrolysis, increased Na+/Ca2+
exchange, increased Na+,Ca2+-ATPase activity, and decreased myosin light chain kinase (MLCK) activity.
β2 Receptors may also couple to KCa via Gs. PDE, cyclic nucleotide phosphodiesterase.
391
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
INFLAMMATORY CELLS
SIDE EFFECTS OF β 2
Eo s ino phil
AGONISTS STRUCTURAL CELLS
Ce ll numbe r
• Muscle tremor (direct e ect on skeletal ( a poptos is ) Airway s mo o th
mus cle
muscle β2 receptors) Bronchodila ta tion
• Tachycardia (direct e ect on atrial β2 recep- T-lympho c yte
tors, re exe ect romincreased peripheral
Cytokine s ,
vasodilation via β2 receptors) tra ffic
Endo the lial c e ll
Cytokine s
Inflammato ry s timuli
e g, IL-1β, TNF-α
Corticos te roid
IKKβ Cytopla s m
GR
NF-κB p65
p50
p65 CBP
κB GR
p50 HDAC2
HAT Nucle us
–
Ace tyla tion De a ce tyla tion
Inflammato ry g e ne s
Cytokine s, che mokine s,
a dhe s ion mole cule s,
infla mma tory re ce ptors, Ge ne Ge ne
e nzyme s, prote ins tra ns cription re pre s s ion
FIGURE 24-3 Mechanism o anti-in ammatory action o corticosteroids in asthma. In ammatory genes are activated by in ammatory stimuli
(IL-1β, TNF-α, etc), resulting in activation o IKKβ (inhibitor o I-κB kinase-β), which activates the transcription actor nuclear actor κB (NF-κB).
A dimer o p50 and p65 NF-κB proteins translocates to the nucleus and binds to speci c κB recognition sites and also to coactivators, such as
CREB-binding protein (CBP), which have intrinsic histone acetyltrans erase (HAT) activity. This results in acetylation o core histones and conse-
quent increased expression o genes encoding multiple in ammatory proteins. Cytosolic glucocorticoid receptors (GR) bind corticosteroids; the
receptor-ligand complexes translocate to the nucleus and bind to coactivators to inhibit HAT activity in 2 ways: directly and, more importantly, by
recruiting histone deacetylase-2 (HDAC2), which reverses histone acetylation, leading to the suppression o activated in ammatory genes.
392
Pulmonary Pharmacology CHAPTER 2 4
FIGURE 24-4 E ect o corticosteroids on in ammatory and structural cells in the airways.
CASE 24-1
An 8-year-old boy has occasional episodes o mild asthma while playing basketball
with his riends.
a. What are the symptoms o asthma and some o the underlying pathogenic events
that cause these symptoms?
Asthma is characterized by variable air ow obstruction caused by airway smooth
muscle contraction. It is a chronic in ammatory disease o the airways that is char-
acterized by activation o mast cells, in ltration o eosinophils and helper 2 ( H2)
lymphocytes. Mast cell activation by allergens and physical stimuli releases broncho-
constrictor mediators, such as histamine, leukotriene D4, and prostaglandin D2, which
cause bronchoconstriction, microvascular leakage, and plasma exudation. Increased
numbers o mast cells in airway smooth muscle are a characteristic o asthma.
T e mechanism o chronic in ammation in asthma is still not well understood. It
may initially be driven by allergen exposure, but it appears to become autonomous
so that asthma is essentially incurable. Asthma usually starts in early childhood,
and then may disappear during adolescence and reappear in adulthood. Asthma
severity usually does not change so that patients with mild asthma rarely progress
to severe asthma, and patients with severe asthma usually have this rom the onset,
although some patients, particularly with late-onset asthma, show a progressive loss
o lung unction like patients with COPD.
b. What treatment, i any, should this patient receive to relieve symptoms during an
asthma attack?
Inhaled short-acting β2 agonists are the most widely used and e ective bronchodi-
lators in the treatment o asthma due to their unctional antagonism o broncho-
constriction. When inhaled rom pressurized metered-dose inhalers (pMDIs) or
dry powder inhalers (DPI), they are convenient, easy to use, rapid in onset, and
without signi cant systemic side e ects. In addition to their acute bronchodilator
e ect, these agents are e ective in protecting against various challenges, such as
exercise, cold air, and allergens.
(Continued)
393
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
CASE 24-2
A 72-year-old woman has chronic di culty in breathing. She has smoked a pack o cig-
arettes every day or the last 55 years and was diagnosed as having COPD 15 years ago.
a. What is COPD and how does it dif er rom asthma?
Chronic obstructive pulmonary disease (COPD) involves in ammation o the
respiratory tract with a pattern that di ers rom that o asthma. In COPD, there
is a predominance o neutrophils, macrophages, and cytotoxic lymphocytes
( c1 cells). T e in ammation predominantly a ects small airways, resulting in
progressive small airway narrowing and brosis (chronic obstructive bronchiolitis)
and destruction o the lung parenchyma with destruction o the alveolar walls
(emphysema). T ese pathological changes result in airway closure on expiration,
leading to air trapping and hyperin ation, particularly on exercise (dynamic
hyperin ation). T is accounts or shortness o breath on exertion and exercise
limitation that are characteristic symptoms o COPD.
In contrast to asthma, the air ow obstruction o COPD tends to be progressive.
T e in ammation in the peripheral lung o COPD patients is mediated by multiple
in ammatory mediators and cytokines, although the pattern o mediators di ers
rom that o asthma. In marked contrast to asthma, the in ammation in patients
with COPD is largely corticosteroid-resistant, and there are currently no e ective
anti-in ammatory treatments or this disease. In addition to pulmonary disease,
many patients with COPD have systemic mani estations (skeletal muscle wasting,
weight loss, depression, osteoporosis, anemia) and comorbid diseases (ischemic
heart disease, hypertension, congestive heart ailure, diabetes). Whether these are
due to spillover o in ammatory mediators rom the lung or due to common causal
mechanisms (such as smoking) is not yet clear, but it may be important to treat the
systemic components in the overall management o COPD.
b. What treatments are available or this patient?
Bronchodilators are the mainstay o treatment in COPD and act to reduce air trap-
ping by dilating peripheral airways. Anticholinergic drugs (ipratropium bromide and
(Continued)
394
Pulmonary Pharmacology CHAPTER 2 4
tiotropium bromide) are the bronchodilators o choice in COPD, and are as e ective as
or even superior to β2 agonists. T eir relatively greater e ect in COPD than in asthma
may be explained by an inhibitory e ect on vagal tone, which, although not necessarily
increased in COPD, may be the only reversible element o airway obstruction and one
that is exaggerated by geometric actors in the narrowed airways o COPD. Anticho-
linergic drugs reduce air trapping and improve exercise tolerance in COPD patients.
Once-daily tiotropium is more e ective than ipratropium 4 times daily. When given
long term, tiotropium improves lung unction and health status and reduces exacerba-
tions and all-cause mortality, although there is no e ect on disease progression. As a
result, tiotropium is becoming the bronchodilator o choice or patients with COPD.
T e long-acting inhaled β2 agonists (LABAs) salmeterol, ormoterol, and ar or-
moterol are also used in COPD therapy. T ese drugs have a bronchodilator action
o more than 12 hours and also protect against bronchoconstriction or a similar
period. LABAs are e ective bronchodilators that may be used alone or in combina-
tion with anticholinergics or ICSs. LABAs improve symptoms and exercise toler-
ance by reducing both air trapping and exacerbations.
Combination inhalers o an anticholinergic and β2 agonist, such as ipratropium/
albuterol, are widely used in patients with COPD. Several studies have demon-
strated additive e ects o these 2 drugs, thus providing an advantage over increas-
ing the dose o β2 agonist in patients who have side e ects.
Combination inhalers that contain a LABA and a corticosteroid (eg, uticasone/salme-
terol, budesonide/ ormoterol) are also used in the treatment o COPD. T ese combina-
tion inhalers are more e ective in patients with COPD than monotherapy with either a
LABA or an ICS. Although patients with COPD occasionally respond to steroids alone,
these patients are likely to have concomitant asthma. Corticosteroids have no objec-
tive short-term bene t on airway unction in patients with true COPD, although these
agents o en produce subjective bene t because o their euphoric e ect. Corticosteroids
do not appear to have any signi cant anti-in ammatory e ect in COPD.
T eophylline, an agent with multiple sites o action (see Figure 24-2), is sometimes
used as a bronchodilator in COPD, but inhaled anticholinergics and β2 agonists are
pre erred. T eophylline tends to be added to these inhaled bronchodilators in more
severe patients and has been shown to give additional clinical improvement when
added to a long-acting β2 agonist.
c. What side ef ects are to be expected with inhaled anticholinergic drugs?
Inhaled anticholinergic drugs are generally well tolerated. On stopping inhaled
anticholinergics, a small rebound increase in airway responsiveness has been
described, but the clinical relevance o this is uncertain. Systemic side e ects a er
ipratropium bromide and tiotropium bromide are uncommon during normal clini-
cal use because there is little systemic absorption. A signi cant unwanted e ect is
the unpleasant bitter taste o inhaled ipratropium, which may contribute to poor
compliance. Nebulized ipratropium bromide may precipitate glaucoma in elderly
patients due to a direct e ect o the nebulized drug on the eye. T is may be pre-
vented by nebulization with a mouthpiece rather than a ace mask. iotropium
causes dryness o the mouth in 10 to 15% o patients, but this usually disappears
during continued therapy. Urinary retention is occasionally seen in elderly patients.
CASE 24-3
A 46-year-old woman has su ered rom severe asthma since she was a girl. She com-
plains o di culty breathing nearly all o the time and occasionally has asthma attacks
that are very severe.
a. What pharmacotherapeutic options are appropriate in this patient to improve
her symptoms?
Because asthma is a chronic in ammatory disease, ICSs are considered as rst-line
therapy in all but the mildest o cases. Corticosteroids inhibit the expression o
(Continued)
395
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
P la s ma
exuda tion
FIGURE 24-5 E ects o cysteinyl-leukotrienes on the airways and their inhibition by antileukot-
rienes. AS, aspirin-sensitive; 5-LO, 5′-lipoxygenase; LT, leukotriene; PAF, platelet-activating actor.
multiple in ammatory genes in airway epithelial cells, probably the most important
action o ICSs in suppressing asthmatic in ammation (see Figure 24-3). Cortico-
steroids also increase the transcription o several anti-in ammatory genes. Steroids
have inhibitory e ects on many in ammatory and structural cells that are activated
in asthma and prevent the recruitment o in ammatory cells into the airways (see
Figure 24-4).
For most patients, ICSs should be used twice daily, a regimen that improves com-
pliance once control o asthma has been achieved (which may require 4-times daily
dosing initially or a course o oral steroids i symptoms are severe). Administration
once daily o some steroids (eg, budesonide, mometasone, and ciclesonide) is e ec-
tive when doses o 400 µg or less are needed. T e dose o ICS should be the mini-
mal dose that controls asthma; once control is achieved, the dose should be slowly
reduced. ICSs have rapid anti-in ammatory e ects, reducing airway hyperrespon-
siveness and in ammatory mediator concentrations within a ew hours. However,
it may take several weeks or months to achieve maximal e ects on airway hyperre-
sponsiveness, presumably re ecting the slow healing o the damaged in amed air-
way. It is important to recognize that corticosteroids suppress in ammation in the
airways but do not cure the underlying disease; when steroids are withdrawn, there
is a recurrence o the same degree o airway hyperresponsiveness.
For this patient’s acute severe asthma attacks, inhaled short-acting β2 agonists
are the bronchodilators o choice. T e LABAs, salmeterol, ormoterol, and ar or-
moterol, are important in controlling asthma in patients with chronic symptoms.
T ese drugs have a bronchodilator action o more than 12 hours and also protect
against bronchoconstriction or a similar period. T ey improve asthma control
(when given twice daily) compared with regular treatment with short-acting β2 ago-
nists (4-6 times daily).
(Continued)
396
Pulmonary Pharmacology CHAPTER 2 4
common problem is hoarseness and weakness o the voice (dysphonia) due to atrophy
o the vocal cords ollowing laryngeal deposition o steroid; it may occur in up to 40%
o patients and is noticed particularly by patients who need to use their voices during
their work (lecturers, teachers, and singers). Oropharyngeal candidiasis occurs in ~5%
o patients. T ere is no evidence or increased lung in ections, including tuberculo-
sis, in patients with asthma. When high doses o an ICS are required, a large volume
spacer is recommended to reduce oropharyngeal deposition and systemic absorption.
Side e ects are not common with inhaled LABA therapy. Muscle tremor is the most
common side e ect, and there are several other side e ects related to stimulation
o extrapulmonary β2 receptors (see Side Bar SIDE EFFEC S OF β2 AGONIS S).
olerance to nonairway β2 receptor–mediated responses, such as tremor and car-
diovascular and metabolic responses, is readily induced in asthmatic patients, but
tolerance to the bronchodilator e ects o β2 agonists has not usually been ound. T e
reason or the relative resistance o airway smooth muscle β2 responses to desensiti-
zation may re ect the large receptor reserve in airway smooth muscle compared to
other tissues. T e sa ety o LABAs in asthma remains controversial based on large-
scale studies o asthma patients prescribed salmeterol and ormoterol that showed
an excess o respiratory deaths and near deaths. However, concomitant treatment
with an ICS appears to obviate such risk, so it is recommended that LABAs should
only be used when ICSs are also prescribed (pre erably in the orm o a combination
inhaler so that the LABA can never be taken without the ICSs). All LABAs approved
in the United States carry a black box warning cautioning against overuse.
CASE 24-4
A 76-year-old woman who complains o di culty breathing due to pulmonary conges-
tion is diagnosed with pulmonary artery hypertension (PAH).
a. What drugs should be considered in treating this patient’s PAH?
PAH involves dys unction o pulmonary vascular endothelial and smooth muscle
cells, and results rom an imbalance in vasoconstrictor and vasodilator mediators
(see Figure 24-6). In PAH, there is an increase in the vasoconstrictor mediators
endothelin-1 (E -1), thromboxane A2, and serotonin, and a decrease in the vaso-
dilating mediators prostacyclin (PGI2), NO, and VIP. Vasodilators are the mainstay
o drug therapy or PAH (see Figure 24-6). However, the vasodilators used to treat
systemic hypertension are problematic; they lower systemic blood pressure, which
may result in reduced pulmonary per usion.
Intravenous epoprostenol (prostacyclin, PGI2) is e ective in lowering pulmonary
arterial pressures, improving exercise per ormance, and prolonging survival in pri-
mary PAH (PPAH), but must be administered by continuous IV in usion because o
its short plasma t1/2; this is inconvenient and therapy is very expensive. More stable
prostacyclin analogs (treprostinil and iloprost) can be administered by other routes,
including inhalation.
Bosentan and ambrisentan are oral endothelin receptor antagonists used or the
treatment o PPAH. T ese agents di er in their selectivity or E receptors. Stimula-
tion o E A receptors by E -1 contracts vascular smooth muscle cells and causes pro-
li eration mainly, whereas E B receptors mediate the release o prostacyclin and NO
rom endothelial cells (see Figure 24-6). Bosentan is an antagonist o both E A and
E B receptors, and is ef cacious orally in reducing symptoms and improving mor-
tality in PPAH. Ambrisentan is a selective E A receptor antagonist. T e theoretical
advantage o blocking only E A receptors is that E B receptors may continue to stim-
ulate release o PGI2 and NO, giving a greater therapeutic e ect. However, the clini-
cal ef cacy o ambrisentan is similar to that o bosentan, as are its adverse e ects.
T e oral phosphodiesterase-5 (PDE5) inhibitors, sildena l and tadala l, are e ec-
tive in improving symptoms o PAH because o their ability to induce vasodilation
by elevating intracellular cyclic guanosine monophosphate (cGMP) concentrations
in pulmonary artery smooth muscle (see Figure 24-6).
(Continued)
398
Pulmonary Pharmacology CHAPTER 2 4
Endothe lium
Ca v1.2 ETA IP
VS M
me mbra ne cAMP s GC
BALANCE IMBALANCE
(favoring contra ction a nd prolife ra tion)
C Drug e ffe c ts in PAH
+
Ca 2
Cha nne l ET-1 P GI2
2+ P DE5
a nta gonis ts Ca a na logs inhibitors
Ca v1.2 ETA IP
s GC
RESTORED BALANCE
FIGURE 24-6 Interactions o endothelium and vascular smooth muscle in pulmonary artery hypertension (PAH).
A. In normal pulmonary artery, there is a balance between constrictor and relaxant in uences that may be viewed as
competition between Ca2+ signaling pathways and cyclic nucleotide signaling pathways in vascular smooth muscle
(VSM). Endothelin (ET-1) binds to the ETA receptor on VSM cells and activates the Gq-PLC-IP3 pathway to increase
cytosolic Ca2+; ET-1 may also couple to Gi to inhibit cyclic adenosine monophosphate (cAMP) production. In depolar-
izing VSM cells, Ca2+ may enter via the L-type Ca2+ channel (Cav1.2). Endothelial cells also produce relaxant actors,
prostacyclin (PGI2) and NO. NO stimulates the soluble guanylyl cyclase (cGC), causing accumulation o cyclic guano-
sine monophosphate (cGMP) in VSM cells; PGI2 binds to the IP prostanoid receptor and stimulates the Gs-adenylyl
cyclase pathway to enhance cAMP accumulation; elevation o these cyclic nucleotides promotes VSM relaxation (see
Chapter 1). B. In PAH, ET-1 production is enhanced, production o PGI2 and NO is reduced, and the balance is shi ted
toward constriction and proli eration o vascular smooth muscle. C. In treating PAH, ETA receptor antagonists can
reduce the constrictor e ects o ET-1, and Ca2+ channel antagonists can urther reduce Ca2+-dependent contraction.
Exogenous PGI2 and NO can be supplied to promote vasodilation (relaxation o VSM); inhibition o PDE5 can enhance
the relaxant e ect o NO by inhibiting the degradation o cGMP, thereby promoting intracellular accumulation o
cGMP and relaxation o VSM. Thus, these drugs can reduce Ca2+ signaling and enhance cyclic nucleotide signaling,
restoring the balance between the orces o contraction/proli eration and relaxation/antiproli eration. Remodeling
and deposition o extracellular matrix by adjacent broblasts is in uenced positively and negatively by the same con-
tractile and relaxant signaling pathways, respectively.
399
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
b. What are the side ef ects associated with each o these agents?
Common side e ects o IV epoprostenol are headache, ushing, diarrhea, nausea,
and jaw pain. Inhaled iloprost is associated with the vasodilator e ects o prostacy-
clin, including syncope. It may also cause cough and bronchoconstriction because
it sensitizes airway sensory nerves.
T e endothelin receptor antagonists are generally well tolerated and have similar
side e ect pro les. Adverse e ects include abnormal liver unction tests, anemia,
headaches, peripheral edema, and nasal congestion. Given the risk o serious liver
injury, liver aminotrans erases should be monitored monthly. All endothelin recep-
tor antagonists carry a risk o testicular atrophy and in ertility. Bosentan is poten-
tially teratogenic.
T e PDE5 inhibitors, side e ects are due in part to systemic hypotension (headache
and ushing). Other side e ects include dyspepsia and visual disturbances. Because
o the risk o severe hypotension, concurrent administration with nitrovasodilators
should be avoided (see Chapter 16).
CASE 24-5
A 54-year-old male patient complains o chronic cough. He is not a smoker, does not
have asthma, but has a history o gastroesophageal re ux disease (GERD).
a. What treatments are most appropriate to reduce this patient’s chronic cough?
Cough is a de ensive re ex and its suppression may be inappropriate because it
could mask the underlying cause. Whenever possible, treat the underlying cause,
not the cough. A likely cause in this patient is GERD. Gastroesophageal re ux is a
common cause o cough through a re ex mechanism and occasionally as a result
o acid aspiration into the lungs. T is cough may respond to suppression o gastric
acid with an H 2 receptor antagonist or a proton pump inhibitor (see Chapter 32),
although even large doses may not always be e ective. Some patients have a chronic
cough with no obvious cause, and this chronic idiopathic cough may be due to air-
way sensory neural hyperesthesia.
Over-the-counter cough medications containing dextromethorphan are largely
ine ective, although they are widely used. Prescription cough suppressants include
opiates such as codeine, and benzonatate, a local anesthetic.
KEY CONCEPTS
Bronchodilators are key drugs in the treatment o asthma and COPD.
When there is a choice o inhaled or oral route or a pulmonary drug (eg, β2
agonist or corticosteroid), the inhaled route is always pre erable, and the oral
route should be reserved or the ew patients unable to use inhalers (eg, small
children, patients with physical problems such as severe arthritis o the hands).
Inhaled β2 agonists are unctional antagonists o bronchoconstriction and
reverse bronchoconstriction irrespective o the contractile agent.
An inhaled β2 agonist is the bronchodilator treatment o choice in asthma
because β2 agonists are the most e ective bronchodilators and have minimal
side e ects when used correctly.
Inhaled anticholinergic drugs are less e ective as bronchodilators than β2 ago-
nists in patients with asthma, but may be as e ective or superior to β2 agonists
in patients with COPD.
ICSs are recommended as f rst-line therapy or all patients with persistent
asthma (ie, patients who require inhaled β2 agonists more than twice a week)
because asthma is a chronic in ammatory disease.
ICSs have limited therapeutic value in patients with COPD except in patients
with concomitant asthma or severe COPD.
400
Pulmonary Pharmacology CHAPTER 2 4
SUMMARY QUIZ
QUESTION 24-1 A 20-year-old woman has occasional asthma symptoms during the
winter when she goes snowshoeing. T e medication o choice to relieve her asthma
symptoms is inhaled
a. albuterol.
b. salmeterol.
c. tiotropium bromide.
d. iloprost.
e. budesonide.
QUESTION 24-2 A 54-year-old man who had occupational exposure to asbestos has devel-
oped COPD and emphysema. T e medication o choice to improve his breathing is inhaled
a. albuterol.
b. salmeterol.
c. tiotropium bromide.
d. iloprost.
e. budesonide.
that long-term use o tiotropium improves lung unction and health status, and reduces
exacerbations and all-cause mortality, although there is no e ect on disease progression.
QUESTION 24-3 Answer is d. Budesonide is an ICS that has benef cial anti-in am-
matory e ects in asthma, and ormoterol is a LABA that has bronchodilator and bron-
choprotective e ects. T ese agents have both complementary and synergistic e ects
in patients with persistent asthma. T e combination inhaler is more convenient or
patients, simplif es therapy, and improves compliance with ICS because the patients
perceive clinical benef t. In addition, delivering the 2 drugs in the same inhaler ensures
they are delivered simultaneously to the same cells in the airways, allowing the benef -
cial molecular interactions between LABA and corticosteroids to occur.
QUESTION 24-4 Answer is c. Sildenaf l relaxes pulmonary artery smooth muscle by
blocking the hydrolysis o cGMP by PDE5 (see Figure 24-6). Much o the cGMP in
vascular smooth muscle is synthesized by soluble guanylate cyclase which is activated
by nitric oxide (NO). T us, sildenaf l enhances the vasodilating e ects o NO produced
endogenously by vascular endothelium.
QUESTION 24-5 Answer is d. Ipratropium is a competitive antagonist o endogenous
acetylcholine (ACh) binding to muscarinic cholinergic receptors in bronchial smooth
muscle (see Chapter 6). Activation o muscarinic receptors on bronchial smooth
muscle causes contraction and bronchoconstriction. Multiple and diverse stimuli cause
re ex increases in parasympathetic activity that contribute to bronchoconstriction.
T e e ects o ACh on the respiratory system include not only bronchoconstriction but
also increased tracheobronchial secretion and stimulation o the chemoreceptors o the
carotid and aortic bodies. T us antimuscarinic drugs antagonizes these various pulmo-
nary e ects o acetylcholine released by parasympathetic neurons.
Acetylcholine may also be released rom other airway cells, including epithelial cells.
T e synthesis o acetylcholine in epithelial cells is increased by in ammatory stimuli (such
as NF-α), which increase the expression o choline acetyltrans erase, which could contrib-
ute to cholinergic e ects in airway diseases. Muscarinic receptors are expressed in airway
smooth muscle o small airways that do not appear to be innervated by cholinergic nerves;
these receptors may be a mechanism o cholinergic narrowing in peripheral airways that
could be relevant in COPD, responding to locally synthesized, non-neuronal ACh.
SUMMARYTABLE: DRUGS USED IN THE TREATMENT OF ASTHMA, COPD, AND OTHER PULMONARY DISORDERS
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
β2 Adrenergic Albuterol The most widely used and Side e ects are not Tolerance develops to the
Agonists—Short- (salbutamol) e ective bronchodilators in the common with inhaled bronchoprotective e ects o high-
Acting (3-6 h) Levalbuterol treatment o asthma due to therapy, but quite dose inhaled β 2 agonists, but not
Metaproterenol their unctional antagonism o common with oral or IV the bronchodilating e ects
Pirbuterol bronchoconstriction administration (see Side Short-acting inhaled β 2 agonists
Terbutaline E ective in protecting against Bar SIDE EFFECTS OF β2 should only be used on demand
various challenges, such as AGONISTS) or symptom control, and i they
exercise, cold air, and allergens are required requently (more than
Bronchodilators o choice in twice weekly), an ICS is needed
treating acute severe asthma
β2 Adrenergic Salmeterol Improve asthma control (when Side e ects are not In asthma patients, LABAs should
Agonists—Long- Formoterol given twice daily) compared common with inhaled never be used alone because they
Acting (Long-Acting Ar ormoterol with regular treatment with therapy, but quite do not treat the underlying chronic
β Agonists [LABAs] Indacaterol short-acting β 2 agonists (4-6 common with oral or IV in ammation; rather, LABAs should
duration >12 h) times daily) administration (see Side always be used in combination
In COPD, LABAs are e ective Bar SIDE EFFECTS OF β2 with ICS (pre erably in a xed-dose
bronchodilators that may be AGONISTS) combination inhaler)
used alone or in combination All LABAs approved in the United
with an anticholinergic or ICS States carry a black box warning
cautioning against overuse in asthma
(Continued)
402
Pulmonary Pharmacology CHAPTER 2 4
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Methylxanthines Theophylline Should be reserved or use as Headache, nausea, At high concentrations, cardiac
add-on maintenance therapy and vomiting (due to arrhythmias
in asthma patients receiving inhibition o PDE4), At very high concentrations, seizures
high- or low-dose ICS or maximal abdominal discom ort, Low doses (5-10 mg/L) largely avoid
β2 agonist alone who require and restlessness side e ects
additional bronchodilator e ect Increased acid secretion
Added to inhaled (due to PDE inhibition)
anticholinergics and β 2 agonists and diuresis (due to
(LABAs) in patients with severe inhibition o adenosine A1
COPD receptors)
Muscarinic Ipratropium Used as an additional Inhaled anticholinergic Unpleasant bitter taste o inhaled
Cholinergic bromide bronchodilator in asthmatic drugs are generally ipratropium which may contribute
Antagonists Tiotropium bromide patients not controlled on a well tolerated with ew to poor compliance
LABA systemic e ects Bronchoconstriction may occur with
In acute and chronic asthma Tiotropium causes ipratropium
therapy, may have an additive dryness o the mouth in
e ect with β2 agonists 10-15% o patients, but
In COPD, may be as e ective as this usually disappears
or even superior to β 2 agonists during continued therapy
Corticosteroids— Beclomethasone ICSs are considered as rst-line See Chapter 29 See Chapter 29 and Side Bar
Inhaled dipropionate therapy in all but the mildest and Side Bar SIDE SIDE EFFECTS OF INHALED
Corticosteroids Triamcinolone o asthma patients and should EFFECTS OF INHALED CORTICOSTEROIDS
(ICSs) Flunisolide be started in any patient who CORTICOSTEROIDS All currently available ICSs are
Budesonide needs to use a β 2 agonist inhaler Budesonide, uticasone, absorbed rom the lung into the
Fluticasone or symptom control more than mometasone, and systemic circulation, so that some
Mometasone twice weekly ciclesonide are subject systemic absorption is inevitable
Ciclesonide ICSs are much less e ective to greater rst-pass To reduce likelihood o systemic
in COPD and should only be hepatic metabolism e ects, use the lowest dose o
used in patients with severe than beclomethasone inhaled steroid needed to control
disease who have requent dipropionate, thus have the asthma, and use a large-volume
exacerbations reduced adverse systemic spacer to reduce oropharyngeal
e ects deposition
Corticosteroids— Hydrocortisone IVsteroids are indicated in acute Adrenal suppression by a Steroid doses a ter prolonged oral
Systemic Methylprednisolone asthma i lung unction is <30% negative eedback e ect therapy must be reduced slowly;
Prednisolone o predicted and there is no on the pituitary gland symptoms o “steroid withdrawal
Prednisone improvement with β2 agonist Signi cant adrenal syndrome”include lassitude,
Short courses o oral steroids suppression a ter short musculoskeletal pains, and,
(30-40 mg prednisolone daily courses o corticosteroid occasionally, ever (see Chapter 29
or 1-2 weeks) are indicated or therapy is not usually a or other toxicities and precautions)
exacerbations o asthma problem, but prolonged
Oral corticosteroids remain suppression may occur
the mainstay o treatment o a ter several months or
several pulmonary diseases, years
such as sarcoidosis, interstitial Long-term oral
lung diseases, and pulmonary corticosteroid side e ects
eosinophilic syndromes include uid retention,
increased appetite,
weight gain, osteoporosis,
capillary ragility,
hypertension, peptic
ulceration, diabetes,
cataracts, and psychosis
(see Chapter 29 or other
toxicities and precautions)
Antileukotrienes— Zileuton Antileukotrienes are indicated Associated with rare cases o hepatic
5’-Lipoxygenase as an add-on therapy in asthma dys unction; thus liver-associated
(5-LOX) Inhibitors patients who are not well enzymes should be monitored
controlled on ICSs
(Continued)
403
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Antileukotrienes— Montelukast Antileukotrienes are indicated Associated with rare cases o hepatic
Leukotriene Za rlukast as an add-on therapy in asthma dys unction; thus liver-associated
Antagonists patients who are not well enzymes should be monitored
controlled on ICSs Cases o Churg-Strauss syndrome
Cys-LT1 receptor antagonists have been reported
have no role in the therapy o
COPD
Anti-IgEMonoclonal Omalizumab Used or the treatment o patients Major side e ect is an anaphylactic
Antibodies with severe asthma who are response, which is uncommon
poorly controlled even on oral (<0.1%)
corticosteroids and in patients
with very severe concomitant
allergic rhinitis
Antitussives Codeine Cough suppression Codeine and other opiates Dextromethorphan can cause
Dextromethorphan (Note: Cough is a de ensive are associated with hallucinations at higher doses and
Benzonatate re ex; whenever possible, treat the sedation and constipation has signi cant abuse potential
underlying cause, not the cough) (see Chapter 10) Seizures and cardiac arrest have
Many over-the-counter cough Benzonatate is associated occurred with acute ingestion o
medications containing with dizziness and benzonatate
dextromethorphan are largely dysphagia Severe allergic reactions in patients
ine ective taking benzonatate who are allergic
to p-aminobenzoic acid
Ventilatory Doxapram Increase ventilatory rate Nausea, sweating, anxiety, Should be used with caution i
Stimulants (Note: The use o doxapram to and hallucinations hepatic or renal unction is impaired
treat ventilatory ailure in COPD At higher doses, In COPD, the in usion o doxapram is
has now largely been replaced by increased pulmonary and restricted to 2 h
noninvasive ventilation) systemic blood pressures
Endothelin-1 Bosentan Oral bosentan is ef cacious Bosentan is generally well Risk o serious liver injury; liver
Receptor Ambrisentan in reducing symptoms and tolerated; adverse e ects aminotrans erases should be
Antagonists improving mortality in PPAH include abnormal liver monitored monthly
unction tests, anemia, Risk o testicular atrophy and
headaches, peripheral in ertility
edema, and nasal Bosentan is potentially teratogenic
congestion
Phosphodiesterase-5 Sildena l E ective in lowering pulmonary Headache, ushing, Should not be used in patients
(PDE5) Inhibitors Tadala l resistance and improving dyspepsia, and visual receiving nitrovasodilators due
exercise tolerance in patients disturbances to risk o severe hypotension (see
with PAH Chapter 16)
404
CHAPTER
HematopoieticAgents 25
T is chapter will be most use ul a er having a basic understanding o the material
DRUGS INCLUDED
in Chapter 37, Hematopoietic Agents: Growth Factors, Minerals, and Vitamins in
Goodman & Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition. In IN THIS CHAPTER
addition to the material presented here, the 12th Edition contains: • Copper sul ate (cupricsul ate)
• A description o hematopoietic cell growth and di erentiation and the role o hema- • Cyanocobalamin (vitamin B12; CALOMIST,
topoietic growth actors in these processes NASCOBAL)
• A discussion o iron metabolism and storage in the body • Darbepoetin al a (ARANESP)
• A discussion o actors that cause iron de ciency anemia • Eltrombopag (PROMACTA)
• A discussion o vitamin de ciencies that can lead to anemia • Epoetin al a (recombinant erythropoietin;
• able 37-3 Iron Requirements or Pregnancy EPOGEN, PROCRIT,EPREX)
• able 37-2 T e Body Content o Iron • Ferrous umarate (HEMCYTE, FEOSTAT,
others)
• able 37-5 Average Response to Oral Iron
• Ferrous gluconate (FERGON, others)
• T e molecular structures o vitamin B12 and olic acid, and their congeners
• Ferrous succinate, aspartate, and other
LEARNING OBJECTIVES errous salts
Understand the mechanisms o action o drugs, minerals, and vitamins used to • Ferrous sul ate (FEOSOL, others)
stimulate hematopoiesis. • Ferumoxytol (FERAHEME)
Know the untoward e ects o drugs used to stimulate hematopoiesis. • Folicacid (pteroylglutamicacid [PteGlu],
l -methyl olate)
Know the clinical application o hematopoietic growth actors and how e cacy
o therapy is monitored. • Folinicacid (leucovorin calcium, citrovorum
actor)
Know how mineral and vitamin de ciencies can lead to speci c anemia, how
these are diagnosed, and how they are treated with individual agents or combi- • G-CSF(recombinant G-CSF, lgrastim;
nations o agents. NEUPOGEN)
Know when iron and vitamin supplementation should be used prophylactically. • GM-CSF(recombinant GM-CSF, sargramos-
tim; LEUKINE)
• Hydroxocobalamin (vitamin B12)
• IL-11 (recombinant IL-11; oprelvekin;
[NEUMEGA]
MECHANISMS OF ACTION OF HEMATOPOIETIC AGENTS
• Iron dextran (DEXFERRUM, INFED,
DRUG CLASS DRUG MECHANISM OF ACTION IMFERON)
Erythropoiesis- Epoetin al a Stimulate proli eration and maturation • Iron sucrose (VENOFER)
Stimulating Agents Darbepoetin al a o committed erythroid progenitors
• Pegylated recombinant G-CSF(peg lgras-
(ESAs) to increase red blood cell (RBC)
production (see Table 25-1 and tim; NEULASTA)
Figure 25-1) • Polysaccharide- errihydrite complex(NIFE-
REX,others)
Myeloid Growth GM-CSF (sargrastim) Stimulate proli eration and
Factors G-CSF ( lgrastim) di erentiation o 1 or more myeloid • Pyridoxine
Pegylated recombinant G-CSF cell lines, and enhance the unction o • Ribo avin
(peg lgrastim) mature granulocytes and monocytes
(see Table 25-1 and Figures 25-1 and • Romiplostim(NPLATE)
25-2) • Sodium erricgluconate (FERRLECIT)
Thrombopoietic IL-11 (oprelvekin) Enhance megakaryocyte maturation
Growth Factors and increases peripheral blood
platelet counts
Copper Supplement Copper sul ate (cupric sul ate) Corrects copper de ciencies
that inter ere with absorption
o iron and release o iron rom
reticuloendothelial cells that result in
anemia
Vitamins—Folic Acid Folic acid (pteroylglutamic acid Co actor required or normal synthesis
and Derivatives [PteGlu], l -methyl olate) o purines and pyrimidines needed
Folinic acid (leucovorin calcium, or DNA synthesis, especially in rapidly
citrovorum actor) dividing cells o the hematopoietic
system (see Figure 25-3)
CASE 25-1
A 64-year-old woman with chronic kidney disease has a low hematocrit and is started
on therapy with epoetin al a.
a. What is the mechanism o action o epoetin al a?
Recombinant human erythropoietin (epoetin al a) is nearly identical to the endog-
enous hormone except that the carbohydrate modi cation pattern o epoetin al a
di ers slightly rom the native protein; this di erence apparently does not alter
kinetics, potency, or immunoreactivity o the drug.
T e endogenous protein is heavily glycosylated and expressed primarily in peri-
tubular interstitial cells o the kidney. A er secretion, erythropoietin binds to a
receptor on the sur ace o committed erythroid progenitors in the marrow and is
internalized. With anemia or hypoxemia, synthesis rapidly increases by 100- old
or more, serum erythropoietin levels rise, and marrow progenitor cell survival,
proli eration, and maturation are dramatically stimulated (see Figure 25-1). T is
nely tuned eedback loop can be disrupted by kidney disease, marrow damage, or
a de ciency in iron or an essential vitamin. With an in ection or an in ammatory
state, erythropoietin secretion, iron delivery, and progenitor proli eration all are
suppressed by in ammatory cytokines. T ere is a clear dose–response relationship
between the epoetin al a dose and the rise in hematocrit in anephric patients, with
eradication o their anemia at higher doses.
More recently, a novel erythropoiesis-stimulating protein, darbepoetin al a,
has been approved or clinical use in patients with indications similar to those
(Continued)
406
Hematopoietic Agents CHAPTER 2 5
BFU, burst- orming unit; CFU, colony- orming unit; E, erythrocyte; G, granulocyte; M, macrophage;
Meg, megakaryocyte; NKcells, natural killer cells; LAKcells, lymphokine-activated killer cells.
ERYTHROPOIETIN
GM-CS F / IL-3 BFU-E/CFU-E
S CF / FL Re d
blood
ce lls
Totipote nt/pluripote nt
s te m ce lls GM-CS F / G-CS F
Gra nulocyte s
CFU-GEMM Ba s ophils
GM-CS F / M-CS F
CFU-Me g Monocyte s
Lymphocyte
Proge nitor
P la te le ts
B ce lls NK ce lls
T ce lls
FIGURE 25-1 Sites o action o hematopoietic growth actors in the di erentiation and maturation
o marrow cell lines. A sel -sustaining pool o marrow stem cells di erentiates under the in uence
o speci c hematopoietic growth actors to orm a variety o hematopoietic and lymphopoietic
cells. Stem cell actor (SCF), ligand (FL), interleukin-3 (IL-3), and granulocyte-macrophage colony-
stimulating actor (GM-CSF), together with cell–cell interactions in the marrow, stimulate stem cells
to orm a series o burst- orming units (BFU) and colony- orming units (CFU): CFU-GEMM (granulo-
cyte, erythrocyte, monocyte, and megakaryocyte), CFU-GM (granulocyte and macrophage), CFU-Meg
(megakaryocyte), BFU-E (erythrocyte), and CFU-E (erythrocyte). A ter considerable proli eration, urther
di erentiation is stimulated by synergistic interactions with growth actors or each o the major cell
lines—granulocyte colony–stimulating actor (G-CSF), monocyte/macrophage-stimulating actor
(M-CSF), thrombopoietin, and erythropoietin. Each o these actors also in uences the proli eration,
maturation, and, in some cases, the unction o the derivative cell line (see Table 25-1).
IL-4
T c e ll B c e ll
IL-2
IFN-γ
Antibody
IL-1 IL-1
IL-3
GM-CS F
Bo ne Marrow
FIGURE 25-2 Cytokine–cell interactions. Macrophages, T cells, B cells, and marrow stem cells
interact via several cytokines (IL-1, IL-2, IL-3, IL-4, IFN [inter eron]-γ, GM-CSF, and G-CSF) in
response to a bacterial or a oreign antigen challenge. See Table 25-1 or the unctional activities
o these various cytokines.
408
Hematopoietic Agents CHAPTER 2 5
Highly competitive athletes have used epoetin al a to increase their hemoglobin levels
(“blood doping”) and improve per ormance. Un ortunately, this misuse o the drug
has been implicated in the deaths o several athletes and is strongly discouraged.
c. What are the therapeutic considerations to optimize therapy with epoetin al a?
During erythropoietin therapy, absolute or unctional iron de ciency may develop.
Functional iron de ciency (ie, normal erritin levels but low trans errin saturation)
presumably results rom the inability to mobilize iron stores rapidly enough to
support the increased erythropoiesis. Virtually all patients eventually will require
supplemental iron to increase or maintain trans errin saturation to levels that will
adequately support stimulated erythropoiesis.
Resistance to epoetin al a therapy is common in patients who develop an in am-
matory illness or become iron de cient, so close monitoring o general health and
iron status is essential. Less common causes o resistance include occult blood loss,
olic acid de ciency, carnitine de ciency, inadequate dialysis, aluminum toxicity,
and osteitis brosa cystica secondary to hyperparathyroidism.
d. What are the possible toxicities and hazards o therapy with epoetin al a?
T e most common side e ect o epoetin al a therapy is aggravation o hyperten-
sion, which occurs in 20 to 30% o patients and most o en is associated with a
rapid rise in hematocrit. Blood pressure usually can be controlled either by increas-
ing antihypertensive therapy, ultra ltration in dialysis patients, or by reducing
the epoetin al a dose to slow the hematocrit response. ESAs should not be used in
patients with preexisting uncontrolled hypertension.
Headache, tachycardia, edema, shortness o breath, nausea, vomiting, diarrhea,
injection site stinging, and u-like symptoms (eg, arthralgias and myalgias) also
have been reported in conjunction with epoetin al a therapy.
During hemodialysis, patients receiving epoetin al a or darbepoetin may require
increased anticoagulation. Serious thromboembolic events have been reported,
including migratory thrombophlebitis, microvascular thrombosis, pulmonary
embolism, and thrombosis o the retinal artery and temporal and renal veins. T e
risk o thrombotic events, including vascular access thromboses, was higher in
adults with ischemic heart disease or congestive heart ailure receiving epoetin al a
therapy with the goal o reaching a normal hematocrit (42%) than in those with
a lower-target hematocrit o 30%. T e higher risk o cardiovascular events rom
erythropoietic therapies may be associated with higher hemoglobin or higher rates
o rise in hemoglobin. T e hemoglobin level should be managed to avoid exceeding
a target level o 12 g/dL.
ESA use is associated with increased rates o cancer recurrence and decreased on-
study survival in patients in whom the drugs are administered or cancer-induced
or or chemotherapy-induced anemia. T e cause(s) o this e ect is presently
unclear, but some studies suggest that tumor cells bearing the erythropoietin recep-
tor are more likely to be a ected by the use o ESAs.
CASE 25-2
A 42-year-old man with leukemia will undergo autologous peripheral blood stem cell
transplant ollowing high-dose chemotherapy.
a. What is the rationale or using myeloid growth actors in this procedure?
T e myeloid growth actors (see Figure 25-1 and able 25-1) are glycoproteins that
stimulate the proli eration and di erentiation o 1 or more myeloid cell lines. T ey
also enhance the unction o mature granulocytes and monocytes. Recombinant
orms o several growth actors have been produced, including granulocyte-
macrophage colony-stimulating actor (GM-CSF), granulocyte colony-stimulating
actor (G-CSF), interleukin-3 (IL-3), macrophage colony-stimulating actor (M-CSF;
also known as colony-stimulating actor, CSF-1), and stem cell actor (SCF).
(Continued)
409
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
411
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
CASE 25-4
A 22-year-old woman is pregnant with her rst child. She is in good health, but her
pediatrician prescribes an oral iron supplement.
a. What is the rationale or supplemental iron in this patient?
In developed countries, the normal adult diet contains ~6 mg o iron per 1000 calo-
ries, providing an average daily intake or adult men o between 12 and 20 mg, and
or adult women a daily intake o between 8 and 15 mg. Normal iron absorption is
~1 mg/d in adult men and 1.4 mg/d in adult women; 3 to 4 mg o dietary iron is the
most that can normally be absorbed.
Pregnancy and lactation impose a greater requirement or iron with the growth o
the etus and expansion o red cell mass (see ables 25-2 and 25-3). A recent study
ound that 18% o pregnant women in the United States had iron de ciency, with
6.9% in the rst trimester, 14.3% in the second trimester, and 29.7% in the third tri-
mester. Iron de ciency during pregnancy increases the risk o maternal and in ant
mortality, premature birth, low birth weight, and impaired cognitive and behavioral
development o the in ant. In ants, especially those born preterm, with low birth
weight, or whose mothers have iron de ciency, are at risk o iron de ciency due to
their rapid growth.
Whereas iron balance in adult men and nonmenstruating women is reasonably
secure, pregnancy and in ancy represent periods o negative iron balance, and men-
struating women also are at risk o iron de ciency. T e di erence between dietary
supply and requirements is re ected in the size o iron stores, which are low or
absent when iron balance is precarious and high when iron balance is avorable (see
able 37-2, Goodman and Gilman’s T e Pharmacological Basis of T erapeutics, 12th
Edition). T us in in ants a er the third month o li e and in pregnant women a er
the rst trimester, stores o iron are negligible. Menstruating women have approxi-
mately one-third the stored iron ound in adult men, indicative o the extent to
which the additional average daily loss o ~0.5 mg o iron a ects iron balance.
b. What are the e ects o iron def ciency in in ants and children?
Iron de ciency in in ants and young children can lead to behavioral disturbances
and can impair development, which may not be ully reversible. Iron de ciency in
children also can lead to an increased risk o lead toxicity secondary to pica and
an increased absorption o heavy metals. Premature and low-birth-weight in ants
are at greatest risk or developing iron de ciency, especially i they are not breast- COMMON CAUSES OF
ed and/or do not receive iron- orti ed ormula. During adolescence there is a FOLATE DEFICIENCY (se e
rapid growth combined with irregular dietary habits and the risk o iron de ciency FIGURE 25-5)
increases again. Adolescent girls are at greatest risk; the dietary iron intake o most
• Inadequate dietarysupply.
girls ages 11 to 18 years is insuf cient to meet their requirements.
• Small intestinal disease.
c. What are some o the considerations in optimizing the e ects o oral medicinal iron?
• In patients with uremia, alcoholism, or
o prevent iron de ciency in pregnant women, doses o 15 to 30 mg o iron per day hepaticdisease there maybe de ects in:
are adequate to meet the daily requirement o the last 2 trimesters. Orally administered
» The concentration o olate binding
errous sul ate is the treatment o choice or iron de ciency. Ferrous salts are absorbed
proteins in plasma
about 3 times as well as erric salts, and the discrepancy becomes even greater at high
dosages. Variations in the particular errous salt have relatively little e ect on bioavail- » The owo CH3H4PteGlu1 into bile or
ability; the sul ate, umarate, succinate, gluconate, aspartate, other errous salts, and reabsorption and transport to tissue
polysaccharide- errihydrite complex are all absorbed to approximately the same extent. (the olate enterohepaticcycle)
T e e ective dose o all o these preparations is based on iron content. It is essential • Vitamin B12 de ciencywill“trap” olate
that the coating o the tablet dissolve rapidly in the stomach because iron usually as CH3H4PteGlu, therebyreducing the
is absorbed in the upper small intestine. Bioavailability o iron ingested with ood is availabilityo H4PteGlu1 or its essential
probably one-hal or one-third o that seen in the asting subject. It is always pre er- roles in purine and pyrimidine synthesis.
able to administer iron in the asting state, even i the dose must be reduced because
o GI side e ects. Antacids also reduce iron absorption i given concurrently.
(Continued)
413
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
Clinically, the e ectiveness o iron therapy is best evaluated by tracking the reticu-
GENERAL PRINCIPLES OF
locyte response and the rise in the hemoglobin or the hematocrit. An increase in
FOLIC ACID THERAPY
the reticulocyte count is not observed or at least 4 to 7 days a er beginning ther-
1. Prophylacticadministration o olicacid apy. A measurable increase in the hemoglobin level takes even longer.
should be undertaken or clear indications.
• Dietarysupplementation is necessary CASE 25-5
when there is a requirement that may
not be met bya“normal”diet. During his annual visit to his amily physician, a 68-year-old man complains o numb-
ness in his hands, occasional tremors and loss o balance, and some loss o memory. He
• The dailyingestion o a multivitamin is ound to be anemic with abnormally large red cells and other blood cell anomalies.
preparation containing 400 to 500 µg He is a strict vegetarian and does not eat eggs or dairy products.
o olicacid has become standard
practice be ore and during pregnancy a. What might be contributing to this patient’s condition?
to reduce the incidence o neural tube T is patient has symptoms consistent with de ciency o either vitamin B12 or olic
de ects and or as long as a woman is acid. An early sign o de ciency is megaloblastic anemia. Abnormal macrocytic red
breast- eeding. blood cells are produced, and the patient becomes severely anemic. T ese vitamins
• In women with a historyo a pregnancy are key co actors in the biochemical pathways that are critical or normal synthe-
complicated bya neural tube de ect, sis o purines and pyrimidines (see Figure 25-3). A de ciency o either vitamin
an even larger dose o 4 mg/d has been impairs DNA synthesis in any cell in which chromosomal replication and division
recommended (MRCVitamin Study are taking place. In addition, a de ciency o either vitamin B12 or olate leads to the
Research Group). decreased synthesis o methionine and S-adenosylmethionine, which inter eres
• Patients on total parenteral nutrition with protein biosynthesis, a number o methylation reactions, and the synthesis o
should receive olicacid supplements as polyamines. Because tissues with the greatest rate o cell turnover show the most
part o their uid regimen because liver dramatic e ects with alterations in these pathways, the hematopoietic system is
olate stores are limited. especially sensitive to de ciencies o these vitamins. Neurological lesions are also
common with vitamin B12 de ciency, although the mechanisms are not well under-
• Adult patients with a disease state
stood. Neurological signs and symptoms include paresthesia o the hands and eet,
characterized byhigh cell turnover (eg,
decreased vibration and position senses with resultant unsteadiness, decreased
hemolyticanemia) generallyrequire
deep tendon re exes, and in the later stages o vitamin B12 de ciency, con usion,
larger doses, 1 mg o olicacid given
moodiness, loss o memory, and even a loss o central vision. T e patient may
once or twice a day.
exhibit delusions, hallucinations, or even overt psychosis. Because the neurological
• The 1-mg dose also has been used in damage can be dissociated rom the changes in the hematopoietic system, vitamin
the treatment o patients with elevated B12 de ciency must be considered in elderly patients with dementia or psychiatric
levels o homocysteine. disorders, even i they are not anemic.
2. As with vitamin B12 de ciency, anypatient
b. Why might this patient be at risk or vitamin B12 or olic acid def ciency?
with olate de ciencyand a megaloblastic
anemia should be evaluated care ullyto T is patient is a strict vegetarian and may be lacking these vitamins because o his diet
determine the underlying cause o the (see Side Bars COMMON CAUSES OF FOLA E DEFICIENCY and CAUSES OF
de ciencystate including: VI AMIN B12 DEFICIENCY). Vegetable products are ree o vitamin B12 unless they
are contaminated with microorganisms that grow in soil, sewage, water, or the intesti-
• The ef ects o medications
nal lumen o animals that synthesize the vitamin. Despite this, strict vegetarians rarely
• The amount o alcohol intake develop vitamin B12 de ciency because some vitamin B12 is available rom legumes,
• The patient’s historyo travel which are contaminated with bacteria capable o synthesizing vitamin B12, and because
• The unction o the GItract vegetarians o en orti y their diets with a wide range o vitamins and minerals.
3. Therapyalways should be as speci cas Although this patient could be de cient in vitamin B12 because o diet, vita-
possible. min B12 de ciency in adults is rarely the result o a de cient diet per se; rather,
it usually re ects a de ect in one or another aspect o the complex sequence o
• Multivitamin preparations should be
steps in vitamin B12 absorption that is depicted in Figure 25-4. Achlorhydria and
avoided unless there is good reason to
decreased secretion o intrinsic actor by parietal cells secondary to gastric atrophy
suspect de ciencyo several vitamins.
or gastric surgery is a common cause o vitamin B12 de ciency in adults. Antibod-
4. The potential danger o mistreating a ies to parietal cells or intrinsic actor complex also can play a prominent role in
patient who has vitamin B12 de ciency producing a de ciency. A number o intestinal diseases can inter ere with absorp-
with olicacid must be kept in mind. tion, including pancreatic disorders (loss o pancreatic protease secretion), bacterial
• The administration o large doses o overgrowth, intestinal parasites, sprue, and localized damage to ileal mucosal cells
olicacid can result in an apparent by disease or as a result o surgery.
improvement in the megaloblasticane- T is patient is not likely to be de cient in dietary intake o olic acid because o his veg-
mia, inasmuch as PteGlu is converted etarian diet since many ood sources are rich in olate, especially resh green vegetables,
(Continued)
414
Hematopoietic Agents CHAPTER 2 5
yeast, and some ruits. (Liver is also rich in olate but would not be part o a vegetar-
GENERAL PRINCIPLES OF
ian diet.) Generally, a standard US diet provides 50 to 500 µg o absorbable olate per
FOLIC ACID THERAPY
day (the recommended daily intake or the normal adult is 400 µg), although individu-
als with high intakes o resh vegetables and meats will ingest as much as 2 mg/d. (Cont.)
Folate de ciency is a common complication o diseases o the small intestine that bydihydro olate reductase to H4PteGlu;
inter ere with the absorption o olate rom ood and the recirculation o olate this circumvents the methyl olate“trap.”
through the enterohepatic cycle (see Figure 25-5). Because most absorption occurs Folate therapydoes not prevent or alle-
in the proximal portion o the small intestine, it is not unusual or olate de ciency to viate the neurological de ects o vitamin
occur when the jejunum is diseased. Both nontropical and tropical sprues are common B12 de ciency, and these mayprogress
causes o olate de ciency and megaloblastic anemia. In acute or chronic alcoholism, and become irreversible.
daily intake o olate in ood may be severely restricted, and the enterohepatic cycle o
the vitamin may be impaired by toxic e ects o alcohol on hepatic parenchymal cells;
this is the most common cause o olate-de cient megaloblastic erythropoiesis.
c. What treatment is indicated or this patient?
T e general principles o therapy are described in the Side Bars GENERAL PRNCI-
PLES OF VI AMIN B12 HERAPY and GENERAL PRNCIPLES OF FOLIC ACID
HERAPY. Because this patient has symptoms o neurological damage, e ective
therapy must not wait or detailed diagnostic tests. Inasmuch as the patient requires
therapy be ore the exact cause o the disease has been de ned, it is important to
avoid the potential problem o a combined de ciency o vitamin B12 and olic acid.
When the patient is de cient in both, therapy with only 1 vitamin will not provide
an optimal response. Long-standing nontropical sprue is 1 example o a disease in
which combined de ciency o B12 and olate is common. Once the megaloblastic
erythropoiesis has been con rmed and suf cient blood collected or later mea-
surements o vitamin B12 and olic acid, the patient should receive intramuscular
injections o 100 µg o cyanocobalamin and 1 to 5 mg o olic acid. For the next 1
to 2 weeks the patient should receive daily intramuscular injections o 100 µg o
cyanocobalamin, together with a daily oral supplement o 1 to 2 mg o olic acid.
T e therapeutic response may be monitored by study o the hematopoietic system.
Within 48 hours o the initiation o appropriate therapy, megaloblastic erythropoi-
esis disappears, and as ef cient erythropoiesis begins, the concentration o iron in
plasma alls to normal or below normal values. T e reticulocyte count begins to rise
on the second or third day and reaches a peak by the h to seventh days; the reticu-
locyte index re ects the proli erative state o the marrow. Finally, the hematocrit
begins to rise during the second week. Patients with complicating iron de ciency, an
in ection or other in ammatory state, or renal disease may be unable to correct their
anemia. T ere ore, it is important to monitor the reticulocyte index over the rst sev-
eral weeks. I it does not continue at elevated levels while the hematocrit is less than
35%, plasma concentrations o iron and olic acid should again be determined and
the patient reevaluated or an illness that could inhibit the response o the marrow.
T e degree and rate o improvement o neurological signs and symptoms depend
on the severity and the duration o the abnormalities. T ose that have been present
or only a ew months usually disappear relatively rapidly. When a de ect has been
present or many months or years, ull return to normal unction may never occur.
Once begun, vitamin B12 therapy must be maintained or li e. T is act must be
impressed on the patient and amily, and a system must be established to guaran-
tee continued monthly injections o cyanocobalamin. Intramuscular injection o
100 µg o cyanocobalamin every 4 weeks is suf cient to maintain a normal con-
centration o vitamin B12 in plasma and an adequate supply or tissues. Patients
with severe neurological symptoms and signs may be treated with larger doses o
vitamin B12 in the period immediately a er the diagnosis. Doses o 100 µg/d or
several times per week may be given or several months with the hope o encour-
aging aster and more complete recovery. It is important to monitor vitamin B12
concentrations in plasma and to obtain peripheral blood counts at intervals o 3 to
6 months to con rm the adequacy o therapy. Because re ractoriness to therapy can
develop at any time, evaluation must continue throughout the patient’s li e.
415
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
KEY CONCEPTS
Recombinant erythropoietin is used routinely or patients with the anemia o
renal insu ciency, inf ammation, and anemia associated with cancer or the
therapy o cancer.
Myeloid growth actors (eg, GM-CSF and G-CSF) are used to hasten the
recovery o granulocytes a er myelosuppressive therapy, to help mobilize
hematopoietic stem cells into the peripheral blood to allow their harvest or
transplantation, and to augment the number o mature leukocytes in the periph-
eral blood so that they can be used in patients with overwhelming in ection.
IL-11 and small molecules that activate the thrombopoietin receptor are used to
treat acquired and hereditary thrombocytopenias.
Iron de ciency is the most common nutritional disorder and can result rom a
variety o causes, including conditions with increased iron requirements such as
pregnancy, in ancy, menstruation, and blood loss.
De ciency o vitamin B12 and olic acid result in a characteristic megaloblastic
anemia, but vitamin B12 de ciency can also lead to serious neurological lesions.
T e megaloblastic anemia that results rom olate de ciency cannot be dis-
tinguished rom that caused by vitamin B12 de ciency; thus it is important to
consider both de ciencies when initiating treatment and monitoring therapy to
avoid irreversible neurologic damage.
SUMMARY QUIZ
QUESTION 25-3 T erapy with olinic acid is used to treat anemia associated with the
a. antituberculosis drugs isoniazid and pyrazinamide.
b. antiparkinson drug levodopa.
c. antibiotic chloramphenicol.
d. anticancer agent carboplatin.
e. anticancer agent methotrexate.
d. red-cell aplasia.
e. megaloblastic anemia.
QUESTION 25-5 Which o the ollowing agents activates the thrombopoietin receptor
on megakaryocytes?
a. Epoetin al a
b. Filgrastim
c. Darbepoetin al a
d. Romiplostim
e. Oprelvekin
QUESTION 25-1 Answer is e. Folate de ciency has been implicated in the incidence
o neural tube de ects, including spina bi da, encephaloceles, and anencephaly. T is
is true even in the absence o olate-de cient anemia or alcoholism. T e daily inges-
tion o a multivitamin preparation containing 400 to 500 µg o olic acid has become
standard practice be ore and during pregnancy to reduce the incidence o neural tube
de ects and or as long as a woman is breast- eeding. In women with a history o a
pregnancy complicated by a neural tube de ect, an even larger dose o 4 mg/d has been
recommended.
QUESTION 25-4 Answer is e. An early sign o olic acid or vitamin B12 de ciency is
megaloblastic anemia. Abnormal macrocytic red blood cells are produced, and the
patient becomes severely anemic. T is pattern o abnormal hematopoiesis is also termed
pernicious anemia. T e characteristic abnormality in red blood cell morphology is impor-
tant or diagnosis and as a therapeutic guide ollowing administration o the vitamins.
417
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
Myeloid Growth Factors GM-CSF Stimulate myelopoiesis in Higher doses are An acute reaction to rst dose
(sargramostim) patients undergoing autologous associated with bone in sensitive patients includes
bone marrow transplant, and pain, malaise, ulike ushing, hypotension, nausea,
in patients receiving intensive symptoms, ever, vomiting, dyspnea, all in
cancer chemotherapy, and some diarrhea, dyspnea, and arterial PO2
patients with cyclic neutropenia, rash Capillary leak syndrome with
myelodysplasia, aplastic anemia, prolonged administration in
or AIDS-associated neutropenia some patients
Transient supraventricular
arrhythmia, dyspnea, elevation
o serum creatinine, bilirubin,
and liver enzymes
G-CSF ( lgrastim) Stimulation o neutrophil Mild to moderate bone Rare cutaneous necrotizing
Pegylated production (and phagocytic pain with high doses vasculitis
recombinant and cytotoxic unctions over long periods Patients with hypersensitivity
G-CSF o neutrophils) in patients Local skin reactions at to proteins produced in
(peg lgrastim) with severe neutropenia site o subcutaneous Escherichia coli should not
a ter autologous stem cell injection receive the drug
transplantation, high-dose Marked granulocytosis in
cancer chemotherapy, severe patients receiving drug
congenital neutropenia, and over prolonged periods,
other neutropenia but not associated with
Used in peripheral blood stem increased morbidity or
cell (PBSC) collection to promote mortality
release o CD34+ progenitor cells Mild to moderate
splenomegaly with long-
term therapy
418
Hematopoietic Agents CHAPTER 2 5
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Thrombopoietic Growth IL-11 (oprelvekin) Used in patients with Fluid retention and
Factors chemotherapy-induced associated cardiac
thrombocytopenia to increase symptoms, such as
platelet production tachycardia, palpitation,
edema, and shortness
o breath; in elderly
patients it o ten requires
concomitant therapy
with diuretics
Blurred vision, injection-
site rash or erythema,
and paresthesia
Romiplostim Approved or use in patients
Eltrombopag with immune thrombocytopenic
purpura (ITP) who have ailed to
respond to more conventional
treatments
Iron Supplements—Oral Ferrous sul ate Treatment o iron de ciency Heartburn, nausea, upper Severe iron poisoning via
Ferrous umarate anemia due to dietary iron gastric discom ort, and accidental ingestion by children
Ferrous succinate, de ciency, blood loss, and as an diarrhea or constipation can be atal; symptoms include
aspartate, and adjunct in patients treated with abdominal pain, diarrhea, or
other errous salts erythropoietin vomiting o brown or bloody
Ferrous gluconate Prophylactic use o oral iron stomach contents containing
Polysaccharide- should be reserved or patients pills; o particular concern are
errihydrite at high risk, including pregnant pallor or cyanosis, lassitude,
complex women, women with excessive drowsiness, hyperventilation
menstrual blood loss, and in ants due to acidosis, and
cardiovascular collapse
Iron Supplements— Iron dextran Used when oral iron therapy ails Reactions to intravenous Parenteral iron therapy
Parenteral Sodium erric Common indications are iron iron include headache, should be used only when
gluconate malabsorption (eg, sprue, short malaise, ever, generalized clearly indicated because
Ferumoxytol bowel syndrome), severe oral lymphadenopathy, acute hypersensitivity,
Iron sucrose iron intolerance, as a routine arthralgia, urticaria, including anaphylactic and
supplement to total parenteral and exacerbation o anaphylactoid reactions, can
nutrition, and in patients who rheumatoid arthritis in occur in 0.2-3% o patients
are receiving erythropoietin, some patients
especially in hemodialysis
patients
Copper Supplement Cupric sul ate Supplementation (beginning
with a therapeutic trial) in
patients when a low plasma
copper concentration is
determined in the presence o
leukopenia and anemia
Vitamins—Pyridoxine Pyridoxine Pyridoxine is used to improve
Ribo avin hematopoiesis in patients with
either hereditary or acquired
sideroblastic anemia (ie,
sideroblastic anemia associated
with the antituberculosis drugs
isoniazid and pyrazinamide)
Ribo avin used in the nutritional
management o patients with
gross, generalized malnutrition to
treat or prevent red cell aplasia
419
SECTION IV Inf ammation, Immunomodulation, and Hematopoiesis
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Vitamins—Vitamin B12 Cyanocobalamin Treatment o vitamin B12 Once begun, vitamin Cyanocobalamin should never
(vitamin B12) de ciency; de ciency can B12 therapy must be be given intravenously due
Hydroxocobalamin mani est as severe megaloblastic maintained or li e; to rare reports o transitory
(vitamin B12) anemia with neurological it is important to exanthema and anaphylaxis
symptoms including paresthesia monitor vitamin B12 a ter injection; i a patient
o the hands and eet, decreased concentrations in plasma reports a previous sensitivity
vibration and position senses and to obtain peripheral to injections o vitamin B12, an
with resultant unsteadiness, blood counts at intervals intradermal skin test should
decreased deep tendon o 3-6 mo to con rm the be per ormed be ore the ull
re exes, and in the later stages, adequacy o therapy and dose is administered
con usion, moodiness, loss o monitor development o
memory, loss o central vision, re ractoriness to therapy
hallucinations, and overt
psychosis (see Side Bars CAUSES
OF VITAMIN B12 DEFICIENCYand
GENERAL PRNCIPLES OF VITAMIN
B12 THERAPY)
Vitamins—Folic Acid and Folic acid Treatment or prevention o olate The megaloblastic Rare reports o reactions
Derivatives (pteroylglutamic de ciency which can cause anemia that results rom to parenteral injections o
acid [PteGlu], olate-de cient megaloblastic olate de ciency cannot olic acid and leucovorin;
l -methyl olate) erythropoiesis and elevated be distinguished rom caution should be exercised
Folinic acid plasma homocysteine that caused by vitamin in patients with a history o a
(leucovorin Prevention o neural tube B12 de ciency (see reaction
calcium, de ects ( olate supplements may Figure 25-3); however, Folic acid in large amounts
citrovorum actor) be required early in pregnancy) olate de ciency is may counteract the
Folinic acid is used to circumvent rarely, i ever, associated antiepileptic e ect o
the inhibition o dihydro olate with neurological phenobarbital, phenytoin,
reductase as a part o high-dose abnormalities; thus and primidone, and increase
methotrexate therapy and to the observation the requency o seizures in
potentiate uorouracil in the o characteristic susceptible children
treatment o colorectal cancer abnormalities in
and as an antidote to counteract vibratory and position
the toxicity o olate antagonists sense and in motor and
such as pyrimethamine or sensory pathways is
trimethoprim incompatible with an
(see Side Bars COMMON CAUSES isolated de ciency o
OF FOLATE DEFICIENCYand olic acid
GENERAL PRINCIPLES OF FOLIC Folic acid and leucovorin
ACID THERAPY) should never be used
or the treatment o
pernicious anemia or
other megaloblastic
anemia secondary to
a de ciency o vitamin
B12 because their
use can result in an
apparent response o the
hematopoietic system,
but neurological damage
may occur or progress i
already present
420
SECTION
31. Drug T erapy o Mineral Ion Homeostasis and Bone urnover Disorders 480
421
CHAPTER
Uro ollitropin (uFSH) FSH preparation that acts the FSH receptor
CASE 26-1
A 43-year-old man o normal height has been diagnosed with acromegaly
a. What is acromegaly and why is this patient’s height normal?
Acromegaly is the result o excess secretion o GH rom an anterior pituitary
adenoma. T e organization o the posterior and anterior pituitary glands is shown
in Figure 26-1. In adults, the signs and symptoms o acromegaly are arthropathy,
carpal tunnel syndrome, visceromegaly, macroglossia, hypertension, glucose intol-
erance, headache, lethargy, excess perspiration, and sleep apnea. I the epiphyses
are unclosed (presumably the epiphyses are closed in this patient), the GH excess
results in increased longitudinal growth and gigantism.
b. How is GH secretion regulated?
Growth hormone–releasing hormone (GHRH) and somatostatin (SS ), released
rom the hypothalamus, stimulate or inhibit the release o GH rom the pituitary,
respectively (see Figure 26-2). Insulin-like growth actor (IGF-1), a product o GH
action on peripheral tissues, causes negative eedback inhibition o GH release at
the level o the hypothalamus and the pituitary.
c. How does GH cause its myriad o ef ects on various tissues?
GH and prolactin act on speci c receptors in target tissues. T e GH receptor is a
widely distributed cell sur ace receptor that consists o an extracellular hormone-
binding domain, a single membrane-spanning region, and an intracellular domain
that mediates signal transduction (see Figure 26-3).
d. What are the options or treatment o acromegaly in this patient?
reatment options include transphenoidal surgery, radiation, and drugs that inhibit
GH secretion. Increased attention has been given to pharmacological treatment
o acromegaly either as primary treatment or or the treatment o persistent GH
(Continued)
423
SECTION V Hormones and Hormone Antagonists
Hypo thalamus
ARC
(GHRH, GnRH,
DA)
Po s te rio r
lo be +
–
Hypo thalamus
Ante rio r Re le a s ing – GHRH S ST
fa ctors –
lo be
–
Porta l + –
sys te m
Ante rio r Growth
AVP, Ghre lin
pituitary – hormone +
OXY
Trophic hormone s
(ACTH, TS H, GH, S toma ch
LH, FS H, prola ctin)
FIGURE 26-1 Organization o the anterior and posterior pituitary gland. S e c o ndary
Hypothalamic neurons in the supraoptic (SON) and paraventricular (PVN) targ e t tis s ue s
nuclei synthesize arginine vasopressin (AVP) or oxytocin (OXY). Most o their
axons project directly to the posterior pituitary, rom which AVP and OXY FIGURE 26-2 Growth hormone secretion and actions. Two
are secreted into the systemic circulation to regulate their target tissues. hypothalamic actors, growth hormone–releasing hormone
Neurons that regulate the anterior lobe cluster in the mediobasal hypo- (GHRH) and somatostatin (SST) stimulate or inhibit the release
thalamus, including the PVN and the arcuate (ARC) nuclei. They secrete o growth hormone (GH) rom the pituitary, respectively.
hypothalamic-releasing hormones, which reach the anterior pituitary via Insulin-like growth actor-1 (IGF-1), a product o GH action on
the hypothalamic-adenohypophyseal portal system and stimulate distinct peripheral tissues, causes negative eedback inhibition o GH
populations o pituitary cells. These cells, in turn, secrete the trophic (sig- release by acting at the hypothalamus and the pituitary. The
nal) hormones, which regulate endocrine organs and other tissues. ACTH, actions o GH can be direct or indirect (mediated by IGF-1).
Adrenocorticotrophic hormone; CRH, corticotropin-releasing hormone; DA, Inhibition, −; stimulation, +.
dopamine; FSH, ollicle-stimulating hormone; GH, growth hormone; GHRH,
growth hormone-releasing hormone; GnRH, gonadotropin-releasing
hormone; LH, luteinizing hormone; TRH, thyrotropin-releasing hormone;
TSH, thyroid-stimulating hormone.
424
Introduction to Endocrinology: The Hypothalamic–Pituitary Axis CHAPTER 2 6
A GH B GH Hypo thalamus
TRH Dopa mine
GH Pe gvis oma nt
G G G G G G Ante rio r
H H H H H H Prola ctin
pituitary
R R R R R R
J J S uc kling
A A
K K
2 2
No GH
RS -1 s igna ling
S HC STAT5 Targ e t Othe r
Bre a s t
tis s ue tis s ue s
P 3K
FIGURE 26-4 Prolactin secretion and
MAP K
Ge ne expre s s ion actions. Prolactin is the only anterior pituitary
(e g, GF-1) hormone or which a unique stimulatory
releasing actor has not been identi ed.
Thyrotropin-releasing hormone (TRH),
Glucos e Nucle us however, can stimulate prolactin release and
tra ns porte r dopamine can inhibit it. Suckling induces
prolactin secretion, and prolactin a ects
lactation and reproductive unctions but
also has varied e ects on many other tissues.
FIGURE 26-3 Mechanisms o growth hormone and prolactin action and o GH receptor Prolactin is not under eedback control by
antagonism. Left (A): The binding o GH to a homodimer o the GH receptor (GHR) induces peripheral hormones.
autophosphorylation o JAK2. JAK2 then phosphorylates cytoplasmic proteins that activate
downstream signaling pathways, including STAT5 and mediators upstream o MAPK, which
ultimately modulate gene expression. The structurally related prolactin receptor also is a ligand-
activated homodimer that recruits the JAK-STAT signaling pathway. The GHR also activates IRS-1,
which may mediate the increased expression o glucose transporters on the plasma membrane.
The diagram does not re ect the localization o the intracellular molecules, which presum-
ably exist in multicomponent signaling complexes. JAK2, janus kinase 2; IRS-1, insulin receptor
substrate-1; PI3K, phosphatidyl inositol-3 kinase; STAT, signal transducer and activator o tran-
scription; MAPK, mitogen-activated protein kinase; SHC, Src homology containing. Right (B):
Pegvisomant, a recombinant pegylated variant o human GH, contains amino acid substitutions
that increase the af nity or 1 site o the GHR but do not activate its downstream signaling cascade.
It thus inter eres with GH signaling in target tissues.
CASE 26-2
A 56-year-old man with advanced prostate cancer is being treated with leuprolide
a. What is leuprolide and why is it used to treat prostate cancer?
Leuprolide is a synthetic gonadotropin-releasing hormone (GnRH) agonist that
has greater receptor a nity, reduced enzymatic degradation, and is more potent
than the naturally occurring GnRH. Endogenous GnRH is released rom the
hypothalamus and acts on the pituitary to release luteinizing hormone (LH) and
ollicle-stimulating hormone (FSH). LH acts on the testes to promote the secretion
o androgens (see Figures 26-1 and 26-5).
Androgens stimulate the growth o normal and cancerous prostate cells (see
Chapter 46). Standard therapy or advanced prostate cancer is surgical or
pharmacological androgen deprivation therapy (see Chapter 46).
b. How does a GnRH agonist suppress androgen secretion?
T e GnRH agonists bind to GnRH receptors on pituitary gonadotropin-producing
cells, causing an initial release o LH and FSH and a subsequent increase in
testosterone production rom testicular Leydig cells. A er approximately 1 week o
therapy, GnRH receptors are downregulated on the gonadotropin-producing cells,
causing a decline in the pituitary response and a subsequent decline in testosterone
production.
(Continued)
425
SECTION V Hormones and Hormone Antagonists
Hypo thalamus c. What untoward ef ects might this patient expect as a result o the leuprolide
GnRH
therapy?
He should be told to expect hot f ashes, possible decreased bone density, and erectile
Ante rio r dys unction. T ere is an apparent increase in the incidence o pituitary apoplexy, a
LH
pituitary syndrome o headache, neurological mani estations, and impaired pituitary unction;
FS H these e ects mimic ones that usually result rom an in arction o a pituitary adenoma.
CASE 26-3
Targ e t
Gona ds
A 32-year-old woman is diagnosed with a prolactin-secreting pituitary adenoma
tis s ue
a. What are the therapeutic options or this patient?
T e therapeutic options or patients with prolactinomas include transphenoidal
surgery, radiation, and treatment with dopamine (DA) receptor agonists. T e DA
receptor agonists are the treatment o choice since the surgical success rate is 75%
or microadenomas and 33% or macroadenomas.
Targ e t S ex
tis s ue Inhibin
s te roids b. Why are the DA receptor agonists ef ective?
pro duc t
T yrotropin-releasing actor ( RH) stimulates prolactin release whereas DA released
rom the hypothalamus inhibits prolactin release (see Figure 26-4). T e DA recep-
tor agonists decrease both prolactin secretion and the size o the adenoma, thereby
S e c o ndary Acce s s ory Othe r improving the endocrine abnormalities and the neurological symptoms (including
targ e t s ex orga ns tis s ue s visual eld de ects).
tis s ue s
c. What DA receptor agonists are used to treat hyperprolactinemia?
FIGURE 26-5 The hypothalamic-pituitary-
gonadal axis. A single hypothalamic- T e drugs in this class include bromocriptine, cabergoline, and quinagolide. Bro-
releasing actor, gonadotropin-releasing mocriptine normalizes serum prolactin concentrations in 70% to 80% o patients
hormone (GnRH), controls the synthesis and decreases tumor size in more than 50% o patients. ypically, hyperprolac-
and release o both gonadotropins (LH tinemia and tumor growth recur upon cessation o therapy.
and FSH) in males and emales. Gonadal
Cabergoline has a higher a nity and greater selectivity or the D2 receptor than
steroid hormones (androgens, estrogens,
and progesterone) exert eedback inhibi- bromocriptine. It is becoming the pre erred drug in this setting. Cabergoline may
tion at the level o the pituitary and the induce remission in a signi cant number o patients with prolactinomas.
hypothalamus. The preovulatory surge Quinagolide is not approved by the FDA but has been used extensively in Europe
o estrogen also can exert a stimulatory and Canada.
e ect at the level o the pituitary and
the hypothalamus. Inhibins, a amily o d. What adverse ef ects might be expected rom therapy with bromocriptine or
polypeptide hormones produced by the cabergoline?
gonads, speci cally inhibit FSH secretion
by the pituitary. Bromocriptine requently causes nausea, vomiting, headache, and postural hypo-
tension, particularly on initial use. Less requently, bromocriptine may cause nasal
congestion, digital vasospasm, and CNS e ects such as psychoses, hallucinations,
nightmares, or insomnia.
Cabergoline causes much less nausea than bromocriptine, but may still cause diz-
ziness and hypotension. Cabergoline has been linked to valvular heart disease and
echocardiographic assessment is appropriate or patients receiving chronic therapy.
KEY CONCEPTS
T e peptide hormones o the anterior pituitary are essential or the regulation
o growth and development, reproduction, response to stress, and intermediary
metabolism
T e synthesis and secretion o the pituitary hormones are controlled by hypo-
thalamic hormones and by hormones rom the peripheral endocrine organs (see
Figure 26-1)
T e most striking physiological e ect o GH is the stimulation o the longitudinal
growth o bones (see Figure 26-2)
(Continued)
426
Introduction to Endocrinology: The Hypothalamic–Pituitary Axis CHAPTER 2 6
SUMMARY QUIZ
QUESTION 26-4 A 4-year-old boy with short stature is diagnosed with growth
hormone (GH) de ciency His GH replacement therapy should be continued until
a he is in the 90th percentile on growth charts
b he is in the 60th percentile on growth charts
c his epiphyses are used
d he begins to develop secondary sex characteristics
e he has permanent teeth
427
SECTION V Hormones and Hormone Antagonists
Growth Hormone Pegvisomant Treatment o acromegaly Lipohypertrophy at Should not be used in patients with
(GH) Antagonist injection site elevated hepatic transaminases
Recombinant GH Recombinant GH Treatment o GH Peripheral edema, Should not be used in patients with
de ciency carpal tunnel syndrome, neoplasia, proli erative retinopathy,
arthralgia, myalgia or acute respiratory ailure
Insulin-like Growth Mecasermin Treatment o impaired Hypoglycemia, Should not be used in patients with
Factor-1 (IGF-1) growth due to mutations lipohypertrophy closed epiphyses or in patients with
in GH receptor or neoplasia
postreceptor pathway
(Continued)
428
Introduction to Endocrinology: The Hypothalamic–Pituitary Axis CHAPTER 2 6
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Gonadotropin- GnRH Problems with availability
Releasing Hormone have limited its use
(GnRH) Agonist
429
SECTION V Hormones and Hormone Antagonists
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Follitropin α Ovarian stimulation
or in vitro ertilization
Development o tests
or the diagnosis o
reproductive disorders
430
CHAPTER
Antithyroid Drugs Propylthiouracil Inter eres with the incorporation o iodine into tyrosyl residues to orm
Methimazole iodothyronine (see Figure 27-1)
Carbimazole
Ionic Thyroid Inhibitors Iodide At high concentrations, iodide inhibits the synthesis o iodotyrosines and
Sodium iodine iodothyronines; high concentrations also inhibit the release o thyroid hormones
Radioactive Iodine Sodium iodine 131I Incorporated into iodoamines and deposited into the colloid o thyroid ollicles
where the destructive β particles are released
431
SECTION V Hormones and Hormone Antagonists
CASE 27-1
A 69-year-old man goes to his amily doctor because he has been eeling atigued and
lethargic. His doctor does a complete evaluation. T is patient had a myocardial in arction
and has a recurrent ventricular arrhythmia. T e patient’s SH is elevated and his 4 is
slightly decreased. T e doctor suspects hypothyroidism and begins replacement therapy
with levothyroxine.
a. Why is the TSH elevated in this patient?
T e regulation o thyroid unction is shown in Figure 27-2. T yrotropin-releasing
hormone ( RH) is released rom the hypothalamus when circulating concen-
trations o thyroid hormone ( 4 and 3) are low. RH stimulates the release o
pre ormed SH granules rom the pituitary. T e released SH binds to a GPCR
receptor on the plasma membrane o thyroid cells and eventually all phases o thy-
roid hormone synthesis and release are stimulated (see Figure 27-2). When thyroid
hormone levels are low, the negative eedback inhibition on the hypothalamic RH
release is removed and SH secretion is increased.
b. What actors might af ect the levothyroxine dose in this patient?
able 27-1 lists some o the actors that may in uence the dose o levothyroxine.
T is patient has had a myocardial in arction and is being treated or a ventricular
arrhythmia with amiodarone (see Chapter 18). Amiodarone is an iodine-contain-
ing drug which may impair the conversion o 4 to 3.
c. What commonly prescribed drugs are associated with iodine-induced
hypothyroidism?
able 27-2 lists the iodine content o commonly prescribed drugs.
d. What is the goal o levothyroxine replacement therapy?
Levothyroxine is the hormone o choice or thyroid hormone replacement therapy.
With this therapy one relies on the type 1 and 2 deiodinases to convert 4 to 3 to
maintain a steady serum concentration o 3 (see Figure 27-1). T e goal o therapy
is to normalize the serum SH (in primary hypothyroidism) or ree 4 (in second-
ary hypothyroidism) and to relieve the symptoms o hypothyroidism.
(Continued)
432
Thyroid and Antithyroid Drugs CHAPTER 2 7
Ba s ola te ra l Apica l
me mbra ne me mbra ne
Colloid
Na + Na + Tg Tg
A NIS TP O TP O
I– I– + I– + DIT
I– I– Pe ndrin H2 O 2 or MIT
Tg DIT H2 O 2
Na + De ha loge na s e I– I– HOI
MIT T4
ATPa s e or T3
K+ DIT EOI
E MIT B C
T4 T3 T4 D
T4 , T3
T3
D1, D2
F
KEY
Hypotha la mus
S ST
– TRH
+
Dopa mine
Glucocorticoids – P ituita ry
Re tinoids
–
TS H
+
–
Hig h I– Thyroid gla nd
T4 and T3
FIGURE 27-2 Regulation o thyroid hormone secretion. Myriad neural inputs in uence hypo-
thalamic secretion o thyrotropin-releasing hormone (TRH). TRH stimulates release o thyrotropin
(TSH, thyroid-stimulating hormone) rom the anterior pituitary; TSH stimulates the synthesis and
release o the thyroid hormones T3 and T4. T3 and T4 eed back to inhibit the synthesis and release
o TRH and TSH. Somatostatin (SST) can inhibit TRH action, as can dopamine and high concen-
trations o glucocorticoids. Low levels o I– are required or thyroxine synthesis, but high levels
inhibit thyroxin synthesis and release.
(Continued)
433
SECTION V Hormones and Hormone Antagonists
TABLE 27-1 Factors Inf uencing Oral Levothyroxine Therapy TABLE 27-2 Commonly Used Iodine-Containing Drugs
Drugs and other factors that may increase levothyroxine DRUGS IODINE CONTENT
dosage requirements Oral or local
Impaired levothyroxine absorption
Aluminum-containing antacids Amiodarone 75 mg/tablet
Bile acid sequestrants (cholestyramine, colestipol, colesevelam)
Calcium carbonate (e ect generally small) Calcium iodide syrup 26 mg/mL
Chromium picolinate
Food Iodoquinol (diiodohydroxyquin) 134-416 mg/tablet
Iron salts
Echothiophate iodide ophthalmic solution 5-41 µg/drop
Lactose intolerance (single case report)
Phosphate binders (lanthanum carbonate, sevelamer) Hydriodic acid syrup 13-15 mg/mL
Proton pump inhibitors
Raloxi ene Iodochlorhydroxyquin 104 mg/tablet
Soy products (e ect generally very small)
Sucral ate Iodine-containing vitamins 0.15 mg/tablet
Increased thyroxine metabolism, CYP3A4 induction of hepatic
Bexarotene Idoxuridine ophthalmic solution 18 µg/drop
Carbamapzepine Kelp/seaweed 0.15 mg/tablet
Phenytoin
Ri ampin Lugol’s solution 6.3 mg/drop
Sertraline
Impaired T4 → T3 conversion PONARIS nasal emollient 5 mg/0.8 mL
Amiodarone
Mechanisms uncertain or multifactorial KI, saturated solution (KISS) 38 mg/drop
Estrogen pregnancy
Ethionamide Topical antiseptics
Tyrosine kinase inhibitors (imatinib, sunitinib) Iodoquinol cream (diiodohydroxyquin) 6 mg/g
Lovastatin, simvastatin
Drugs and other factors that may decrease levothyroxine Iodine tincture 40 mg/mL
dosage requirements
Advancing age (>65 years) Iodochlorhydroxyquin cream 12 mg/g
Androgen therapy in women
Drugs that may decrease TSH without changing free T4 in Iodo orm gauze 4.8 mg/100 mg
levothyroxine treated patients gauze
Met ormin
Povidone–iodine 10 mg/mL
CASE 27-2
A 26-year-old rst trimester pregnant woman is diagnosed with hyperthyroidism.
a. What are the treatment options or this woman?
T yrotoxicosis occurs in approximately 0.2% o pregnancies and is caused by Graves
disease. Graves disease is an autoimmune disorder characterized by increased thyroid
hormone production, di use goiter, and immunoglobulin (Ig)G antibodies that
bind and activate the SH receptor. T e characteristic exophthalmos associated with
Graves disease is an in ltrative opthalmopathy. Antithyroid drugs are the treatment
o choice; radioactive iodine is clearly contraindicated. Both propylthiouracil and
methimazole cross the placenta equally and both may be used sa ely although con-
cern or liver ailure in pregnancy may avor the use o methimazole. Methimazole
is rarely associated with congenital gut anomalies and should be used af er organo-
genesis in the rst trimester. Graves disease of en improves during the course o
pregnancy and it is not uncommon or patients either to be on very low doses or
o antithyroid drugs completely by the end o pregnancy.
b. What is the mechanism o action o methimazole?
Antithyroid drugs inhibit the ormation o thyroid hormones by inter ering with
the incorporation o iodine into tyrosyl residues o thyroglobulin; they also inhibit
the coupling o these iodotyrosyl residues to orm iodothyronines (see Figure 27-1).
c. What other compounds (other than the typical antithyroid drugs) are inhibitors
o thyroid unction?
able 27-3 is a list o compounds that inhibit thyroid unction and the process that
is a ected.
(Continued)
Amiodarone
Hormone excretion/inactivation Inducers o hepatic drug-metabolizing enzymes: phenobarbital, ri ampin, carbamazepine, phenytoin
Data adapted rom Meier C.A., Burger A.C. E ects o drugs and other substances on thyroid hormone synthesis and metabolism.
In: Werner and Ingbar’s The Thyroid, 9th ed. (Braverman L.E. and Utiger R.D. eds.) Lippincott Williams &Wilkins, Philadelphia, 2005.
435
SECTION V Hormones and Hormone Antagonists
CASE 27-3
A 58-year-old woman has been diagnosed with well-di erentiated papillary
thyroid cancer.
a. What are the treatment options with this patient?
T e mainstays o therapy or well-di erentiated thyroid cancer (papillary, ollicular)
are surgical thyroidectomy, radioiodine, and levothyroxine to suppress SH. T e
rationale or SH suppression is that SH is a growth actor or these cancers.
b. What is the standard course o treatment or this patient i metastatic disease is
suspected?
Because most well-di erentiated thyroid carcinomas accumulate very little iodine,
stimulation o iodine uptake with SH is required to treat metastases e ectively.
Currently, endogenous SH stimulation is evoked by withdrawal o thyroid hor-
mone replacement therapy (or by the administration o recombinant human SH) in
patients previously treated with near-total thyroidectomy. otal body 131I scanning and
measurement o thyroglobulin when the patient is hypothyroid ( SH >35 mU/L) help
to identi y metastatic disease or residual thyroid bed tissue. Depending on the residual
uptake or the presence o metastatic disease, an ablative dose o 131I is administered,
with a repeat total body scan 1 week later.
SH-suppressive therapy with levothyroxine is indicated in all patients af er treatment
or thyroid cancer.
Anaplastic cancer is the exception: it is highly malignant with survival usually less
than 1 year. Medullary thyroid carcinomas do not accumulate iodine and cannot be
treated with 131I.
KEY CONCEPTS
Replacement therapy or hypothyroidism typically uses oral thyroxine given
once daily.
T e goals o therapy or hypothyroidism are to restore serum SH concentration
to the normal range, and to relieve the signs and symptoms o hypothyroidism.
In pregnancy, the standard replacement dose o thyroid hormone is usually
increased.
Options available or treating hyperthyroid patients include antithyroid drugs
(eg, propylthiouracil and methimazole), radioactive iodine, and surgery.
Radioactive iodine may aggravate ophthalmopathy.
Medical therapy with antithyroid drugs to reduce the concentration o thyroid
hormone is the pre erred approach in younger patients with hyperthyroidism.
In older patients or those with cardiac disease, radioactive iodine is usually
recommended a er the patient has been rendered euthyroid with antithyroid
medication.
(Continued)
436
Thyroid and Antithyroid Drugs CHAPTER 2 7
SUMMARY QUIZ
QUESTION 27-2 A 38-year-old South American woman has a large protrusion on her
neck but is otherwise asymptomatic. Her condition is caused by a dietary de ciency o
a. iron.
b. magnesium.
c. potassium.
d. sodium.
e. iodine.
QUESTION 27-4 A 68-year-old woman has increasing lethargy, slight weight gain, and
the onset o cognitive impairment. A serum SH is slightly elevated and a 4
is within
normal limits. She is a candidate or
a. RH.
b. levothyroxine.
c. methimazole.
d. iodide.
e. radioactive iodine.
QUESTION 27-5 A 25-year-old woman has been treated with thyroxine or hypothy-
roidism. She has become pregnant. She complains now o being constantly atigued.
T e proper course o action would be to
a. do nothing, atigue is normal during pregnancy.
b. increase the iodine in her diet.
c. measure her serum SH during the rst trimester and adjust her thyroxine dose
based on the result.
(Continued)
437
SECTION V Hormones and Hormone Antagonists
QUESTION 27-6 A 48-year-old woman with Graves disease with severe hyperthyroid-
ism is being treated with radioactive iodine. She is also being treated with methimazole
because o
a. the long period o time be ore hyperthyroidism is controlled by radioactive iodine.
b. the expectation that radioactive iodine will be ine ective.
c. methimazole is better absorbed than radioactive iodine.
d. methimazole will counteract the side e ects o radioactive iodine.
e. radioactive iodine is not active unless administered with methimazole.
QUESTION 27-7 A 73-year-old man with a history o surgery or a benign thyroid nod-
ule when he was 50 years old is now euthyroid but has developed a cardiac arrhythmia.
Which o the antiarrhythmic drugs listed below might cause him to develop iodine-
induced hypothyroidism?
a. Quinidine
b. Amiodarone
c. Diltiazam
d. Propranolol
e. Digoxin
QUESTION 27-8 A 53-year-old woman with the diagnosis o Graves disease is being
treated with radioactive iodine. She should be warned o the high likelihood o
a. hyperthyroidism.
b. iodism.
c. hypothyroidism.
d. thyroid nodules.
e. thyroid cancer.
QUESTION 27-1 Answer is c. Low levels o iodine are required or thyroid synthesis,
but high levels o iodine inhibit thyroid synthesis and release.
QUESTION 27-2 Answer is e. In some areas o the world, simple or nontoxic goiter is
prevalent because o insuf cient dietary iodine. Normal thyroid unction obviously
requires an adequate intake o iodine; without it, normal amounts o thyroid hormone
cannot be made, SH is secreted in excess (see Figures 27-1 and 27-2), and the thyroid
becomes hyperplastic and hypertrophic. T e enlarged and stimulated thyroid becomes
remarkably ef cient at extracting residual traces o iodine rom the blood and usually
succeeds in producing suf cient thyroid hormones. In more severe iodine de ciency,
adult hypothyroidism and cretinism may occur.
QUESTION 27-3 Answer is d. In patients with normal pituitary unction, serum mea-
surement o SH is the thyroid unction test o choice because pituitary secretion o
SH is sensitively regulated in response to circulating concentrations o thyroid hormone.
or pregnancy, and those patients who have nonspeci c symptoms that could be due to
hypothyroidism. T e decision to use levothyroxine therapy in these patients must be on
an individual basis because treatment may not be appropriate or all patients.
Triiodothyroxine Used when more rapid onset Same as or levothyroxine Same as or levothyroxine
o action is needed such as
myxedema coma or or more
rapid termination o action such
as in preparing a cancer patient
or 131I therapy
Antithyroid Drugs Propylthiouracil Used in treatment o Purpuric urticarial popular rash Agranulocytosis
hyperthyroidism in the Pain, sti ness o joints, Hepatic ailure; requent
ollowing ways: def nitive paresthesia, headache, monitoring o liver unction
treatment; to hasten recovery nausea, skin pigmentation, is recommended
while awaiting e ects o loss o hair
radioactive iodine; preparation
or surgical treatment
(Continued)
439
SECTION V Hormones and Hormone Antagonists
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
440
CHAPTER
442
Estrogens, Progestins, Androgens, and Contraception CHAPTER 2 8
ORTHO-CEPT 30 0.15
Ethinyl estradiol/drospirenone YASMIN 30 3
Ethinyl estradiol/ethynodiol DEMULEN 1/35 35 1
DEMULEN 1/50 50 1
Ethinyl estradiol/levonorgestrel ALESSE 20 0.1
LEVLITE 20 0.1
LYBREL 20 0.09
NORDETTE 30 0.15
Ethinyl estradiol/norgestrel LO/OVRAL 30 0.3
OVRAL 50 0.5
Ethinyl estradiol/norethindrone BREVICON 35 0.5
FEMCON 35 0.4
LOESTRIN 1/20 20 1
LOESTRIN 1.5/30 30 1.5
NORINYL 1+35 35 1
ORTHO-NOVUM 1/35 35 1
OVCON 35 35 0.4
OVCON 50 50 1
Ethinyl estradiol/norgestimate ORTHO-CYCLEN 35 0.25
Mestranol/norethindrone NORINYL 1+50 50 1
ORTHO-NOVUM 1/50 50 1
Combination biphasic Estrogen (µg) Progestin (mg)
Ethinyl estradiol/desogestrel MIRCETTE 20 0.15 (21 tabs)
10 — (5 tabs)
Ethinyl estradiol/norethindrone ORTHO-NOVUM 10/11 35 0.5 (10 tabs)
35 1 (11 tabs)
Combination triphasic Estrogen (µg) Progestin (mg)
Ethinyl estradiol/desogestrel CYCLESSA 25 0.1 (7 tabs)
25 0.125 (7 tabs)
25 0.15 (7 tabs)
Ethinyl estradiol/levonorgestrel TRI-LEVLEN 30 0.05 (6 tabs)
40 0.075 (5 tabs)
30 0.125 (10 tabs)
(Continued)
443
SECTION V Hormones and Hormone Antagonists
444
Estrogens, Progestins, Androgens, and Contraception CHAPTER 2 8
TABLE 28-2 Brand Names and Formulations of Agents Used for Hormone Replacement Therapy
PREPARATION BRAND DOSE mg FREQUENCY
Oral estrogen (tablets)
PREMARIN
Transdermal estradiol
Vaginal estrogen
Oral progestin
Norethindrone AYGESTIN 5 mg
445
SECTION V Hormones and Hormone Antagonists
1 5 µg
Transdermal estrogen
plus progesterone
CASE 28 1
A 49-year-old woman has been 6 months without menstruation. She is now experiencing
severe “hot ashes” that are impacting her daily li e. She would like some therapy that
would make her more com ortable.
a. What hormone replacement therapy is available or her?
able 28-2 lists the brand names and ormulations used or hormone replacement
therapy. Regardless o the speci c agent or regimen, menopausal hormone therapy
with estrogens should use the lowest dose and shortest duration necessary to
achieve an appropriate therapeutic goal.
(Continued)
H3 C O H3 C O H3 C O
16α -OHa s e OH 3β-OH-S DH OH
H3 C H3 C H3 C
HO HO O
De hydroe pia ndros te rone 16α -Hydroxyde hydro- 16α -Hydroxya ndros te ne dione
e pia ndros te rone
17-OH-S DH,
3β-OH-S DH a roma ta s e
H3 C O H3 C O H3 C OH
a roma ta s e 17-OH-S DH OH
H3 C
16α -OHa s e
O HO HO
Andros te ne dione Es trone Es triol
hypotha la mic
puls e
A Ne urona l
Activity
(dis cha rge s
ge ne ra tor pe r min)
LH
(ng/ml)
a rc ua te
nuc le us
p ituita ry D 0 1 2 3 4
me d ia l TIME (hrs )
basal
hyp otha la mus
opioid NE
dopa mine – +
GABA – – ++
proge s te rone
B
GnRH
GnRH p ituita ry
ne uron p orta l
va s c ula ture
C e s troge n
proge s te rone
LH / FS H
e s troge n e s troge n
E proge s te rone proge s te rone
E
ute rus ova ry
FIGURE 28-2 Neuroendocrine control o gonadotropin secretion in emales. The hypothalamic pulse generator located in the arcuate nucleus
o the hypothalamus unctions as a neuronal “clock”that res at regular hourly intervals. A. This results in the periodic release o gonadotropin-
releasing hormone (GnRH) rom GnRH-containing neurons into the hypothalamic-pituitary portal vasculature B. GnRH neurons receive inhibitory
input rom opioid, dopamine, and GABA neurons and stimulatory input rom noradrenergic neurons (NE, norepinephrine). The pulses o GnRH
trigger the intermittent release o luteinizing hormone (LH) and ollicle-stimulating hormone (FSH) rom pituitary gonadotropes C, resulting in
the pulsatile plasma pro le D. FSH and LH regulate ovarian production o estrogen and progesterone, which exert eedback controls E.
A
TA
TA
ER
ER
GGTCAnnnTGACC
Ag onis t E
Anta g onis t
E
T
T
C
B S RC-1
HDAC1
E
E NCoR
S WI/S NF
ER ER T T
ER ER
GGTCAnnnTGACC
GGTCAnnnTGACC
p300 GTA
E
ER TRAP
GGTCAnnnTGACC
CASE 28 2
A 22-year-old woman is asking or an oral contraceptive.
a. What are the options available or her?
able 28-1 lists the brand names and ormulations o oral contraceptives. T e major-
ity o available products contain estrogen and progestin in a constant amount o the
estrogen and progestin (monophasic) that are packaged with 21 pills containing active
hormone and 7 placebo tablets. In an e ort to maximize the antiovulatory e ects and
(Continued)
448
Estrogens, Progestins, Androgens, and Contraception CHAPTER 2 8
21
H3 C 20 CH3
H3 C
17 CH3
11
CH3
1
a ce ta te
3 ce llula r pla s ma chole s te rol
HO chole s te rol
s ide cha in
cle ava ge
pre gne nolone 17α OH-pre gne nolone de hydroe pia ndros te rone a ndros te ne diol
(DHEA)
3β-hydroxys te roid
de hydroge na s e
pre ge s te rone 17α OH-proge s te rone a ndros te ne dione te s tos te rone
OH
17α -hydroxyla s e 17, 20 lya s e H3 C
H3 C
FIGURE 28-4 Pathway o synthesis o testosterone in the Leydig cells o the testes. In Leydig cells, the 11 and 21 hydroxylases (present in
adrenal cortex) are absent but CYP17 (17 α-hydroxylase) is present. Thus androgens and estrogens are synthesized; corticosterone and cortisol
are not ormed. Bold arrows indicate avored pathways.
(Continued)
O HO
H H
5α - 18 OH
17
re ducta s e
19
C D TESTOSTERONE
A B
O 3 5
4
CYP 19 (a roma ta s e )
O
OH
HO
HO H
ESTRADIOL ETIOCHOLANOLONE
FIGURE 28-5 Metabolism o testosterone to its major active and inactive metabolites.
449
SECTION V Hormones and Hormone Antagonists
TESTOSTERONE CYP 19
5α - (a roma ta s e )
re ducta s e
Dihydro te s to s te ro ne Es tradio l
FIGURE 28-6 Direct e ects o testosterone and e ects mediated indirectly via dihydrotestosterone
or estradiol.
A weekly transdermal patch (OR HO EVRA) releases ethinyl estradiol and norel-
gestromin. Pharmacokinetic data suggests that it provides higher estrogen exposure
than the low-dose oral contraceptives and the FDA has required a warning that this
product may have increased risk o venous thromboembolism.
A vaginal ring (NUVARING) also is available that releases ethinyl estradiol and
etonogestrel.
b. Why do some products contain a progesterone?
T e structural eatures o the various progestins are shown in Figure 28-7. T e
major unctions o the estrogen components are to sensitize the hypothalamus and
pituitary gonadotropes (see Figure 28-2) to the eedback inhibitory e ects o the
progestin and to minimize breakthrough bleeding. T e progestin exerts negative
eedback, which suppresses the LH surge and thereby prevents ovulation and pro-
tects against uterine cancer by opposing the proli erative e ects o the estrogen on
the uterine endometrium.
c. What are progestin-only contraceptives?
T e progestin-only contraceptives contain derivatives o 17α-alkyl-19-nortestosterone
but do not contain an estrogen. Although they do inhibit ovulation to some degree,
their ef cacy also re ects changes in the cervical mucosa that inhibit ertilization and
endometrial changes that inhibit implantation. T ey are slightly less e ective than the
combination estrogen/progestin ormulations, particularly when doses are missed,
but provide an alternative in settings when estrogen-containing ormulations are
contraindicated.
Progestins are also used or long-acting contraception. A depot ormulation o
medroxyprogesterone (DEPO-PROVERA) injected subcutaneously or intramuscu-
larly provides e ective contraception or 3 months.
d. What are the risks and side e ects that should be discussed with this patient?
T romboembolic disease, largely due to the estrogenic component, is the most
common serious side e ect. Other side e ects include hypertension, edema, gall-
bladder disease, and elevations in serum triglycerides. Pills containing drospire-
none, which antagonizes the mineralocorticoid receptor, should be accompanied
(Continued)
450
Estrogens, Progestins, Androgens, and Contraception CHAPTER 2 8
21 CH3 C O
OAc
20 C O
18
17
11
19
O
3
6 CH3
O
P ROGESTERONE MEDROXYP ROGESTERONE
ACETATE
O O
19-NORTESTOSTERONE NORETHINDRONE
O HON
NORGESTREL NORGESTIMATE
CASE 28-3
A 53-year-old woman is diagnosed with breast cancer. T e “lump” is removed and
lymph nodes are negative or signs o cancer. She is started on tamoxi en, a selective
estrogen receptor modulator (SERM).
a. What are SERMs?
Selective estrogen receptor modulators, or SERMs, are compounds with
tissue-selective actions. T e pharmacological goals o these drugs are to produce
bene cial estrogenic actions in certain tissues (eg, bone, brain, and liver) dur-
ing postmenopausal hormone therapy but antagonist activity in tissues such as
breast and endometrium, where estrogenic actions (eg, carcinogenesis) might be
deleterious. amoxi en is highly ef cacious in the treatment o breast cancer (see
Chapter 46).
b. What are the untoward e ects and risk o tamoxi en therapy?
amoxi en treatment causes a 2- to 3- old increase in the relative risk o deep vein
thrombosis and pulmonary embolism and a roughly 2- old increase in endometrial
carcinoma. T e most common side e ect is hot ashes.
451
SECTION V Hormones and Hormone Antagonists
CASE 28-4
A 24-year-old woman with polycystic ovary syndrome is being treated with clomiphene
or in ertility.
a. What kind o drug is clomiphene and what is its mechanism o action?
Clomiphene is an antiestrogen and is a pure estrogen antagonist in all tissues studied.
Clomiphene binds to estrogen receptors (see Figure 28-3), increases gonadotropin
secretion and stimulates ovulation. It increases the amplitude o LH and FSH pulses
(see Figure 28-2) without changing pulse requency by acting largely at the pituitary
level to block inhibitory actions o estrogen on gonadotropin release and/or somehow
causing the hypothalamus to release larger amounts o GnRH per pulse.
b. What are the untoward e ects o clomiphene?
Clomiphene should not be administered to pregnant women due to reports o
teratogenicity in animals. Its untoward e ects include ovarian hyperstimulation,
increased incidence o multiple births, ovarian cysts, hot ashes, headaches, and
blurred vision. Prolonged use may increase the risk o ovarian cancer.
CASE 28-5
A 23-year-old woman comes into the clinic requesting emergency contraception ollowing
unprotected sexual intercourse 12 hours earlier. She is given ulipristal.
a. What kind o drug is ulipristal and what is its mechanism o action?
Ulipristal unctions as a selective progesterone receptor modulator (SPRM), acting
as a partial agonist at progesterone receptors. It has antiproli erative e ects in the
uterus; however, its most relevant actions to date involve its capacity to inhibit
ovulation. Ulipristal’s antiovulatory actions likely occur due to progesterone
regulation at many levels, including inhibition o LH release through the hypo-
thalamus and pituitary, and inhibition o LH-induced ollicular rupture within the
ovary. It is e ective up to 120 hours (5 days) a er intercourse.
b. What other treatment options are available or this patient?
Plan B (see able 28-1) contains 2 tablets o the progestin levonorgestrel and may
be obtained in the United States without prescription by women who are 18 years
o age or older. Other options or postcoital contraception include mi epristone
that is not FDA approved or this use but is highly e ective, and copper intrauterine
devices when inserted within 4 days o unprotected intercourse.
c. What side e ects might be expected ollowing ulipristal administration?
T e most severe side e ect in clinical trials using ulipristal has been a sel -limited
headache and abdominal pain.
CASE 28-6
A 46-year-old man is diagnosed with hypogonadism and low serum testosterone.
a. What options are available or his testosterone replacement?
Figure 28-8 shows the androgens that are available or therapeutic use. Even though
ingested testosterone is readily absorbed into the hepatic circulation, the rapid
hepatic catabolism ensures that hypogonadal men generally cannot ingest it in
suf cient amounts and with suf cient requency to maintain a normal serum
testosterone concentration. Most pharmaceutical preparations o androgens,
there ore, are designed to bypass hepatic catabolism o testosterone.
Esteri ying a atty acid to the 17α hydroxyl group o testosterone creates a com-
pound that is even more lipophilic than testosterone itsel . When an ester such
as testosterone enthanthate or cypionate is dissolved in oil and administered
(Continued)
452
Estrogens, Progestins, Androgens, and Contraception CHAPTER 2 8
Te s to s te ro ne
(HISTERONE, othe rs )
OH
Te s to s te ro ne Es te rs O
O O O
Te s to s te ro ne e nanthate Te s to s te ro ne c ypio nate Te s to s te ro ne unde c ano ate
(DELATESTRYL, othe rs ) (DEPO-TESTOSTERONE, othe rs ) (ANDRIOL)
CH3
O N
HN
O O
H
Me thylte s to s te ro ne
(ORETIN METHYL, othe rs ) Oxandro lo ne S tano zo lo l
(OXANDRIN) (WINSTROL)
OH OH
HO CH3 C CH
F
N
O
O
Fluoxyme s te ro ne Danazo l
(HALOTESTIN) (DANOCRINE)
Othe r 3
OH
O CH3
A testosterone gel, a testosterone patch, and a testosterone buccal tablet are also
available.
T e 17α-alkylated androgens also are less prone to hepatic catabolism; however,
they are less androgenic than testosterone and can cause hepatotoxicity.
b. What are the risks and untoward e ects o testosterone therapy that should be
discussed with this patient?
T e major side e ects o testosterone administration are acne, gynecomastia, and
aggressive sexual behavior. Prolonged administration may be associated with benign
prostatic hypertrophy and prostate cancer. T e 17α-alkylated androgens are the only
androgens that cause hepatotoxicity.
CASE 28-7
A 29-year-old male cyclist has been taking testosterone on the advice o his trainer. His
trainer has rationalized that since testosterone is an endogenous substance, it will be
di cult to detect.
a. What side e ects might this athlete expect to experience?
T e pathways o synthesis o testosterone are shown in Figure 28-4. All androgens
suppress gonadotropin secretion when taken in high doses and thereby suppress
endogenous testicular unction. T us, there is decreased endogenous testosterone
and sperm production with resultant diminished ertility. Chronic administration
may result in reduced testicular size. Androgens in high doses can be converted to
estrogens, which may cause gynecomastia. T e 17α-alkylated androgens can cause
hepatotoxicity, including cholestasis and peliosis hepatis, blood- lled cysts.
b. Is it sound rationale that testosterone will be di cult to detect?
Endogenous testosterone can be detected by 1 o 2 methods. One is /E ratio, the
ratio o testosterone glucuronide to its endogenous epimer, epitestosterone gluc-
uronide in urine. Administration o exogenous testosterone suppresses secretion
o both endogenous testosterone and epitestosterone and replaces them with only
the exogenous testosterone, so the /E ratio is higher than normal. Both testos-
terone and epitestosterone are measured in urine by gas chromatography-mass
spectrometry.
A second method or detecting the administration o exogenous testosterone
employs gas chromatography-combustion isotope ratio mass spectrometry to detect
the presence o 13C and 12C compounds. Urinary steroids with a low 13C/ 12C ratio are
likely to have originated rom pharmaceutical sources as opposed to endogenous
physiological sources.
CASE 28-8
A 56-year-old man with metastatic prostate cancer is being treated with utamide.
a. What is f utamide and what are its mechanisms o actions?
Flutamide is an androgen receptor antagonist that is used in the treatment o
metastatic prostate cancer (see Chapter 46). When used alone utamide causes an
increased secretion o LH, which in turn increases serum testosterone concentra-
tions. Androgen receptor antagonists are used primarily in conjunction with a
GnRH agonist which during chronic therapy downregulates GnRH receptors caus-
ing a decline in the pituitary response. T e all in LH results in decreased serum
testosterone concentrations. In this setting, utamide blocks the actions o adrenal
androgens, which are not inhibited by GnRH agonists.
b. What are the untoward e ects o f utamide?
Common side e ects o utamide are diarrhea, breast tenderness, and nipple
tenderness. Less commonly nausea, vomiting, and hepatotoxicity occur.
454
Estrogens, Progestins, Androgens, and Contraception CHAPTER 2 8
KEY CONCEPTS
In postmenopausal woman, hormone replacement therapy is most commonly
used to treat vasomotor disturbances (“hot ashes”).
In postmenopausal women with an intact uterus, a progestin is included in
the hormone replacement therapy to prevent endometrial cancer.
Regardless o the specif c drug(s), hormone replacement therapy should use
the minimum dose and duration or the desired therapeutic end point.
Estrogens and progestins are widely used as combination contraceptives and
are 99% e ective in preventing ovulation.
amoxi en is a selective estrogen receptor modulator widely used or the adjuvant
treatment o breast cancer and or prophylaxis in high-risk women, but treatment
should be limited to 5 years.
Fulvestrant, a pure estrogen antagonist, is used to treat breast cancer.
Clomiphene is an estrogen antagonist used to treat in ertility.
Progestin-only contraceptives are available when estrogen-containing products
are contraindicated.
A levonorgestrel-only product and ulipristal are available or emergency contra-
ception within 72 hours or 120 hours o unprotected intercourse, respectively.
Mi epristone, administered with a prostaglandin, is used as an antiprogestin or
medical abortion.
estosterone delivery systems are designed to avoid hepatic catabolism that
occurs when testosterone is ingested orally.
Androgen receptor antagonists such as utamide are used to treat metastatic
prostate cancer.
Finasteride, a 5α-reductase inhibitor, is used to treat benign prostatic hypertrophy.
T e 17α-alkylated androgens are the only androgens that cause hepatotoxicity.
SUMMARY QUIZ
QUESTION 28-1 A 30-year-old woman is being started on birth control pills or the
f rst time. She has a history o migraine headaches with aura. T erapy with which one
o the ollowing contraceptive ormulations is contraindicated in this patient?
a. Levonorgestrel
b. Mi epristone
c. Norethindrone
d. Ethinyl estradiol/norethindrone
e. Ulipristal
QUESTION 28-2 A 56-year-old woman with an intact uterus is being treated with
hormone replacement therapy with a product that contains an estrogen/progestin
combination (estradiol/norethindrone). T e progestin is added to
a. decrease the risk o endometrial cancer.
b. decrease the incidence o breast cancer.
c. increase the e ectiveness in treating vasomotor symptoms.
d. decrease the risk o coronary heart disease.
e. decrease the risk o cognitive impairment.
QUESTION 28-3 A 25-year-old woman is being treated with clomiphene or ertility.
Clomiphene acts by
a. blocking estrogen e ects on the uterus.
b. increasing FSH concentrations. (Continued)
455
SECTION V Hormones and Hormone Antagonists
QUESTION 28-7 A 55-year-old man with benign prostatic hypertrophy is being treated
with f nasteride. Finasteride acts by blocking the conversion o
a. testosterone to estradiol.
b. testosterone to dihydrotestosterone.
c. cortisol to cortisone.
d. cholesterol to pregnenolone.
e. progesterone to androstenedione.
QUESTION 28-8 A 53-year-old woman with breast cancer is being treated with tamox-
i en. amoxi en is a(n)
a. progesterone antagonist.
b. androgen agonist.
c. inhibitor o 5α-reductase.
d. inhibitor o aromatase.
e. selective estrogen receptor modulator.
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Selective Estrogen Tamoxi en Treatment o breast Increased risk o endometrial
Receptor Modulators Raloxi ene cancer (see Chapter 46) cancer and thromboembolic
Toremi ene Raloxi ene used to treat disease
osteoporosis
Estrogen Synthesis Formestane Used to treat breast Hot f ashes Do not increase the risk o uterine
Inhibitors Exemestane cancer (see Chapter 46) cancer or thromboembolic disease
Anastrozole
Letrozole
Progesterone Mi epristone Used in combination with Nausea, vomiting, Vaginal bleeding, abdominal pain,
Antagonist misoprostol (see Chapter and diarrhea uterine cramps
32) or other prostaglandin
or the termination o
early pregnancy
Oral Contraceptive See Table 28-1 Oral contraception Nausea, edema, Thromboembolic disease
and headache
458
ACTH, Adrenal Steroids, CHAPTER
Corticotropin-Releasing Corticorelin Binds to speci c membrane receptors on corticotropes in the anterior pituitary
Hormone (CRH) (see Figure 29-2)
Adrenocortical Steroids See Table 29-1 or Binds to speci c receptor proteins in target tissues to regulate the expression o
speci c drugs corticosteroid-responsive genes, thereby changing the levels and array o proteins
synthesized by the various target tissues (see Figure 29-3)
Inhibitors o the Biosynthesis o Ketoconazole In doses higher than those employed in anti ungal therapy, it is an e ective inhibitor
Adrenocortical Steroids o adrenal and gonadal steroidogenesis, primarily because o its inhibition o the
activity o CYP17 (17α-hydroxylase)
Aminoglutethimide Inhibits CYP11A1, which catalyzes the initial and rate-limiting step in the biosynthesis
o all steroids; also inhibits CYP11B1 and CYP19 (aromatase)
Adrenocorticolytic Agent Mitotane Cytolytic action is due to its metabolic conversion to a reactive acyl chloride by
adrenal mitochondria and subsequent reaction with cellular proteins
459
SECTION V Hormones and Hormone Antagonists
TABLE 29-1 Available Preparations of Adrenocortical Steroids and Their Synthetic Analogs
NONPROPRIETARY NAME TRADE NAME TYPE OF PREPARATION
CORTEF Oral
Hydroxycortisone acetate MICORT-HC Topical
CORTIFOAM Rectal
Hydroxycortisone butyrate LOCOID Topical
Hydrocortisone cypionate CORTEF Oral
Hydrocortisone sodium succinate A-HYDROCORT, SOLU-CORTEF Injectable
Hydrocortisone valerate WESTCORT Topical
Methylprednisolone acetate MEDROL Oral
DEPO-MEDROL Injectable
(Continued)
460
ACTH, Adrenal Steroids, and Pharmacology of the Adrenal Cortex CHAPTER 2 9
Zo na
CYP 11B2
Glo me rulo s a IL-1
Hypo thalamus IL-2
Ang II Aldos te rone CRH ne urons IL-6
K+ TNF-α
ACTH CRH
CYP 11B1 Immune Sys te m
Zo nae
Fas c ic ulata/ CYP 17 Ante rio r Pituitary Lymphocyte s
Re tic ularis Corticotrope s Ma cropha ge s /Monocyte s
Cortis ol Ne utrophils
ACTH
FIGURE 29-1 The adrenal cortex contains 3 anatomically and unction- Co rtis o l
ally distinct compartments. The major unctional compartments o the
adrenal cortex are shown, along with the steroidogenic enzymes that FIGURE 29-2 Overview o the hypothalamic-pituitary-
determine the unique pro les o corticosteroid products. Also shown adrenal (HPA) axis and the immune in ammatory network.
are the predominant physiological regulators o steroid production: Also shown are inputs rom higher neuronal centers that
angiotensin II (Ang II) and K+ or the zona glomerulosa and ACTH or regulate corticotropin-releasing hormone (CRH) secretion. +
the zona asciculata. The physiological regulator(s) o dehydroepian- indicates a positive regulator, − indicates a negative regulator,
drosterone (DHEA) production by the zona reticularis are not known, + and − indicates a mixed e ect, as or NE (norepinephrine). In
although ACTH acutely increases DHEA biosynthesis. addition, arginine vasopressin stimulates release o ACTH rom
corticotropes.
461
SECTION V Hormones and Hormone Antagonists
CBG CBG
S
S
IP
S HS P 70
GR
HS P 70 IP GR
HS P 90 HS P 90
nucle us
S S
Tra ns cription
GR GR
GRE GRE
ge ne
mRNA
cytopla s m
pro te in
FIGURE 29-3 Intracellular mechanism o action o the glucocorticoid receptor. The gure
shows the molecular pathway by which cortisol (labeled S) enters cells and interacts with the
glucocorticoid receptor (GR) to change GR con ormation (indicated by the change in shape o
the GR), induce GR nuclear translocation, and activate transcription o target genes. The example
shown is one in which glucocorticoids activate expression o target genes; the expression o cer-
tain genes, including proopiomelanocortin (POMC) expression by corticotropes, is inhibited by
glucocorticoid treatment. CBG, corticosteroid-binding globulin; GR, glucocorticoid receptor; GRE,
glucocorticoid-response elements in the DNA that are bound by GR, thus providing speci city to
induction o gene transcription by glucocorticoids; HSP70, the 70-Kd heat-shock protein; IP, the
56-Kd immunophilin; HSP90, the 90-Kd heat-shock protein; S, steroid hormone. Within the gene
are introns (gray) and exons (blue); transcription and mRNA processing leads to splicing and
removal o introns and assembly o exons into mRNA.
Lipid Metabolism Redistributes body at; increased at in the back o neck, ace, and supraclavicular area with loss o at in the
extremities
Permissive acilitation o the lipolytic e ect o growth hormone and β adrenergic agonists resulting in an
increase in ree atty acids
Electrolyte and Water Balance Mineralocorticoids act on the distal tubules and collecting ducts to enhance reabsorption o Na+, and to
enhance urinary excretion o K+ and H+
Decreases total body Ca2+ stores by lowering Ca2+ uptake rom the gut and increasing Ca2+ excretion by the kidney
Cardiovascular System Mineralocorticoid-induced changes in renal Na+ exacerbate congestive heart ailure
Enhanced vascular reactivity o other vasoactive substances such as norepinephrine and angiotensin II and
exacerbation o hypertension
Skeletal Muscle Corticosteroids are required or the normal unction o skeletal muscle; adrenocortical insuf ciency results in
muscle weakness; in aldosteronism, muscle weakness results rom hypokalemia; glucocorticoid excess results
in muscle wasting termed “steroid myopathy”
(Continued)
462
ACTH, Adrenal Steroids, and Pharmacology of the Adrenal Cortex CHAPTER 2 9
PHYSIOLOGIC FUNCTION
OR ORGAN AFFECTED MECHANISM
Central Nervous System Adrenocortical steroids exert direct e ects on the CNS such as e ects on mood, behavior, and brain
excitability; rank psychosis has also been noted
Formed Elements o Blood Corticosteroids exert e ects on erythrocytes and produce a decrease in circulating lymphocytes, monocytes,
basophils, and eosinophiles; certain lymphoid malignancies are destroyed by glucocorticoid treatment
Anti-In ammatory and Glucocorticoids pro oundly alter the immune response o lymphocytes and suppress in ammation; they are
Immunosuppressive Actions use ul in managing the in ammatory response to diseases o humoral immunity such as urticarial as well
as diseases o cellular immunity such as transplantation rejection (see Side Bar THE THERAPEUTIC USES OF
ADRENOCORTICAL STEROIDS)
6α-Methylprednisolone 5 0.5 I 4
Triamcinolone 5 0 I 4
Betamethasone 25 0 L 0.75
Dexamethasone 25 0 L 0.75
a
S, short (ie, 8-12 hour biological t1/2); I, intermediate (ie, 12-36 hour biological I1/2); L, long
(ie, 36-72 hour biological t1/2).
b
These dose relationships apply only to oral or intravenous administration, as glucocorticoid
potencies may di er greatly ollowing intramuscular or intraarticular administration.
c
This agent is not used or glucocorticoid e ects.
463
SECTION V Hormones and Hormone Antagonists
CASE 29-3
T e patient in Case 29-1 was treated with 40 mg o prednisone daily or 2 weeks and
then the dose was lowered to 20 mg daily. Attempts to urther lower the dose have
resulted in a are-up o her disease. A er 2 months o prednisone therapy, she became
uncom ortable with her increased weight and the development o roundness in her
ace. Despite warnings not to do so, she stopped the use o her prednisone.
a. What side e ects is she likely to experience?
T e most severe complication o steroid cessation is the li e-threatening condition
o acute adrenal insu ciency characterized by nausea, vomiting, abdominal pain,
hyponatremia, hyperkalemia, weakness, lethargy, and hypotension.
b. How could this situation possibly have been avoided?
Patients who are taking chronic glucocorticoid therapy should be cautioned against
discontinuing the therapy without a signif cant tapering o the dose. T ere is signi -
icant variation among patients with respect to the degree and duration o adrenal
suppression a er glucocorticoid therapy. Patients who have received supraphysi-
ological doses o glucocorticoids or a period o 2 to 4 weeks should be considered
to have some hypothalamic-pituitary-adrenal (HPA) suppression. A gradual reduc-
tion in their glucocorticoid dose is required. Many patients recover rom glucocor-
ticoid-induced HPA suppression within several weeks to months; however, in some
patients the time to recovery can be a year or longer.
CASE 29-4
A 22-year-old woman with the diagnosis o Crohn’s disease has been success ully
treated with sul asalazine (see Chapter 33). A recent exacerbation o her disease has
necessitated the addition o prednisone to her therapeutic regimen. She has noted,
since starting the prednisone that she has been nervous and has had di culty sleeping.
a. What are the potential toxicities o adrenocortical steroids to warn the
patient about?
T e toxicities o glucocorticoid therapy are listed in the Side Bar OXICI IES OF
ADRENOCOR ICAL S EROIDS. Behavioral changes are particularly common.
T ese might include nervousness, insomnia, changes in mood, and even overt
psychosis. Suicidal tendencies are not uncommon.
b. What are other treatment options available to this patient?
Budesonide, (see Chapter 33) a potent glucocorticoid that is inactivated by f rst-
pass hepatic metabolism, has diminished systemic side e ects commonly associated
with glucocorticoids. T e drug can be administered by a delayed-release capsule
that delivers steroid to the ileum and ascending colon, or as a retention enema or
the treatment o ulcerative colitis.
CASE 29-5
A 36-year-old woman is suspected o having Cushing’s syndrome. It is recommended
that she have a dexamethasone suppression test.
a. What is a dexamethasone suppression test and how is it interpreted?
o determine i patients with clinical mani estations o hypercortisolism have
biochemical evidence o increased cortisol biosynthesis, an overnight dexamethasone
suppression test has been devised in which patients are given 1 mg o dexamethasone
orally at 11 PM, and plasma cortisol is measured at 8 AM the ollowing morning.
Suppression o plasma cortisol to less than 1.8 µg/dL suggests that the patient does
not have Cushing’s syndrome.
(Continued)
465
SECTION V Hormones and Hormone Antagonists
CASE 29-6
A 68-year-old man is diagnosed with bacterial conjunctivitis. He is prescribed a combi-
nation eye drop that contains dexamethasone and an antibiotic.
a. Why use an adrenocorticoal steroid in an eye in ection?
Glucocorticoids can dramatically decrease in ammation in the conjunctiva when
administered topically into the conjunctival sac (see Chapter 47).
b. What are the concerns with the use o this combination product?
opical glucocorticoid therapy requently increases intraocular pressure in nor-
mal eyes and exacerbates intraocular hypertension in patients with antecedent
glaucoma. T e glaucoma is not always reversible on cessation o the glucocorti-
coid therapy. Intraocular pressure should be monitored when glucocorticoids are
applied to the eye or more than 2 weeks.
CASE 29-7
A 28-year-old woman is diagnosed with Cushing’s syndrome rom an ectopic AC H-
producing tumor. She is being treated with metyrapone.
a. What is metyrapone and how does it act?
Metyrapone is a relatively selective inhibitor o CYP11B (11β-hydroxylase), which
converts 11-deoxycortisol to cortisol in the terminal reaction in the glucocorticoid
biosynthetic pathway. T us, the biosynthesis o cortisol is markedly impaired.
b. What are the untoward e ects o long-term metyrapone therapy?
Chronic administration o metyrapone can cause hirsutism, which results rom
increased synthesis o androgens upstream rom the enzymatic block. Metyra-
pone can also cause hypertension, which results rom increased concentrations o
11-deoxycortisol. Other side e ects include nausea, headache, sedation, and rash.
KEY CONCEPTS
T e rate o glucocorticoid secretion is determined by uctuations in the release
o AC H by the pituitary corticotropes (see Figure 29-2).
Adrenocortical steroids act by activating glucocorticoid receptors or mineralo-
corticoid receptors in various tissues (see Figure 29-3).
Glucocorticoids are administered in many ormulations (oral, parenteral, and
topical) or disorders that share an in ammatory or immunological basis
(see able 29-1).
Except or replacement therapy or adrenal insu ciency, glucocorticoids are
neither specif c nor curative.
Corticosteroid preparations vary widely in their anti-in ammatory e ects and
duration o action. Some corticosteroids possess mineralocorticoid activity
while others do not (see able 29-2).
Glucocorticoids have several potentially serious side e ects (see Side Bar OX-
ICI IES OF ADRENOCOR ICAL S EROIDS), which necessitates:
Limiting the dose to the minimal needed to achieve a therapeutic e ect.
Periodic reevaluation.
(Continued)
466
ACTH, Adrenal Steroids, and Pharmacology of the Adrenal Cortex CHAPTER 2 9
SUMMARY QUIZ
QUESTION 29-1 A 34-year-old man is diagnosed with secondary adrenal insu ciency.
He does not require the administration o a mineralocorticoid because
a. the adrenal medulla is intact.
b. the zona glomerulosa is intact.
c. the zona reticularis is intact.
d. the zona asciculata is intact.
e. 11β-hydroxylase is not inhibited.
QUESTION 29-2 A 54-year-old man has been diagnosed with hypertension caused by his
excessive consumption o licorice. Licorice is a known inhibitor o 11β-hydroxysteroid
dehydrogenase that is involved in the inactivation o
a. cortisol.
b. aldosterone.
c. AC H.
d. dehydroepiandrosterone.
e. progesterone.
QUESTION 29-3 A 34-year-old woman with Crohn’s disease has been taking predni-
sone daily or 1 year. She has been experiencing a thickness in the back o her neck.
T is is likely due to a(n)
a. edema.
b. increase in muscle growth.
c. redistribution o lipid.
d. protein deposition.
e. ectopic thyroid tissue.
QUESTION 29-4 A 63-year-old man with type 2 diabetes and osteoarthritis in his le
knee is given an intra-articular injection o a glucocorticoid to decrease pain in his
knee. An elevation in his blood sugar or the next 3 days is likely due to an e ect o the
glucocorticoid on
a. diminished peripheral glucose utilization.
b. increased protein breakdown.
c. activation o lipolysis.
d. increased glucose synthesis in the liver.
e. all o the above.
QUESTION 29-5 A 48-year-old woman with a chronic pulmonary disease is being
treated with an inhaled glucocorticoid product. She is likely to experience which o the
ollowing side e ects?
a. Bu alo hump
b. Acute adrenal insu ciency
c. Hyperglycemia
d. Oral candidiasis
e. Hepatitis
467
SECTION V Hormones and Hormone Antagonists
Adrenocortical Steroids See Table 29-1 or See Side Bar THERAPEUTIC Acute adrenal insuf ciency i
speci c drugs USES OF ADRENOCORTICAL withdrawal o chronic therapy
STEROIDS or the therapeutic is not tapered
use o adrenocortical steroids Pseudotumor cerebri rarely
or selected speci c examples, associated with withdrawal
and the Side Bar GENERAL o therapy
PRINCIPLES FORTHE USE See Side Bar TOXICITIES OF
OF GLUCOCORTICOIDS or ADRENOCORTICAL STEROIDS
principles related to the use o or side e ects o adrenocortical
adrenocortical steroids steroid therapy
(Continued)
468
ACTH, Adrenal Steroids, and Pharmacology of the Adrenal Cortex CHAPTER 2 9
TOXICITIES
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Inhibitors o the Ketoconazole Anti ungal agent used to Hepatic dys unction
Biosynthesis o inhibit steroid biosynthesis in Inhibition o CYPs may lead to
Adrenocortical Steroids patients with hypercortisolism serious drug interactions
Metyrapone Used to impair the biosynthesis Nausea, headache, Precipitation o acute adrenal
o cortisol in patients with sedation, rash insuf ciency
adrenal neoplasms or tumors Chronic administration may cause
producing ACTH ectopically hirsutism
469
CHAPTER
Endocrine Pancreas and
30 Pharmacotherapyof Diabetes
Mellitus and Hypoglycemia
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN
Chapter 43, Endocrine Pancreas and Pharmacotherapy o Diabetes Mellitus and Hypo-
glycemia in Goodman & Gilman’s T e Pharmacological Basis of T erapeutics, 12th THIS CHAPTER
Edition. In addition to the material presented here, the 12th Edition includes: Acarbose (PRECOSE, others)
• A detailed discussion o the regulation o blood glucose Alogliptin (NESINA)
• A description o pancreatic islet cell physiology and the synthesis and processing Bromocriptine (CYCLOSET,not yet available
o insulin in the United States for treatment
• A discussion o the signaling pathway that is activated by insulin resulting in its of diabetes)
e ects on target cells Colesevelam(WELCHOL)
• A description o the pathogenesis o type 1 and type 2 diabetes Diazoxide (PROGLYCEM)
• Drugs that are in development or type 2 diabetes Exenatide (BYETTA)
• able 43-5 Properties o Insulin Preparations Gliclazide (DIAMICRON, others, unavailable
in the United States)
LEARNING OBJECTIVES Glimepiride (AMARYL)
Understand the mechanisms o action o insulin and the oral antidiabetic drugs. Glipizide (GLUCOTROL, others)
Describe the components or management o the diabetic patient including the Glucagon
goals o therapy. Glyburide (Glibenclamide; MICRONASE,
Describe the pharmacotherapeutic options or the treatment o patients with DIABETA, others)
type 1 or type 2 diabetes. Insulin aspart (NOVOLOG)
Learn about the adverse e ects o insulin and the oral antidiabetic drugs. Insulin determir (LEVEMIR)
Understand the treatment o hypoglycemia. Insulin glargine (LANTUS)
Insulin glulisine (APIDRA)
MECHANISMS OF ACTION INSULIN AND ORAL ANTIDIABETIC DRUGS Insulin lispro (HUMALOG)
DRUG CLASS DRUGS MECHANISM OF ACTION Insulin protamine hagedorn
Insulin Insulin Insulin binds to a plasma membrane receptor that initiates
(NPH, insulin isophane)
a cascade o signaling events, which results in glucose Liraglutide (VICTOZA)
utilization and glycogen synthesis (see Figure 30-1) Metformin (GLUCOPHAGE, others)
Biguanides Met ormin Increases the activity o AMP-dependent protein kinase Miglitol (GLYSET)
(AMPK); activated AMPKstimulates atty acid oxidation,
Nateglinide (STARLIX)
glucose uptake, and nonoxidative metabolism, and it
reduces lipogenesis and gluconeogenesis; the net result Pioglitazone (ACTOS)
is increased glycogen storage in skeletal muscle, lower Pramlintide (SYMLIN)
rates o hepatic glucose production, increased insulin
sensitivity, and lower blood glucose concentrations Repaglinide (PRANDIN)
Rosiglitazone (AVANDIA)
Insulin Glyburide Stimulate insulin release by binding to a speci c site on
Secretagogues— Glipizide the β cell KATP channel complex and inhibiting its activity Saxagliptin (ONGLYZA)
Sul onylureas Gliclazide (see Figure 30-2) Sitagliptin (JANIVIA)
Glimepiride
Vidagliptin (GALVUS, ZOMELIS, JAIRA, not
Insulin Repaglinide Stimulates insulin release by closing KATP channels in available in the United States)
Secretagogues— Nateglinide pancreatic β cells (see Figure 30-2)
Voglibose (VOGLIB, not available in the
Nonsul onylureas
United States)
Thiazolidinediones Rosiglitazone Ligands or the peroxisome proli eration activating
Pioglitazone receptor γ (PPARγ) that are involved in the regulation o
genes related to glucose and lipid metabolism
(Continued)
470
Endocrine Pancreas and Pharmacotherapy CHAPTER 3 0
Amylin Agonists Pramlintide Synthetic orm o amylin; it acts through the amylin
receptor in the brain causing reduction in glucagon
release, delayed gastric emptying, and satiety
Bile Acid Colesevelam Mechanism by which bile acid binding and removal rom
Sequestrants the enterohepatic circulation lowers blood glucose has
not been established
Agents Used to Glucagon Interacts with GPCR receptor on target cells; the e ects o
Treat Hypoglycemia glucagon on the liver are mediated by cAMP
Ins ulin
Ins ulin
re ce ptor Ins ulin
Glucos e
α cave ola extra c e llula r
flotillin Cav intra c e llula r
β
Y- -Y P-Y- -Y-P AP S Tra ns loca tion
of GLUT 4 Glucos e
CbI CAP Hexokina s e
S hc CrkII
GTP GLUT4
exch C3G G-6-P
TC10
Ga b1 GDP
P KB
IRS prote ins (Akt) a P KC
1-4
MAP Intra ce llula r
P IP 3 P DK1
kina s e (me mbra ne ) ve s icle
P I3-kina s e
FIGURE 30-1 Pathways o insulin signaling. The binding o insulin to its plasma membrane receptor activates a cascade o downstream signaling
events. Insulin binding activates the intrinsic tyrosine kinase activity o the receptor dimer, resulting in the tyrosine phosphorylation (Y-P) o the recep-
tor’s β subunits and a small number o speci c substrates (light blue shapes): the insulin receptor substrate (IRS) proteins, Gab-1 and SHC; within the
membrane, a caveolar pool o insulin receptor phosphorylates caveolin (Cav), APS, and Cbl. These tyrosine-phosphorylated proteins interact with
signaling cascades via SH2 and SH3 domains to mediate the e ects o insulin, with speci c e ects resulting rom each pathway. In target tissues such
as skeletal muscle and adipocytes, a key event is the translocation o the Glut4 glucose transporter rom intracellular vesicles to the plasma membrane;
this translocation is stimulated by both the caveolar and noncaveolar pathways. In the noncaveolar pathway, the activation o PI3Kis crucial, and PKB/
Akt (anchored at the membrane by PIP3) and/or an atypical orm o PKC is involved. In the caveolar pathway, caveolar protein otillin localizes the
signaling complex to the caveola; the signaling pathway involves a series o SH2 domain interactions that add the adaptor protein CrkII, the guanine
nucleotide exchange protein C3G, and small GTP-binding protein, TC10. The pathways are inactivated by speci c phosphoprotein phosphatases (eg,
PTB1B). In addition to the actions shown, insulin also stimulates the plasma membrane Na+,K+-ATPase by a mechanism that is still being elucidated;
the result is an increase in pump activity and a net accumulation o K+ in the cell. Abbreviations: aPKC, atypical iso orm o protein kinase C; APS, adap-
tor protein with PH and SH2 domains; CAP, Cbl associated protein; CrkII, chicken tumor virus regulator o kinase II; GLUT4, glucose transporter 4; Gab-1,
Grb-2 associated binder; MAP kinase, mitogen-activated protein kinase; PDK, phosphoinositide-dependent kinase; PI3 kinase, phosphatidylinositol-
3-kinase; PIP3, phosphatidylinositol trisphosphate; PKB, protein kinase B(also called Akt); Y, tyrosine residue; Y-P, phosphorylated tyrosine residue.
471
SECTION V Hormones and Hormone Antagonists
ATP-s e ns itive
Kir6.2 K+ K+ cha nne l
Glucos e
Dia zoxide Ca 2 +
S UR1 S ulfonylure a /me glitinide Incre tins
(a c ting via
GP CR-G s -AC)
GLUT De pola riza tion
K+
glucokina s e K+
Ca 2 +
G-6-P ATP
cAMP
S tore d
ins ulin
+
Me ta bolis m
Exocytos is
Plas ma
ins ulin
Pa ncre a tic β ce ll
FIGURE 30-2 Regulation o insulin secretion rom a pancreatic β cell. The pancreatic β cell in a resting state
( asting blood glucose) is hyperpolarized. Glucose, entering via GLUT transporters (primarily GLUT1 in humans,
GLUT2 in rodents), is metabolized and elevates cellular ATP, which inhibits K+ entry through the KATP channel; the
decreased K+ conductance results in depolarization, leading to Ca2+-dependent exocytosis o stored insulin. The
KATP channel, actually a hetero-octamer composed o SUR1 and Kir 6.2 subunits, is the site o action o several
classes o drugs: ATP binds to and inhibits Kir6.2; sul onylureas and meglitinides bind to and inhibit SUR1; all
3 agents thereby promote insulin secretion. Diazoxide and ADP-Mg 2+ (low ATP) bind to and activate SUR1,
thereby inhibiting insulin secretion. Incretins enhance insulin secretion.
GIP-1 [3-42]
DP P-4
Me a l DP P-4 inhibitor Me a l inhibitor
1
-
P
P
I
L
G
G
No drug No drug
t
c
t
c
a
t
a
n
t
I
n
I
Time Time
FIGURE 30-3 Pharmacological e ects o DDP-4 inhibition. DPP-4, an ectoenzyme located on the luminal side
o capillary endothelial cells metabolizes the incretins, glucagon-like peptide 1 (GLP-1), and glucose-dependent
insulinotropic polypeptide (GIP), by removing the 2 N-terminal amino acids. The target or DPP-4 cleavage is a
proline or alanine residue in the second position o the primary peptide sequence. The truncated metabolites
GLP-1 [9-36] and GIP [3-42] are the major orms o the incretins in plasma and are inactive as insulin secreta-
gogues. Treatment with a DPP-4 inhibitor increases the concentrations o intact GLP-1 and GIP.
472
Endocrine Pancreas and Pharmacotherapy CHAPTER 3 0
CASE 30-1
A 10-year-old girl is diagnosed with type 1 diabetes. She will start on insulin therapy.
a. How is the diagnosis o type 1 diabetes made?
T e diagnosis o diabetes mellitus is currently based on the correlation o diabetes-
speci c complications with a particular level o glycemia, that is, the level o glyce-
mia at which a diabetes-speci c complication like retinopathy begins to appear. T e
criterion or the diagnosis o diabetes is shown in able 30-1.
b. How should diabetes in this patient be managed? What are the goals o therapy?
T erapy o diabetes has to be individualized or each patient. Figure 30-4 shows the
components o sound diabetes management. able 30-2 lists the indexes o therapy
and the goals or diabetic patients in general.
c. What is hemoglobin A1c (A1C) and how does it di er rom asting blood glucose?
Exposure o proteins to an elevated glucose concentration produces nonenzymatic
glycation o proteins including hemoglobin (Hb). T us, the level o HbA1c (A1C)
represents the average glucose concentration to which the Hb has been exposed
over the past 2 to 3 months.
d. What is the mechanism o action o insulin?
T e pancreatic β cell is a highly specialized cell that quickly senses and responds
to the external glucose concentration. T e transport o glucose into the pancreatic
β cell via a acilitative transporter (see Figure 30-2) results in increased intracellular
calcium which, in turn, results in exocytotic release o insulin rom storage vesicles.
Once in the circulation, insulin binds, in various tissues, to its plasma membrane
receptor (see Figure 30-1) that activates a cascade o downstream intracellular
signaling events. T e tissues that are considered critical or the regulation o blood
glucose are liver, skeletal muscle, and at.
(Continued)
Ma na ge me nt of
dia be te s
A1C <7.0%c
Lipidse
e. What are the options with insulin therapy with this patient?
Insulin preparations are classif ed according to their duration o action into
short-acting and long-acting (see able 45-3 in Goodman and Gilman’s T e Phar-
macological Basis of T erapeutics, 12th Edition). In most patients, insulin-replace-
ment therapy includes long-acting insulin (basal) and short-acting
insulin to provide postprandial needs. Most insulin is injected subcutaneously.
Short-acting insulins are the only orm o the hormone used in subcutaneous
in usion pumps.
CASE 30-2
A 53-year-old man is diagnosed with type 2 diabetes. His doctor ollows the treatment
algorithm or the management o type 2 diabetes as shown in Figure 30-5. T e patient’s
initial A1C is 8.1%. Af er attempts at weight reduction, increased physical activity, and
met ormin pharmacotherapy his A1C is 7.8%.
a. How is the diagnosis of type 2 diabetes made?
T e diagnosis o type 2 diabetes is made using the same criteria as shown in able 30-1.
b. What are the goals of therapy in a patient with type 2 diabetes?
T erapy o type 2 diabetes has to be individualized or each patient. Figure 30-4
shows the components o sound diabetes management and is applicable to type 1
and type 2 diabetes patients. able 30-2 lists the indexes o therapy and the goals or
diabetic patients in general.
(Continued)
474
Endocrine Pancreas and Pharmacotherapy CHAPTER 3 0
Type 2 Dia be te s
As s e s s
A1C
Me tformin Me tformin
+ +
2 Ora l Age nts Ins ulin
Re a s s e s s
A1C
c. What are the options to lower his A1C in addition to li estyle modif cations?
One option that is commonly ollowed is to add a sul onylurea drug. Other
options include the insulin secretagogues that are nonsul onylureas or the
thiazolidinediones.
d. What are the untoward e ects o sul onylurea drugs?
T e most severe untoward e ect o the sul onylurea drugs is hypoglycemia.
Weight gain is also a common side e ect o this class o drugs. Less common
e ects include nausea, vomiting, cholestatic jaundice, blood dyscrasias, and
dermatological reactions.
CASE 30-3
T e patient in Case 30-2 has an A1C that is 7.5% a er pharmacotherapy with met ormin
plus a sul onylurea.
a. What are the options with this patient?
T e progressive insulin de ciency in type 2 diabetes o en makes it increasingly
dif cult to achieve tight glycemic control solely with oral antihyperglycemic agents
(see Figure 30-5). One option would be the addition o a thiazolidinedione drug
such as rosiglitazone or pioglitazone. I this does not achieve the desired goal then
the addition o insulin is another option.
(Continued)
475
SECTION V Hormones and Hormone Antagonists
CASE 30-4
A 49-year-old woman without diabetes is diagnosed with recurring hypoglycemia. T is
is particularly troublesome because she awakes every morning with a headache.
a. What are the options or treating hypoglycemia?
wo agents are available or the treatment o hypoglycemia: glucagon and diazoxide.
b. What is the mechanism o action o glucagon?
Glucagon is used to treat severe hypoglycemia, particularly in diabetic patients
when the patient cannot sa ely consume oral glucose and intravenous glucose is not
available. Glucagon interacts with a GPCR on the plasma membrane o target cells.
c. What is the mechanism o action o diazoxide?
Diazoxide is an antihypertensive with potent hyperglycemic actions when given
orally. T e hyperglycemic action o diazoxide is primarily through the inhibition o
insulin secretion (see Figure 30-2).
KEY CONCEPTS
Insulin is the primary treatment o type 1 diabetes.
T ere are many di erent types o insulin (see able 45-3 in Goodman and
Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition), including
subcutaneous insulin pumps.
Short-acting insulin is the only orm o the hormone used in insulin pumps.
Some drugs may promote hyperglycemia or hypoglycemia (see able 30-3).
ype 2 diabetes is a complex disease that requires multiple orms o treatment
(see Figure 30-5) including diet, exercise, and medications.
T e goals o therapy or type 1 and type 2 diabetes are shown in able 30-2.
Insulin is the cornerstone o treatment o hyperglycemia in hospitalized patients.
(Continued)
476
Endocrine Pancreas and Pharmacotherapy CHAPTER 3 0
Met ormin is the consensus rst line o therapy or type 2 diabetes and should
be started at the time o diagnosis.
T e most common and serious adverse e ect o diabetes therapy is hypoglyce-
mia. T e more vigorous the attempt to achieve euglycemia, the more requent
are episodes o hypoglycemia.
SUMMARY QUIZ
QUESTION 30-3 A 56-year-old woman with type 2 diabetes is being treated with
met ormin and glimepiride. T ese two drugs act synergistically because glimepiride
a. decreases the clearance o met ormin.
b. acts to increase glycogen stores in the liver.
c. stimulates insulin release by binding to a speci c site on β cells.
d. increases the activity o AMP-dependent protein kinase (AMPK).
e. decreases glucose reabsorption in the kidney.
477
SECTION V Hormones and Hormone Antagonists
QUESTION 30-4 In the patient in Question 30-3, the met ormin and glimepiride act
synergistically because met ormin
a. decreases the clearance o glimepiride.
b. acts to decrease glycogen stores in the liver.
c. stimulates insulin release by binding to a speci c site on β cells.
d. increases the activity o AMP-dependent protein kinase (AMPK).
e. decreases glucose reabsorption in the kidney.
QUESTION 30-5 A 48-year-old man with type 2 diabetes is treated with glargine insulin
once daily and lispro insulin with each meal. T e main clinical di erence in these 2 types
o insulin is in their
a. e ective duration o action.
b. the way they are administered.
c. storage.
d. metabolism by the liver.
e. penetration into the central nervous system.
QUESTION 30-6 T e patient in Question 30-3 has developed onychomycosis and she
is now being treated with f uconazole. She is at increased risk o hypoglycemia because
f uconazole can
a. decrease the hepatic metabolism o met ormin.
b. decrease the hepatic metabolism o glimepiride.
c. increase glucose uptake by skeletal muscle.
d. inhibit insulin secretion.
e. inhibit the action o glucagon.
QUESTION 30-4 Answer is d. Met ormin increases the activity o the AMP-dependent
protein kinase (AMPK). Activated AMPK stimulates atty acid oxidation, glucose
uptake and nonoxidative metabolism, and reduced lipogenesis and gluconeogen-
esis. T e net result is increased glycogen storage in skeletal muscle, lower rates o
hepatic glucose production, increased insulin sensitivity, and lower blood glucose
concentrations.
QUESTION 30-5 Answer is a. See able 45-3 in Goodman and Gilman’s T e Pharma-
cological Basis of T erapeutics, 12th Edition . T e major clinical di erence between
glargine and lispro insulin is in their e ective duration o action.
478
Endocrine Pancreas and Pharmacotherapy CHAPTER 3 0
Biguanides Met ormin First-line treatment o Nausea, diarrhea, Lower blood concentrations o vitamin B12
type 2 diabetes indigestion, and Lactic acidosis
abdominal pain
Insulin Glyburide Treatment o type 2 diabetes Weight gain Hypoglycemia, cholestatic jaundice, agranulocytosis,
Secretagogues— Glipizide Nausea and aplastic anemia, hemolytic anemia, generalized
Sul onylureas Gliclazide vomiting hypersensitivity reactions, and dermatological reactions
Glimepiride Ethanol may enhance the action o sul onylureas
and cause hypoglycemia
Drug interactions with many drugs including azole
anti ungal agents and histamine H2 antagonists
Thiazolidinediones Rosiglitazone Treatment o type 2 diabetes Weight gain Increased incidence o congestive heart ailure
Pioglitazone and edema Rosiglitazone, but not pioglitazone may increase the
risk o myocardial in arction and stroke
Thiazolidinediones increase the risk o bone racture
in women
GLP-1 Agonists Exenatide Treatment o type 2 diabetes Nausea and Hypoglycemia is rare
Liraglutide vomiting
Dipeptidyl Sitagliptin Treatment o type 2 diabetes Saxagliptin is metabolized by CYP3A4 and dose
Peptidase-4 Saxagliptin should be adjusted when coadministered with
(DPP-4) Inhibitors Vidagliptin drugs that inhibit this enzyme
Alogliptin
α-Glucosidase Acarbose Adjuncts to diet and exercise Malabsorption, Hypoglycemia when added to insulin or an insulin
Inhibitors Miglitol in type 2 diabetic patients not atulence, secretagogue
Voglibose reaching glycemic targets diarrhea, and Acarbose can decrease absorption o digoxin
abdominal Miglitol can decrease the absorption o propranolol
bloating and ranitidine
Bile Acid Colesevelam Treatment o Constipation, Inter eres with the absorption o many commonly
Sequestrants hypercholesterolemia (see dyspepsia, used drugs; most medications should be given
Chapter 20); may be used as abdominal pain, 4 hours be ore colesevelam
an adjunct to diet and exercise and nausea
to treat patients with
type 2 diabetes
479
CHAPTER
Drug Therapyof Mineral
31 Ion Homeostasis and Bone
Turnover Disorders
T is chapter will be most use ul a er having a basic understanding o the material
DRUGS INCLUDED
in Chapter 44, Agents A ecting Mineral Ion Homeostasis and Bone urnover in
IN THIS CHAPTER Goodman & Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition.
1α-hydroxycholecalciferol (1-OHD, alphacal- In addition to the material presented here, the 12th Edition contains:
cidol, ONE-ALPHA) • A detailed discussion o the physiology o mineral ion homeostasis
22-Oxacalcitrol (1,25-dihydroxy-22- • A description o the hormonal regulation o calcium and phosphorous homeostasis
oxavitamin D3, OCT,maxacalcitol, OXAROL)
• A discussion o bone physiology
Alendronate (FOSAMAX)
• A detailed discussion o the pharmacological treatment o disorders o mineral ion
Calcipotriene (DOVONEX,others) homeostasis and bone metabolism, including the therapeutic uses o vitamin D, cal-
Calcitonin (CALCIMAR, MIACALCIN) citonin, bisphosphonates, parathyroid hormone (P H), and calcium sensor mimetics
Calcitriol (1,25-dihydroxycholecalciferol; • A description o an integrated approach to the prevention and treatment o
CALCIJEX,ROCALTROL) osteoporosis
Calciumsalts
LEARNING OBJECTIVES
Cinacalcet (SENSIPAR)
Understand calcium and phosphorous homeostasis.
Denosumab (investigational)
Dihydrotachysterol (DHT,ROXANE) Describe the roles o P H, calcitonin, and vitamin D in calcium homeostasis.
Doxercalciferol (1α-hydroxyvitamin D2, Understand the concept o bone resorption and bone ormation.
HECTOROL) Describe the mechanism o action and untoward e ects o bisphosphonates.
Ergocalciferol (calciferol, DRISDOL) Describe the role o bisphosphonates in the prevention and treatment o
Etidronate sodium(DIDRONEL) osteoporosis.
Ibandronate (BONIVA) Describe the pharmacological management o hypocalcemia and
Lanthanumcarbonate (FOSRENOL) hypercalcemia.
Pamidronate (AREDIA)
Paricalcitol (1,25-dihydroxy-19-norvitamin MECHANISMS OF ACTION OF DRUGS USED IN MINERAL HOMEOSTASIS AND BONE
D2, ZEMPLAR) TURNOVER DISORDERS
Plicamycin (MITHRACIN) DRUG CLASS DRUGS MECHANISM OF ACTION
Risedronate (ACTONEL) Hormones Calcitonin Calcitonin actions are
Teriparatide mediated by the calcitonin
Sevelamer hydrochloride (RENAGEL)
receptor (CTR), which is a
Teriparatide (FORTEO) member o the parathyroid
Tiludronate (SKELID) PTH/secretin sub amily o
GPCRs; the hypocalcemic and
Zoledronate (ZOMETA) hypophosphatemic e ects
o calcitonin are caused by
direct inhibition o osteoclastic
bone resorption
Teriparatide is a synthetic PTH
ragment (1-34); intermittant
exposure to PTH promotes
anabolic actions on bone and
is the basis or teriparatide’s
use in treating severe
osteoporosis
(Continued)
480
Drug Therapy of Mineral Ion Homeostasis and Bone Turnover Disorders CHAPTER 3 1
481
SECTION V Hormones and Hormone Antagonists
OH
Bone
Os te ocla s ts
CH2
HO
P TH P TH
Ca 2 +, phos pha te Ca 2 +, phos pha te Os te obla s ts Re s orption by
(e s troge n, prola ctin) re building os te ocla s ts
1, 25-(OH)2 D
OH
Os te obla s ts
induction
CH2
HO OH FIGURE 31-2 The bone remodeling cycle. Osteoclast precursors use and are activated to
resorb a lacuna in a previously quiescent sur ace. These cells are replaced by osteoblasts that
FIGURE 31-1 Regulation o 1α-hydroxylase deposit new bone to restore the integrity o the tissue. (Adapted with permission from Skerry
activity. Changes in the plasma levels o PTH, TM, Gowen M. Bone cells and bone in remodelling in rheumatoid arthritis. In: Henderson B, Edwards
Ca2+, and phosphate modulate the hydroxyl- JCW, Pettipher ER, eds. Mechanisms and Models in Rheumatoid Arthritis. London: Academic Press;
ation o 25-OH vitamin D to the active orm, 1995, pp 205-220.)
1,25-dihydroxyvitamin D. 25-OHD, 25-hydroxy-
cholecalci erol; 1,25-(OH)2-D, calcitriol; PTH,
parathyroid hormone.
RANKL
Ina ctive
RANKL/
OP G
OP G complex
RANK
Os te obla s t Os te ocla s t
pre curs or
FIGURE 31-3 Receptor or activating NF-κB ligand (RANKL) and osteoclast ormation. RANKL,
acting on RANK, promotes osteoclast ormation and subsequent resorption o bone matrix.
Osteoprotegerin (OPG) binds to RANKL, reducing its binding to RANKand thereby inhibiting
osteoclast di erentiation.
482
Drug Therapy of Mineral Ion Homeostasis and Bone Turnover Disorders CHAPTER 3 1
CASE 31-1
A 56-year-old man with a diagnosis o lung cancer is hospitalized because o lethargy,
weakness, and polyuria. His serum calcium is 13 mg/dL.
a. Why is his serum calcium elevated?
Newly diagnosed hypercalcemia in hospitalized patients is most o en caused by
systemic malignancy, either with or without bone metastasis. P H-related protein
(P HrP) is a primitive, highly conserved protein that may be abnormally expressed
in malignant tissue, particularly in squamous cell and other epithelial cancers. Other
tumors release cytokines or prostaglandins that stimulate bone resorption.
b. How does P H cause hypercalcemia?
T e primary unction o P H is to maintain a constant concentration o calcium and
phosphorous in the extracellular uid. T e principal processes regulated are renal
calcium and phosphorous absorption and mobilization o bone calcium (Figure 31-4).
T e actions o P H on target tissues are mediated by at least 2 receptors: the P H 1
receptor which binds both P H and P HrP; and the P H 2 receptor ound in
vascular tissue, brain, pancreas, and placenta which binds only P H.
c. What are the treatment options or this patient?
Calcitonin may be use ul in managing hypercalcemia. Reduction in serum calcium can
be rapid, although “escape” rom the hormone commonly occurs within several days.
Intravenous bisphosphonates (pamidronate and zoledronate) have proven very
e ective in the management o hypercalcemia. T ey act by inhibiting bone resorp-
tion (see Case 31-3).
(Continued)
Parathyro ids
Kidney
PTH
Bo ne
Urine Ca 2 +
Urine P la s ma Ca 2 +
phos pha te
Calc itrio l
Inte s tine
P hos pha te Ca 2 +
a bs orption a bs orption
FIGURE 31-4 Calcium homeostasis and its regulation by parathyroid hormone (PTH) and 1,25-
dihydroxyvitamin D. PTH has stimulatory e ects on bone and kidney, including the stimulation
o 1α-hydroxylase activity in kidney mitochondria leading to the increased production o
1,25-dihydroxyvitamin D (calcitriol) rom 25-hydroxycholecalci erol, the monohydroxylated
vitamin D metabolite. Calcitriol is the biologically active metabolite o vitamin D.
483
SECTION V Hormones and Hormone Antagonists
CASE 31-2
A 42-year-old man with chronic renal disease is showing signs o decreased bone
density. T is was rst diagnosed as osteomalacia, but later the diagnosis was changed
to renal osteodystrophy.
a. What are osteomalacia and renal osteodystrophy?
Patients with chronic renal disease are at risk or developing osteomalacia (under-
mineralization o bone matrix), which occurs commonly during sustained phos-
phate depletion. Patients with chronic renal disease are also at risk or developing a
complex bone disease called renal osteodystrophy. In this setting, bone metabolism
is stimulated by an increase in P H and by a delay in bone mineralization that is
due to decreased renal synthesis o calcitriol. In renal osteodystrophy, low bone
mineral density (BMD) may accompany high-turnover bone lesions typically seen
in patients with uncontrolled hyperparathyroidism. In another orm o the disease,
low mineral density is accompanied by low bone remodeling activity seen in
patients with adynamic bone disease.
b. What is the role o phosphate binders in managing renal osteodystrophy?
T e therapeutic approach to the patient with renal osteodystrophy o the high-turnover
disease with de cient mineralization is dietary phosphate restriction, generally in com-
bination with a phosphate binder. Highly e ective phosphate binders have been devel-
oped. Sevelamer is a nonabsorbable phosphate-binding polymer that e ectively lowers
the serum phosphate concentration, with a corresponding reduction in the calcium ×
phosphate product. Lanthanum carbonate is a poorly permeable trivalent cation that is
use ul in treating the hyperphosphatemia associated with renal osteodystrophy.
c. What is the role o vitamin D in the management o renal osteodystrophy?
Renal osteodystrophy associated with low bone turnover is increasingly common
and may be due to oversuppression o P H with aggressive use o either calcitriol
or other vitamin D analog. Current guidelines suggest that treatment with an active
vitamin D preparation (see Figure 31-1) is indicated i serum 25-hydroxy vitamin D
(25-OHD) levels are less than 30 ng/mL and serum calcium is less than 9.5 mg/dL.
However, i 25-OHD and serum calcium levels are elevated, vitamin D supplemen-
tation should be discontinued. I the serum calcium is less than 9.5 mg/dL, treat-
ment with a vitamin D analog is warranted irrespective o the 25-OHD level.
CASE 31-3
A 55-year-old woman is concerned because her mother and sister developed ractures
in their legs and vertebra a er menopause. She wants to know what osteoporosis is
and i she is susceptible when she has never had a broken bone. She is also asking or a
medication and other advice that will prevent osteoporosis. She wants to know i taking
only a calcium supplement will prevent her rom having ractures.
a. How is bone physiology involved in the development o osteoporosis?
Osteoporosis is a condition o low bone mass and microarchitectural disruption that
results in ractures with minimal trauma. Osteoporosis can be categorized as primary
or secondary. Primary osteoporosis represents 2 undamentally di erent conditions:
type I osteoporosis is characterized by loss o trabecular bone owing to estrogen lack
at menopause, and type II osteoporosis is characterized by loss o cortical and tra-
becular bone in men and women due to long-term remodeling inef ciency, dietary
inadequacy, and activation o the parathyroid axis with age. Secondary osteoporosis is
due to systemic illness or medications such as glucocorticoids. (Continued)
484
Drug Therapy of Mineral Ion Homeostasis and Bone Turnover Disorders CHAPTER 3 1
KEY CONCEPTS
T e steady-state content o calcium in bone re ects the net e ect o bone
resorption and bone ormation.
P H is a polypeptide hormone that helps regulate plasma calcium by a ecting
bone resorption/ ormation, renal calcium excretion/reabsorption, and calcitriol
synthesis (thus GI calcium absorption).
T e primary active metabolite o vitamin D is 1,25-hydroxyvitamin D. T e
enzyme system responsible or the 1α-hydroxylation o 25-hydroxyvitamin D
(25-OHD) is located in the proximal tubules o the kidney.
Calcitonin is a hypocalcemic hormone produced and secreted by the thyroid
para ollicular C cells. T e actions o calcitonin generally oppose those o P H.
(Continued)
485
SECTION V Hormones and Hormone Antagonists
In women, loss o estrogen at menopause accelerates the rate o bone loss (see
Figures 31-2 and 31-3).
Patients with chronic renal disease are at risk or developing osteomalacia or
a complex bone disease called renal osteodystrophy.
Osteoporosis is a condition o low bone mass and microarchitectural disrup-
tion that results in ractures with minimal trauma.
Bisphosphonates are the most requently used drugs or the prevention and
treatment o osteoporosis.
Bisphosphonates are associated with severe untoward e ects such as esophageal
distress and osteonecrosis o the jaw.
eriparatide is a P H ragment used or the treatment o severe osteoporosis.
SUMMARY QUIZ
QUESTION 31-1 A 43-year-old man with intestinal bypass surgery is at risk o devel-
oping a de ciency o
a. vitamin D.
b. calcium.
c. phosphorous.
d. vitamin C.
e. parathyroid hormone.
QUESTION 31-3 Calcitonin is a hormone produced and secreted rom the thyroid
para ollicular C cells and is regulated by the serum concentration o
a. potassium.
b. calcium.
c. zinc.
d. iron.
e. sodium.
QUESTION 31-4 A 42-year-old man with lung cancer had a serum calcium measure-
ment 1 month ago that was 9.0 mg/dL. He is hospitalized now with severe muscle
weakness, atigue, anorexia, and constipation. His serum calcium is 13.5 mg/dL. T e
severity o his symptoms is due to the
a. rate o rise in his serum calcium.
b. decrease in the intestinal excretion o calcium.
c. malabsorption o vitamin D.
d. ormation o a parathyroid adenoma.
e. ingestion o large quantities o calcium.
486
Drug Therapy of Mineral Ion Homeostasis and Bone Turnover Disorders CHAPTER 3 1
QUESTION 31-5 Answer is e. Calcimimetics are drugs that mimic the stimulatory
e ect o calcium on the calcium-sensing receptor (CaSR) to inhibit P H secretion
by the parathyroid glands. T e principal adverse event with calcimimetics is
hypocalcemia.
487
SECTION V Hormones and Hormone Antagonists
Bisphosphonates Etidronate sodium Treatment o Paget disease Heartburn, esophageal Osteonecrosis o the jaw
Pamidronate Ibandronate is approved irritation esophagitis, Parenteral in usion o pamidronate
Tiludronate or the prevention and abdominal pain, may cause f ushing, f u-like
Alendronate treatment o postmenopausal and diarrhea symptoms, nausea and vomiting
Risedronate osteoporosis Zoledronate is capable o causing
Zoledronate Pamidronate and zoledronate severe hypocalcemia
Ibandronate are use ul in treating
hypercalcemia associated with
malignancy
488
SECTION
Drugs A ecting
Gastrointestinal Function VI
32. Pharmacotherapy o Gastric Acidity, Peptic Ulcers,
and Gastroesophageal Re ux Disease 490
489
CHAPTER
Pharmacotherapyo Gastric
32 Acidity, PepticUlcers, and
Gastroesophageal Ref uxDisease
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN
Chapter 45, Pharmacotherapy o Gastric Acidity, Peptic Ulcers, and Gastroesophageal
THIS CHAPTER Re ux Disease in Goodman & Gilman's T e Pharmacological Basis of T erapeutics, 12th
Cimetidine (TAGAMET,others) Edition In addition to the material presented here, the 12th Edition contains:
Dexlansoprazole (KAPIDEX) • A description o the physiology o gastric secretion
Esomeprazole (NEXIUM) • T erapeutic strategies or the treatment o speci c acid-peptic disorders
Famotidine (PEPSID, others) • able 45-2 which shows the composition and acid neutralizing capacities o popular
Lansoprazole (PREVACID) antacid preparations
Misoprostol (CYTOTEC)
LEARNING OBJECTIVES
Nizatidine (AXID, others)
Identi y the sites in the gastric parietal cell where drugs act to suppress acid
Omeprazole (PRILOSEC, others) secretion
Pantoprazole (PROTONIX) Describe the mechanism o action o proton pump inhibitors, H 2 receptor
Rabeprazole (ACIPHEX) antagonists, and prostaglandin analogs to suppress gastric acid secretion
Ranitidine (ZANTEC, others) Describe the limitations to the use o H 2 receptor antagonists in chronic acid
Sucralfate (CARAFATE, others) suppression
Identi y potential drug interactions with proton pump inhibitors and H 2 receptor
antagonists
Describe the mechanism o action o drugs that enhance gastric cytoprotection
Describe the recommendations or therapy o gastroesophageal re ux disease
(GERD) and peptic ulcer disease
Understand the role o Helicobacter pylori in ection in peptic ulcer disease and
the therapeutic principles or its eradication
Describe appropriate therapy or NSAID-induced ulcers
Proton Pump Lansoprazole The activated orm binds covalently with sul hydryl groups on cysteine in the H+,K+-ATPase
Inhibitors Pantoprazole located on the luminal membrane o the parietal cell to suppress acid secretion
Omeprazole (see Figure 32-1)
Esomeprazole
Dexlansoprazole
Rabeprazole
Prostaglandin Analog Misoprostol Binds to the EP3 receptor on parietal cells decreasing cyclic AMP and gastric acid secretion
(see Figure 32-1)
Cytoprotective Agent Sucral ate Forms a viscous, sticky polymer that adheres to epithelial cells and ulcer craters and is
cytoprotective
Bismuth Various OTC products Binds to the base o ulcers and promotes mucin and bicarbonate production
490
Pharmacotherapy of Gastric Acidity CHAPTER 3 2
Mus ca rinic
Gas trin a nta gonis ts
1 M3
K+ K+
ACh
Cl– Cl–
CCK2 H2
a nta gonis ts
CCK2 Ca 2 +-de pe nde nt
pa thway
K+
HIST HIST H2 H+, K+
cAMP-de pe nde nt Proton pump
ATPa s e inhibitors
M? ECL c e ll pa thway
NSAIDS H+ Anta cids
ACh EP 3
Parie tal c e ll
Bis muth
C 20 fa tty P GE 2
Me tronida zole
a cids P GI2
Mis opros tol H. pylori Te tra cycline
ENS Cla rithromycin
N ce ll Amoxicillin
Mus ca rinic
a nta gonis ts
M1 EP 3 Mucus
AC h S ucra lfa te
Cyto-
prote ction Ca rbe n-
oxolone
M?
2 P ire nze pine 3 ACh HCO 3 –
S upe rfic ial e pithe lial c e ll
FIGURE 32-1 Physiological and pharmacological regulation o gastric secretion: the basis or therapy o acid-peptic disorders. Shown are the
interactions among an enterochroma n-like (ECL) cell that secretes histamine, a ganglion cell o the enteric nervous system (ENS), a parietal
cell that secretes acid, and a super cial epithelial cell that secretes mucus and bicarbonate. Physiological pathways, shown in solid black, may
be stimulatory (+) or inhibitory (−). 1 and 3 indicate possible inputs rom postganglionic cholinergic bers; 2 shows neural input rom the vagus
nerve. Physiological agonists and their respective membrane receptors include acetylcholine (ACh), muscarinic (M), and nicotinic (N) receptors;
gastrin, cholecystokinin receptor 2 (CCK2); histamine (HIST), H2 receptor; and prostaglandin E2 (PGE2), EP3 receptor. A gray indicates targets o
pharmacological antagonism. A blue dashed arrow indicates a drug action that mimics or enhances a physiological pathway. Shown in gray are
drugs used to treat acid-peptic disorders. NSAIDs are nonsteroidal anti-in ammatory drugs, which can induce ulcers via inhibition o cyclooxy-
genase (see Chapter 22).
CASE 32-1
A 42-year-old woman is seen because o worsening heartburn during the past week She
was rst diagnosed with GERD 1 month ago and treatment was begun with cimetidine
400 mg once daily wo weeks later the cimetidine dosage was increased to 400 mg
twice daily
a. What is the reason or the worsening o her GERD symptoms?
Cimetidine is an H 2 receptor antagonist and tolerance to acid suppressing e ects o
these drugs has been shown to develop as early as 2 to 5 days a er beginning treat-
ment. One mechanism or this phenomenon is secondary to the hypergastrinemia
that stimulates histamine release and overcomes the H 2 receptor blockade.
b. What are the mechanisms o action o H2 receptor blockers and proton pump
inhibitors?
T e mechanisms o action o these drugs is shown in Figure 32-1. T e H 2 receptor
blockers suppress gastric acid secretion by competing with histamine or binding to
H 2 receptors on the basolateral membrane o parietal cells. T e structural similarity
o the H 2 receptor antagonists and histamine is shown in Figure 32-2.
(Continued)
491
SECTION VI Drugs Af ecting Gastrointestinal Function
CH2 CH2 NH2 T e proton pump inhibitors are prodrugs that require activation in an acid environ-
NH N
ment (see Figure 32-3). T e activated orm binds covalently with sul ydryl groups
on cysteine in the H+,K+-A Pase located on the luminal membrane o the parietal cell.
HISTAMINE Despite the short plasma hal -lives (0.5-2 h) o the parent drug, acid suppression
continues or 24 to 48 hours or until new pump molecules are synthesized.
c. What is a rational approach to her treatment?
H3 C CH2 S CH2 CH2 N CNHCH3
A rational choice would be to switch her to a proton pump inhibitor. Although these
HN HN C N drugs can also cause a hypergastrinemia, it does not result in tolerance because the
CIMETIDINE inhibition occurs at the H +,K+-A Pase which is the nal step in gastric acid secretion.
Figure 32-4 shows the general guidelines or medical management o GERD.
d. I the patient is switched to a proton pump inhibitor, o what adverse ef ects
CH2 S CH2 CH2 NHCNHCH3
should she be warned?
O CHNO 2 Proton pump inhibitors are metabolized by hepatic CYPs and they may inter ere
with the elimination o other drugs cleared by this route. Chronic treatment with
CH2 N(CH3 )2
proton pump inhibitors decreases the absorption o vitamin B12. T e loss o gastric
RANITIDINE acidity may a ect the bioavailability o drugs, most notably iron salts. T is may
result in an iron de ciency anemia.
CH2 S CH2 CH2 CNH2
CASE 32-3
A 64-year-old man is re erred because o stomach pain He has been diagnosed with
osteoarthritis and has been taking a COX-1 inhibitor or the past 3 months Workup
shows that he has a duodenal ulcer that you suspect is a result o his NSAID use
a. Describe the pathogenesis o NSAID-induced ulcers.
NSAIDs diminish prostaglandin ormation by inhibiting cyclooxygenase. T is e ect
can result in enhanced gastric acid secretion (prostaglandins may lower gastric acid
secretion). In addition, prostaglandins stimulate gastric mucin production that pro-
vides a cytoprotective e ect to the gastric mucosa which is diminished by NSAIDs.
b. What are your therapeutic options?
One option is to change this patient to an NSAID that is a selective inhibitor o
COX-2, although this may not completely eliminate the risk o ulcer ormation.
(Continued)
492
Pharmacotherapy of Gastric Acidity CHAPTER 3 2
N N N N
N S N S N S N S
O O O O
F 2 HCO
NH NH NH N
OCH3
LANS OP RAZOLE OMEPRAZOLE RABERP RAZOLE PANTOP RAZOLE
H+
OCH3
OCH3 OCH3
ENZYME-INHIBITOR COMPLEX
FIGURE 32-3 Proton pump inhibitors. A. Inhibitors o gastric H+,K+-ATPase (proton pump). B. Conversion o omeprazole to a
sul enamide in the acidic secretory canaliculi o the parietal cell. The sul enamide interacts covalently with sul hydryl groups in
the proton pump, thereby irreversibly inhibiting its activity. The other 3 proton pump inhibitors undergo analogous conversions.
Lansoprazole: 30 mg Famotidine: 20 mg
Esomeprazole: 40 mg
KEY CONCEPTS
Proton pump inhibitors are superior to H 2 receptor antagonists or acid
suppression in patients with GERD and peptic ulcers
olerance to the acid-suppressing e ects o the H 2 receptor antagonists is
commonly observed and limits their continuous use
H. pylori is e ectively eradicated with a combination o acid-suppressing drugs
and multiple antibiotics administered or 10 to 14 days
NSAID-induced ulcers can be e ectively treated with a proton pump inhibitor
even during continued NSAID administration
SUMMARY QUIZ
QUESTION 32-2 A 48-year-old man with a duodenal ulcer disease is treated with
cimetidine A er 6 weeks o treatment, he complains that his stomach pain is returning
and wonders i the dose o cimetidine should be increased T e most likely reason or
the decreased e ectiveness o cimetidine in this patient is
a tolerance
b diminished GI absorption
c enhanced plasma protein binding
d increased hepatic metabolism
e poor patient compliance
494
Pharmacotherapy of Gastric Acidity CHAPTER 3 2
QUESTION 32-3 Esomeprazole has a plasma hal -li e o a ew hours yet suppresses acid
secretion or 24 to 48 hours T e reason or this paradox is
a acid suppression continues until new H +,K+-A Pase molecules are synthesized
b gastrin depletion occurs long a er esomeprazole disappears rom the plasma
c prostaglandin synthesis is enhanced by esomeprazole
d H. pylori is e ectively suppressed by esomeprazole or 24 to 48 hours
e acid suppression continues until new H 2 receptors are synthesized
QUESTION 32-4 A 48-year-old woman has been diagnosed with a duodenal ulcer that
is complicated by H. pylori in ection A suitable therapeutic regimen or this patient
would be
a a single antibiotic
b a single antibiotic plus a proton pump inhibitor
c misoprostol plus a proton pump inhibitor
d an H 2 receptor antagonist
e 2 antibiotics plus a proton pump inhibitor
QUESTION 32-3 Answer is a. Proton pump inhibitors irreversible bind to the H +,K+-
A Pase and suppress acid secretion by the gastric parietal cell until new pump mol-
ecules are synthesized
QUESTION 32-5 Answer is d. Proton pump inhibitors are so e ective at the suppres-
sion o gastric acid secretion that the absorption o many substances that require an
acidic environment is a ected One o these substances is iron salts and the resulting
iron de ciency can be mani ested by a hypochromic, microcytic anemia T e absorption
o olic acid and vitamin B12 may also be decreased in the presence o acid-suppressing
drugs but a de ciency in these would not result in a hypochromic, microcytic anemia
(see AccessMedicine, Harrison's Principles of Internal Medicine, 18th Edition Online,
Chapter 57, Anemia and Polycythemia)
495
SECTION VI Drugs Af ecting Gastrointestinal Function
SUMMARY: DRUGS USED TO TREAT GASTRIC ACIDITY, PEPTIC ULCERS, AND GASTROESOPHAGEAL REFLUX DISEASE
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
H2 Receptor Cimetidine Promote healing o gastric Diarrhea, headache, drowsiness, Inhibition o hepatic CYPs
Antagonists Ranitidine and duodenal ulcers, atigue, muscular pain, and Delirium and con usion with
treatment o uncomplicated constipation IVuse in elderly patients
GERD, and to prevent Tolerance occurs with long-term use Gynecomastia in men
occurrence o stress ulcers Galactorrhea in women
Proton Pump Omeprazole Treatment o gastric and Nausea, atulence, abdominal pain, Metabolized by hepatic CYPs
Inhibitors Esomeprazole duodenal ulcers and GERD constipation and may af ect other drugs
Lansoprazole that are metabolized by
Pantoprazole hepatic CYPs
Rabeprazole Decreased absorption o olic
acid, vitamin B12, and iron salts
Cytoprotective Sucral ate Treatment o peptic ulcer Constipation Avoid in patients with renal
Agents disease ailure
May inhibit the absorption o
other drugs
Bismuth OTC products Treatment o peptic ulcer Black tongue and stools Bismuth subsalicylate is
particularly in patients with associated with salicylate
H. pylori in ection (see poisoning
Table 32-1)
Antacids Various OTC OTC or heartburn and See Goodman and Gilman's Gilman's The Decreased drug absorption by
products excess gastric acidity Pharmacological Basis of Therapeutics, increasing gastric pH
12th Edition, Chapter 45, or a
discussion o the common adverse
ef ects o the various antacids
496
CHAPTER
497
SECTION VI Drugs Af ecting Gastrointestinal Function
Rate Io n Co nc e ntratio ns
(lite rs /day) (mEq/lite r) Os mo lality
H2 O _ _
Flow Na + K+ Cl HCO 3
Upta ke
9.0 60 15 60 15 va ria ble
6.0
1.5
1.4
0.1 40 90 15 30 is otonic
FIGURE 33-1 The approximate volume and composition o uid that traverses the small and
large intestines daily. O the 9 L o uid typically presented to the small intestine each day, 2 L are
rom the diet and 7 L are rom secretions (salivary, gastric, pancreatic, and biliary). The absorptive
capacity o the colon is 4 to 5 L per day.
499
SECTION VI Drugs Af ecting Gastrointestinal Function
CASE 33-2
A 36-year-old woman presents with a 2-day history o diarrhea and abdominal pain
ollowing a weekend camping trip. She appears acutely ill and is dehydrated.
a. What are the issues to address in this particular patient?
T e presumptive diagnosis in this patient is giardiasis which has resulted rom the
ingestion o Giardia intestinalis in contaminated drinking water (see Chapter 36).
T e diagnosis is made by identi cation o cysts or trophozoites in ecal specimens
or trophozoites in duodenal contents. While waiting on a de nitive diagnosis,
treatment with an antimicrobial such as metronidazole can be started, and her
dehydration should be addressed.
b. What drugs might be used to treat her diarrhea?
An opioid that acts through peripheral opioid receptors such as loperamide or
diphenoxylate/atropine should be e ective in decreasing the diarrhea. Neither drug
should be used or a prolonged period o time.
(Continued)
Magnesium ↓ — ↑ ↑ ↑↑
Lactulose ↓ ? ? ? ↑↑
Metoclopramide ↓ ? ↑ ? —
Cisapride ↓ ? ↑ ? ↑
Erythromycin ↓ ? ? ? ?
Naloxone ↓ ↓ — — ↑
Anthraquinones ↓ ↓ ↑ ↑ ↑↑
Diphenylmethanes ↓ ↓ ↑ ↑ ↑↑
Docusates — ? ? ? —
Modi ed rom Kreek, M.J. Constipation syndromes. In, A Pharmacological Approach to Gastrointestinal Disorders. (Lewis, J.H., ed.) Williams &
Wilkins, Baltimore, 1994, pp. 179–208. With permission. http://lww.com.
500
Drugs Used or the Treatment o Bowel Disorders CHAPTER 3 3
CASE 33-3
A 57-year-old man comes to hospital or his rst cycle o chemotherapy or small cell
lung cancer.
a. What drug is a good choice or prophylactic antiemesis therapy or this patient?
Figure 33-2 shows the myriad o signaling pathways that are involved in the control
o emesis and shows that cytotoxic drugs stimulate 5-H 3 receptors in the GI system
and chemoreceptor trigger zone. able 33-3 is a general classi cation o antiemetic
agents and shows drugs that are e ective in treating cytotoxic drug-induced emesis.
Ondansetron is one o the 5-H 3 receptor antagonists that are e ective in this
setting. It should be administered intravenously 30 minutes be ore chemotherapy.
b. Is there any clinical situation in which the dose o ondansetron should
be altered?
Ondansetron is extensively metabolized in the liver by CYP1A2, CYP2D6, and
CYP3A4. Patients with hepatic dys unction have reduced plasma clearance and
some adjustment o the dosage is advisable.
(Continued)
Me mory, fe a r,
HIGHER
dre a d, a nd
CENTERS
a nticipa tion
(me dulla )
EMETIC CENTER S OLITARY TRACT
CEREBELLUM NUCLEUS
(5-HT3 , D2 , M, H1 , NK1 , CB 1 )
CNS (H1 , M)
(are a po s tre ma)
blood-bra in CHEMO-RECEPTOR
ba rrie r TRIGGER ZONE
(5-HT3 , D2 , M1 , CB 1 )
INNER EAR
PERIPHERY va ga l a nd
(motion)
sympa the tic
a minog lyc os id e s STOMACH a ffe re nts
S MALL INTESTINE
S ENS ORY INP UT (5-HT3 )
(pa in, s me ll, s ight)
glos s opha rynge a l
a nd trige mina l
BLOOD-BORNE EMETICS
a ffe re nts
cytotoxic d rug s
op ioid s
LOCAL IRRITANTS
c holinomime tic s
cytotoxic d rug s
ca rd ia c g lyc os id e s P HARYNX
CuS O 4
L-DOPA (ga gging)
ra d ia tion
b romoc rip tine
b a c te ria
a p omorp hine
virus e s
e me tine (ip e ca c )
FIGURE 33-2 Pharmacologist’s view o emetic stimuli. Myriad signaling pathways lead rom the periphery to the emetic center. Stimulants o
these pathways are noted in italics. These pathways involve speci c neurotransmitters and their receptors (bold type). Receptors are shown or
dopamine (D2), acetylcholine (muscarinic, M), histamine (H1), cannabinoids (CB1), substance P (NK1), and 5-hydroxytryptamine (5-HT3). Some o
these receptors also may mediate signaling in the emetic center.
501
SECTION VI Drugs Af ecting Gastrointestinal Function
CASE 33-4
A 42-year-old man with ulcerative colitis is having a are in symptoms with severe
abdominal pain and bloody diarrhea or the past 24 hours. He is being treated with sul-
asalazine but has not been compliant because o a persistent annoying rash.
a. What are options with his therapy?
T e rst option that should be considered is glucocorticoid therapy to rapidly alle-
viate his intestinal in ammation and curtail his diarrhea. I he is volume depleted,
this should also be addressed.
b. What are the side ef ects o sul asalazine therapy and what might be done to
increase this patient’s compliance?
Figure 33-3 shows the structures o sul asalazine and related agents. Since the side
e ects o sul asalazine are mostly related to the sul apyridine moiety, an option in
this patient would be to switch rom sul asalazine to a newer preparation such as
olsalazine or balsalazide which does not contain sul apyridine.
CASE 33-5
A 37-year-old man with ulcerative colitis has been treated in the past with azathioprine
but a er 6 months o therapy, there was no signi cant improvement in his symptoms.
a. How is azathioprine metabolized?
Figure 33-4 shows the metabolism o azathioprine. Azathioprine is a prodrug that
is converted to mercaptopurine. Mercaptopurine is metabolized by thiopurine
(Continued)
502
Drugs Used or the Treatment o Bowel Disorders CHAPTER 3 3
Bals alazide
COONa
O
Na OOCCH2 CH2 NH C N N OH
CASE 33-6
A 32-year-old woman with the diagnosis o Crohn’s disease initially had a good
response to glucocorticoid therapy with a one-year remission. However, despite
glucocorticoid therapy, she is now having requent ares o abdominal pain and
bloody diarrhea.
a. What options are available or her treatment o this relapse?
Patients who relapse requently may be treated with immunosuppressive agents such
as azathioprine-mercaptopurine. In iximab is an immunoglobulin that neutralizes
NFα and is particularly use ul in closing stulas associated with Crohn’s disease.
T e combination o in iximab and azathioprine is more e ective than in iximab
alone in induction o remission and mucosal healing in steroid-resistant patients.
(Continued)
503
SECTION VI Drugs Af ecting Gastrointestinal Function
b. How should this patient be monitored or the appearance o serious side ef ects?
T e most serious idiosyncratic reaction to azathioprine is pancreatitis. T e most
serious dose-related adverse reaction to azathioprine is bone marrow suppression.
Circulating blood counts should be monitored closely when azathioprine therapy
is initiated and at 3-month intervals during maintenance therapy. Antibodies to
in iximab can decrease its clinical ef cacy. In iximab is also associated with
increased incidence o respiratory in ections. O particular concern is reactivation
o tuberculosis or other granulomatous in ections with subsequent dissemination.
KEY CONCEPTS
Although many choices exist or treating constipation, most therapies are
empirical and nonspeci c.
Most cases o constipation can be addressed by increasing ber intake, avoiding
constipating medications, and the judicious use o osmotic laxatives on an
as-needed basis.
Stimulant laxatives, although e ective, should be avoided or long-term use.
I no underlying cause can be determined, chronic diarrhea can be treated
empirically with bulk- orming and hygroscopic agents ollowed by opiates such
as loperamide.
5-H 3 receptor antagonists, such as ondansetron, are primary therapy or nausea
and vomiting, especially in the postchemotherapy and postoperative settings.
T e cannabinoids, dronabinol or nabilone, may be e ective or re ractive cases
o nausea and vomiting.
Acute exacerbations o ulcerative colitis are treated with colonic-release
preparations o mesalamine (5-ASA) and glucocorticoids.
Maintenance therapy or patients with ulcerative colitis is with one o the
5-ASA compounds; in patients who relapse, azathioprine-mercaptopurine
may be used.
Monitoring the activity o PM and the metabolites o mercaptopurine may
provide personalized therapy with this drug.
Drugs used in mild to moderately active Crohn’s disease include sul asalazine,
budesonide, and oral corticosteroids.
In iximab and other biological agents are use ul in closing stulas associated
with Crohn’s disease, but their use in maintaining patients in remission must be
balanced against the risk o adverse e ects.
Antibiotics, particularly metronidazole, are used or the acute treatment o com-
plications associated with Crohn’s disease, but are not used as a routine therapy.
SUMMARY QUIZ
QUESTION 33-1 A 23-year-old woman with a history o type 1 diabetes since age
6 presents with nausea and vomiting associated with gastroparesis and delayed gastric
emptying. Which o the ollowing medications would be the most suitable treatment o
the nausea and vomiting in this patient?
a. Dephenoxylate
b. Metoclopramide
c. Ondansetron
d. Dronabinol
e. Loperamide
(Continued)
504
Drugs Used or the Treatment o Bowel Disorders CHAPTER 3 3
QUESTION 33-3 A 35-year-old woman has severe irritable bowel syndrome character-
ized by requent and pro use diarrhea. She is being treated with alosetron because she
has not responded to other orms o antidiarrheal therapy. T e physician treating this
patient must diligently monitor or
a. ischemic colitis.
b. congestive heart ailure.
c. drug-induced hepatitis.
d. renal ailure.
e. pulmonary brosis.
QUESTION 33-4 A 44-year-old man has been treated or chronic back pain with opioid
narcotics. He has been plagued with constipation that he has managed to treat by increas-
ing the ber in his diet. T is is no longer e ective. Which o the ollowing medications is
likely to be o bene t in this patient?
a. Naltrexone
b. Metoclopramide
c. Methylnaltrexone
d. Bisacodyl
e. Lactulose
QUESTION 33-5 A 53-year-old man with a long history o alcohol abuse and hepatic
cirrhosis is now developing hepatic encephalopathy. Which o the ollowing agents
may be most e ective in reducing the signs and symptoms o this patient’s hepatic
encephalopathy?
a. Loperamide
b. Bisacodyl
c. Glycerin
d. Docusate sodium
e. Lactulose
QUESTION 33-6 A 27-year-old woman with ulcerative colitis is being treated with
sul asalazine. She should be closely monitored or which o the ollowing common
adverse e ects with this drug?
a. Hearing loss
b. Skin rash
c. Blood in her urine
d. Heart arrhythmia
e. Onset o seizures
QUESTION 33-7 A 42-year-old woman with Crohn’s disease has been treated
with glucocorticoid therapy. During her initial high dose therapy, she responded
well and the dose was tapered over 3 months. However, she relapsed with severe
(Continued)
505
SECTION VI Drugs Af ecting Gastrointestinal Function
symptoms during the last month o her taper. T e reason or her relapse is most
likely because
a. her taper was too rapid.
b. she is glucocorticoid-responsive.
c. she is glucocorticoid-unresponsive.
d. she was noncompliant with her steroid therapy.
e. she is glucocorticoid-dependent.
QUESTION 33-8 A 56-year-old man with ulcerative colitis is being treated with azathi-
oprine. It is determined that his blood concentration ratio o 6-thioguanine/6-methyl-
mercaptopurine is lower than normal. T e most likely reason or this nding is that he
has increased activity o which o ollowing enzymes?
a. Xanthine oxidase
b. Hypoxanthine-guanine phosphoribosyl trans erase (HGPR )
c. Acetyl trans erase
d. T iopurine methyltrans erase ( PM )
e. Cytochrome P450 3A4
QUESTION 33-9 A 19-year-old woman with ulcerative colitis had to stop taking sul-
asalazine because o a skin rash. She is now taking olsalazine which is also converted
to 5-ASA but she has experienced no side e ects. T e most likely reason or the lack o
side e ects with olsalazine in this patient is because the olsalazine
a. is absorbed in the jejunum a er oral use.
b. does not contain a sul a moiety.
c. has a pH-sensitive release ormulation.
d. is given intravenously.
e. is given by enema.
QUESTION 33-6 Answer is b. Sul apyridine, the sul a moiety o sul asalazine (see
Figure 33-3), is responsible or most o its adverse reactions. Skin rash is a particu-
larly common reaction with sul a drugs and may be a harbinger o Stevens-Johnson
syndrome.
QUESTION 33-8 Answer is d. Patients who are rapid metabolizers with respect to
PM shunt mercaptopurine metabolism away rom 6-thioguanine nucleotides and
toward 6-MMP (see Figure 33-4 and Case 33-5).
QUESTION 33-9 Answer is b. Olsalazine does not contain a sul apyridine moiety
(see Figure 33-3).
Domperidone Gastroparesis
TOXICITIES
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Diphenoxylate Treatment o diarrhea Combined with low High doses cause CNS depression
combined with atropine dose o atropine to and anticholinergic e ects
Di enoxin combined prevent abuse
with atropine
Octreotide Treatment o hormone- Nausea and bloating Long-term treatment can lead
secreting tumors o the to gallstones and hypo- or
pancreas and GI tract hyperglycemia
508
Drugs Used or the Treatment o Bowel Disorders CHAPTER 3 3
TOXICITIES
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Agents to Treat Sul asalazine Treatment o IBD particularly Headache, nausea, Rash, bone marrow suppression,
In ammatory Bowel ulcerative colitis atigue Stevens-Johnson syndrome,
Disease (IBD) hepatitis, pneumonia: All due to
sul a moiety
Mesalamine (5-ASA) Treatment o IBD particularly Headache, Has been associated with
ulcerative colitis dyspepsia, skin rash interstitial nephritis; renal unction
should be monitored in all
patients
509
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SECTION
Chemotherapyof
Microbial Diseases VII
34. General Principles o Antimicrobial T erapy 512
511
CHAPTER
34 General Principles of
Antimicrobial Therapy
T is chapter will be most use ul a er having a basic understanding o the material in
CLASSIFICATION OF
Chapter 48, General Principles o Antimicrobial T erapy in Goodman & Gilman’s T e
ANTIMICROBIAL AGENTS Pharmacological Basis of T erapeutics, 12th Edition Neither Mechanisms o Action nor
• The rst broad classi cation o antimicro- Clinical Summary ables are included in this chapter because this in ormation is pro-
bial agents is according to the microorgan- vided in subsequent chapters
isms theyare active against: antibacterial,
In addition to the material presented here, Chapter 48 o the 12th Edition contains:
antiviral, anti ungal, antiparasitic.
• A detailed discussion o the pharmacokinetic basis or antimicrobial therapy
• Further classi cation o an antibioticis
based on: • A thorough discussion o the types and goals o antimicrobial therapy
The class and spectrumo the
LEARNING OBJECTIVES
»
microorganisms it kills
Describe the pharmacokinetic basis o antimicrobial therapy
» The biochemical pathwayit inter eres
with Identi y the importance o susceptibility testing o antimicrobial agents
» The chemical structure o its Identi y the actors that orm the basis or selection o an antimicrobial dose
pharmacophore (the chemical moiety and dosing schedule
o the drug that binds to a microbial Describe the types and goals o antimicrobial therapy
receptor)
Identi y the mechanisms o resistance to antimicrobial agents
8
)
l
m
/
U
F
6
C
10
E ma x
g
o
l
(
4
n
e
d
r
u
b
m
2 EC 50
s
i
n
a
g
r
O
0
0
[Antimicrobia l]
FIGURE 34-1 Inhibitory sigmoid Emax curve. CFU, colony orming units.
CASE 34-2
A 62-year-old man with chronic obstructive pulmonary disease develops a pumonary
in ection that rapidly becomes a systemic bacteremia requiring antibiotic therapy T e
microorganism has been isolated and susceptibility testing has been completed T e
minimum inhibitor concentration (MIC) is 0 5 mg/L and the serum t½ o the antibiotic
is 3 hours
a. In choosing a drug and dose regimen that will be most e ecitve in this patient
what must be considered?
T e microbiology laboratory plays a central role in the decision to choose a par-
ticular antimicrobial agent over others. T eir rst unction is the identi cation and
isolation o the pathogenic organism. Once this is accomplished, the rational choice
o the class o antibiotics to administer to the patient can be made. T en the labora-
tory per orms susceptibility testing to narrow down the list o possible antimicro-
bials that could be used. Susceptibility testing or bacteria employs antibiotics in
serially diluted concentrations o solid agar or in broth medium that contains a cul-
ture o the test microorganism. T e lowest concentration o the agent that prevents
visible growth a er 18 to 24 hours o incubation is known as the MIC.
In choosing a dose regimen, the rst consideration is to index drug exposure to
the MIC. Second, dose itsel is a poor measure o drug exposure, given between-
patient and within-patient pharmacokinetic variability. T e optimal dose o the
antibiotic or a patient is the dose that achieves inhibitory concentration (IC) o
IC80 to IC90 exposures at the site o in ection. A third consideration is that optimal
microbial kill by the antibiotic may be best achieved by optimizing certain shapes
(Continued)
513
SECTION VII Chemotherapy of Microbial Diseases
o the concentration-time curve (see answer to Case 34-2b below). Last, changes in
susceptibility to drug (ie, drug-resistance) can occur during therapy. T e change in
drug susceptibility o an organism is depicted in Figure 34-2. A shi to the right o
the antimicrobial concentration versus response curve, that is, an increase in the
IC50 (see Figure 34-2A), means that much higher concentrations are now needed to
show a speci c response to the drug and re ects increasing resistance to a particu-
lar antibiotic. A second possible change in the curve is a decrease in Emax (see Fig-
ure 34-2B), such that increasing the dose o the antibiotic beyond a certain point
will achieve no urther e ect. T is occurs because the available microbial target
proteins have been reduced or the microbe has developed an alternative pathway
to overcome the biochemical inhibition.
b. How does the dose administration schedule (once daily or 3 divided doses) a ect
the drug concentration-time pro le?
Figure 34-3A depicts the concentration-time curve o an antibiotic in which the
peak concentration (CPmax), area under the curve (AUC), and the raction o the
dosing interval ( ) or which the drug concentration remains above the MIC
( > MIC) are shown. Figure 34-3B shows concentration-time curves when the
same dose o the antibiotic is given as 3 equal doses administered at 0, 8, and
16 hours. T e AUC0-24 will be similar whether the dose was given once a day or
3 times a day. T us, or the same pathogen, the change in dose schedule does not
change the AUC0-24/MIC. However, the CPmax will decrease by a third when the total
dose is split into 3 doses and administered more requently (see Figure 34-3B). In
addition, the time that the drug concentration persists above MIC ( > MIC) is
slightly increased with the more requent dosing schedule.
(Continued)
A 100
80
60
e
s
n
o
p
s
40
e
R
20
B 100
80
60
e
s
n
o
p
E ma x
s
40
e
R
20
0
0 100
[Antimicrobia l]
FIGURE 34-2 Changes in sigmoid Emax model with increases in drug resistance. Increase in
resistance may show changes in IC50 (panel A: the IC50 increases rom 70 [gray line] to 100 [black
line], to 140 [blue line]) or decrease in Emax (panel B: e cacy decreases rom ull response [gray line]
to 70% [black line]).
514
General Principles of Antimicrobial Therapy CHAPTER 3 4
FIGURE 34-3 Ef ect o dif erent dose schedules on shape o concentration-time curve. The
total AUC or the ractionated dose in curve B is determined by adding AUC0-8h, AUC8-16h, and
AUC 16-24h, which adds up to the same AUC0-24h in curve A. The time concentration exceeds MIC
is also determined by adding up T1>MIC, T2>MIC, and T3>MIC, which results in a raction greater
than that or curve A.
515
SECTION VII Chemotherapy of Microbial Diseases
CASE 34-4
A 59-year-old transient man comes to the emergency department with ever and di -
culty breathing He is diagnosed with pneumonia and a er blood and sputum cultures
are obtained he is started on a β-lactam antibiotic T e next day his cultures show that
the pathogen is resistant to the β-lactam antibiotic and he is switched to a combination
o a uoroquinolone and an aminoglycoside
(Continued)
FIGURE 34-4 Antimicrobial therapy-disease progression timeline. Stages o disease progression are
below the horizontal arrow; categories o antimicrobial therapy are above the arrow.
516
General Principles of Antimicrobial Therapy CHAPTER 3 4
517
SECTION VII Chemotherapy of Microbial Diseases
CASE 34-5
A 35-year-old patient with HIV in ection is started on 3 drugs in combination
a. What are the problems o using combination therapy?
Using multiple antimicrobial agents where only one is required leads to increased
toxicity and unnecessary damage to the patient’s otherwise protective ungal and
bacterial ora.
b. Why is this patient started on 3 drugs?
T ere are special circumstances where evidence is unequivocal in avor o com-
bination therapy. T ese are listed in the Side Bar SPECIAL CIRCUMS ANCES
HA FAVOR COMBINA ION AN IMICROBIAL HERAPY. Clinical situations
or which combination therapy is used are discussed in the relevant chapters but
include antiretroviral therapy or AIDS (see Chapter 44), antiviral therapy or hepa-
titis B and C (see Chapter 44), and the treatment o tuberculosis (see Chapter 42).
KEY CONCEPTS
Antimicrobial agents should be viewed as ligands whose receptors are microbial
proteins
Knowledge o an antibiotic’s pharmacokinetic variability (due to such actors as
genetics, age, weight, disease status) leads to better dose adjustments
Proper interpretation o microbial susceptibility testing (minimum inhibitory
concentration, MIC) is the rst step in the selection o an antibiotic dose and
dosing schedule
Maximizing the antibiotic concentration-time curve by selection o the proper
dosing schedule is critical to obtaining optimal microbial kill
Monotherapy o antibiotics is pre erred in order to limit the risk o toxicity and
the emergence o resistance; however, there are circumstances that avor combi-
nation antibiotic therapy
Resistance to antibiotics develops when there is acquisition o genetic elements
that code or one o several resistance mechanisms, or when mutations develop
under antibiotic pressure, or under constitutive induction
Mutations that result in drug resistance are not caused by drug exposure per
se, rather they are random events that con er a survival advantage when drug is
present
SUMMARY QUIZ
518
General Principles of Antimicrobial Therapy CHAPTER 3 4
QUESTION 34-2 ypically the time when the antibiotic concentration is greater than
the MIC is less with once-daily dosing than i the antibiotic were administered in
3 equally divided doses However, aminoglycoside antibiotics are commonly administered
once daily T e e cacy o once-daily dosing o aminoglycosides is due to
a decreased toxicity
b increased renal excretion at higher doses
c less bacterial resistance to the antibiotic
d postantibiotic e ect
e the rate o increase in the initial plasma concentration
QUESTION 34-4 A 35-year-old patient with HIV in ection is being started on 3 drugs
in combination T e primary reason he is started on 3 drugs rather than 1 is
a the drugs only come in combinations o 3
b the potential or reducing toxicity
c preventing resistance to monotherapy
d enhanced antiviral e ect o each drug
e a decrease in urinary excretion o each drug
QUESTION 34-4 Answer is c. It is standard o care to start patients with HIV in ection
on a regimen o 3 drugs primarily to prevent the development o resistant virus (see
Chapter 44)
519
CHAPTER
35 Chemotherapyof Malaria
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN Chapter 49, Chemotherapy o Malaria in Goodman & Gilman’s T e Pharmacological
THIS CHAPTER Basis of T erapeutics, 12th Edition. In addition to the material presented here, Chapter 49 in
Artemisinin and Artemisinin—combination the 12th Edition contains:
therapies • ables 49-2, 49-3, and 49-4 which provide in ormation about appropriate regimens,
Atovaquone/Proguanil (MALARONE) including adult and pediatric dosages, or the prevention, treatment, and presumptive
Chloroquine (ARALEN) sel -treatment o malaria
Doxycycline—see Chapter 41 • Figure 49-4 which is an algorithm approach to the treatment o malaria
Hydroxychloroquine (PLAQUENIL) LEARNING OBJECTIVES
Mefoquine (LARIUM)
Know the stages o the malaria parasite in the human body.
Primaquine
Classi y antimalarial drugs into those that are e ective against only the blood
Pyrimethamine (DARAPRIM) stages o the parasite, those that are e ective against both the blood and liver
Quinine/Quinidine stages, and those that are e ective against only the liver stages o the parasite.
Sul adoxine/Pyrimethamine (FANSIDAR) Understand the use o antimalarial drugs in clinical context, particularly with
regard to their mechanism o action, therapeutic uses, and toxicities.
Describe the principles and guidelines or the chemoprophylaxis and treatment
o malaria.
520
Chemotherapy of Malaria CHAPTER 3 5
CASE 35 1
A 43-year-old woman develops the signs and symptoms o uncomplicated malaria
caused by Plasmodium falciparum. Her symptoms include ever, chills, malaise, and
headache. A microscopic examination o a blood smear con rms the diagnosis. She is
treated with the combination therapy artemether-lume antrine.
a. Why is she treated with the combination product rather than either artemether
or lume antrine alone?
Artemether-lume antrine is one o several artemisinin-based combination
therapies (AC s). T e artemisinins are very potent and ast-acting antimalarials.
However, the emergence o P. falciparum isolates with an increased tolerance
to artemisinins has recently been ound. T e primary goal o these combina-
tion products is to increase treatment e cacy and reduce selection pressure
or the emergence o drug resistance. T e short t ½ o the artemisinins results in
substantial treatment ailure rates when artemisinins are used as monotherapy.
Combining an artemisinin with a longer-lasting partner drug assures sustained
antimalarial activity.
b. What are the pharmacokinetic properties o lume antrine that make it a good
choice in combination with artemether?
Artemisinins rapidly achieve peak serum concentrations; intramuscular artemether
peaks at 2 to 6 hours, due to a depot e ect at the injection site. Lume antrine has a
large apparent volume o distribution and a terminal elimination t½ o 4 to 5 days.
Administration with a high- at meal is recommended because it signi cantly
increases lume antrine absorption. T e advantages and disadvantages o the other
combination drugs are discussed in detail in Chapter 49 in Goodman and Gilman’s
T e Pharmacological Basis of T erapeutics, 12th Edition.
CASE 35 2
A 23-year-old emale college student is planning a trip to an area o A rica that is endemic
or chloroquine-resistant P. falciparum. She has been advised to take atovaquone-
proguanil or chemoprophylaxis.
a. When should the drug be started?
Chemoprophylaxis or malaria should begin be ore exposure and pre erably be ore
the traveler leaves home. T is is to establish therapeutic blood concentrations
and to detect early signs or symptoms o intolerance so that the regimen can be
(Continued)
521
SECTION VII Chemotherapy of Microbial Diseases
modi ed be ore departing. T e regimen should be taken daily while in the malari-
ous area and or 7 days a er leaving the area. (see able 35-1 below and able 49-2
in Goodman and Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition
or detailed chemoprophylactic regimens.)
b. What side e ects might this patient expect?
T is combination is generally considered sa e with no serious side e ects. T e most
common side e ects are nausea, vomiting, diarrhea, and headache.
c. Why is the combination atovaquone-proguanil used rather than either drug alone?
Resistance to atovaquone when used alone occurs easily. T e addition o proguanil
markedly reduces the requency o atovaquone resistance. However, once atovaquone
resistance is present the e ect o adding the proguanil diminishes.
d. How do the mechanisms o atovaquone and proguanil work synergistically?
Atovaquone acts selectively on the mitochondrial cytochrome bc1 complex to
inhibit electron transport and collapse the mitochondrial membrane potential.
T e antimalarial activity o proguanil is ascribed to cycloguanil (structurally
similar to pyrimethamine), a selective inhibitor o the bi unctional plasmodial
dihydro olate reductase-thymidylate synthetase that is crucial or parasite purine
and pyrimidine synthesis. Inhibition o this enzyme causes inhibition o DNA
synthesis and depletion o olate co actors. T e synergy between proguanil and
atovaquone results rom the ability o proguanil to enhance the mitochondrial
toxicity o atovaquone.
TABLE 35-1 Regimens for the Prevention of Malaria in Nonimmune Individuals (For complete details see Table 49-2 in
Goodman &Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition, Chapter 49)
DRUG USAGE COMMENTS
Atovaquone/Proguanil Prophylaxis in all areas Begin 1-2 days be ore travel to malarious areas; take daily at the
same time each day while in the malarious area and or 7 days a ter
leaving such area
Chloroquine Phosphate Prophylaxis only in areas with Begin 1-2 weeks be ore travel to malarious areas; take weekly
chloroquine-sensitive malaria on the same day o the week while in the malarious area and or
4 weeks a ter leaving such area
Doxycycline Prophylaxis in all areas Begin 1-2 days be ore travel to malarious areas; take daily at the
same time each day while in the malarious area and or 4 weeks
a ter leaving such area
Hydroxychloroquine Sul ate Alternative to chloroquine or prophylaxis Begin 1-2 weeks be ore travel to malarious areas; take weekly
only in areas with chloroquine-sensitive on the same day o the week while in the malarious area and or
malaria 4 weeks a ter leaving such area
Mef oquine Prophylaxis in areas with mef oquine- Begin 1-2 weeks be ore travel to malarious areas; take weekly
sensitive malaria on the same day o the week while in the malarious area and or
4 weeks a ter leaving such area
Primaquine Prophylaxis or short duration travel to Begin 1-2 days be ore travel to malarious areas; take daily at the
areas principally with Plasmodium vivax same time each day while in the malarious area and or 7 days a ter
leaving such area
For presumptive antirelapse therapy Indicated or persons with prolonged exposure to P. vivax and
(terminal prophylaxis) to decrease the risk P. ovale or both
o relapse (P. vivax, Plasmodium ovale)
Source: From the United States Centers or Disease Control and Prevention, Health In ormation or International Travel 2010 (Yellow Book).
http://wwwnc.cdc.gov/travel/content/yellowbook/home-2010.aspx. Accessed January 12, 2010.
522
Chemotherapy of Malaria CHAPTER 3 5
CASE 35 3
A 28-year-old emale university student in urkey contracts uncomplicated malaria
with symptoms o ever, chills, malaise, myalgia, and headache. T e director o the
clinic in which you work wants to treat her with chloroquine.
a. Is chloroquine an appropriate drug to treat uncomplicated malaria in the
country o Turkey?
Chloroquine is highly e ective against the erythrocytic orms o Plasmodium
ovale, Plasmodium vivax, Plasmodium malariae, Plasmodium knowlesi, and chlo-
roquine-sensitive strains o Plasmodium falciparum. urkey is a country in which
(Continued)
Ita ly Arme nia Uzbe kis ta n
Ge orgia Aze rba ija n Turkme nis ta n
Fra nce Mongolia
Gre e ce
S pa in Kyrgyzs ta n North
Turkey Afgha nis ta n Kore a
Portuga l
Tunis ia Cyprus Syria Ne pa l China
Morocco Is ra e l Ira q Ira n Ja pa n
Bhuta n
S outh
Alge ria Libya J orda n Kuwa it Kore a
We s te rn Egypt
Sa ha ra Qa ta r Mya nma r
Sa udi India Ta iwa n
Ma urita nia Ara bia UAE Ma ca u
Ma li Nige r Pa kis ta n
S e ne ga l Oma n La os
Ba ngla de s h P hilippine s
Cha d S uda n
The Ga mbia Eritre a Ye me n Tha ila nd
Guine a - Nige ria
Bis s a u Be nin Djibouti Vie tna m Pa cific Is la nds
CAR Ethiopia
Guine a Ma lays ia (Pa la u)
Togo S oma lia
S ie rra Le one Gha na DROC S ri La nka
Libe ria Ke nya Pa pua Ne w Guine a
Ca me roon Rwa nda
Burkina Fa s o Equa toria l Uga nda S inga pore Indone s ia
Burundi S olomon Is la nds
^ Guine a Ta nza nia
Cote d'Ivoire
Ga bon Ma lawi
Angola Va nua tu
Congo Moza mbique
Za mbia Fiji
Na mibia Ma da ga s ca r
Aus tra lia Ne w Ca le donia
Botswa na Zimba bwe
S outh Swa zila nd
Africa Le s otho
New Ze a la nd
Dominica n
Mexico Re public
Be lize
Ha iti
Hondura s
Gua te ma la
Guya na
El Sa lva dor S urina me
Ve ne zue la
Nica ra gua Fre nch
Pa na ma Colombia Guia na
Cos ta Rica
Ecua dor
Ga la pa gos
Is la nds
Pe ru Bra zil
Bolivia
Pa ra guay
Chile
KEY
Ma la ria -Ende mic Are a s
Chloroquine -re s is ta nt Arge ntina Uruguay
Chloroquine -s e ns itive
None
Fa lkla nd
Is la nds
FIGURE 35-1 Malaria-endemic countries in the Americas (bottom) and in A rica, the Middle East, Asia, and the South Paci c (top), 2007. CAR,
Central A rican Republic; DCOR, Democratic Republic o the Congo; UAE, United Arab Emirates. (Reproduced with permission from Anthony S. Fauci,
Eugene Braunwald, Dennis LKasper, et al, Eds. Harrison’s Principles of Internal Medicine, 17 ed. McGraw-Hill, Inc., New York, 2008. Figure 203-2, p. 1282.)
523
SECTION VII Chemotherapy of Microbial Diseases
CASE 35 4
A 34-year-old man has developed uncomplicated malaria in an area that is known to
have chloroquine-resistant P. falciparum (see Figure 35-1) and is being treated with
quinine plus doxycycline.
a. What are the common toxicities o quinine that should be watched or in this
patient?
Quinine has a triad o dose-related toxicities: cinchonism, hypoglycemia, and hypo-
tension. Cinchonism consists o tinnitus, high-tone dea ness, visual disturbances,
headache, dysphoria, nausea, vomiting, and postural hypotension. T ese e ects
disappear soon a er the drug is withdrawn. Hypoglycemia is also common and can
be li e-threatening i not treated promptly with intravenous glucose.
b. What are the more severe and rare toxicities and precautions o quinine use?
Quinine rarely causes cardiac complications (ie, arrhythmias) unless therapeutic
plasma concentrations are exceeded. Severe hemolysis can result rom hypersensitivity
to quinine and therapy should be discontinued immediately i evidence o hemolysis
appears. Quinine should be avoided in patients with tinnitus or optic neuritis and in
patients with cardiac arrhythmias, the same precautions as or quinidine (see Chapter
29 in Goodman and Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition).
c. What are other therapeutic options?
Other possible choices or treatment o P. falciparum malaria in a chloroquine-resistant
area are artemether-lume antrine, atovaquone-proguanil, clindamycin (used in
combination with quinine or quinidine), or mef oquine (except in Southeast Asia).
CASE 35 5
A 34-year-old-man in Cambodia has been treated with me oquine or severe malaria.
He returns to the clinic because his symptoms have not subsided.
a. What is a major limitation to the use o mef oquine in Southeast Asia?
Mef oquine is reserved or the prevention and treatment o drug-resistant P. falciparum
and P. vivax, but is no longer considered rst-line treatment. In areas where malaria
is due to multiple drug-resistant strains o P. falciparum, such as Southeast Asia,
mef oquine is used in combination with an artemisinin compound.
(Continued)
524
Chemotherapy of Malaria CHAPTER 3 5
CASE 35 6
A 46-year-old man with a primary hepatic stage o P. falciparum is treated with
primaquine.
a. Why was primaquine chosen and what are its major therapeutic uses?
Figure 35-2 shows the li e cycle o malaria parasites and able 35-2 shows the
malarial parasite developmental stages targeted by antimalarial drugs. Primaquine
acts against primary and latent hepatic stages o Plasmodium spp. and prevents
relapses in P. vivax and P. ovale in ections. Primaquine is used primarily or the
(Continued)
Bite from
infe cte d
mos quito
Infe cte d
mos quito
Uninfe cte d
Prima ry a ttack Re la ps e (due to P. viva x or P. ova le ) mos quito
Erythrocytic
s ta ge of infe ction
ERYTHROCYTIC
CYCLE
S chizonts Me rozoite s
Chloroquine – – – + +/–
Mef oquine – – – + –
Quinine/Quinidine – – – + +/–
Pyrimethamine – – – + –
Sul adoxine – – – + –
Tetracycline – – – + –
2 Atovaquone/ – + – + +/–
Proguanil
3 Primaquine – + + – +
CASE 35 7
T e student in Case 35-3 asks your general advice regarding malaria therapy.
a. What is your advice to her (beside what you told her in Case 35-3) regarding
chemoprophylaxis or malaria?
Regimens or malaria chemoprophylaxis include primarily 3 drugs: atovaquone-
proguanil and doxycycline that can both be used in all areas, and mef oquine
that can be used in areas with mef oquine-sensitive malaria. Other options
include chloroquine or hydroxychloroquine in the ew areas with chloroquine-
sensitive malaria, and primaquine or short duration travel to areas with
principally P. vivax.
b. She also asks or advice about treatment should she contract malaria.
For uncomplicated malaria, chloroquine is the drug o choice or P. ovale, P. knowlesi,
P. malariae, and chloroquine-sensitive strains o P. vivax and P. falciparum. Primaquine
(Continued)
526
Chemotherapy of Malaria CHAPTER 3 5
must not be given to patients with G6PD de ciency. For uncomplicated malaria caused
by chloroquine-resistant P. falciparum, 4 treatment options are available:
• Artemether-lume antrine
• Atovaquone-proguanil
• Oral quinine with other e ective but slower-acting blood schizonticides such as
doxycycline or clindamycin
• Mef oquine
For the treatment o severe malaria, no matter the region where the in ection was
acquired, the recommended treatments are based on intravenous artesunate or
quinidine plus a second drug.
c. She is also concerned about getting pregnant during her stay in Turkey and asks
i there is a recommended treatment or malaria in pregnant patients?
Chemoprophylaxis during pregnancy is complex, and women should evaluate with
expert medical sta the bene ts and risks o di erent strategies. Severe malaria
during pregnancy should be treated with intravenous antimalarial treatment
according to the general guidelines, taking into account the drugs that should be
avoided during pregnancy such as primaquine, mef oquine, and tetracycline.
KEY CONCEPTS
P. falciparum has become progressively more resistant to antimalarial drugs.
E ective chemoprophylaxis regimens include atovaquone-proguanil, doxycycline,
or me oquine.
Chemoprophylaxis should be started be ore exposure, ideally be ore the traveler
leaves home, and continued a er returning rom a malarious region.
First-line therapy or uncomplicated malaria is artemether-lume antrine.
First-line therapy or severe malaria is IV artesunate ollowed by atovaquone-
proguanil, doxycycline, or me oquine.
Primaquine and me oquine should not be used in pregnant women and prima-
quine should not be used in patients with G6PD de ciency.
SUMMARY QUIZ
QUESTION 35-1 A physician is planning to treat a 27-year-old woman with primaquine
or a documented P. vivax in ection. Prior to beginning treatment the physician must
test the patient or
a. elevated serum amylase.
b. glucose-6-phosphate dehydrogenase de ciency.
c. iron de ciency.
d. elevated serum calcium.
e. vitamin B12 de ciency.
527
SECTION VII Chemotherapy of Microbial Diseases
528
Chemotherapy of Malaria CHAPTER 3 5
Atovaquone MEPRONE Rarely used by itsel Resistance i used Nausea, vomiting, diarrhea, May compete with
alone and headache other drugs or plasma
protein binding
Ri ampin and tetracycline
reduce plasma
concentrations
Proguanil Rarely used by itsel Resistance develops Nausea and diarrhea Polymorphism in
i used alone CYP2C amily may alter
metabolism
Atovaquone- MALARONE Prophylaxis and Resistance to Nausea, vomiting, Not indicated or use in
Proguanil treatment o drug- the combination abdominal pain, mild pregnant women due
resistant strains o is uncommon reversible elevations in to limited data
P. falciparum or unless strain is liver transaminases
P. vivax initially resistant to
atovaquone
Chloroquine ARALEN Used to treat P. ovale, Resistance o Well tolerated in Not to be used in
P. vivax, P. malariae, P. falciparum is therapeutic doses patients with epilepsy or
P. knowlesi, and extensive myasthenia gravis
chloroquine-sensitive Hemolysis in patients
P. falciparum with G6PD de ciency
529
CHAPTER
ChemotherapyofProtozoalInfections:
36 Amebiasis, Giardiasis, Trichomoniasis,
Trypanosomiasis, Leishmaniasis, and
Other Protozoal Infections
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN
Chapter 50, Chemotherapy o Protozoal In ections in Goodman & Gilman’s T e
THIS CHAPTER Pharmacological Basis of T erapeutics, 12th Edition. In addition to the material
Amphotericin B(see Chapter 43) presented here, the 12th Edition contains:
Efornithine (ORNIDYL) • A detailed discussion o protozoal in ections, including amebiasis, giardiasis, toxoplas-
Fumagillin (FUMIDIL) mosis, trichomoniasis, cryptosporidiosis, trypanosomiasis, leishmaniasis, babesiosis,
balantidiasis, Isospora belli, and microsporidia
8-Hydroxyquinolines (iodoquinol; YODOXIN)
Melarsoprol LEARNING OBJECTIVES
Metronidazole (FLAGYL) Understand the most common protozoal in ections, the clinical symptoms,
Milte osine (IMPAVIDO) and the mainstays o therapy.
Nitazoxanide (ALINA) Describe the mechanisms o action o antiprotozoal drugs.
Ni urtimox(LAMPIT) Understand the treatment o giardiasis, amebiasis, and cryptosporidiosis.
Benznidazole (ROCHAGAN) Identi y the therapeutic uses o antiprotozoal drugs.
Paromomycin Describe the toxicities and precautions to the use o antiprotozoal drugs.
Pentamidine
Sodiumstibogluconate
MECHANISMS OF ACTION AND RESISTANCE OF ANTI-PROTOZOAL DRUGS
Suramin
DRUG MECHANISM OF ACTION MECHANISM OF RESISTANCE
Amphotericin Binds ergosterol in protozoal membranes No signi cant protozoal
to orm pores and increase membrane resistance
PROTOZOAL INFECTIONS permeability
DISCUSSED IN E ornithine Inhibition o ornithine decarboxylase Mutations in ornithine
THIS CHAPTER decarboxylase
Amebiasis Fumagillin Inhibition o methionine-aminopeptidase-2
Giardiasis
Melarsoprol Inhibition o many enzymes Mutations in drug transporters
Cryptosporidiosis
Metronidazole Forms highly reactive nitro radical Impaired O2 scavenging
anion that targets DNA and other vital capabilities leading to higher local
biomolecules O2 concentrations and decreased
Inter eres with the pyruvate: erredoxin activation o metronidazole
oxidoreductase (PFOR) enzyme-dependent Also mutations in nitroreductase
electron-trans er reaction, which is essential
to anaerobic metabolism in protozoan
and bacterial species
530
Chemotherapy of Protozoal Infections CHAPTER 3 6
CASE 36-1
A 35-year-old woman comes into your o ce complaining o diarrhea and abdominal
pain or the past 3 days. She has recently returned rom a white-water ra ing trip. On
the trip she ell out o the boat and although she had a li e preserver on, she believes
that she swallowed considerable amounts o river water.
a. You suspect giardiasis and want to begin treatment a er obtaining appropriate
specimens. What is giardiasis?
Giardiasis is caused by the protozoan Giardia intestinalis, is prevalent world-
wide, and is the most common intestinal protozoal in ection in the United
States. Giardia is a zoonosis and cysts shed in the eces o animals and humans
can contaminate recreational and drinking water supplies. In ection with
Giardia results in an asymptomatic carrier state, acute sel -limited diarrhea,
or chronic diarrhea.
b. How is the diagnosis o giardiasis made?
T e diagnosis o giardiasis is made by identi cation o cysts or trophozoites in ecal
specimens or o trophozoites in duodenal contents.
(Continued)
531
SECTION VII Chemotherapy of Microbial Diseases
c. A er instructing your patient in how to collect ecal specimens, what is the most
COMMON ROUTES
appropriate therapy to limit the acute diarrhea, to prevent the development o
OF TOXOPLASMOSIS
chronic diarrhea, and to prevent the development o a “carrier state”?
INFECTION IN HUMANS
Chemotherapy with a 5-day course o metronidazole or a single dose o tinidazole
• Ingestion o undercooked meat is usually success ul. Paromomycin has been used to treat pregnant women to avoid
containing cysts any possible mutagenic e ects o the other drugs.
• Ingestion o vegetables contami-
d. What are the potential side e ects o metronidazole therapy which this patient
nated with soil containing cysts
should be in ormed about?
• Direct oral contact with eces o
T e most common side e ects o metronidazole are headache, nausea, dry mouth,
cats shedding cysts
vomiting, and diarrhea, and are rarely severe enough to discontinue therapy. More
• ransplacental etal in ection severe neuropathies may include dizziness, vertigo, and rarely encephalopathy,
with tachyzoites rom acutely seizures, incoordination, ataxia, and numbness or paresthesias o the extremities;
in ected mothers these neuropathies warrant discontinuation o metronidazole.
Metronidazole has a well-documented disul ram-like e ect (see Chapter 9) and
patients should be warned not to drink alcoholic beverages during or within 3 days
o therapy.
CASE 36-2
A 10-year-old boy is brought into the emergency department with a 2-day history o
severe diarrhea. T e child is otherwise well with no chronic diseases but appears dehy-
drated and lethargic. It is summer and the child has been swimming in the public pool
every day or the past week.
a. What organism is most likely causing this child’s diarrhea?
Cryptosporidia protozoa cause diarrhea in a number o animal species including
humans. Cryptosporidium parvum and Cryptosporidium hominis account or almost
all in ections in humans. Oocysts in eces may be spread by direct human-to-human
contact or by contaminated water supplies.
b. Are there special populations that are vulnerable to cryptosporidiosis?
T ose at risk include travelers, children in day-care acilities, male homosexuals,
animal handlers, and health care personnel. Immunocompromised individuals are
especially vulnerable.
c. Are there specif c treatments or cryptosporidiosis?
In most individuals, the in ection is sel -limited. However, immunocompromised
individuals may require hospitalization and supportive care. T e most e ective
therapy or cryptosporidiosis in AIDS patients is the restoration o their immune
unction. Nitazoxanide is currently the only drug approved or the treatment o
cryptosporidiosis in the United States.
CASE 36-3
A 56-year-old woman is diagnosed with amebic colitis. She is started on metronidazole
but an in ectious disease consultant recommends adding paromomycin to her thera-
peutic regimen.
a. Why add the paromomycin when Entamoeba histolytica is usually susceptible to
metronidazole?
T e cornerstone o therapy or amebiasis is metronidazole which is the drug o choice
or the treatment o amebic colitis, amebic liver abscess, and any other extraintestinal
orm o amebiasis. Because metronidazole is so well absorbed in the gut, concentra-
tions may not be therapeutic in the colonic lumen such that the drug is less e ective
(Continued)
532
Chemotherapy of Protozoal Infections CHAPTER 3 6
against cysts. Patients with amebic colitis or amebic liver abscess also should receive
a luminal agent such as paromomycin or the 8-hydroxyquinoline compound, iodo-
quinol. Nitazoxanide, a drug approved or the treatment o cryptosporidiosis and
giardiasis, is also active against E. histolytica.
b. What is paromomycin and what toxicities and side e ects should this patient
be warned o ?
Paromomycin (aminosidine) is an aminoglycoside used as an oral agent to treat
E. histolytica in ection. Adverse e ects af er oral administration are rare but include
abdominal pain and cramping, epigastric pain, nausea, vomiting, steatorrhea, and
diarrhea.
Parenteral administration carries the same risks o nephrotoxicity and ototoxicity
as with other aminoglycosides (see Chapter 40).
KEY CONCEPTS
Amebiasis, giardiasis, trichomoniasis, toxoplasmosis, cryptosporidiosis,
trypanosomiasis, and leishmaniasis are common protozoal in ections seen
worldwide.
Protozoa multiply rapidly in their hosts and e ective vaccines are
unavailable.
T erapy o protozoal in ections o en requires multiple drugs.
Antiprotozoal drugs have severe toxicities that require care ul monitoring.
Giardiasis, prevalent worldwide, is the most commonly reported protozoal
in ection in the United States.
richomoniasis is a sexually transmitted disease common in the United States.
reatment o patients with giardiasis or trichomoniasis using either metronida-
zole or tinidazole is usually success ul.
SUMMARY QUIZ
QUESTION 36-2 A 24-year-old man with the diagnosis o late stage trypanosomiasis
caused by . brucei gambiense is being treated with e ornithine. E ornithine is an
inhibitor o ornithine decarboxylase. T e parasite and human enzyme are equally
susceptible to inhibition by e ornithine. T e selective toxicity o e ornithine in parasites
is because the
a. human enzyme is protected within vacuoles.
b. parasite accumulates the drug in high concentrations.
c. human enzyme is turned over more rapidly than the parasitic enzyme.
d. human enzyme contains a di erent molecular site o binding o e ornithine.
e. product o the enzyme in parasites is putrescine.
533
SECTION VII Chemotherapy of Microbial Diseases
QUESTION 36-3 Milte osine is the f rst orally active drug or the treatment o visceral
leishmaniasis. However, because o its teratogenic potential, milte osine is contraindi-
cated in pregnant women. A suitable alternative in a pregnant woman might be
a. metronidazole.
b. umagillin.
c. melarsoprol.
d. sodium stibogluconate.
e. pentamidine.
534
Chemotherapy of Protozoal Infections CHAPTER 3 6
535
CHAPTER
37 Chemotherapyof
Helminth Infections
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN
Chapter 51, Chemotherapy o Helminth In ections in Goodman & Gilman’s T e Phar-
THIS CHAPTER macological Basis o T erapeutics, 12th Edition. In addition to the material presented
Albendazole (ALBENZAand ZENTEL) here, the 12th Edition contains:
Diethylcarbamazine (DEC) • A detailed discussion o helminth in ections and their treatment including nema-
Doxycycline todes (roundworms), cestodes ( atworms), and trematodes ( ukes)
Ivermectin (MECTIZAN, STROMECTOL)
LEARNING OBJECTIVES
Mebendazole (VERMOX,others)
Understand the common helminth in ections, the clinical symptoms, and the
Metrifonate (trichlorfon; BILARCIL) mainstays o therapy.
Niclosamide Describe the therapeutic uses o antihelmintic drugs.
Oxamniquine
Understand the mechanisms o actions o antihelmintic drugs.
Piperazine
Identi y the toxicities and contraindications o antihelmintic drugs.
Praziquantel (BILTRICIDE, DISTOCIDE)
Pyrantel Pamoate (PIN-X,others)
CASE 37-1
A 3-year-old boy is brought into your o ce. His mother is complaining that her child
is scratching between his legs which has caused irritation and redness.
a. Although you suspect a pinworm (Enterobius vermicularis) in ection, how is the
diagnosis made?
O en the worms or their eggs can be seen in the perianal area early in the morning.
A “tape test” is used to diagnose pinworm. In the morning be ore bathing or using the
toilet a piece o cellophane tape is pressed in the skin around the anus, and removed.
T e tape is then examined with a microscope to look or the worms or their eggs.
b. What is the appropriate treatment o this child?
T e relative incidence o common helminthic in ections in humans worldwide is
illustrated in Figure 37-1. Enterobius, pinworm, is one o the most common hel-
minth in ections in temperate climates, including the United States. Although this
parasite rarely causes serious complications, pruritus in the perianal region can be
severe, and scratching may cause secondary in ection. Salpingitis or even peritonitis
is a rare complication in emale patients.
Pyrantel pamoate, mebendazole, or albendazole as a single dose are highly e ec-
tive in the treatment o Enterobius in ection. A second dose is o en recommended
to be administered 2 weeks a er the rst. T e in ection easily spreads throughout
members o a amily, a school, or an institution, and may require treatment o all
individuals in close contact with an in ected person.
CASE 37 2
A 53-year-old man comes into your o ce with a 3-month history o weight loss,
abdominal pain, and atigue. His history is also signi cant or the consumption o par-
tially cooked sh during a camping trip 6 months previously. A physical examination
reveals a blood pressure o 140/60 mm Hg, pulse o 72 beats/min, and a respiratory rate
o 16 breaths/min. T e remainder o his physical examination is also normal with the
exception o pale nail beds and skin. A complete blood count shows the presence o
a megaloblastic anemia. An examination o a resh stool specimen reveals the eggs and
segments o a worm.
(Continued)
536
Chemotherapy of Helminth Infections CHAPTER 3 7
Infe ctions
(pe rce nta ge of world popula tion)
0 10 20 30
Trichine lla
S trongyloide s
Ta peworms
S chis tos ome s
Ente robius
Fila ria s
Trichuris
Hookworms
As ca ris
CASE 37 3
As a medical missionary to sub-Saharan A rica you are involved with the administra-
tion o ivermectin to rural communities or the treatment o onchocerciasis caused by
Onchocerca volvulus.
a. What is onchocerciasis?
Onchocerca volvulus is transmitted by black ies near ast- owing streams and rivers
in sub-Saharan A rica. In ammatory reactions, primarily to micro lariae rather
than adult worms, a ect the subcutaneous tissues, lymph nodes, and eyes. Oncho-
cerciasis is a leading cause o in ectious blindness worldwide and results rom the
cumulative destruction o micro lariae in the eyes that occurs over decades.
b. What are the usual therapeutic uses o ivermectin?
Ivermectin is the drug o choice or treatment o onchocerciasis, in adults and
children 5 years or older. It is also given in mass drug administration programs in
(Continued)
537
SECTION VII Chemotherapy of Microbial Diseases
the Americas and in sub-Saharan A rica. Ivermectin is not curative because it has
little e ect on adult Onchocerca volvulus.
A single annual dose o ivermectin is e ective and sa e or mass chemotherapy o
in ections with Wuchereria bancrof i and Brugia malayi. Ivermectin is as e ective
as diethylcarbamazine (DEC) or controlling lymphatic lariasis, and unlike DEC,
it can be used in regions where onchocerciasis, loiasis, or both are endemic.
Ivermectin administration is the drug o choice or treatment o human
strongyloidiasis.
c. Describe the mechanism o action o ivermectin?
Ivermectin immobilizes a ected organisms by inducing a tonic paralysis o the mus-
culature. T is appears to occur by binding to glutamate-activated Cl– channels ound
in nematode nerve or muscle cells, which causes hyperpolarization by increasing
intracellular chloride concentration.
Ivermectin has no discernible e ect on adult parasites, even in high doses, but
a ects developing larvae and blocks egress o micro lariae rom the uterus o adult
emale worms.
d. How is ivermectin administered and how is it metabolized?
Peak concentrations o ivermectin in plasma are achieved within 4 to 5 hours a er
oral administration. T e long terminal t½ o approximately 57 hours re ects a low
systemic clearance and a large apparent volume o distribution. Ivermectin is
extensively metabolized by hepatic CYP3A4 to at least 10 metabolites.
A P-glycoprotein ef ux pump drug transporter located in the endothelium o brain
microvasculature appears to reduce ivermectin penetration into the CNS and may
explain the paucity o CNS side e ects in humans.
e. What are the common side ef ects associated with the use o ivermectin and what
precautions should be considered in the treatment o onchocerciasis?
Ivermectin is well tolerated by unin ected humans. In larial in ections, ivermectin
therapy requently causes a Mazzotti-like reaction to dying micro lariae. T e intensity
o these reactions relates to the micro larial burden.
Ivermectin is not approved or use in children younger than 5 years or pregnant
women.
KEY CONCEPTS
Worms pathogenic or humans are classi ed into roundworms (nematodes),
atworms and ukes (trematodes), and tapeworms (cestodes).
Anthelmintics are drugs that act either locally within the GI tract to cause
expulsion o worms, or systemically against helminthes residing outside the
GI tract.
Acquired resistance to anthelmintics in humans has yet to become a major
clinical problem.
reatment o loiasis or onchocerciasis should proceed with caution in patients
with large parasite burden due to tissue damage caused by destruction o the
micro lariae (Mazzotti-like reaction).
SUMMARY QUIZ
QUESTION 37-1 A 32-year-old man is seen because o megaloblastic anemia o
unknown origin. A er considerable workup, he is discovered to have an intestinal sh
tapeworm, Diphyllobothrium latum. reatment with praziquantel eliminates the worm
(Continued)
538
Chemotherapy of Helminth Infections CHAPTER 3 7
and cures his anemia. T e cause o the anemia in patients with Diphyllobothrium latum
in ection is
a. iron de ciency.
b. vitamin B12 de ciency.
c. olic acid de ciency.
d. vitamin E de ciency.
e. intestinal blood loss.
QUESTION 37-2 A 23-year-old woman returns rom several years in sub-Saharan A rica.
She has lymphadenitis and decreasing eyesight. She is diagnosed with onchocerciasis. Both
ivermectin and diethylcarbamazine (DEC) are known to be ef ective against Onchocerca
volvulus. Why is ivermectin chosen over DEC in the treatment o onchocerciasis?
a. DEC may worsen ocular lesions.
b. DEC is not absorbed rom the GI tract.
c. Ivermectin may be given by intramuscular injection.
d. Resistance to DEC is common.
e. DEC is contraindicated in women.
QUESTION 37-3 A 4-year-old boy is brought into your o ce because o a possible
pinworm in ection. Examination o the anal area con rms the diagnosis o Enterobius
(pinworm). Which o the ollowing drugs would you recommend to treat this in ection?
a. Ivermectin
b. DEC
c. Praziquantel
d. Pyrantel pamoate
e. Metri onate
QUESTION 37-4 A 25-year-old woman immigrant rom Guatemala is diagnosed with
aenia solium (pork tapeworm) upon examination o a stool specimen. ests reveal
that she has cysticercosis although a magnetic resonance image o the brain with a
contrast agent shows no signs o neurocysticercosis. Which o the ollowing drugs
would be appropriate or her treatment?
a. Ivermectin
b. DEC
c. Pyrantel pamoate
d. Metri onate
e. Albendazole
QUESTION 37-5 A 28-year-old man returns to the United States a er living 2 years
in Brazil. He complains o lethargy. Examination reveals mild liver dys unction. He is
diagnosed with Schistosoma mansoni. Which o the ollowing drugs is most appropriate
or treating this patient?
a. Praziquantel
b. Ivermectin
c. DEC
d. Albendazole
e. Metri onate
539
SECTION VII Chemotherapy of Microbial Diseases
Praziquantel BILTRICIDE Most cestodes and trematodes Not o clinical GI symptoms, In neurocysticercosis,
DISTOCIDE that in ect humans signi cance headache, in ammatory
Schistosomiasis and liver uke dizziness reactions may produce
in ections meningismus and seizures
(Continued)
540
Chemotherapy of Helminth Infections CHAPTER 3 7
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES RESISTANCE COMMON IMPORTANT
Metri onate Trichlor on Schistosoma haematobium Not o clinical
signi cance
Pyrantel pamoate PIN-X, others Pinworm, roundworm, and Not o clinical Mild GI symptoms, Not recommended in
hookworm in ections signi cance headache, pregnant women or
dizziness children <2 years
541
CHAPTER
Sulfonamides, Trimethoprim-
38 Sulfamethoxazole, Quinolones, and
Agents for UrinaryTract Infections
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN
Chapter 52, Sul onamides, rimethoprim-Sul amethoxazole, Quinolones, and Agents or
THIS CHAPTER Urinary ract In ections in Goodman & Gilman’s T e Pharmacological Basis o T erapeutics,
Ma enide (SULFAMYLON) Methenamine 12th Edition. In addition to the material presented here, the 12th Edition contains:
Nitro urantoin (FURADANTIN, • Structural ormulas or each o the drugs in this chapter, in addition to the gures
MICROBID,others) reproduced here
Phenazopyridine (PYRIDIUM, others) • able 52-2 which is a compilation o the structural ormulas or selected quinolones
Quinolones (nor oxacin [NOROXIN, and uoroquinolones
others], o oxacin, [FLOXIN, others],
cipro oxacin [CIPRO, others], moxi oxacin LEARNING OBJECTIVES
[AVELOX]) Understand the mechanism o action o sul onamide drugs.
Silver sul adiazine (SILVADENE, others) Identi y the various sul onamide drugs and categorize them according to their
Sul acetamide absorption rom the gastrointestinal (GI) tract.
Sul adiazine Identi y the therapeutic uses and untoward e ects o sul onamide drugs includ-
Sul adoxine (FANSIDAR) ing trimethoprim-sul amethoxazole.
Sul amethoxazole Describe the therapeutic uses, mechanisms o action, and toxicities o quino-
lone antibiotic drugs.
Sul asalazine (AZULFADINE, others)
Sul soxazole Identi y the uses and limitations o antiseptic and analgesic drugs or the treat-
ment o urinary tract in ections.
Trimethoprim-sul amethoxazole (BACTRIM,
SEPTRA, others) T e mechanism o action o sul onamides is shown in Figure 38-2 and the resis-
tance to sul onamides is described in the side bar BAC ERIAL RESIS ANCE O
SULFONAMIDES
T e mechanism o action o quinolines is shown in Figure 38-3 and the resistance to
BACTERIAL RESISTANCE
quinolines is described in the side bar BAC ERIAL RESIS ANCE O QUINOLINES.
TO SULFONAMIDES
Resistance to sul onamides is the conse-
CASE 38-1
quence o altered enzymaticconstitution
o the bacterial cell characterized by: A 56-year-old woman presents with symptoms o her second urinary tract in ection
• Alower a nityo dihydropteroate within 2 months. She has no ever and her white blood cell count is not elevated. A
synthesis enzymes. previous culture showed Escherichia coli, and she responded well to the combination o
trimethoprim-sul amethoxazole. A er obtaining the appropriate cultures and sensitivi-
• Decreased bacterial permeabilityor active
ties you decide to treat her again with this combination.
ef uxo the drug.
• An alternative metabolicpathway or a. What is unique about the mechanism o action o this combination that makes it
synthesis o an essential metabolite. ef ective in treating bacterial in ections?
• Increased production o an essential T e sul onamides can be classi ed on the basis o the rapidity with which they are
metabolite or drug antagonist. absorbed and excreted (see able 38-1). T e structural ormulas o selected mem-
bers o this class are shown in Figure 38-1.
T e antimicrobial activity o the combination o trimethoprim and sul amethoxa-
zole results rom its actions on 2 steps o the enzymatic pathway or the synthesis o
BACTERIAL RESISTANCE tetrahydro olic acid (see Figure 38-2). Mammalian cells use pre ormed olates rom
TO QUINOLINES the diet and do not synthesize the compound. rimethoprim is a highly selective
inhibitor o dihydro olate reductase o lower organisms. T is relative selectivity is
Resistance toquinolines maydevelop dur-
vital because dihydro olate reductase unction is essential to all species.
ing therapyvia mutations in the bacterial
chromosomal genes encoding DNAgyrase or b. T e culture o the urine shows again Escherichia coli sensitive to the combination
topoisomerase IV(see Figure 38-3), or byactive o trimethoprim-sul amethoxazole. Why is this step necessary in this patient
transport o the drug out o the bacteria. with a previous urinary tract in ection?
(Continued)
542
Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents CHAPTER 3 8
4 1 N
H2 N S O 2 NH2 H2 N S O 2 NH
N
S ULFANILAMIDE S ULFADIAZINE
H2 N S O 2 NH H2 N S O 2 NH O
N
N CID
O CH3 H3 C CH3
S ULFAMETHOXAZOLE S ULFIS OXAZOLE
O
H2 N S O 2 NH C CH3 H2 N COOH
FIGURE 38-1 Structural ormulas o selected sul onamides and para-aminobenzoic acid. The N
o the para-NH2 group is designated as N4; that o the amide NH2, as N1.
TABLE 38-1 Classif cation o Sul onamides According to Absorption and Dihydropte roic a cid
Elimination Kinetics gluta ma te
CLASS SULFONAMIDE SERUM t ½ (hours)
Absorbed and eliminated Sulf soxazole 5-6
rapidly Sul amethoxazole 11
Sul adiazine 10 Dihydrofolic a cid
NADP H
Poorly absorbed, active in Sul asalazine – trime thoprim
bowel
NADP
Used topically Sul acetamide –
Silver sul adiazine – Te tra hydrofolic a cid
Long-acting (absorbed rapidly Sul adoxine 100-230 FIGURE 38-2 Steps in olate metabolism
but eliminated slowly) blocked by sul onamides and trimethoprim.
PABA, para-amino benzoic acid
543
SECTION VI Chemotherapy of Microbial Diseases
CASE 38-2
A 42-year-old man has been treated with cipro oxacin or a known Hemophilus inf u-
enza in ection o the respiratory tract or 2 weeks without improvement o symptoms.
Although an initial culture showed sensitivity o the organism to cipro oxacin, a repeat
culture shows that the organism is now resistant.
a. How does resistance develop to the quinolones?
Resistance to the quinolone drugs may develop during therapy via mutations in
the bacterial chromosomal genes encoding DNA gyrase or topoisomerase IV, or by
active transport o the drug out o the bacteria (see Side Bar BAC ERIAL RESIS-
ANCE O QUINOLINES). Resistance has increased a er the introduction o the
f uoroquinolones, especially in Pseudomonas and Staphylococci. Increasing resis-
tance is being observed in C. jejuni, Salmonella, N. gonorrhoeae, and S. pneumoniae.
b. How can the manner in which quinolones are administered af ect the develop-
ment o resistance?
As mentioned in Chapter 34, the pharmacokinetic and pharmacodynamic
parameters o antimicrobial agents are important in preventing the selection and
spread o resistant strains and have led to the concept o the mutation-prevention
concentration, which is the lowest concentration o antimicrobial that prevents
selection o resistant bacteria rom high bacterial inocula. β-Lactams are time-
dependent agents without signi cant post-antibiotic e ects, resulting in bacterial
eradication when unbound serum concentrations exceed MICs o these agents
against in ecting pathogens or more than 40 to 50% o the dosing interval. By
contrast, f uoroquinolones are concentration- and time-dependent agents, result-
ing in bacterial eradication when unbound serum area-under-the-curve-to-MIC
ratios exceed 25 to 30. An extended release ormulation o ciprof oxacin exempli-
es this principle.
c. What is the mechanism o action o the quinolones?
T e quinolone antibiotics target bacterial DNA gyrase and topoisomerase IV (see
Figure 38-3). For many gram-positive bacteria (such as S. aureus), topoisomerase
IV is the primary activity inhibited by the quinolones. In contrast, DNA gyrase is
the primary quinolone target in many gram-negative microbes (such as E. coli).
T e quinolones inhibit gyrase-mediated DNA supercoiling at concentrations
that correlate well with those required to inhibit bacterial growth. Mutations o
the gene that encodes the gyrase A subunit polypeptide can con er resistance to
these drugs.
opoisomerase IV separates interlinked (catenated) daughter DNA molecules that
are the product o DNA replication. Eukaryotic cells do not contain DNA gyrase,
but they do contain a conceptually and mechanistically similar type II DNA topoi-
somerase that removes positive supercoils rom DNA to prevent its tangling during
replication. Quinolones inhibit eukaryotic type II topoisomerase only at concentra-
tions much higher than those that inhibit bacterial DNA gyrase.
FIGURE 38-3 Model o the ormation o negative DNA supercoils by DNA gyrase. The enzyme binds to 2 segments o DNA
(1), creating a node o positive (+) superhelix. The enzyme then introduces a double-strand break in the DNA and passes the
ront segment through the break (2). The break is then resealed (3), creating a negative (–) supercoil. Quinolones inhibit the
nicking and closing activity o the gyrase and, at higher concentrations, block the decatenating activity o topoisomerase IV.
(From Cozzarelli NR. DNAgyrase and the supercoiling of DNA. Science, 1980, 207:953-960. Reprinted with permission from AAAS.)
544
Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents CHAPTER 3 8
CASE 38-3
A 48-year-old man has had chronic urinary tract in ections due to loss o bladder control ol-
lowing a spinal cord injury. He is now being treated with nitro urantoin chronically to sup-
press E. coli which has been the organism most commonly cultured rom his urinary tract.
a. What kind o a drug is nitro urantoin and what is its mechanism o action?
Nitro urantoin is used or the prevention and treatment o in ections o the urinary
tract. Enzymes capable o reducing nitro urantoin result in the ormation o reac-
tive intermediates that damage DNA. T e selective antimicrobial activity is due to
the act that bacteria reduce nitro urantoin more rapidly than do mammalian cells.
T e antibacterial activity is higher in an acidic urine. Nitro urantoin is approved
only or the treatment o urinary tract in ections caused by microorganisms known
to be susceptible to the drug. Resistance to nitro urantoin occurs more requently
than resistance to f uoroquinolones or trimethoprim-sul amethoxazole, making
nitro urantoin a second-line agent or treatment o urinary tract in ections.
b. Should this patient develop a systemic in ection, would nitro urantoin be ef ective?
Nitro urantoin is absorbed rapidly and completely rom the GI tract, but antibacte-
rial concentrations are not achieved in plasma because the drug is eliminated
rapidly. Forty percent o nitro urantoin is excreted unchanged into the urine.
c. What are the common untoward ef ects o nitro urantoin?
T e most common untoward e ects o nitro urantoin are nausea, vomiting, and
diarrhea. Hypersensitivity reactions include chills, ever, leucopenia, granulocy-
topenia, hemolytic anemia (associated with glucose-6-phosphate dehydrogenase
[G6PD] de ciency), cholestatic jaundice, and hepatocellular damage. Chronic active
hepatitis is an uncommon but serious side e ect. Interstitial pulmonary brosis can
occur in patients taking the drug chronically. Nitro urantoin colors the urine brown.
KEY CONCEPTS
Sul onamides inhibit the incorporation o para-amino-benzoic acid (PABA)
into tetrahydro olic acid (see Figure 38-2).
rimethoprim prevents the reduction o dihydro olate to tetrahydro olate (see
Figure 38-2).
T e combination o sul amethoxazole and trimethoprim inhibits 2 sequential
steps in the bacterial synthesis o tetrahydro olate, thus increasing its antibacte-
rial activity and reducing the development o resistance.
Sul onamide drugs (see able 38-1) can be divided into:
T ose that are well-absorbed and rapidly excreted
T ose that are poorly absorbed and are e ective in bowel lumen or
used topically
T ose that are long-acting
Sul onamides have activity against gram-positive and gram-negative organisms.
Resistant strains have become common.
Adverse reactions to sul onamides requently involve the skin and some are serious.
Hypersensitivity reactions to repeated use o sul onamides are common.
Quinolones are e ective orally or a wide variety o microorganisms and are
commonly used to treat urinary tract in ections, traveler’s diarrhea, and respira-
tory tract in ections.
Urinary antiseptics are commonly used to prevent or suppress urinary tract
in ections in susceptible patients.
Phenazopyridine, a urinary analgesic, is used to treat the symptoms o dysuria
and requency.
545
SECTION VI Chemotherapy of Microbial Diseases
SUMMARY QUIZ
QUESTION 38-1 Sul onamide drugs are selective or sensitive bacteria as compared to
mammalian cells because
a. mammalian cells have the ability to extrude sul onamide drugs.
b. mammalian cells do not take up sul onamide drugs.
c. mammalian cells require pre ormed olic acid.
d. bacterial cells accumulate sul onamide drugs more than mammalian cells.
e. sul onamide drugs inter ere with the synthesis o vitamin B12 in bacterial cells but
not mammalian cells.
QUESTION 38-2 Ma enide is a sul onamide drug that is used topically in burn patients.
I the burn area is extensive and ma enide is suf ciently absorbed, a metabolic acidosis
may occur because the ma enide
a. inhibits carbonic anhydrase.
b. is an acid.
c. inhibits olic acid excretion.
d. depresses respiration and causes the accumulation o carbon dioxide.
e. causes an accumulation o dihydropteroic acid.
QUESTION 38-4 A 23-year-old pregnant woman presents with the signs and
symptoms o a urinary tract in ection. She is 3 months pregnant. T e choice o a
trimethoprim-sul soxazole drug over a uoroquinolone drug might be recom-
mended because
a. the likely bacteria involved in a U I during pregnancy are not sensitive to
uoroquinolones.
b. in pregnancy, the uoroquinolone drugs are not absorbed a er oral administration.
c. the uoroquinolones are contraindicated in pregnancy.
d. trimethoprim-sul soxazole achieves much higher plasma concentrations than uo-
roquinolone drugs in pregnancy.
e. trimethoprim-sul amethoxazole also has urinary analgesic e ects.
QUESTION 38-5 A 46-year-old woman has a urinary tract in ection which has become
a systemic in ection with ever and lethargy. Nitro urantoin, an e ective urinary anti-
septic, would not be recommend or her treatment because
a. the bacterial organism is likely not sensitive to nitro urantoin.
b. nitro urantoin is bacteriostatic.
c. e ective concentrations o nitro urantoin are not achieved in the kidney or bladder.
d. e ective concentrations o nitro urantoin are not achieved in the plasma.
e. bacterial resistance to nitro urantoin is common.
546
Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents CHAPTER 3 8
QUESTION 38-1 Answer is c. In sensitive bacteria, sul onamide drugs inhibit the
enzyme responsible or the incorporation o PABA into dihydropteroic acid, the imme-
diate precursor o olic acid (see Figure 38-2). Mammalian cells require pre ormed olic
acid, cannot synthesize it, and are insensitive to drugs that act by inhibiting the synthe-
sis o olic acid.
QUESTION 38-2 Answer is a. Ma enide and its metabolite inhibit carbonic anhydrase,
and the urine becomes alkaline. Metabolic acidosis with compensatory tachypnea and
hyperventilation may ensue.
Sul asalazine (see Poorly absorbed and Side e ects and In ertility in males
Chapter 33) is used or ulcerative toxicities are due to the Should not be used in
colitis and regional sul apyridine moiety patients with known sul a
enteritis drug hypersensitivity
Silver sul adiazine Used topically to Resistance is Burning, itching, Should not be used in
reduce the incidence o known to occur and rash patients with known
in ections rom burns hypersensitivity to sul a drugs
547
SECTION VI Chemotherapy of Microbial Diseases
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES RESISTANCE COMMON IMPORTANT
Ma enide Used topically to Intense pain at site o Superin ection with Candida
prevent colonization o application may be a problem
burns Due to inhibition o carbonic
anhydrase metabolic
acidosis may occur
Trimethoprim— Urinary tract in ections The emergence o Skin rashes and other Should not be used in
Sul amethoxazole Treatment o resistant bacteria dermatologic reactions patients with known
Pneumocystis jirovecii in may limit its Glossitis and stomatitis hypersensitivity to sul a
AIDS patients use ulness are common drugs
Quinolones Ciprof oxacin Urinary tract in ections, Resistance may Nausea, vomiting, Headache and dizziness
Of oxacin prostatitis, sexually develop during abdominal discom ort Photosensitivity
Norf oxacin transmitted diseases, therapy Achilles tendon rupture in
Levof oxacin traveler’s diarrhea, patients >60 years o age
Moxif oxacin respiratory in ections, Should be used with
bone, joint, and so t caution in patients taking
tissue in ections antiarrhythmic agents that
prolong QT interval
Nitro urantoin Urinary tract in ections; Resistance is more Nausea, vomiting, Colors urine brown
cannot be used or common than to diarrhea Hypersensitivity reactions
systemic in ections f uoroquinolones Interstitial pulmonary brosis
Should not be used in
pregnant women or patients
with impaired renal unction
548
CHAPTER
549
SECTION VII Chemotherapy of Microbial Diseases
Pe nicillina s e
Amida s e
O S CH3 O S CH3
R CH NH2 CH CH C R C NH CH CH C
CH3 CH3
O C N CH COOH O C N CH COOH
O OH H
Amphiphillic
drug
Cha nne l
Oute r
me mbra ne
Efflux
tra ns porte r
gram-positive an gram-negative cells. In the synthesis o the bacterial cell wall, the
terminal glycine resi ue o the pentaglycine bri ge is linke to the ourth resi ue
o the pentapepti e (d-alanine), releasing the h resi ue (also d-alanine). It is
this step in pepti oglycan synthesis that is inhibite by the β-lactam antibiotics an
glycopepti e antibiotics such as vancomycin (see Chapter 41). T ere are a itional
targets or the actions o penicillins an cephalosporins that are collectively terme
penicillin-bin ing proteins (PBP). T e PBPs vary in their a nities or if erent
β-lactam antibiotics, although the interactions eventually become covalent.
b. What is the mechanism o bacterial resistance to the penicillins?
β-Lactam antibiotics are capable o being inactivate by β-lactamases that are
present in large quantities (see Figure 39-2). T e β-lactamases are groupe into
4 classes (see Si e Bar CLASSES OF β-LAC AMASE ENZYMES). Some Class A
an D enzymes are inhibite by β-lactamase inhibitors such as clavulanate an
tazobactam. Bacterial resistance to the β-lactam antibiotics may also evelop by
mechanisms other than estruction by β-lactamases (see Si e Bar MECHANISMS
OF BAC ERIAL RESIS ANCE O PENICILLINS AND CHEPHALOSPORINS).
CASE 39-2
A 68-year-old woman has contracted an S. epidermidis in ection that is not methicillin-
resistant. An in ectious disease consultant recommends the use o a penicillinase-
resistant penicillin.
a. What are the penicillinase-resistant penicillins?
T e penicillinase-resistant penicillins (oxacillin, icloxacillin, an cloxacillin) are
resistant to hy rolysis by staphylococcal penicillinase (see able 39-1). Na cillin is
a semisynthetic penicillin that is highly resistant to penicillinase an has proven
ef ective against in ections cause by penicillinase-pro ucing strains o S. aureus.
b. What are their therapeutic uses?
T e role o these penicillins as the agents o choice or most staphylococcal isease
is changing with the increasing inci ence o isolates o methicillin-resistant (MRSA)
microorganisms. T is term enotes resistance o these bacteria to all the penicil-
linase-resistant penicillins an cephalosporins. Hospital-acquire strains usually
are resistant to the aminoglycosi es, tetracyclines, erythromycin, an clin amycin
as well. Vancomycin (see Chapter 41) is consi ere the rug o choice or hospital-
acquire resistant strains, although resistance to vancomycin is also emerging.
551
SECTION VII Chemotherapy of Microbial Diseases
CASE 39-3
A 7-year-old girl is treated with amoxicillin or an otitis media o 3 days duration. A er
the rst dose, the girl’s mother notices swelling o the child’s lips and mild dif culty
breathing. T e girl is seen in the emergency room where the diagnosis o penicillin
allergy is made, and the amoxicillin is discontinued.
a. T e mother does not recall her daughter ever taking penicillin. Is this possible?
Hypersensitivity reactions are by ar the most common a verse ef ects note
with the penicillins, which probably are the most common cause o rug allergy.
Hypersensitivity reactions may occur with any osage orm o penicillin; allergy to 1
penicillin exposes the patient to a greater risk o reaction i another penicillin is given.
Hypersensitivity reactions may appear in the absence o a previous known exposure
to the rug. A etaile iscussion o hypersensitivity reactions an the management
o the patient potentially allergic to penicillin can be oun in Chapter 53 o the 12th
E ition o Goodman and Gilman’s T e Pharmacological Basis o T erapeutics.
b. What is the cause o penicillin allergy?
Penicillins an their break own pro ucts act as haptens a er covalent reaction to
proteins. T e most abun ant break own pro uct is the penicilloyl moiety (major
eterminant moiety, MDM), which is orme when the β-lactam ring is opene
(see Figure 39-2). A large percentage o immunoglobulin (Ig)E-me iate reactions
are to the MDM, but at least 25% o reactions are to other break own pro ucts
(minor eterminants). T ese pro ucts are orme in vivo an also can be oun in
solutions o penicillin prepare or a ministration. Anaphylactic reactions to peni-
cillin usually are me iate by IgE antibo ies against the minor eterminants.
c. Is there a means o detecting penicillin allergy prior to giving a dose o penicillin?
Evaluation o the patient’s history is the most practical way to avoi the use o penicil-
lin in patients who are at the greatest risk o a verse reaction. Most patients who give
a history o allergy to penicillin shoul be treate with another antibiotic. Un ortu-
nately, there is no totally reliable means to con rm a history o allergy to penicillin.
552
Penicillins, Cephalosporins, and Other β-Lactam Antibiotics CHAPTER 3 9
CASE 39-5
A 43-year-old man is being treated with aztreonam or a gram-negative bacterial in ection.
a. How is aztreonam di erent rom the penicillins or cephalosporins?
Aztreonam belongs to the subclass o β-lactam rugs calle carbapenems. But even
within this subclass, aztreonam is unique. Carbapenems have a broa er spectrum
o activity than most other β-lactam antibiotics. Aztreonam has activity only
against gram-negative bacteria; it has no activity against gram-positive bacteria an
anaerobic organisms. However, activity against Enterobacteriaceae an P. aeruginosa
is excellent. It is also highly active in vitro against H. inf uenzae an gonococci.
b. How is aztreonam administered and what precautions should be ollowed?
Aztreonam is a ministere either intramuscularly or intravenously an most o the
rug is recovere unaltere in the urine. T e usual ose o aztreonam shoul be
re uce in patients with renal insu ciency.
CASE 39-6
A 64-year-old woman with type 2 diabetes develops a severe sore throat. She has been
caring or her 3-year-old grandchild who has similar symptoms. She is treated with a
combination o amoxicillin and clavulanic acid because o a concern that the organism
may be resistant to amoxicillin alone.
a. What are β-lactamase inhibitors and how are they used to prevent bacterial
resistance to the penicillins?
β-Lactamase inhibitors (clavulanic aci , sulbactam, an tazobactam) prevent the
estruction o β-lactam antibiotics by β-lactamase. T ey are most active against
plasmi -enco e β-lactamases; they are inactive at clinically achievable concentra-
tions against the type I chromosomal β-lactamase.
b. What other antibiotics are combined with β-lactamase inhibitors?
Sulbactam is combine with ampicillin. azobactam is combine with piperacillin.
553
SECTION VII Chemotherapy of Microbial Diseases
KEY CONCEPTS
Penicillins and cephalosporins act by inhibiting bacterial cell wall synthesis.
Bacterial resistance to the penicillins and cephalosporins is a serious clinical
problem.
Penicillinase-resistant penicillins (na cillin, oxacillin, dicloxacillin, and cloxa-
cillin) are less active against microorganisms sensitive to penicillin but are the
agents o rst choice or the treatment o penicillinase-producing S. aureus and
S. epidermidis that are not methicillin resistant.
T e cephalosporins can be divided into rst-, second-, third-, and ourth-genera-
tion agents, with each generation having a di erent spectrum o activity.
T e carbapenems (imipenem, meropenem, doripenem, ertapenem, and aztreo-
nam) are β-lactam antibiotics with a broader spectrum o activity than most
other β-lactam antibiotics.
β-Lactamase inhibitors are added to some β-lactam antibiotics to extend their
activity against strains o bacteria that produce β-lactamase.
SUMMARY QUIZ
QUESTION 39-1 A 23-year-old woman develops a rash ollowing her rst dose o peni-
cillin V. T e most likely cause o the rash is an allergy to penicillin. What component o
penicillin is the most requent cause o an allergic reaction?
a. T e intact penicillin molecule
b. T e penicilloic acid moiety (major determinant moiety)
c. T e 6-aminopenicillanic acid moiety
d. Other breakdown products (minor determinant moiety)
e. T e side chain attached to the β-lactam ring through the amide linkage
QUESTION 39-2 A 48-year-old woman has an in ection that cultures a S. aureus known
to elaborate penicillinase. It is appropriate that she be treated with na cillin because
a. blood concentrations o na cillin are suf ciently high to kill all S. aureus.
b. na cillin is more potent against S. aureus than penicillin G.
c. na cillin is resistant to penicillinase.
d. na cillin is active against methicillin-resistant microorganisms (MRSA).
e. na cillin is a naturally occurring penicillin.
QUESTION 39-4 A 37-year-old woman is being treated with the combination drug,
imipenem and cilastatin. Cilastatin is added to imipenem because the cilastatin
a. inhibits the destruction o imipenem by a renal tubular dipeptidase.
b. inhibits β-lactamase.
c. increases the oral absorption o imipenem.
(Continued)
554
Penicillins, Cephalosporins, and Other β-Lactam Antibiotics CHAPTER 3 9
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES RESISTANCE COMMON IMPORTANT
Cephalosporins- Ce uroxime Similar to ce aclor with Resistant to bacteria that Allergic reactions
Second Generation broader gram-negative produce β-lactamases
activity and MRSA
556
Penicillins, Cephalosporins, and Other β-Lactam Antibiotics CHAPTER 3 9
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES RESISTANCE COMMON IMPORTANT
557
SECTION VII Chemotherapy of Microbial Diseases
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES RESISTANCE COMMON IMPORTANT
558
CHAPTER
Aminoglycosides 40
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN
Chapter 54, Aminoglycosides in Goodman & Gilman’s T e Pharmacological Basis of T era-
peutics, 12th Edition. In addition to the material presented here, the 12th Edition contains: THIS CHAPTER
• Figure 54-1 which shows the sites o activity o various plasmid-mediated enzymes • Amikacin
capable o inactivating aminoglycosides • Gentamicin (GARAMYCIN, others)
• able 54-1 which provides the minimal inhibitory concentrations o aminoglycosides • Kanamycin
that will inhibit 90% (MIC90) o clinical isolates or several bacterial species • Neomycin
• able 54-2 which provides an algorithm or dose reduction o aminoglycosides based • Netilmicin (NETROMYCIN)
on creatinine clearance
• Streptomycin
LEARNING OBJECTIVES • Tobramycin (TOBREX,others)
Understand aminoglycoside mechanisms o action and resistance.
Describe the advantages and disadvantages o multiple daily dosing versus once
daily extended-interval dosing regimens or aminoglycosides. MECHANISMS OF ACTION
Describe the rationale and the methods o plasma concentration monitoring OF AMINOGLYCOSIDES
o aminoglycoside therapy. • The aminoglycosides are rapidlybac-
Describe the causes and clinical signs o aminoglycoside ototoxicity and nephro- tericidal and their bacterial killing is
toxicity and the best means o monitoring therapy to avoid these serious toxicities. concentration-dependent
Understand the unique clinical di erences among the aminoglycosides. • Aminoglycosides exhibit a postantibiotic
ef ect, that is, the bactericidal activity
T e mechanisms o action and resistance o the aminoglycosides are shown in the persists a ter serumconcentration alls
side bars MECHANISMS OF AC ION OF AMINOGLYCOSIDE and MECHANISMS belowthe MIC
OF AMINOGLYCOSIDE RESIS ANCE, respectively.
• Duration o postantibioticef ect is also
concentration-dependent
CASE 40-1
• Inside the bacterial cell, the aminoglyco-
A 56-year-old woman is in hospital or the treatment o pneumonia. Her case is com- sides bind to polysomes and inter ere with
plicated because she acquired the pneumonia in another hospital while undergoing protein synthesis bycausing misreading
post-surgical rehabilitation or a hysterectomy. She was being treated with a cephalo- and premature termination o mRNAtrans-
sporin at the other hospital, but gentamicin is now added. lation (see Figure 40-1)
a. Why was the aminoglycoside added to her therapeutic regimen?
An aminoglycoside in combination with a β-lactam antibiotic is recommended as stan-
dard therapy or hospital-acquired pneumonia in which a multiple-drug resistant gram- MECHANISMS OF
negative aerobe is a likely causative agent. I it is established that the β-lactam is active AMINOGLYCOSIDE
against the causative agent, there is generally no need to continue the aminoglycoside.
RESISTANCE
b. Why is the combination o a β-lactam antibiotic and an aminoglycoside e ective?
• Failure o the aminoglycoside to penetrate
T ese 2 antibiotic classes have distinctly di erent mechanisms o action and their the bacteria cell
e ectiveness should be complementary. β-Lactam antibiotics inhibit cell wall synthesis
• Inactivation o the aminoglycoside by
(see Chapter 39). Aminoglycosides act at the 30S ribosomal subunit to disrupt the nor-
microbial enzymes
mal cycle o ribosomal unction by inter ering with the initiation o protein synthesis,
also by leading to accumulation o abnormal initiation complexes and premature • Lowa nityo the aminoglycoside or the
termination, and by causing misreading o the mRNA template and incorporation o bacterial ribosome
incorrect amino acids into the growing polypeptide chains (see Figure 40-1).
CASE 40-2
A 23-year-old woman is being treated with gentamicin or an enterococci in ection.
wenty- our hours a er beginning treatment it is learned that the organism is resistant
to gentamicin. (Continued)
559
SECTION VII Chemotherapy of Microbial Diseases
FIGURE 40-1 E ects o aminoglycosides on protein synthesis. A. Aminoglycoside (represented by dark grey circles) binds to the 30S
ribosomal subunit and inter eres with initiation o protein synthesis by xing the 30S to 50S ribosomal complex at the start codon (AUG) o
mRNA. As 30S to 50S complexes downstream complete translation o mRNA and detach, the abnormal initiation complexes, the so-called
streptomycin monosomes, accumulate, blocking urther translation o the message. Aminoglycoside binding to the 30S subunit also causes
misreading o mRNA, leading to B, premature termination o translation with detachment o the ribosomal complex and incompletely
synthesized protein or C, incorporation o incorrect amino acids (indicated by the grey X), resulting in the production o abnormal or
non unctional proteins.
CASE 40-3
A 65-year-old man is in hospital or the treatment o community-acquired pneumonia
that is sensitive to an aminoglycoside. He is being treated with 5.1 mg/kg o gentamicin
as a single dose once every 24 hours.
a. Based on a hal -li e o 2 to 3 hours, aminoglycosides have been historically
administered in 3 equally divided doses over a 24-hour period. Is this patient’s
single dose expected to be e ective?
Numerous studies and meta-analyses demonstrate that administration o the total
dose o aminoglycoside once daily is just as e ective as multiple-dose regimens. In
addition, extended-interval administration costs less, is administered more easily,
and is associated with less nephrotoxicity.
(Continued)
560
Aminoglycosides CHAPTER 4 0
FIGURE 40-2 Plasma concentrations (µg/mL) a ter administration o 5.1 mg/kg o gentamicin intravenously to a
hypothetical patient either as a single dose (every 24 hours) or as 3 divided doses (every 8 hours). The threshold or
toxicity has been chosen to correspond to a plasma concentration o 2 µg/mL, the maximum recommended. The
high-dose, extended-interval (once-daily) regimen produces a 3- old higher plasma concentration, which enhances
ef cacy that otherwise might be compromised due to prolonged sub-MIC concentrations later in the dosing inter-
val compared with the every-8-hours regimen. The once-daily regimen provides a 12-hour period during which
plasma concentrations are below the threshold or toxicity, thereby minimizing the toxicity that otherwise might
result rom the high plasma concentrations early on. The every-8-hours regimen, in contrast, provides only a brie
period during which plasma concentrations are below the threshold or toxicity.
561
SECTION VII Chemotherapy of Microbial Diseases
determined routinely (these will be 3-4 times higher than the peak achieved with a
multiple-daily-dosing regimen).
T e most accurate method or monitoring plasma concentrations or dose adjust-
ment during an extended-interval dosing regimen is to measure the concentration
o 2 plasma samples drawn several hours apart (eg, at 2 and 12 hours a er a dose).
T e clearance can then be calculated and the dose adjusted to achieve the desired
target range.
CASE 40-4
A 46-year-old man with chronic renal insu ciency is brought into the emergency depart-
ment su ering rom an elevated temperature o 104 °F. His medical chart is not available.
It is decided to treat him with gentamicin, but his last creatinine clearance is not known.
a. T e dose o aminoglycoside should be decreased in patients with poor renal
unction. Since this patient’s creatinine clearance is unknown, what initial dose
should he be started on?
T e concentration o aminoglycoside in plasma produced by the initial dose depends
only on the volume o distribution o the drug. T us (assuming his volume o distri-
bution is normal), this patient can be treated initially with a standard dose o gen-
tamicin, or example, 5 mg/kg given over 30 to 60 minutes. T e next dose (24 hours
later) can be adjusted or his reduced renal unction which should then be known.
b. Why is it important to reduce the dose o aminoglycosides in patients with
decreased renal unction?
T e elimination o aminoglycosides depends almost entirely on the kidney and a
linear relationship exists between the concentration o creatinine in the plasma and
the t½ o all aminoglycosides in patients with moderately compromised renal unc-
tion. In anephric patients, the t½ varies rom 20 to 40 times that o normal individu-
als. Because the incidence o nephrotoxicity and ototoxicity is likely related to the
overall drug exposure to aminoglycosides, it is critical to reduce the maintenance
dosage o these drugs in patients with impaired renal unction.
c. How is a maintenance dose determined?
For patients with impaired renal unction, it is common to rely upon algorithms
such as the one shown in able 54-2 in the 12th Edition o T e Pharmacologi-
cal Basis of T erapeutics or those published in other medical texts and re erence
books. It should be understood that such algorithms are only a guideline and that
plasma concentrations must be monitored as discussed in Case 40-3 above and in
Appendix II o the T e Pharmacological Basis of T erapeutics, 12th Edition. Deter-
mination o the concentration o drug in plasma is an essential guide to the proper
administration o aminoglycosides. In patients with li e-threatening systemic in ec-
tions, aminoglycoside concentrations should be determined several times per week
(more requently i renal unction is changing) and should be determined within
24 to 48 hours o any change in dosage.
CASE 40-5
During a course o gentamicin therapy, a 76-year-old man develops ringing in his ears.
a. What are the clinical symptoms o ototoxicity with aminoglycosides?
A high-pitched tinnitus o en is the rst sign o cochlear toxicity. I the drug is not
stopped, auditory impairment may develop a er a ew days. T e a ected individual
is not always aware o the di culty, and it will not be detected except by care ul
auditory examination.
Moderately intense headache lasting 1 to 2 days may precede the onset o vestibu-
lar toxicity. T is is ollowed immediately by nausea and vomiting. Di culty with
equilibrium may develop and persist or 1 to 2 weeks. Prominent symptoms o
(Continued)
562
Aminoglycosides CHAPTER 4 0
vestibular toxicity include vertigo in the upright position, inability to perceive ter-
mination o movement, and di culty in sitting or standing without visual clues.
b. What are the risk actors or producing ototoxicity?
It is generally thought the ototoxicity seen with aminoglycosides is more likely to
occur in patients with persistently elevated concentration o drug in plasma.
Ototoxicity is largely irreversible and results rom progressive destruction o vestib-
ular or cochlear sensory cells. Accumulation within the perilymph and endolymph
occurs predominantly when aminoglycoside concentrations in plasma are high.
Di usion back into the bloodstream is slow; the hal -lives o the aminoglycosides
are 5 to 6 times longer in otic f uids than in plasma. Back di usion is concentra-
tion-dependent and acilitated at the trough concentration o the drug in plasma.
However, studies have not consistently shown an association between ototoxicity
and risk actors such as aminoglycoside plasma concentrations, total dose, duration
o exposure, and renal dys unction.
c. How should aminoglycosides be monitored to avoid ototoxicity?
I it is anticipated that the patient will be treated with an aminoglycoside or more
than 3 to 4 days then plasma concentrations should be monitored to avoid drug
accumulation. See the answer to Case 40-3d or a description o a rational approach
to aminoglycoside plasma concentration monitoring.
CASE 40-6
A 63-year-old woman has been treated with gentamicin or 7 days. During these
7 days, her serum creatinine has risen rom 1.0 mg/dL to 2.2 mg/dL and there is con-
cern or the development o nephrotoxicity. She is scheduled or another 3 days o
gentamicin therapy.
a. What variables are important or the development o aminoglycoside
nephrotoxicity?
Approximately 8 to 26% o patients who receive an aminoglycoside or several days
develop mild renal impairment that is almost always reversible. T e toxicity cor-
relates with the total amount o drug administered and consequently with longer
courses o therapy. Advanced age, liver disease, diabetes, and septic shock have
been suggested as risk actors or the development o aminoglycoside nephrotoxic-
ity. T e nephrotoxic potential varies among individual aminoglycosides. Neomycin
concentrates to the greatest degree in the renal cortex, is highly nephrotoxic, and
should not be administered systemically. Streptomycin does not concentrate in
the renal cortex and is the least nephrotoxic. T e di erence in the nephrotoxic-
ity o gentamicin and tobramycin is slight. Other drugs such as amphotericin B,
cyclosporin, vancomycin, angiotensin-converting enzyme inhibitors, and cisplatin
may potentiate the nephrotoxicity o the aminoglycosides. Clinical studies have not
proven conclusively that urosemide potentiates aminoglycoside nephrotoxicity, but
the volume depletion and K+ wasting that accompany the use o urosemide may
predispose to aminoglycoside toxicity.
b. What are the mechanisms o aminoglycoside nephrotoxicity?
Aminoglycoside nephrotoxicity results rom the accumulation and retention o the
aminoglycoside in the renal proximal tubular cells. T e biochemical events leading
to tubular cell damage and glomerular dys unction probably involve perturba-
tions o the structure o cellular membranes. T e initial mani estation o damage
is excretion o enzymes o the renal tubular brush border. A er several days, there
is a de ect in the renal concentrating ability, mild proteinuria, and the appearance
o hyaline and granular casts. T e glomerular ltration rate is reduced a er sev-
eral additional days. Aminoglycoside renal impairment is almost always reversible
because the proximal tubular cells have the capacity to regenerate.
(Continued)
563
SECTION VII Chemotherapy of Microbial Diseases
KEY CONCEPTS
Aminoglycosides are bactericidal by disrupting the normal cycle o ribosomal
unctioning thereby inter ering with bacterial protein synthesis.
Resistance to aminoglycosides is most commonly caused by drug-inactivating
enzymes produced by bacteria.
Aminoglycosides are characterized by a postantibiotic e ect, that is, residual
bactericidal activity persisting a er the serum concentration has allen below
the minimum inhibitory concentration (MIC).
High-dose, extended-interval dosing regimens are e ective in most instances
and may reduce the characteristic oto- and nephrotoxicity o aminoglycosides.
Plasma concentration monitoring o aminoglycosides is an essential guide to
the proper administration o aminoglycosides.
All aminoglycosides have the potential to produce irreversible cochlear and
vestibular toxicity.
All aminoglycosides have the potential to produce nephrotoxicity that is almost
always reversible.
SUMMARY QUIZ
QUESTION 40-2 A 64-year-old man is su ering rom a gas gangrene in ection o his right
oot due to a mid-cal arterial clot. T e bacteria involved is Clostridium perfringens. An
aminoglycoside is not a good choice or antibiotic therapy because aminoglycosides are
a. bacteriostatic.
b. not active against anaerobic bacteria.
c. more toxic under anaerobic conditions.
d. only e ective i they are injected directly into anaerobic tissue.
e. metabolized more rapidly under anaerobic conditions.
QUESTION 40-4 A 40-year-old woman is being treated with intravenous gentamicin 3 times
daily. Her therapy was begun 3 days ago and is expected to continue or an additional
10 days. What is the recommended monitoring o plasma gentamicin concentrations?
a. No plasma concentration monitoring is necessary.
b. Measure peak and trough concentrations several times per week.
c. Measure only peak plasma concentrations.
d. Measure only trough concentration once a er 3 days o therapy.
e. Monitor peak and trough plasma concentrations only i renal dys unction is
apparent.
QUESTION 40-5 A 43-year-old man is being treated with gentamicin and penicillin
mixed in the same IV solution or a serious pulmonary in ection that is sensitive to
gentamicin. A er 3 days o therapy, his temperature remains elevated and his pulmo-
nary congestion is worsening. A possible cause is that the
a. gentamicin is inactivated by the penicillin in the IV mixture in vitro.
b. penicillin enhances the elimination o gentamicin.
c. gentamicin causes a destruction o penicillin in vivo.
d. penicillin inhibits the entry o gentamicin into the bacterial cell.
e. penicillin prevents the ribosomal binding o gentamicin.
Peak plasma concentrations o aminoglycosides are used to determine that the dose
produces a therapeutic concentration; trough plasma concentrations are used to moni-
tor drug accumulation. Peak concentrations are not routinely measured during an
extended-interval dosing regimen.
SUMMARY: AMINOGLYCOSIDES
TOXICITY
UNIQUE;
CLASS AND CLINICALLY
SUBCLASSES NAME CLINICAL USES RESISTANCE COMMON IMPORTANT
Aminoglycosides Gentamicin Urinary tract in ection: not indicated or Clinical bacterial Nephrotoxicity
routine use resistance is increasingly (reversible),
Pneumonia: in combination with a common irreversible
β-lactam antibiotic or the treatment o Aminoglycosides have ototoxicity
hospital-acquired pneumonia in which little activity against When applied
a multiple drug-resistant gram-negative anaerobic bacteria or topically to
aerobe is a likely causative agent acultative bacteria large areas
Bacterial endocarditis: low-dose under aerobic conditions o denuded
gentamicin (3 mg/kg/d in divided Aminoglycoside activity skin, plasma
doses) in combination against most gram- concentrations
with penicillin or vancomycin or positive bacteria is may reach the
treatment due to gram-positive limited and they should toxic range
organisms; in cases o enterococcal not be used as a single
endocarditis, the administration o agent in the treatment
penicillin and gentamicin or 4-6 weeks o in ections caused by
is recommended because o the gram-positive bacteria
unacceptably high relapse rate
with penicillin alone
Sepsis: inclusion o an aminoglycoside
is recommended or the ebrile patient
with granulocytopenia and when
P. aeruginosa is a potential pathogen
Tobramycin Similar to gentamicin Similar to gentamicin Similar to
gentamicin
(Continued)
566
Aminoglycosides CHAPTER 4 0
TOXICITY
UNIQUE;
CLASS AND CLINICALLY
SUBCLASSES NAME CLINICAL USES RESISTANCE COMMON IMPORTANT
567
CHAPTER
568
Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents CHAPTER 4 1
Vancomycin, Teicoplanin Inhibit cell wall synthesis by Bacterial alteration o drug target
binding to d -alanyl-d -alanine
terminus o cell wall precursor
units (see Figure 41-4)
Aminoa cyl
Na s ce nt
tRNA
polype ptide Na s ce nt 50S
cha in polype ptide
Tra ns fe ra s e cha in
s ite aa Tra ns fe ra s e
Te tra cycline s ite
mRNA
te mpla te mRNA
te mpla te
30S
30S
FIGURE 41-1 Inhibition o bacterial protein synthesis by tetra-
cyclines. Messenger RNA (mRNA) attaches to the 30S subunit o FIGURE 41-2 Inhibition o bacterial protein synthesis by
bacterial ribosomal RNA. The P (peptidyl) site o the 50S ribosomal chloramphenicol. Chloramphenicol binds to the 50S ribosomal
RNA subunit contains the nascent polypeptide chain; normally, the subunit at the peptidyltrans erase site and inhibits the trans-
aminoacyl tRNA charged with the next amino acid (aa) to be added peptidation reaction. Chloramphenicol binds to the 50S ribo-
to the chain moves into the A (acceptor) site, with complementary somal subunit near the site o action o clindamycin and the
base pairing between the anticodon sequence o tRNA and the macrolide antibiotics. These agents inter ere with the binding
codon sequence o mRNA. Tetracyclines inhibit bacterial protein o chloramphenicol and thus may inter ere with each other’s
synthesis by binding to the 30S subunit and blocking tRNA binding actions i given concurrently. See Figure 41-1 and its legend or
to the A site. additional in ormation.
569
SECTION VII Chemotherapy of Microbial Diseases
A s ite
Na s ce nt
polype ptide
cha in 50S
P s ite
aa Tra ns fe ra s e
s ite
Ma crolide s
mRNA
te mpla te
tRNA
30S
FIGURE 41-3 Inhibition o bacterial protein synthesis by the macrolide antibiotics erythromycin,
clarithromycin, and azithromycin. Macrolide antibiotics are bacteriostatic agents that inhibit pro-
tein synthesis by binding reversibly to the 50S ribosomal subunits o sensitive organisms. Erythro-
mycin appears to inhibit the translocation step such that the nascent peptide chain temporarily
residing at the A site o the trans erase reaction ails to move to the P, or donor, site. Alternatively,
macrolides may bind and cause a con ormational change that terminates protein synthesis by
indirectly inter ering with transpeptidation and translocation. See Figure 41-1 and its legend or
additional in ormation.
Va ncomycin
+
tra ns glycosyla s e s
LCP
B. Cros s linking
(NAM–NAG)n
(NAM–NAG)n (NAM–NAG)n (NAM–NAG)n
β-La cta m
a ge nts
tra ns pe ptida s e s
KEY
FIGURE 41-4 Inhibition o bacterial cell wall synthesis: vancomycin and β-lactam agents. Vancomycin inhibits the
polymerization or transglycosylase reaction (A) by binding to the d -alanyl-d -alanine terminus o the cell wall precur-
sor unit attached to its lipid carrier and blocks linkage to the glycopeptide polymer (indicated by the subscript n).
These (NAM–NAG)n peptidoglycan polymers are located within the cell wall. Van A-type resistance is due to
expression o enzymes that modi y cell wall precursor by substituting a terminal d -lactate or d -alanine, reducing
vancomycin binding af nity by 1000 times. β-Lactam antibiotics inhibit the cross-linking or transpeptidase reaction
(B) that links glycopeptide polymer chains by ormation o a cross-bridge with the stem peptide (the 5 glycines in
this example) o 1 chain, displacing the terminal d -alanine o an adjacent chain. See also Figure 39-1.
570
Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents CHAPTER 4 1
CASE 41 1
A 56-year-old man has developed a community-acquired skin in ection that is shown
to be methicillin-resistant S. aureus. An in ectious disease consultant recommends ini-
tial treatment with doxycycline.
a. Why doxycycline?
etracyclines, oxycycline, an minocycline have generally retaine excellent lev-
els o activity against staphylococci, inclu ing methicillin-resistant Staphylococcus
aureus (MRSA). Community-acquire strains o MRSA o en are susceptible to
tetracycline, oxycycline, or minocycline.
b. What is the mechanism o action o doxycycline?
etracyclines an glycylcyclines inhibit bacterial protein synthesis by bin ing to the
30S bacterial ribosome an preventing access o aminoacyl tRNA to the acceptor
site on the mRNA-ribosome complex (see Figure 41-1).
c. Another consultant has recommended chloramphenicol. Is this a good choice?
Chloramphenicol use shoul be limite to in ections or which the bene ts o the
rug outweigh the risks o the potential toxicities. In this case, the bene ts o not
outweigh the risks.
Chloramphenicol is potentially toxic to the bone marrow in two ways: (1) a ose-
relate toxicity that presents as anemia, leukopenia, or thrombocytopenia, an
(2) an i iosyncratic response mani este by aplastic anemia. T is latter response
may be atal i the bone marrow aplasia is complete. T e risk o aplastic anemia
oes not contrain icate the use o chloramphenicol in situations in which it may
be li esaving. However, the rug shoul never be use in un e ne situations
or in iseases that are rea ily, sa ely, an e ectively treate with other less toxic
antibiotics.
CASE 41 2
A 23-year-old woman college student is given a prescription or clarithromycin or
a Haemophilus in uenzae in ection.
a. What is the mechanism o action o clarithromycin and how does it dif er rom
that o tetracycline and chloramphenicol?
Clarithromycin acts by bin ing to the bacterial 50S ribosome (see Figure 41-3) to
inhibit bacterial protein synthesis. T is is the same site o action or chloramphenicol
an clin amycin an these agents (macroli es, clin amycin, an chloramphenicol)
may inter ere with each other’s actions i given concurrently. etracycline bin s to
the 30S subunit o the bacterial ribosome.
b. What atypical in ectious disease is commonly treated with clarithromycin?
Clarithromycin is use in combination with omeprazole (or other proton pump
inhibitor) an amoxicillin or the treatment o peptic ulcer isease cause by
H. pylori (see Chapter 32).
c. What toxicities should this patient be warned against?
Macroli es commonly cause GI upset which may inclu e nausea, vomiting, an
ab ominal pain. Erythromycin, clarithromycin, an telithromycin have been
reporte to cause car iac arrhythmias, inclu ing Q prolongation an ventricu-
lar tachycar ia. Most patients who experience car iac toxicity have un erlying
risk actors, such as here itary long Q syn rome, hypokalemia or hypomagne-
semia, pro oun bra ycar ia, or are receiving certain antiarrhythmic rugs (eg,
quini ine, procainami e, amio arone) or other agents that prolong Q c (see
Chapter 18).
(Continued)
571
SECTION VII Chemotherapy of Microbial Diseases
CASE 41 3
A 34-year-old woman in hospital has developed an E. aecium in ection that is resistant
to vancomycin. An in ectious disease consultant has recommended she be treated with
quinupristin/dal opristin.
a. Why is quinupristin given in combination with dal opristin?
Quinupristin bin s at the same site (on the 50S bacterial ribosome) as the macro-
li es an has a similar e ect. Dal opristin bin s at a site nearby, resulting in a
con ormational change in the 50S ribosome, synergistically enhancing the bin ing
o quinupristin at its target site.
b. What are the hazards o using this combination?
Quinupristin/ al opristin inhibits CYP3A4. T e concomitant a ministration o
other CYP3A4 substrates may result in signi cant toxicity. Appropriate caution an
monitoring are recommen e or rugs in which the toxic/therapeutic win ow is
narrow or or rugs that prolong the Q c interval.
c. Linezolid is another drug that might be use ul in treating this patient. Why
might this drug be an ef ective alternative?
Linezoli is FDA approve or the treatment o in ections cause by vancomycin-
resistant E. aecium. However, this agent is associate with some signi icant
a verse e ects.
d. What are the hazards o linezolid therapy?
Patients receiving long-term therapy with linezoli have evelope peripheral neu-
ropathy, optic neuritis, an lactic aci osis. T ese e ects are not always reversible.
Linezoli is a weak nonspeci c inhibitor o monoamine oxi ase an patients
receiving concomitant therapy with an SSRI may evelop serotonin syn rome.
CASE 41 4
A 62-year-old man has developed a so tissue in ection ollowing an auto accident.
Cultures are pending.
a. Is empirical treatment with vancomycin warranted?
Vancomycin is requently use in the empirical an e nitive treatment o skin/
so -tissue an bone/joint in ections, where gram-positive organisms inclu ing
MRSA are the lea ing pathogens. Vancomycin an teicoplanin have been use to
treat a wi e variety o in ections, inclu ing osteomyelitis an en ocar itis, cause
by methicillin-resistant an methicillin-susceptible staphylococci, streptococci, an
enterococci.
b. What is the mechanism o action o vancomycin
Vancomycin inhibits the polymerization or transglycosylase reaction by bin ing to
the d-alanyl-d-alanine terminus o the cell wall precursor unit attache to its lipi
carrier thus blocking linkage to the glycoprotein polymer (see Figure 41-4).
(Continued)
572
Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents CHAPTER 4 1
CASE 41 5
Cultures rom the patient in Case 41-4 are methicillin-resistant S. aureus that is also resistant
to vancomycin. T e decision has been made to switch the patient to daptomycin.
a. Why daptomycin?
Daptomycin may be active against vancomycin-resistant strains, although minimum
inhibitory concentrations (MICs) ten to be higher or these organisms than or
their vancomycin-susceptible counterparts.
b. What is the mechanism o action o daptomycin?
Daptomycin is an ionophore that bin s to bacterial membranes resulting in
epolarization, loss o membrane potential, an cell eath.
CASE 41 6
A 6-year-old boy has allen and scraped his knee. His mother goes to the pharmacy
to obtain an antibiotic ointment. T e pharmacist recommends an over-the-counter
preparation containing polymyxin, bacitracin, and neosporin.
a. Why is this combination o drugs available over-the-counter?
Polymyxin an bacitracin are available or the topical treatment o minor skin
in ections. Neosporin is an aminoglycosi e that is also available in topical prepa-
rations. Pro ucts that contain these antibiotics or otic or ophthalmic use are not
available over-the-counter.
b. What are the mechanisms o actions o the miscellaneous antibiotic agents
bacitracin, polymyxin, and mupirocin?
Polymyxins are sur ace-active amphipathic agents that interact with phospholipi s
an isrupt the structure o cell membranes. Bacitracin is an inhibitor o bacterial
cell wall synthesis. Mupirocin inhibits bacterial protein synthesis by reversibly
bin ing an inhibiting isoleucyl trans er-RNA synthetase.
KEY CONCEPTS
Doxycycline is a drug o choice or sexually transmitted diseases, rickettsial
in ections, plague, brucellosis, tularemia, and spirochetal in ections.
Macrolide antibiotics are e ective or treatment o respiratory tract in ections
caused by the common pathogens o community-acquired pneumonia,
including S. pneumoniae, Haemophilus spp., Chlamydia, mycoplasma, and
Legionella.
(Continued)
573
SECTION VII Chemotherapy of Microbial Diseases
SUMMARY QUIZ
574
Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents CHAPTER 4 1
QUESTION 41-6 Answer is e. Daptomycin neither inhibits nor induces CYPs, and
there are no signif cant drug–drug interactions.
575
SECTION VII Chemotherapy of Microbial Diseases
Chloramphenicol Chloramphenicol Limited to use in in ections or Resistance is reported Hypersensitivity Bone marrow toxicity
which the bene ts outweigh resulting in aplastic
the potential toxicities anemia
“Gray baby syndrome”
in neonates
Macrolides and Erythromycin, Respiratory tract in ections Resistance is common GI distress Cardiac arrhythmias in
Ketolides Clarithromycin, caused by Streptococcus patients with risk actors
Telithromycin, pneumonia and H. in uenzae such as prolonged QT
Azithromycin Alternatives or treatment o syndrome
erysipelas and cellulitis Inhibition o CYP3A4,
Chlamydial in ections associated with drug
Pertussis and Campylobacter interactions with other
in ections drugs metabolized by
Helicobacter pylori this CYP
(clarithromycin)
Disseminated mycobacterial
in ections (clarithromycin)
Streptogramins Quinupristin/ Bacteriocidal against Similar to macrolides Pain and Inhibition o CYP3A4
Dal opristin streptococci and many phlebitis at which may cause
strains o staphylococci but in usion site toxicity o other drugs
bacteriostatic against E. metabolized by this
aecium enzyme
Polymyxins Polymyxin B Not absorbed orally; available Emergence o resistance None, probably
Polymyxin E or ophthalmic, otic, and while on therapy is due to poor
topical use in combination documented systemic
with other agents absorption
(Continued)
576
Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents CHAPTER 4 1
Glycopeptides Vancomycin, Used to treat in ections caused Resistant strains o Hypersensitivity “Red man”syndrome rom
Teicoplanin by methicillin-sensitive and enterococci have reactions rapid IVin usion
methicillin-resistant strains o emerged as major Auditory impairment
staphylococci, streptococci, nosocomial pathogens
and enterococci
Bacitracin Bacitracin Use restricted to topical Not a major clinical Hypersensitivity reactions
application including problem are rare
ophthalmic and skin
ointments
Mupirocin Mupirocin Available or topical use No cross-resistance Irritation and Polyethylene glycol in the
or treatment o traumatic with other classes o sensitization ointment can be absorbed
skin lesions and impetigo antibiotics at the site o rom damaged skin
secondarily in ected with S. application
aureus or S. pyogenes
Nasal ointment is approved
or the eradication o S. aureus
nasal carriage
577
CHAPTER
Chemotherapyof Tuberculosis,
42 MycobacteriumAviumComplex
Disease, and Leprosy
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN THIS
Chapter 56, Chemotherapy o uberculosis, Mycobacterium Avium Complex Disease,
CHAPTER and Leprosy in Goodman & Gilman’s T e Pharmacological Basis o T erapeutics, 12th
• Aminoglycosides (streptomycin, amikacin, Edition. In addition to the material presented here, the 12th Edition contains:
kanamycin) (See Chapter 40) • able 56-1 Pathogenic Mycobacterial Rapid and Slow Growers (Runyon Classi cation)
• Capreomycin (CAPASTAT) • able 56-2 Population Pharmacokinetic Parameter Estimates or Antimycobacteial
• Clo azimine (LAMPRENE) Drugs in Adult Patients
• Cycloserine (SEROMYCIN) • able 56-3 Pharmacokinetic Parameters o Ri ampin, Ri abutin, and Ri apentine
• Dapsone • able 56-5 Drugs Used in the reatment o Mycobacteria Other T an or uberculo-
• Ethambutol (MYAMBUTOL) sis, Leprosy, or MAC (Mycobacterium Avium Complex)
• Ethionamide (TRECATOR) • Figure 56-4 Multimodal distribution o isoniazide (INH) clearance due to NA 2
polymorphisms
• Fluoroquinolones (o oxacin, cipro oxacin,
moxi oxacin) (See Chapter 38)
LEARNING OBJECTIVES
• Isoniazid (NYDRAZID)
Understand the rationale or combination drug therapy in the treatment o
• PA-824 tuberculosis ( B).
• Pyrazinamide Know the mechanisms o action and resistance or drugs used to treat B
• Ri amycins: Ri ampin (RIFADIN, RIMAC- and leprosy.
TANE, others), Ri apentine (PRIFTIN),
Describe the adverse e ects and drug interactions commonly associated with
Ri abutin (MYCOBUTIN)
anti- B drugs.
• TMC-207
Know the principles o anti- B chemotherapy.
Understand the principles o therapy o Mycobacterium Avium Complex
(MAC) disease.
Understand the principles o antileprosy therapy.
MECHANISMS OF ACTION AND RESISTANCE OF DRUGS USED TO TREAT TUBERCULOSIS AND LEPROSY
MECHANISM OF ACTION MECHANISM OF RESISTANCE
DRUG see Figure 42 1 see Figure 42 2
Ri amycins Binds to the β subunit o DNA-dependent RNA polymerase to orm a Mutations causing an alteration in the drug target
stable drug-enzyme complex thus suppressing chain ormation in RNA
synthesis
Pyrazinamide In Mycobacterium tuberculosis pyrazinamidase deaminates pyrazinamide Pyrazinamidases with reduced a nity or
to pyrazinoic acid (POA) which is protonated in an acidic environment to pyrazinamide
POAH which is responsible or microbial killing (see Side Bar PROPOSED
MECHANISMS FOR MICROBIAL KILLING BYPYRAZINAMIDE)
Isoniazid Activated in bacilli by catalase-peroxidase (KatG) to an isonicotinoyl Preexistent resistance can be expected in
radical that reacts with mycobacterial NAD and NADP to orm protein pulmonary TB cavities o untreated patients;
adducts; adduct ormation inhibits the ormation o mycolic acid and these resistant mycobacteria are selected and
mycobacterial dihydro olate reductase, thereby inter ering with nucleic ampli ed by isoniazid monotherapy; resistance is
acid synthesis (see Figure 42-3) associated with mutation or deletion o KatG, also
by enhancement o e ux pump activity
Ethambutol Inhibition o arabinosyl trans erase III with disruption o mycobacterial Mutations in the embBgene and possibly by
cell wall enhanced e ux pump activity
(Continued)
578
Chemotherapy of TB, MAC Disease, and Leprosy CHAPTER 4 2
Ethionamide Mycobacteria convert ethionamide to a sul oxide and another toxic Resistance occurs via changes in the enzyme that
intermediate; this results in inhibition o mycolic acid biosynthesis and activates ethionamide
impairment o cell wall synthesis
TMC-207 Targets subunit c o ATP synthase resulting in inhibition o proton pump Mutation o ATP synthase c subunit
and inter erence o energy metabolism
PA-824 Inhibition o mycolic acid and protein synthesis Mutation in target protein
Cycloserine Inhibition o alanine racemase and stopping reactions in which Resistance in clinical isolates has been
d -alanine is incorporated into cell wall synthesis demonstrated although mechanism is unknown
Capreomycin Inhibition o protein synthesis similar to aminoglycosides Resistance develops when given alone; there is
cross-resistance with kanamycin and neomycin
Dapsone Structural analog o para-aminobenzoic acid (PABA) and inhibitor o Mutations in genes encoding dihydropteroate
dihydropteroate synthase in olate pathway (see Figure 42-4) synthase
Approve d Drug s
RNA Polyme ra s e
Fluo ro quino lo ne :
mRNA inhibits DNA synthe s is a nd s upe rcoiling by
ta rge ting topois ome ra se
Rifamyc in:
30S DNA inhibits RNA synthe s is by ta rge ting RNA polyme ra s e
S tre pto myc in:
inhibits prote in synthe s is by ta rge ting the 30S
ribos oma l s ubunit
Mac ro lide s :
ta rge t 23S ribos oma l RNA, inhibiting Mycolic
pe ptidyl tra ns fe ra s e a cid
Ce ll wa ll
FIGURE 42-1 Mechanisms o action o established and experimental drugs used or the chemotherapy o mycobac-
terial in ections. Shown at the top are the sites o action o approved drugs or the chemotherapy o mycobacterial
diseases. Ri amycin is used as a generic term or several drugs, o which ri ampin is used most requently. Also included
are 2 experimental drugs now under investigation: TMC-207 and PA-824. Clo azimine, whose mode o action is not
understood, is omitted.
579
SECTION VII Chemotherapy of Microbial Diseases
Enzyme
pro-drug
H+ H+
+ +
H+ H H+ H
H+ H+
Muta tions in DNA RNA Polyme ra s e
re pa ir ge ne s le a d to
Low pH re nde rs
multiple drug re s is ta nce
drug ina ctive
(s tre ptomycin)
DNA
Drug exporte d from ce ll
be fore it re a che s ta rge t
(s tre ptomycin, is onia zid, e tha mbutol) Alte ra tion of ta rge t prote in s tructure
preve nts drug re cognition
(rifa mycin, e tha mbutol, s tre ptomycin,
fluoroquinolone, ma crolide )
PROPOSED MECHANISMS
FIGURE 42-2 Mechanisms o resistance o Mycobacteria to di erent chemotherapeutic drugs.
FOR MICROBIAL KILLING Shown are the various mechanisms by which mycobacteria resist antibacterial e ects o the
BY PYRAZINAMIDE currently approved chemotherapeutic agents.
• Inhibition o attyacid synthesis type I
leading to inter erence with mycolic
acid synthesis
• Reduction o intracellular pH
• Disruption o membrane transport by
protonated pyrazinoicacid (POAH)
Is o niazid N-ac e tyl is o niazid
(pro-drug) (ma jor me ta bolite )
CRITERION FOR O
PROPHYLACTIC H H
O N NH2 O N N C CH3
ANTITUBERCULOSIS THERAPY C C H
580
Chemotherapy of TB, MAC Disease, and Leprosy CHAPTER 4 2
CASE 42-1
On a recent trip to India, a 45-year-old man contracted tuberculosis that was con rmed
by culture. Antimicrobial susceptibility was per ormed and the patient was started on
isoniazid, ri ampin, and pyrazinamide as de nitive therapy or tuberculosis.
a. Why did this patient receive three drugs?
Only combination anti- B therapy is currently recommended or treatment o B.
When anti- B drug monotherapy was administered to B patients, resistance emer-
gence terminated the e ectiveness o these drugs. T e mutation rates to rst-line B
drugs are between 10−7 and 10−10 so that the likelihood o resistance is high to any
single anti- B drug in patients with cavitary B who have ~109 CFU (colony orm-
ing units) o bacilli in a 3-cm pulmonary lesion. However, the likelihood that bacilli
would develop mutations to 2 or more di erent drugs is the product o 2 mutation
rates which makes the probability o resistance emergence to more than 2 drugs
acceptably small. Multidrug therapy has also led to a reduction in length o therapy.
b. What is the mechanism o action o ri ampin?
Ri ampin enters bacilli in a concentration-dependent manner where it binds to the
β subunit o DNA-dependent RNA polymerase to orm a stable drug-enzyme com-
plex. Drug binding suppresses chain ormation in RNA synthesis (see Figure 42-1).
c. How should ri ampin therapy be optimized?
Ri ampin’s bactericidal activity is best optimized by a regimen to achieve a high
AUC/MIC (area under the curve/minimal inhibitory concentration) ratio, but
resistance suppression and ri ampin’s enduring postantibiotic e ect are best opti-
mized by high CPmax/MIC therapy (see Chapter 34). T ere ore, the duration o time
that the ri ampin concentration persists above the MIC is o less importance than
reaching a high CPmax. T e t ½ o ri ampin is less o an issue in optimizing therapy,
and i patients could tolerate it, higher doses would lead to higher bactericidal
activities while suppressing resistance.
d. For what clinical diseases, other than TB, might ri ampin be use ul?
Ri ampin is also use ul or the prophylaxis o meningococcal disease and Haemoph-
ilus inf uenza meningitis. Combined with a β-lactam antibiotic or vancomycin,
ri ampin may be use ul or therapy in selected cases o staphylococcal endocarditis
(Continued)
581
SECTION VII Chemotherapy of Microbial Diseases
CASE 42-2
A 35-year-old woman hospital employee has a routine tuberculin skin test reaction
o 18 mm. She is started on prophylactic isoniazid therapy o 300 mg daily. She is also
started on pyridoxine (vitamin B6).
a. What is the mechanism o action o isoniazid?
Isoniazid is activated within the bacillus to an isonicotinoyl radical by KatG, a
multi unctional catalase-peroxidase (see Figure 42-3). T is radical interacts with
mycobacterial NAD and NAPD to orm adducts that inhibit the activities o
enzymes responsible or the synthesis o mycolic acid, an essential component o
the mycobacterial cell wall. T e adducts also inhibit mycobacterial dihydro olate
reductase and inter ere with nucleic acid synthesis.
b. How is isoniazid metabolized?
Isoniazid is metabolized by hepatic arylamine N-acetyltrans erase type 2 (see
Figure 42-3). Isoniazid clearance in patients can be classi ed into 2 phenotypic
groups: slow and ast acetylators as seen in Figure 56-4 o Goodman and Gilman’s T e
Pharmacological Basis o T erapeutics, 12th Edition. Recently the phenotypic groups
have been expanded to ast, intermediate, and slow acetylators. T e number o NA 2*4
alleles accounts or 88% o the variability o isoniazid clearance. Slow acetylators may
be a greater risk or adverse e ects rom isoniazid, sul onamides, and procainamide.
Fast acetylators may have diminished responses to standard doses o these agents but a
greater risk rom bioactivation by NA 2 o arylamine/hydrazine carcinogens.
CASE 42-3
In the patient in Case 42-2:
a. What are the potential side e ects o isoniazid therapy in this otherwise healthy
woman?
Isoniazid is converted to acetylisoniazid which can be converted to acetylhydrazine
and hepatotoxic metabolites by CYP2E1. Rapid acetylators will orm diacetylhy-
drazine which is nontoxic, while slow acetylators or CYP2E1 induction will lead to
more hepatotoxic metabolites. Ri ampin, a potent inducer o CYP2E1, potentiates
isoniazid hepatotoxicity.
Isoniazid also can cause a peripheral neuritis (see answer to Case 42-3c below).
b. What drug interactions should she be warned o ?
Isoniazid is a potent inhibitor o CYP2C19, CYP3A, and a weak inhibitor o
CYP2D6. Isoniazide induces CYP2E1. Drugs metabolized by these enzymes will
potentially be a ected. able 42-1 lists the potential drug interactions that might
occur with isoniazid and their adverse e ects.
c. Why is she also given a vitamin?
As mentioned above in the answer to question a o this case, isoniazid causes a
peripheral neuritis (most commonly paresthesias o the eet and hands). T is
neuropathy is more requent in slow acetylators and in individuals with diabetes
mellitus, poor nutrition, or anemia. T e prophylactic administration o pyridoxine
(vitamin B6) prevents the development o peripheral neuritis even when therapy
lasts as long as 2 years.
582
Chemotherapy of TB, MAC Disease, and Leprosy CHAPTER 4 2
CASE 42-4
A 25-year-old medical resident has developed active B a er being exposed in the hos-
pital. It is known that the patient she was exposed to had a strain o M. tuberculosis that
was resistant to isoniazid. She is started on ri ampin, pyrazinamide, and ethambutol.
a. What is the mechanism o action o ethambutol?
Ethambutol inhibits arabinosyl trans erase III which disrupts the assembly o the
mycobacterial cell wall.
b. I this patient’s M. tuberculosis is resistant to isoniazid, might it also be resistant
to ethambutol?
Mycobacterial resistance to ethambutol develops via mutations in the embB gene.
However, enhanced e ux pump activity may induce resistance to both isoniazid
and ethambutol. T us, resistance to isoniazid does not necessarily predict resis-
tance to ethambutol.
c. What serious side e ect o ethambutol should this patient be warned about?
About 1% o patients receiving ethambutol experience diminished visual acuity.
Approximately 15% o patients receiving a dose o ethambutol o 50 mg/kg/d will
develop optic neuritis resulting in decreased visual acuity and an inability to dis-
tinguish red rom green. T e incidence o this reaction is proportional to the dose
o ethambutol with approximately 1% o patients who receive a dose o 15 mg/kg/d
experiencing this e ect.
CASE 42-5
A 36-year-old man in Central A rica has developed leprosy. He is being treated with
ri ampin, clo azimine, and dapsone.
a. Why 3 drugs?
T e reasons or using combination therapy in the treatment o leprosy include
reduction in the development o resistance, the need or adequate therapy when
primary resistance already exists, and reduction in the duration o therapy. Ri ampin
is the most bactericidal drug in the regimen. Clo azimine is only bacteriostatic
against Myocobacterium leprae; however, it also has anti-in ammatory e ects.
(Continued)
583
SECTION VII Chemotherapy of Microbial Diseases
584
Chemotherapy of TB, MAC Disease, and Leprosy CHAPTER 4 2
SUMMARY QUIZ
QUESTION 42-1 A 35-year-old man has developed a tuberculin skin reaction that is 20 mm
in size. He is being treated with a triple-drug regimen o isoniazid, ri ampin, and pyra-
zinamide but is concerned because o the number o medications he must take every
day. He is a slow acetylator o isoniazid. He asks why other antibiotics like penicillin are
not e ective in treating tuberculosis. Your answer is that the tuberculosis bacteria
a. have developed a resistance to penicillin.
b. have a rigid cell wall that does not allow penicillin to get inside the cell.
c. destroy the penicillin.
d. multiply too rapidly or the penicillin to be e ective.
e. are anaerobic.
QUESTION 42-2 T e patient in Case 42-1 should be instructed to take his ri ampin on
an empty stomach because
a. ood decreases the peak plasma concentration o ri ampin by one-third.
b. ri ampin may a ect the taste o ood.
c. ood increases the absorption o ri ampin and may cause toxicity.
d. ood increases gastric transit.
e. ood increases gastric acid secretion which may destroy the ri ampin.
QUESTION 42-6 A 63-year-old woman has developed leprosy and is being treated with
a combination o ri ampin, clo azimine, and dapsone. A de ciency o which o the
ollowing enzymes is o speci c concern with dapsone therapy?
a. N-acetyltrans erase
b. DNA gyrase (Continued)
585
SECTION VII Chemotherapy of Microbial Diseases
c. Pyrazinamidase
d. Glucose-6-phosphate dehydrogenase
e. Glutathione trans erase
586
Chemotherapy of TB, MAC Disease, and Leprosy CHAPTER 4 2
TOXICITY
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAME CLINICAL USES RESISTANCE COMMON IMPORTANT
Isoniazid NYDRAZID Available to treat TB either alone, Prevalence o resistance Hepatic injury due to the
or in combination with ri ampin is about 1 in 106 bacilli; ormation o hepatotoxic
or pyrazinamide preexisting resistance metabolites
can be expected in Peripheral neuropathy
pulmonary TB cavities o that is prevented
untreated patients by the prophylactic
administration o
pyridoxine
Ethambutol MYAMBUTOL Oral administration or the treatment 30-70% o clinical Lowered visual Optic neuritis with loss
o TB, disseminated MAC, and isolates are resistant to acuity, rash, o visual acuity
Mycobacterium kansaii in ection ethambutol drug ever
Clo azimine LAMPRENE Part o multiple drug therapy with Abdominal pain, Body f uid discoloration
ri ampin and dapsone or the diarrhea, nausea,
treatment o leprosy and vomiting
TMC-207 Good activity against M. tuberculosis, Nausea and Full side-e ect pro le is
MAC, M. leprae, Mycobacterium diarrhea not clear at this time
bovis, Mycobacterium marinum,
M. kansaii, Mycobacterium
ulcerans, Mycobacterium ortuitum,
Mycobacterium szulgai, and
Mycobacterium abscessus
PA-824 In vitro it kills non-replicating M. Not known at Not known at this time
tuberculosis under aerobic conditions this time
and replicating bacilli in ambient air
Ethionamide TRECATOR Second-line drug or the Resistance occurs GI upset Severe postural
treatment o TB via mutations in the hypotension
enzyme that activates Mental depression,
ethionamide drowsiness, blurred
vision, diplopia, dizziness,
paresthesias; neurologic
symptoms are relieved by
pyridoxine (vitamin B6)
Capreomycin CAPASTA Second-line drug or the treatment Resistance develops Hearing loss, Should not be
o TB when given alone tinnitus, administered with other
Antimicrobial activity is similar to proteinuria drugs that damage
aminoglycosides cranial nerve VIII
Dapsone Bacteriostatic against M. leprae Resistance occurs Skin rashes Hemolysis in patients with
Highly e ective against rom mutations in G6PD de ciency treated
Plasmodium alciparum genes encoding with 200-300 mg/d
dihydropteroate synthase Rarely psychosis
587
CHAPTER
43 Antifungal Agents
T is chapter will be most use ul a er having a basic understanding o the material
DRUGS INCLUDED IN
in Chapter 57, Anti ungal Agents in Goodman & Gilman’s T e Pharmacological
THIS CHAPTER Basis of T erapeutics, 12th Edition. In addition to the material presented here,
• Amphotericin B(FUNGIZONE); colloidal the 12th Edition contains:
dispersion (AMPHOTEC, AMPHOCIL); • Structural ormulas or each o the anti ungal agents in addition to the gures
liposomal ormulation (AMBISOME); lipid reproduced here
complex(ABELCET)
• able 57-1 Pharmacotherapy o Mycoses which lists the drugs used or di erent
• Anidula ungin (ERAXIS) mycoses
• Butenafne (MENTAX,LOTRIMINULTRA) • able 57-7 Pharmacokinetics o Echinocandins in Humans which shows the
• Butoconazole (FEMSTAT3, others) pharmacokinetic di erences among caspo ungin, mica ungin, and anidula ungin
• Caspo ungin (CANCIDAS)
LEARNING OBJECTIVES
• Ciclopiroxolamine (LOPROX,others)
Understand the mechanisms o action and resistance o anti ungal agents.
• Clotrimazole (LOTRIMIN, MYCELEX,GYNE-
LOTRIMIN, others) Describe the therapeutic uses o anti ungal agents in the context o treatment
• Fluconazole (DIFLUCAN, others) or ungal diseases.
• Flucytosine (ANCOBON) Develop knowledge o the common and unique toxicities o anti ungal agents.
• Griseo ulvin (GRIFULVINand GRIS-PEG) Understand the drug–drug interactions that can occur with the use o azole
anti ungal agents.
• Haloprogin (HALOTEX)
• Isavuconazole (BAL8557) (investigational) Know the di erences in treating invasive ungal in ections with systemic drugs
versus super cial in ections with topical anti ungal agents.
• Itraconazole (SPORANOX,others)
• Ketoconazole (NIZORAL, others)
• Mica ungin (MYCAMINE) MECHANISMS OF ACTION AND RESISTANCE OF ANTIFUNGAL DRUGS
• Miconazole (MICATIN, ZEASORB-AF, MECHANISM OF ACTION
MONISTAT7, MONISTAT3, MONISTAT1, DRUG (see Figure 43-1) MECHANISM OF RESISTANCE
others) Amphotericin B Binds to ergosterol in ungi Resistance is rare, but may be caused
• Na tifne (NAFTIN) membranes to orm pores and by replacement o ergosterol with
increase membrane permeability precursor sterols
• Nystatin (MYCOSTATIN, NILSTAT,
NYOTRAN, others) Flucytosine Converted in ungi to 5- uorouracil Resistance is due to a loss o the
(5-FU), which is incorporated into ungal permease necessary or
• Oxiconazole (OXISTAT)
RNA and inhibits nucleic acid cytosine transport or a decrease in
• Posaconazole (NOXAFIL) synthesis (see Figure 43-2) ungal cytosine deaminase activity
• Sertaconazole (ERTACZO) Imidazoles and Impaired ergosterol synthesis Mutation in ERG11, the gene coding
• Sulconazole (EXELDERM, SULCOSYN) Triazoles due to inhibition o 14-α-sterol or the 14-α-sterol demethylase
demethylase
• Terbinafne (LAMISIL, others)
• Terconazole (TERAZOL, others) Echinocandins Inhibition o 1,3-β-d -glucan Mutations in glucan synthase
synthesis in ungal cell wall resulting complex genes
• Tioconazole (VAGISTAT1, others)
in loss o structural integrity,
• Tolna tate (AFTATE, TINACTIN, others) osmotic instability, and cell death
• Undecylenicacid (DESENEX,others); Cal- Griseo ulvin Inhibition o microtubule unction De cient energy-dependent
ciumundecylenate (CALDESENE, CRUEX) and inhibition o ungal mitosis transport system used to get
• Voriconazole (VFEND) anti ungal agent to microtubules
• Whitfeld’s Ointment Terbina ne Inhibition o ungal squalene Mutations in squalene epoxidase
epoxidase, blocking ergosterol
biosynthesis, and disruption o
ungal cell membrane
588
Antifungal Agents CHAPTER 4 3
cytos ine
de a mina s e
5-FU Flucytos ine
Me mbrane func tio n
a mphote ricin B
uP RTa s e
Erg o s te ro l s ynthe s is
flucona zole
itra cona zole 5-FUMP 5-FUDP 5-FUTP
voricona zole
na ftifine
te rbina fine ribonucle otide
re ducta s e
5-FdUMP RNA
CASE 43 1
A 56-year-old woman is diagnosed with mucormycoses involving the maxillary
sinuses. An in ectious disease consultant recommends that she be treated with
amphotericin B.
a. What di erent ormulations o amphotericin B are available or her treatment?
T ere are currently 4 ormulations o amphotericin B commercially available:
conventional amphotericin B (C-AMB), liposomal amphotericin B (L-AMB),
amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion
(ABCD). able 43-1 summarizes the pharmacokinetic properties o these di erent
preparations.
b. What are the major di erences in these ormulations?
C-AMB is insoluble in water, but is ormulated or intravenous use by complexing
it with the bile salt, deoxycholate. ABCD orms a colloidal solution when
dispersed in water and provides much lower blood concentrations than C-AMB.
(Continued)
TABLE 43-1 Pharmocokinetic Parameters for Amphotericin B Formulations after Multiple Administrations in Humans
PRODUCT DOSE (mg/kg) CMAX (µg/mL) AUC(1-24hr) (µg .hr/mL) V (L/kg) Cl (mL/hr/kg)
AmBisome (L-AMB) 5 83±35.2 555±311 0.11±0.08 11±6
For details, see Boswell et al. (1998). From Boswell GW, Buell D, Bekersky I. AmBisome (Liposomal Amphotericin B): A comparative review. J Clin
Pharmacol, 1998, 38:583-592. © 1998 The American College o Clinical Pharmacology. Reprinted by permission o SAGE Publications.
589
SECTION VII Chemotherapy of Microbial Diseases
In usion reactions o chills and ever are more common with ABCD than with
C-AMB. L-AMB is supplied as a lyophilized powder and has equivalent blood
concentrations as C-AMB. L-AMB is approved or empirical therapy o ever in the
neutropenic host not responding to appropriate antibacterial agents, as well as or
salvage therapy o aspirgillosis and candidiasis. ABLC provides blood concentra-
tions o amphotericin B that are much lower than with the same dose o C-AMB.
ABLC is approved or salvage therapy o deep mycoses.
he lipid ormulations appear to reduce the risk o nephrotoxicity during
therapy. T e cost o the lipid ormulations o amphotericin B greatly exceeds that
o C-AMB.
c. What is the mechanism o action o amphotericin?
T e aniti ungal activity o amphotericin B depends principally on its binding to a
sterol moiety, primarily ergosterol, in the membrane o sensitive ungi. By virtue o
their interaction with these sterols, polyenes, appear to orm pores or channels that
increase the permeability o the membrane, allowing the outward leakage o a vari-
ety o small molecules (see Figure 43-1).
d. What untoward e ects should be watched or in this patient?
Major untoward e ects o amphotericin B are in usion-related reactions such as
ever and chills. T ese are most severe with ABCD, slightly less with C-AMB, even
less with ABLC, and least with L-AMB.
Nephrotoxicity with amphotericin, a major concern, is dose-dependent, usually
transient, and increased by concurrent therapy with other nephrotoxic agents such
as aminoglycosides or cyclosporine. Permanent unctional renal impairment is
uncommon in adults with normal renal unction prior to treatment.
Hypochromic, normocytic anemia commonly occurs during treatment
with C-AMB.
CASE 43 2
A 19-year-old woman with coccidiodal meningitis is being treated with uconazole.
a. Why is f uconazole chosen instead o amphotericin B?
Fluconazole is the drug o choice or the treatment o coccidioidal meningitis
because o good penetration into the cerebrospinal uid and much less morbidity
than with intrathecal amphotericin B.
b. What are the limitations to the use o f uconazole?
Fluconazole is a Category C agent that should be avoided during pregnancy unless
the potential bene t justi es the possible risk to the etus.
Fluconazole is an inhibitor o CYP3A4 and CYP2C9, and drug–drug interactions
(shown in ables 43-2 to 43-5) are a limitation to the use o this drug.
590
Antifungal Agents CHAPTER 4 3
TABLE 43-3 Drugs Exhibiting Elevated Plasma Concentrations When Co-Administered with Azole Anti-Fungal Agents
Mechanism o interaction presumably occurs largely at the level o hepatic CYPs, especially CYPs 3 A4, 2C9, and 2D6, but can also involve
P-glycoprotein and other mechanisms. Not all drugs listed interact equally with all azoles.
TABLE 43-4 Some Drugs That Decrease Azole Concentration When Co-Administered
DRUG FLUCONAZOLE VORICONAZOLE ITRACONAZOLE POSACONAZOLE
Antacids (simultaneous) - + -
Barbiturates + +a
Carbamazepine + + + +
H2 antagonists + +
Didanosine +
E avirenz + +
Nevirapine + +
Phenytoin - + + +
Ri ampin + + + +
Ri abutin + + +
Ritonavir +
a
Phenobarbital only.
b
Omeprazole and voriconazole increase each other’s concentrations in plasma; reduce omeprazole dose by 50% when initiating voriconazole
therapy.
Reproduced with permission rom Zonios DI, Bennett JE. Update on azole anti ungals. Sem Respir Crit Care Med. 2008;29:192–210.
591
SECTION VII Chemotherapy of Microbial Diseases
Artemether X X
Bepridil X
Clopidogrel X
Conivaptan X X X X
Dabigatran X
Darunavir X
Dronedarone X X X X
Everolimus X X X X
Lopinavir X
Lume antrine X X
Mesoridazine X
Nilotinib X X X X
Quinine X X
Rivaroxaban X X
Salmeterol X X X
Silodosin X X X
Tetrabenazine X X
Thioridazine X X
Tolvaptan X X X
Tolvaptan X X
Topotecan X
Ziprasidone X X
CASE 43 3
A 26-year-old woman has developed esophageal candidiasis. She is being treated with
oral voriconazole. She is also being treated or a seizure disorder and depression, and
during the course o her anti ungal therapy, she will be taking several other drugs.
a. What is the mechanism o action o voriconazole?
Voriconazole, a triazole, is an inhibitor o 14-α-sterol demethylase and impairs
the biosynthesis o ergosterol required or the ungal cytoplasmic membrane and
thereby inhibits growth o ungi (see Figure 43-1).
(Continued)
592
Antifungal Agents CHAPTER 4 3
Extra c e llula r s p a c e
Ce ll wa ll
Gluca n syntha s e
complex
Pe rip la s m
P la s ma me mb ra ne
Cytop la s m
Echinoca ndin
a nti-funga l
FIGURE 43-3 The ungal cell wall and membrane and the action o echinocandins. The strength
o the ungal cell wall is maintained by brillar polysaccharides, largely β-1,3-glucan and chitin,
which bind covalently to each other and to proteins. A glucan synthase complex in the plasma
membrane catalyzes the synthesis o β-1,3-glucan; the glucan is extruded into the periplasm and
incorporated into the cell wall. Echinocandins inhibit the activity o the glucan synthase complex,
resulting in loss o the structural integrity o the cell wall. A subunit o glucan synthase desig-
nated Fks1p is thought to be the target o the echinocandin. Mutations in Fks1p, coded or by
FSK1, cause resistance to echinocandins.
b. What drug interactions are o concern while this patient is taking voriconazole?
Voriconazole is metabolized by, and inhibits, CYPs 2C19, 2C9, and 3A4. Drug
interactions with voriconazole are summarized in ables 43-2, 43-3, 43-4, and 43-5.
c. What other untoward e ects should this patient be warned o ?
Voriconazole is contraindicated in pregnancy (Category D). Voriconazole also
causes a prolongation o the Q c interval, which can become signi cant in patients
with other risk actors or torsades de pointes.
CASE 43 4
An in ectious disease consultant has suggested that the patient in Case 43-3 could be
treated with caspo ungin.
a. What is caspo ungin and what is its role in the treatment o esophageal candidiasis?
Caspo ungin belongs to the Echinocandin class o anti ungal agents. Caspo ungin is
approved or initial therapy o deeply invasive candidiasis and as salvage therapy or
patients with invasive aspergillosis who are ailing or intolerant o approved drugs such
as amphotericin B or voriconzaole. Caspo ungin is approved or esophageal candidiasis.
b. What is the mechanism o action o the Echinocandin class o anti ungal agents?
Echinocandins inhibit the activity o the glucan synthase complex, resulting in loss
o the structural integrity o the ungal cell wall, osmotic instability, and cell death
(see Figure 43-3).
CASE 43 5
A 47-year-old man has developed an irritated and itchy beard. T e cause is diagnosed
as tinea ( richophyton spp.). He is being treated with griseo ulvin orally.
a. What is the mechanism o action o griseo ulvin and why is it e ective in
treating this patient?
Griseo ulvin inhibits ungal microtubule unction and thereby disrupts assembly
o the mitotic spindle with inhibition o ungal mitosis. It is deposited in keratin
(Continued)
593
SECTION VII Chemotherapy of Microbial Diseases
precursor cells; when these cells di erentiate, the drug is tightly bound to, and per-
sists in keratin, providing prolonged resistance to ungal in ection. T us, the new
growth o hair or nails is the rst to become ree o disease. As the ungus-containing
keratin is shed, it is replaced by normal tissue.
b. T ere are numerous anti ungal creams available, why not use one o these?
opical treatment is use ul in many super cial ungal in ections, that is, those
con ned to the stratum corneum, squamous mucosa, or cornea. opical admin-
istration o anti ungal agents usually is not success ul or mycoses o the nails
(onychomycosis) and hair (tinea capitis), and has no place in the treatment o
subcutaneous mycoses, such as sporotrichosis and chromoblastomycosis.
c. What are the untoward e ects o griseo ulvin therapy?
T e incidence o serious reactions due to griseo ulvin is very low. Headache,
which may be severe, usually disappears as therapy is continued. Hepatotoxicity
has been reported. Leukopenia and neutropenia warrant the monitoring o weekly
blood studies during the rst month o therapy.
Griseo ulvin induces hepatic CYPs and may increase the metabolism o war arin
and may reduce the ef cacy o low-estrogen oral contraceptive agents.
CASE 43 6
A 36-year-old woman has developed vaginal candidiasis and is being treated with
miconazole vaginal suppositories.
a. What are the advantages o using topical anti ungal creams?
Vaginal creams, suppositories, and tablets, e ective or the treatment o vaginal
candidiasis, are all used once a day or 1 to 7 days, pre erably at bedtime to acilitate
retention. Approximately 3 to 10% o the vaginal dose is absorbed. T e most common
side e ect is vaginal burning or itching. A male sexual partner may experience mild
penile irritation.
KEY CONCEPTS
Anti ungal agents have 3 mechanisms o action: inhibit synthesis o cell wall
components, inhibit synthesis o nucleic acids, or inhibit microtubule/mitotic
spindle unction.
Amphotericin B comes in 4 ormulations that have speci c advantages and
disadvantages.
Imidazoles and triazoles are anti ungal agents that share the same spectrum o
activity and mechanism o action.
T e azoles interact with hepatic CYPs as substrates and inhibitors, and drug–drug
interactions may limit their use in certain patients (see ables 43-2, 43-3, 43-4,
and 43-5).
T e echinocandins are well-tolerated anti ungal agents, and are used mainly or
invasive candidiasis and aspergillosis.
Griseo ulvin therapy is used or mycotic disease o the skin, hair, and nails due
to Microsporum, richophyton, or Epidermophyton.
opical anti ungal treatment is use ul or super cial in ections con ned to the
stratum corneum, squamous mucosa, or cornea.
Anti ungal agents are ormulated in creams or vaginal use to treat vaginal
candidiasis.
594
Antifungal Agents CHAPTER 4 3
SUMMARY QUIZ
QUESTION 43-2 A 56-year-old man with cryptococcal meningitis is being treated with
ucytosine and amphotericin B. Flucytosine is metabolized to 5- urouracil by ungal
cells which inhibits DNA synthesis. T e selectivity o ucytosine is due to a lack o
which enzyme in mammalian cells:
a. Cytosine deaminase
b. N-acetyltrans erase
c. Fluorine oxidase
d. Uracil phosphoribosyl trans erase
e. T ymidylate synthetase
QUESTION 43-5 A 69-year-old man with onychomycosis is being treated with griseo-
ulvin. His treatment has been going on or 1 month and he has been told that it may
last or 1 year. Although he has had no serious side e ects, his compliance is waning.
reatment o onchomycosis with griseo ulvin is prolonged because it is
a. absorbed slowly.
b. metabolized rapidly.
c. metabolized completely and the metabolites are inactive.
d. excreted rapidly in the urine.
e. bound to keratin and requires shedding o ungal-containing keratin.
595
SECTION VII Chemotherapy of Microbial Diseases
TOXICITY
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAME CLINICAL USES RESISTANCE COMMON IMPORTANT
Imidazoles and Itraconazole In ections due to B. Resistance emerges Drug interactions, Doses o 300 mg
triazoles dermatitides, H. capsulatum, P. gradually during see Tables 43-2, twice daily have
braziliensis, and C. immitis prolonged azole therapy 43-3, 43-4, and led to adrenal
43-5 insu ciency and
hypertension
Imidazoles and Clotrimazole, cream, Cutaneous dermatophyte Recurrences common in Local irritation, No serious systemic
triazoles or lotion, powder, in ections, including cutaneous all in ections including vaginal toxicities
topical use aerosol solution, and vulvovaginal candidiasis burning; sexual
and solution; vaginal partner may
cream or tablets; experience penile
troches irritation
597
SECTION VII Chemotherapy of Microbial Diseases
TOXICITY
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAME CLINICAL USES RESISTANCE COMMON IMPORTANT
Griseo ulvin Micro-sized powder; Mycotic diseases o the Headache usually Induction o CYP
Ultra-micro-sized skin, hair, and nails due to disappears and increases the
powder Microsporum, Trichophyton, or as therapy is rate o metabolism
Epidermophyton; itraconazole stopped o war arin requiring
or terbina ne is more ef ective an adjustment o
or onychomycosis war arin dose
Terbina ne LAMASIL, others Onychomycosis, tinea capitus, Low incidence Not recommended
ring worm o GI distress, or treatment
Cream or spray is used to treat headache, or rash o patients with
tinea corporis, tinea cruris, and azotemia or hepatic
tinea pedis ailure
Pregnancy Category B
Tolna tate AFTATE, TINACTIN Cream, gel, powder, aerosol No toxic or allergic
powder, topical solution, reaction have
topical aerosol liquid are used been noted
or treatment o tinea pedis
(Continued)
598
Antifungal Agents CHAPTER 4 3
TOXICITY
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAME CLINICAL USES RESISTANCE COMMON IMPORTANT
Na ti ne NAFTIN Cream or gel ef ective or Local irritation
treatment o tinea cruris and and contact
tinea corporis dermatitis
599
CHAPTER
LEARNING OBJECTIVES
Understand the treatment o herpes virus in ections and the use o antiherpes
drugs.
Know the treatment strategies or chronic hepatitis B and C in ections.
Understand the mechanisms o action and resistance, and the therapeutic use
o the anti-in uenza agents.
Know the principles o HIV chemotherapy.
Know the mechanisms o action and resistance, the untoward ef ects, and the
therapeutic uses o the drugs used to treat HIV in ections.
600
Antiviral Agents and Treatment of HIV Infection CHAPTER 4 4
Integrase Inhibitor
Raltegravir ISENTRESS
a
Not currently approved in the United States.
b
A number o xed-dose combinations are available: zidovudine + lamivudine (COMBIVIR); zidovudine + lamivudine + abacavir
(TRIZIVIR); abacavir + lamivudine (EPZICOM); teno ovir + emtricitabine (TRUVADA); teno ovir + e avirenz + emtricitabine (ATRIPLA).
c
Lopinavir is available only as a xed-dose combination with ritonavir (KALETRA/ALUVIA).
Cido ovir Inhibits viral DNA synthesis by slowing and eventually Resistance in cytomegalovirus (CMV) is due to
terminating chain elongation; the diphosphate acts as mutations in DNA polymerase
a competitive inhibitor o deoxycytidine triphosphate
(dCTP) and as alternative substrate or DNA polymerase
601
SECTION VII Chemotherapy of Microbial Diseases
Penciclovir Inhibits viral DNA synthesis by competitive inhibition o Mutations in thymidine kinase or viral
viral DNA polymerase (see Figures 44-1 and 44-2) DNA polymerase
Foscarnet Inhibits viral nucleic acid synthesis by interacting with Mutations in herpes virus DNA polymerase
herpes virus DNA polymerase or HIVreverse transcriptase
(see Figure 44-1)
Ganciclovir Competitive inhibitor o deoxyguanosine triphosphate CMVresistance is due to either mutations in viral
incorporation into DNA and inhibition o viral DNA phosphotrans erase which reduces intracellular
polymerase (see Figures 44-1 and 44-2) ganciclovir phosphorylation or mutations in viral
DNA polymerase
Tri uridine The monophosphate inhibits thymidylate synthesis Tri uridine-resistant HSVhave altered thymidine
and the triphosphate inhibits thymidine triphosphate substrate speci city
incorporation into DNA
Ribavirin Alteration o cellular nucleotide pool and inhibition Not documented, but cells that do not
o viral mRNA synthesis phosphorylate ribavirin to its active orm have
been reported
Ade ovir dipivoxil Competitive inhibition o viral DNA polymerase and Point mutations in hepatitis B virus (HBV)
reverse transcriptases polymerase
Inter eron Activates JAK-STAT pathway that leads to synthesis o Block production or activity o inter eron-inducible
over 2 dozen proteins that contribute to antiviral activity proteins
at various stages o viral penetration (see Figure 44-3)
Lamivudine Inhibitor o DNA polymerase/reverse transcriptase o HIV Point mutations in HBVDNA polymerase
and HBV(see Figures 44-4 and 44-5)
Amantadine Inhibits viral replication by inhibition o viral uncoating Mutation in the RNA sequence encoding or
(see Figure 44-1) the M2 protein transmembrane domain
Oseltamivir Selective inhibitor o viral neuraminidase which leads to Mutations in viral hemagglutinin and/or
virus aggregation at the cell sur ace and reduced virus neuraminidase
spread (see Figure 44-1)
Rimantadine Inhibits viral replication by inhibition o viral uncoating Mutation in the RNA sequence encoding or the
(see Figure 44-1) M2 protein transmembrane domain
Zanamivir Inhibition o viral neuraminidase which leads to virus Mutations in viral hemagglutinin and/or
aggregation at the cell sur ace and reduced virus spread neuraminidase
(see Figure 44-1)
Teno ovir disoproxil Reverse transcriptase inhibitor o HIVand HBV(see Mutations in reverse transcriptase
Figures 44-4 and 44-5)
Imiquimod Induces cytokines and chemokines with antiviral and None known
immunomodulating e ects
Zidovudine Inhibition o nucleoside reverse transcriptase (see Figures Mutations in reverse transcriptase
44-4 and 44-5)
(Continued)
602
Antiviral Agents and Treatment of HIV Infection CHAPTER 4 4
Stavudine Reverse transcriptase inhibitor (see Figures 44-4 Mutations in reverse transcriptase
and 44-5)
Abacavir Reverse transcriptase inhibitor (see Figures 44-4 Mutations in reverse transcriptase
and 44-5)
Emtricitabine Reverse transcriptase inhibitor (see Figures 44-4 Mutations in reverse transcriptase
and 44-5)
Saquinavir HIVprotease inhibitor (see Figures 44-5 and 44-6) Accumulation o multiple resistance mutations
Indinavir HIVprotease inhibitor (see Figures 44-5 and 44-6) Accumulation o multiple resistance mutations
Ritonavir HIVprotease inhibitor (see Figures 44-5 and 44-6) Mostly used as a pharmacokinetic enhancer
(CYP3A4 inhibitor) and at the low doses used is not
known to induce resistance
Nel navir Nonpeptidic protease inhibitor (see Figures 44-5 Mutation in HIVprotease
and 44-6)
Amprenavir HIVprotease inhibitor (see Figures 44-5 and 44-6) Mutation in HIVprotease
Lopinavir HIVprotease inhibitor (see Figures 44-5 and 44-6) Mutation in HIVprotease
Atazanavir HIVprotease inhibitor (see Figures 44-5 and 44-6) Mutation in HIVprotease
Tipranavir HIVprotease inhibitor (see Figures 44-5 and 44-6) Resistance requires accumulation o multiple
mutations
Darunavir HIVprotease inhibitor (see Figures 44-5 and 44-6) Resistance requires accumulation o multiple
mutations
Nevirapine Non-nucleoside reverse transcriptase inhibitor (see Mutation in reverse transcriptase; cross-resistance
Figures 44-5 and 44-7) extends to e avirenz and delavirdine
E avirenz Non-nucleoside reverse transcriptase inhibitor (see Mutation in reverse transcriptase; cross-resistance
Figures 44-5 and 44-7) extends to nevirapine and delavirdine
Delavirdine Non-nucleoside reverse transcriptase inhibitor (see Mutation in reverse transcriptase; cross-resistance
Figures 44-5 and 44-7) extends to nevirapine and e avirenz
Etravirine Non-nucleoside reverse transcriptase inhibitor (see Mutation in reverse transcriptase; activity o
Figures 44-5 and 44-7) etravirine is not a ected by mutations that con er
high-level resistance to e avirenz, delavirdine,
and nevirapine
En uvirtide Prevents ormation o a complex critical or membrane Retains activity against viruses that have become
usion and viral entry into the host cell (see Figures 44-5 resistant to antiviral agents o other classes
and 44-8)
Maraviroc A chemokine receptor antagonist that binds to host HIVthat is predominantly CCR5-tropic shi ts
CCR5 receptor to block binding o viral gp120 (see tropism to CXCR4; or there is a mutation in
Figures 44-5 and 44-8) gp120 that allows virus binding in the presence
o inhibitor
Raltegravir Blocks the catalytic activity o HIV-encoded integrase, Mutations in the integrase gene
thus preventing the integration o virus DNA into the
host chromosome (see Figures 44-5 and 44-9)
603
SECTION VII Chemotherapy of Microbial Diseases
A a tta chme nt re le a s e
budding
uncoa ting
a nd tra ns fe r of
vira l DNA to a s s e mbly
hos t nucle us of virion
vira l
DNA prote in
synthe s is
tra ns cription by hos t ce ll
into vira l ribos ome s tructura l
synthe s is mRNA prote ins
of vira l vira l
DNA e nzyme s
re gula tory
prote ins
inhibition of vira l DNA polyme ra s e
a cyclovir, vida ra bine, fos ca rne t, ga nciclovir
B binding to
re le a s e
ce ll s urfa ce
za na mivir
HEMAGGLUTININ
os e lta mivir
e ndocytos is
budding
e ndos ome
H+
M2 prote in intra -
ce llula r
vRNA
tra ns port
RNA re plica tion
a nd a s s e mbly
HEMAGGLUTININ p
fus ion
vRNA cRNA R NA
p
R NA s tructura l
uncoa ting prote ins
M2 R NAp
prote in nons tructura l
synthe s is prote ins
mRNA
a ma nta dine
rima nta dine
ribavirin
FIGURE 44-1 Replicative cycles o DNA (A) and RNA (B) viruses. The replicative cycles o herpes-
virus (A) and in uenza (B) are examples o DNA-encoded and RNA-encoded viruses, respectively.
Sites o action o antiviral agents also are shown. cDNA, complementary DNA; cRNA, comple-
mentary RNA; DNAp, DNA polymerase; mRNA, messenger RNA; RNAp, RNA polymerase; vRNA,
viral RNA. The symbol (“T-line”) indicates a block to virus growth. A. Replicative cycles o herpes
simplex virus, a DNA virus, and the probable sites o action o antiviral agents. Herpesvirus replica-
tion is a regulated multistep process. A ter in ection, a small number o immediate-early genes
are transcribed; these genes encode proteins that regulate their own synthesis and are respon-
sible or synthesis o early genes involved in genome replication, such as thymidine kinases, DNA
polymerases, etc. A ter DNA replication, the bulk o the herpesvirus genes (called late genes)
are expressed and encode proteins that either are incorporated into or aid in the assembly o
progeny virions. B. Replicative cycles o in uenza, an RNA virus, and the loci or e ects o antiviral
agents. The mammalian cell shown is an airway epithelial cell. The M2 protein o in uenza virus
allows an in ux o hydrogen ions into the virion interior, which in turn promotes dissociation o
the RNP (ribonuclear protein) segments and release into the cytoplasm (uncoating). In uenza
virus mRNA synthesis requires a primer cleared rom cellular mRNA and used by the viral RNAp
complex. The neuraminidase inhibitors zanamivir and oseltamivir speci cally inhibit release o
progeny virus. Small capitals indicate virus proteins.
604
Antiviral Agents and Treatment of HIV Infection CHAPTER 4 4
He rpe s
s implex Cytopla s m
O
H2 C
CH2
O O
O– P O O P O–
O O
Nucle us
HO O
O H2 C
Ce ll Acyclovir CH2
me mbra ne
He rpe s thymidine O
kina s e
OH O P O–
O O
O
O P O
P O O P O
O O CH2
P O– O–
Acyclovir
monophos pha te O– O– O
He rpe s DNA O P O–
polyme ra s e
O
P P O
O
Acyclovir
diphos pha te P P P O
O
Acyclovir
triphos pha te
FIGURE 44-2 Mechanism o action o acyclovir in cells in ected by herpes simplex virus. A herpes simplex virion is shown attaching to a
susceptible host cell, using its envelope with the cell membrane, and releasing naked capsids that deliver viral DNA into the nucleus, where it
initiates synthesis o viral DNA. Acyclovir molecules entering the cell are converted to acyclovir monophosphate by virus-induced thymidine
kinase. Host-cell enzymes add 2 more phosphates to orm acyclovir triphosphate, which is transported into the nucleus. A ter the herpes DNA
polymerase cleaves pyrophosphate rom acyclovir triphosphate (indicated by the blue arrow in the inset), viral DNA polymerase inserts acyclovir
monophosphate rather than 2'-deoxyguanosine monophosphate into the viral DNA (indicated by black arrows in the inset). Further elongation o
the chain is impossible because acyclovir monophosphate lacks the 3' hydroxyl group necessary or the insertion o an additional nucleotide, and
the exonuclease associated with the viral DNA polymerase cannot remove the acyclovir moiety. In contrast, ganciclovir and penciclovir have a
3' hydroxyl group; there ore, urther synthesis o viral DNA is possible in the presence o these drugs. Foscarnet acts at the pyrophosphate-binding
site o viral DNA polymerase and prevents cleavage o the pyrophosphate rom nucleoside triphosphates, thus stalling urther primer template
extension. The blue bands between the viral DNA strands in the inset indicate hydrogen bonding o the base pairs. (Adapted rom Bal our HH.
Antiviral drugs. N Engl J Med. 1999, 340:1255–1268. )
CASE 44-1
A 47-year-old man is immunocompromised because o the medications he is taking to
prevent a heart transplant rejection. He develops a herpes simplex virus (HSV) in ec-
tion o his lower lip.
a. What are his treatment options?
In ection with herpes simplex virus 1 (HSV-1) typically causes diseases o the
mouth, ace, skin, esophagus, or brain. Herpes simplex virus 2 (HSV-2) causes
in ections o the genitals, rectum, skin, hands, or meninges. Acyclovir and its ester
prodrug, valacyclovir, are the prototypes o a class o drugs that are phosphorylated
intracellularly to become inhibitors o viral DNA synthesis. Other drugs that use
the same strategy include penciclovir, its prodrug amciclovir, and ganciclovir, and
its prodrug valganciclovir. Cido ovir and oscarnet are available to treat acyclovir-
resistant HSV in ections. Idoxuridine is available or the topical (ophthalmic)
(Continued)
605
SECTION VII Chemotherapy of Microbial Diseases
A B1 B2
Virus e s
A. DNA
B. RNA
1. orthomyxovirus e s a nd re trovirus e s
2. picornavirus e s a nd mos t RNA virus e s
uncoa ting
IFN Effe c ts
1 inhibitio n o f trans c riptio n
a ctiva te s Mx prote in
blocks mRNA synthe s is
nucle us
2 inhibitio n o f trans latio n
a ctiva te s me thyla s e, the re by re ducing
1
mRNA ca p me thyla tion
FIGURE 44-3 Inter eron-mediated antiviral activity occurs via multiple mechanisms. The binding
o inter eron (IFN) to speci c cell sur ace receptor molecules signals the cell to produce a series o
antiviral proteins. The stages o viral replication that are inhibited by various IFN-induced antiviral
proteins are shown. Most o these act to inhibit the translation o viral proteins (mechanism 2),
but other steps in viral replication also are a ected (mechanisms 1, 3, and 4). The roles o these
mechanisms in the other actions o IFNs are under study. 2'5'A, 2'-5'-oligoadenylates; eIF-2α, protein
synthesis initiation actor; IFN, inter eron; mRNA, messenger RNA; Mx, IFN-induced cellular protein
with antiviral activity; RNase L, latent cellular endoribonuclease; tRNA, trans er RNA. (Modif ed rom
Baron, S., Coppenhaver, D.H., and Dianzani, F., et al. Introduction to the inter eron system. In, Inter erons:
Principles and Medical Applications. [Baron, S., Dianzani, F., Stanton, G.J., et al., eds.] University o Texas
Medical Branch Dept. o Microbiology, Galveston, TX, 1992, pp. 1–15. With permission.)
O P O P O P HO O Pa re nt RNA s tra nd
O O O
N– N+ N
2. Incorpora tion
a nd cha in
te rmina tion
O
CH3
HN
HIV reve rs e tra ns cripta s e
O N
O
O P O
N– N+ N
N3
607
SECTION VII Chemotherapy of Microbial Diseases
Ma raviroc
Ce ll me mbra ne Nucle us
HIV pa rticle
(ma ture virion)
CASE 44-2
An otherwise healthy 76-year-old woman developed a rash on her side and back 5 days
ago. She now describes considerable pain in the area. Her physician suspects varicella
zoster virus (VZV) in ection, commonly known as shingles.
a. What are the treatment options or this woman?
T e 2 drugs most commonly used or VZV in ections are acyclovir and penciclovir,
or their prodrugs, valacyclovir, and amciclovir, respectively. Both drugs are e ec-
tive i started within 24 hours o the rash.
b. Her physician elects to use amciclovir. Is it likely to be e ective?
In immunocompetent adults with herpes zoster o less than or equal to 3 days’
duration, amciclovir (500 mg 3 times a day or 10 days) is at least as e ective as
acyclovir (800 mg 5 times daily) in reducing healing time and zoster-associated
pain, particularly in those more than or equal to 50 years o age. T e act that the
rash started 5 days prior to the start o treatment makes it less likely that the treat-
ment will be e ective.
c. How is amciclovir absorbed and metabolized?
Famciclovir is well absorbed orally and is converted rapidly to penciclovir by
deacetylation. T e bioavailability o penciclovir is approximately 75% ollowing oral
administration o amciclovir.
608
Antiviral Agents and Treatment of HIV Infection CHAPTER 4 4
H O
N
N N N
H Tra ns ition s ta te pe ptidomime tic
O OH prote a s e inhibitor (s a quinavir)
O H
O NH
H2 N
H3 C CH3
CH3
N
HN
O CO
HIV prote a s e
(C 2 –a xis of symme try)
Ga g or ga g/pol
pre curs or polype ptide
ζ
ε1 ε2 γ
δ1 δ2 δ
γ β
+
β CH2
H2 N
α
+ pK2 = 11.0
H3 N CH C O C O
– –
pK2 = 9.1 O pK1 = 1.8 O pK1 = 2.0
P he nyla la nine Proline
FIGURE 44-6 Mechanism o action o an HIVprotease inhibitor. Shown here is a phenylalanine-proline target peptide sequence
(in blue) or the protease enzyme (in black) with chemical structures o the native amino acids (in lower box) to emphasize
homology o their structures to that o saquinavir (at top).
CASE 44-3
A 23-year-old man with AIDS has begun to develop blurred vision in the le eye. T e diag-
nosis o cytomegalovirus (CMV) retinitis is made. He is started on intravenous oscarnet.
a. What treatment options, other than oscarnet, are available or the treatment o
CMV retinitis?
Other than oscarnet, the treatment options or CMV retinitis include ganciclovir,
omivirsen, and cido ovir. Fomivirsen is given by intravitreal injection or patients
intolerant o or unresponsive to other therapies.
(Continued)
609
SECTION VII Chemotherapy of Microbial Diseases
Da ughte r
DNA s tra nd
Pa re nt
RNA s tra nd
HIV reve rs e
tra ns cripta s e
F 3C
Cl
O
N O
H
Efavire nz binds to a
non-e s s e ntia l s ite dis ta nt from
the e nzyme ca ta lytic s ite.
CH3
O CH CH3
CH3 H
N H
CH3 S O2 N NH
N N N N N
N C
H N
O
Nevira pine De lavirdine
NH2
F3C
Cl N Br
O N
N O N N O
H H
Efavire nz Etravirine
N
FIGURE 44-7 Structures and mechanism o non-nucleoside reverse transcriptase inhibitors.
HIV virus
me mbra ne
Nucle oca ps id
core
HIV fus ion 2 CCR5 che mokine re ce ptor binding s ta bilize s complex
prote in gp41 a nd a llows gp41-me dia te d fus ion of virus me mbra ne
with ta rge t ce ll me mbra ne .
N
1 gp 120 a nchors F
HIV to ta rge t ce ll HN
by binding to CD4. F
O
CD4 CCR5
Ralte g ravir O
H3 C OH F
N N N
H H
H3 C N N
O N
O H3 C CH3 Provira l DNA
O
Ra lte gra vir binds to HIV inte gra s e,
preve nts DNA s tra nd tra ns fe r.
Ra lte gra vir Ra lte gra vir
Hos t Hos t
chromos oma l chromos oma l
DNA DNA
HIV inte gra s e binds to
provira l 3 LTR’s
FIGURE 44-9 Mechanism o action o the HIVintegrase inhibitor raltegravir.
611
SECTION VII Chemotherapy of Microbial Diseases
TABLE 44-1 Stages of Virus Replication and Possible Targets of Action of Antiviral Agents
STAGE OF REPLICATION CLASSES OF SELECTIVE INHIBITORS
Cell entry
Penetration
Transcription o viral genome a Inhibitors o viral DNA polymerase, RNA polymerase, reverse transcriptase, helicase, primase, or integrase
Myristoylation, glycosylation
resistant to oscarnet have point mutations in the viral DNA polymerase and are
associated with 3- to 7- old reductions in oscarnet activity in vitro.
d. T is patient should be monitored or what major untoward e ects?
Foscarnet’s major dose-limiting toxicities are nephrotoxicity and symptomatic
hypocalcemia. Acute tubular necrosis, crystalline glomerulopathy, nephrogenic
diabetes insipidus, and interstitial nephritis have been described. Saline loading
may reduce the risk o nephrotoxicity.
Foscarnet is highly ionized at physiological pH, and metabolic abnormalities are
common. T ese include increases or decreases in calcium and phosphate, hypo-
magnesemia, and hypokalemia. Decreased serum ionized calcium may cause pares-
thesia, arrhythmias, tetany, seizures, and other CNS disturbances.
CASE 44-4
A 46-year-old woman is considered immunocompromised because o therapy or a
bone marrow transplant. In uenza A is identi ed in the community in which she lives.
Although she is asymptomatic, she is started on amantadine.
a. Why is she started on amantadine while she is asymptomatic?
Seasonal prophylaxis with amantadine is an alternative in high-risk patients i the
in uenza vaccine cannot be administered. Prophylaxis should be started as soon
as in uenza is identi ed in the community or region and should be continued
throughout the period o risk because any protective e ects are lost several days
af er cessation o therapy.
(Continued)
612
Antiviral Agents and Treatment of HIV Infection CHAPTER 4 4
CASE 44-5
A 37-year-old man with chronic hepatitis C virus (HCV) in ection is being treated with
inter eron and ribavirin.
a. What are this patient’s therapeutic options?
Current standard o care or treatment o HCV in ection is a combination o pegin-
ter eron alpha and ribavirin, which produces a high cure rate in selected virus
genotypes only. Recent advances in the development o highly e ective oral agents
include HCV protease inhibitors and polymerase inhibitors that are selective or
this pathogen. It is likely that treatment recommendations will change radically in
the near uture.
b. What inter eron products are available and how do they di er?
Inter erons (IFNs) are potent cytokines that possess antiviral, immunomodulatory,
and antiproli erative activities. T ree classes o human inter erons with signi cant
antiviral activity currently are recognized: α, β, and γ. IFN-α and IFN-β may be
produced in nearly all cells in response to viral in ection. T ey exhibit antiviral and
antiproli erative actions and stimulate the cytotoxic activity o lymphocytes, natu-
ral killer cells, and macrophages. Because IFNs induce long-lasting cellular e ects,
their activities are not easily predictable rom the usual pharmacokinetic measures.
Attachment o IFN to large inert polyethylene glycol (PEG) molecules (pegylation)
slows absorption, decreases clearance, and provides higher and more prolonged
serum concentrations that enable once weekly dosing. T e pegylated IFNs are gen-
erally better tolerated than standard IFNs.
c. What is the mechanism o action o inter erons?
Following binding to speci c cellular receptors, IFNs activate the JAK-S A signal
transduction pathway and lead to nuclear translocation o a cellular protein that
binds to genes containing an IFN-speci c response element. T is in turn leads to
synthesis o over 2 dozen proteins that contribute to viral resistance mediated at
di erent stages o viral penetration (see Figure 44-3).
d. What is ribavirin and why is it added to this patient’s treatment regimen?
Ribavirin is a purine nucleoside analog that inhibits the replication o RNA and
DNA viruses. Oral ribavirin in combination with pegIFN al a-2A or -2B has
become the standard treatment or chronic HCV in ection.
(Continued)
613
SECTION VII Chemotherapy of Microbial Diseases
CASE 44-6
A 42-year-old woman with recently diagnosed HIV in ection is being started on medi-
cation to treat her disease.
a. What clinical decisions are important or making treatment recommendations?
Current treatment recommendations center on making 2 important clinical deci-
sions: (1) When to start therapy in treatment-naïve individuals; and (2) when to
change therapy in individuals that are ailing their current regimen.
Several expert panels issue periodic recommendations or the use o antiretroviral
drugs or treatment-naïve and treatment-experienced adults and children. In the
United States, the Panel on Clinical Practices or treatment o HIV In ection issues
updated guidelines approximately every 6 months; their most recent guidelines can
be accessed at http://www.aidsin o.nih.gov/Guidelines (Department o Health and
Human Services).
b. What principles drive treatment guidelines?
In each clinical setting there is a complex algorithm o possible drug choices
depending on patient and viral characteristics. T e speci c drugs recommended
may change rom year to year as new choices become available and clinical research
data accumulate. However, it is likely that uture treatment guidelines will continue
to be driven by 3 principles: (1) Use o combination therapy to prevent the emer-
gence o resistant virus; (2) Emphasis on regimen convenience, tolerability, and
adherence to chronically suppress HIV replication; and (3) Realization o the need
or li elong treatment under most circumstances.
c. What concerns about drug resistance should be considered in all patients?
T ere is a high likelihood that all untreated in ected individuals harbor viruses with
single-amino acid mutations con erring some degree o resistance to every known
antiretroviral drug because o the high mutation rate o HIV and the tremendous
number o in ectious virions. Drug therapy does not cause mutation but rather pro-
vides the necessary selective pressure to promote growth o drug-resistant viruses
that arise naturally. A combination o active agents there ore is required to prevent
drug resistance, analogous to strategies employed in the treatment o tuberculosis
(see Chapter 42). T e current standard o care is to use at least 3 drugs simultane-
ously or the entire duration o treatment.
CASE 44-7
A 45-year-old man with HIV in ection is being treated with a combination o zidovu-
dine, lamivudine, and abacavir.
a. What are the mechanisms o action o these drugs?
T ese drugs are nucleoside reverse transcriptase inhibitors (NR Is). T eir mecha-
nism o action is summarized in Figures 44-1 and 44-5. T e HIV-encoded, RNA-
dependent DNA polymerase, also called reverse transcriptase, converts viral
RNA into proviral DNA that is then incorporated into a host cell chromosome.
Zidovudine, lamivudine, and abacavir are phosphorylated and their triphosphates
(Continued)
614
Antiviral Agents and Treatment of HIV Infection CHAPTER 4 4
CASE 44-8
A 25-year-old man with HIV in ection is being treated with nevirapine as a single agent.
a. What is the mechanism o action o nevirapine?
Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNR I) that binds
to a hydrophobic pocket o the HIV reverse transcriptase where it induces a con-
ormational change in the enzyme that greatly reduces its activity (see Figures 44-1
and 44-7). Unlike nucleoside reverse transcriptase inhibitors (NR Is), the NNR Is
do not require intracellular phosphorylation to attain activity.
b. What is the problem in using this drug as a sole agent to treat HIV?
When nevirapine was used as monotherapy, there was a rapid all in plasma HIV
RNA concentrations that was ollowed by a return toward baseline within 8 weeks
because o rapid emergence o resistance. Nevirapine should never be used as a
single agent or as the sole addition to a ailing regimen.
CASE 44-9
A 38-year-old woman with HIV in ection is being treated with a combination product
containing lopinavir and ritonavir.
a. What is the mechanism o action o these drugs?
Lopinavir and ritonavir are HIV protease inhibitors (see Figure 44-6). T ese drugs
prevent the proteolytic cleavage o peptides and proteins that are essential struc-
tural and enzymatic components o HIV. Viral proteases are homodimers; human
proteases (renin, pepsin, gastricsin, cathepsins) contain only 1 polypeptide chain
and are not signi cantly inhibited by HIV protease inhibitors.
b. Why is the combination product used?
Ritonavir is one o the most potent known inhibitors o CYP3A4. Because lopinavir
undergoes extensive hepatic oxidative metabolism by CYP3A4, ritonavir is used to
inhibit the metabolism o lopinavir and increase its concentrations.
c. What precautions should be taken with the combination o lopinavir and ritonavir?
T e most common adverse events with lopinavir/ritonavir are loose stools, diar-
rhea, nausea, and vomiting.
Because lopinavir is dependent on CYP3A4, the concomitant administration o
agents that induce CYP3A4 such as ri ampin and St. John’s wort may lower plasma
concentrations o lopinavir and loss o antiviral e ectiveness.
(Continued)
615
SECTION VII Chemotherapy of Microbial Diseases
CASE 44-10
A 56-year-old man with HIV in ection has been treated with 3 other antiretroviral
agents. Despite this treatment, he has evidence o HIV replication. reatment with
en uvirtide is recommended.
a. What is the mechanism o action o en uvirtide?
En uvirtide is a synthetic peptide that prevents membrane usion and viral entry
into the host cell (see Figure 44-5). En uvirtide retains activity against viruses that
have become resistant to antiretroviral agents o other classes because o its unique
mechanism o action.
b. Why is en uvirtide recommended only af er treatment with other antiretroviral
agents has ailed?
Most patients develop local injection site reactions to the parenteral administration
o en uvirtide. Given the cost, inconvenience, and cutaneous toxicity o en uvirtide,
it is generally reserved or patients who have ailed all other easible antiretroviral
agents. In act, en uvirtide is FDA approved or use only in treatment-experienced
adults who have evidence o HIV replication despite ongoing antiretroviral therapy.
KEY CONCEPTS
T ere are distinct stages o viral replication. T e classes o antiviral agents that
can act at each stage are shown in able 44-1.
Acyclovir is the prototype o a group o antiherpes viral agents that are phos-
phorylated intracellularly by a virus kinase and subsequently by host enzymes
to become inhibitors o viral DNA synthesis.
Amantadine and rimantadine are anti-in uenza agents that inhibit viral rep-
lication by inhibiting viral uncoating; zanamivir and oseltamivir inhibit viral
neuraminidase.
T e anti-in uenza drugs are used or the prevention and treatment o in uenza
A, and some or in uenza B.
Drugs used to treat chronic hepatitis C virus in ection are the inter erons
and ribavirin.
Inter eron and ribavirin can cure patients with chronic hepatitis B virus in ec-
tion but are associated with a high rate o side ef ects, o en leading to premature
treatment discontinuation.
Several antiretroviral nucleoside or nucleotide analog polymerase inhibitors,
including lamivudine, telbivudine, and teno ovir, have potent anti-HBV activity
and provide alternative therapy to inter eron and ribavirin. Ade ovir, dipivoxil,
and entecavir also provide alternative therapy or chronic HBV in ection.
T ree-drug combinations are the minimum standard o care or HIV in ection.
Starting therapy with only a single agent inevitably provokes the emergence o
drug-resistant virus.
Drugs used to treat HIV in ection generally all into 3 classes:
Nucleoside reverse transcriptase inhibitors (NR Is).
Non-nucleoside reverse transcriptase inhibitors (NNR Is).
Protease inhibitors.
Ritonavir is a protease inhibitor that is a very potent inhibitor o CYP3A4. It is o en
added in combination with other drugs to enhance their pharmacokinetic pro le.
(Continued)
616
Antiviral Agents and Treatment of HIV Infection CHAPTER 4 4
T ere are 2 drugs, maraviroc and en uvirtide, that block the entry o HIV
into host cells; raltegravir prevents the integration o virus DNA into the host
chromosome.
Prescribers o antiretroviral therapy must maintain a comprehensive and cur-
rent und o knowledge regarding the disease and its pharmacotherapy. T e
prescribing o antiretroviral agents to patients with HIV in ection should be
limited to those with specialized training.
SUMMARY QUIZ
QUESTION 44-1 A 48-year-old man with AIDS is diagnosed with CMV retinitis. He is
being treated with intravenous oscarnet. A laboratory blood test or which o the ol-
lowing should be monitored closely?
a. Copper
b. Alanine aminotrans erase
c. Calcium
d. Zinc
e. Bilirubin
QUESTION 44-2 Which o the ollowing drugs is an option or the treatment o CMV
retinitis in the patient in Question 44-1?
a. Acyclovir
b. Gancyclovir
c. Rimantadine
d. Oseltamivir
e. Ribavirin
QUESTION 44-3 A 36-year-old woman has been diagnosed with chronic hepatitis C.
She is prescribed oral ribavirin in combination with which o the ollowing agents or
her treatment?
a. eno ovir
b. elbivudine
c. En uvirtide
d. PegINF alpha-2A
e. Cido ovir
QUESTION 44-4 A 27-year-old man with newly diagnosed HIV in ection is started
on zidovudine alone. T is treatment regimen is unlikely to be therapeutically ef ective
because
a. zidovudine is not active against HIV.
b. zidovudine is metabolized by hepatic CYPs.
c. the side ef ects o zidovudine do not warrant its use.
d. the use o zidovudine is limited by its absorption rom the gastrointestinal tract.
e. resistance o the HIV is likely to develop rom the use o a single agent.
QUESTION 44-5 A 43-year-old woman with HIV in ection is treated with atazanavir
and ritonavir. Ritonavir is added to the regiment because it
a. inhibits CYP3A4, decreases the metabolism o atazanavir, and raises its plasma
concentrations.
b. prevents the renal excretion o atazanavir.
c. increases the oral absorption o atazanavir.
(Continued)
617
SECTION VII Chemotherapy of Microbial Diseases
QUESTION 44-6 A 56-year-old man has been treated or HIV in ection or 10 years.
His HIV is now resistant to all previous antiretroviral drugs and there is evidence
o HIV replication despite his treatment with 3 concomitant drugs. He is now being
treated with en uvirtide because it
a. is less expensive.
b. is less toxic.
c. is more ef ective against HIV.
d. has an unique mechanism o action.
e. can be administered orally.
QUESTION 44-7 A 35-year-old woman with HIV in ection also has developed chronic
hepatitis B. She is being treated with entecavir or her chronic HBV in ection. Because
she has recently developed symptoms o atigue and nausea, she has stopped her ente-
cavir therapy. She is at risk or developing
a. acute renal ailure.
b. acute pancreatitis.
c. acute exacerbation o hepatitis B.
d. chronic hepatitis C.
e. acute neurotoxicity.
QUESTION 44-8 A 28-year-old man with HIV is being treated with lopinavir. He
admits to using nutritional supplements bought over the Internet because it makes him
eel in control o his therapy. T is patient should be cautioned about the ef ect nutri-
tional supplements may have on
a. HIV.
b. the metabolism o lopinavir.
c. the renal excretion o lopinavir.
d. the cardiac toxicity o lopinavir.
e. the skin toxicity o lopinavir.
CYP3A4. Ritonavir inhibits the metabolism o all current HIV protease inhibitors
and is requently used in combination with most o these drugs, except nel navir, to
enhance their pharmacokinetic pro le and allow a reduction in dose and dosing re-
quency o the coadministered drug.
QUESTION 44-6 Answer is d. En uvirtide has a unique mechanism o antiretroviral
action. It prevents viral entry into the host cell. Because o this unique mechanism o
action, it retains activity against viruses that have become resistant to antiretroviral
agents o other classes.
QUESTION 44-7 Answer is c. Severe acute exacerbations o hepatitis B have been
reported in patients who have discontinued anti-HBV therapy. Hepatic unction should
be monitored closely with both clinical and laboratory ollow-up or at least several
months in patients who discontinue anti-HBV therapy.
QUESTION 44-8 Answer is b. Because lopinavir metabolism is highly dependent on
CYP3A4, concomitant administration o agents that induce CYP3A4 may lower plasma
lopinavir concentrations considerably. St. John’s wort is a known inducer o CYP3A4,
leading to lower concentrations o lopinavir and possible loss o antiviral ef ectiveness.
Foscarnet Use ul or treatment Mutations in herpes virus Rash, ever, nausea Nephrotoxicity
o CMVretinitis and DNA polymerase and symptomatic
acyclovir-resistant HSV hypocalcemia
and VZVin ections
Ganciclovir Chronic suppression CMVresistance is due Rash, ever, nausea, Neutropenia and
o CMVretinitis and to either mutations in vomiting thrombocytopenia
other CMVsyndromes viral phosphotrans erase Phlebitis CNS toxicity, including
in AIDS patients which reduces headache and seizures
intracellular ganciclovir
phosphorylation or
mutations in viral DNA
polymerase
TOXICITY
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAME CLINICAL USES RESISTANCE COMMON IMPORTANT
Antihepatitis Ade ovir dipivoxil Treatment o chronic Point mutations in HBV Headache, Pregnancy Category C
Agents hepatitis B virus (HBV) polymerase abdominal Dose-related
in ections discom ort nephrotoxicity
Other Antiviral Ribavirin Oral ribavirin in Resistance not Conjunctival Pregnancy Category X
Agents combination with documented, but irritation, rash, Dose-related anemia due
pegIFN al a-2A or -2B cells that do not transient wheezing to extravascular hemolysis
is standard treatment phosphorylate ribavirin to and bone marrow
or chronic hepatitis C its active orm have been suppression
virus (HCV) in ection reported
Ribavirin aerosol
is or treatment o
RSVbronchiolitis
and pneumonia in
children
620
Antiviral Agents and Treatment of HIV Infection CHAPTER 4 4
TOXICITY
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAME CLINICAL USES RESISTANCE COMMON IMPORTANT
Nucleoside Reverse Zidovudine Treatment o HIV Mutations in reverse Fatigue, nausea, Bone marrow suppression
Transcriptase in ection in adults and transcriptase malaise, myalgia, with anemia
Inhibitors (NRTIs) children anorexia, insomnia
Lamivudine Treatment o chronic Point mutations in DNA Few signi cant adverse
HBVhepatitis and HIV polymerase e ects
in ection
Emtricitabine Treatment o HIV Mutations in reverse Prolonged Few signi cant adverse
in ection in adults transcriptase exposure causes e ects
hyperpigmentation
Protease Inhibitors Saquinavir Treatment o HIV Accumulation o multiple Nausea, vomiting, Metabolized by intestinal
in ection in adults resistance mutations diarrhea and hepatic CYP3A4;
Predominantly used substances that inhibit
in combination intestinal CYP3A4 increase
with ritonavir AUC by 3 old
Long-term use associated
with lipodystrophy
621
SECTION VII Chemotherapy of Microbial Diseases
TOXICITY
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAME CLINICAL USES RESISTANCE COMMON IMPORTANT
Ritonavir Used in requently Mostly used as a Nausea, vomiting, Reduces the ethinyl
alone; ritonavir is pharmacokinetic and diarrhea estradiol AUC by 40%;
a potent inhibitor enhancer (CYP3A4 alternative orms o
o CYP3A4 and is inhibitor) and at the low contraception should be
used in combination doses use is not known ound
to enhance the to induce resistance
pharmacokinetic
pro le o other
protease inhibitors
Tipranavir Used in treatment- Resistance requires Rash Associated with rare atal
experienced adults accumulation o multiple hepatotoxicity
and children whose mutations Tipranavir is a substrate,
HIVis resistant to inducer, and inhibitor o
other protease CYP enzymes
inhibitors
Non-Nucleoside Nevirapine Treatment o HIV Mutations in reverse Rash, ever, atigue Elevated hepatic
Reverse in ection in adults and transcriptase; cross- transaminases
Transcriptase children resistance extends to
Inhibitors (NNRTIs) e avirenz and delavirdine
(Continued)
622
Antiviral Agents and Treatment of HIV Infection CHAPTER 4 4
TOXICITY
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAME CLINICAL USES RESISTANCE COMMON IMPORTANT
E avirenz Treatment o HIV Mutations in reverse Headache and CNS symptoms including
in ection in adults and transcriptase; cross- elevated hepatic dizziness, impaired
children resistance extends trans-aminases concentration, dysphoria,
to nevirapine and insomnia; rank psychosis
delavirdine Use should be avoided in
women o childbearing
potential unless 2 orms
o birth control are used
Metabolized by CYP2B6
and CYP 3A4; drugs that
induced these enzymes
should be avoided
Maraviroc Use in HIV-in ected HIVthat is pre- Little signi cant toxicity
adults who have dominantly CCR5-tropic CYP3A4 substrate;
evidence o CCR5- shi ts tropism to CXCR4; susceptible to drug
tropic virus or there is a mutation in interactions with drugs
gp120 that allows virus that are CYP3A4 inhibitors
binding in the presence or inducers
o inhibitor
Integrase Inhibitor Raltegravir Treatment o HIV- Mutations in the Headache, nausea, Little clinical toxicity
in ected adults integrase gene atigue
623
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SECTION
Chemotherapyof
NeoplasticDiseases VIII
45. Cancer Chemotherapy and Cytotoxic Agents 626
625
CHAPTER
45 Cancer Chemotherapy
and CytotoxicAgents
T is chapter wi be most use u a er having a basic understanding o the materia in
DRUGS INCLUDED IN THIS
Chapter 60 Genera Princip es o Cancer Chemotherapy and Chapter 61 Cytotoxic
CHAPTER Agents in Goodman & Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition
• 2-Mercaptoethanesul onate (mesna; In addition to the materia presented here, Chapters 60 and 61 o the 12th Edition
MESNEX)—reacts with acrolein in urine contain:
and protects against severe hemorrhagic • A description o the ce cyc e, and ce cyc e checkpoints and regu ation
cystitis in high-dose cyclophosphamide
• T e c inica pharmaco ogy and toxicities o speci c agents
regimens
• T e mo ecu ar structures o cytotoxic agents used to treat cancer and other diseases
• 5-Fluorouracil (5-FU)
such as immune disorders
• 6-Mercaptopurine (6-MP; PURINETHOL,
others) LEARNING OBJECTIVES
• 6-Thioguanine (6-TG) Understand the mechanisms o action o cytotoxic antineop astic agents on
• Altretamine (hexamethylmelamine; tumor ce s (see Figure 45-1)
HEXALEN) Understand the mechanisms o toxicity o cytotoxic antineop astic agents on
• Ami ostine (WR-2721; ETHYOL, norma ce s and strategies or reducing toxic e ects
others)—thiophosphate cytoprotective
Understand the mechanisms o drug resistance to individua agents and
agent (see cisplatin clinical toxicities)
strategies to avoid resistance
• Arsenictrioxide (ATO; TRISENOX)
Know how pharmacogenetics can impact tumor sensitivity and toxicities o
• Azacytidine (5-azacytidine) speci c agents
• Bendamustine (TREANDA, others) Know the signs o acute toxicity and when chemotherapy shou d be a tered
• Bleomycin (BLENOXANE, others) or discontinued
• Busul an (MYLERAN, BUSULFEX) Know the risk o ong-term toxicities that can occur with individua chemo-
• Carmustine (BCNU; BICNU, GLIADEL) therapeutic agents
• Capecitabine (XELODA) Know the therapeutic strategies that can reduce acute and chronic toxicities
• Carboplatin (CBDCA, JM-8; PARAPLATIN) Know which c asses o agents are typica y used in treating speci c cancers
• Carboxypeptidase G2 (a methotrexate- Know which drugs are used in combination to improve tumor ce ki ing and
cleaving enzyme used to reduce metho- reduce the risk o resistance deve opment
trexate in plasma)
• Chlorambucil (LEUKERAN)
• Cisplatin (PLATINOL, others) CASE 45-1
• Cladribine (2-chlorodeoxyadenosine, 2-CdA; A patient with a chronic ymphocytic eukemia is started on chemotherapy with
LEUSTATIN, others) cyc ophosphamide
• Clo arabine (2-chloro-2′- uoro- a. What is the mechanism o action o cyclophosphamide?
arabinosyladenine) Cyclophosphamide is a nitrogen mustard and is now the most widely used agent
• Cyclophosphamide (LYOPHILIZED o this class o alkylating agents. Alkylating agents have in common the property
CYTOXAN, others) o orming highly reactive carbonium ion intermediates. T ese reactive intermedi-
• Cytarabine(1-β-D-arabino uranosylcytosine, ates covalently link to sites o high electron density, such as phosphates, amines,
cytosine arabinoside, Ara-C; CYTOSAR-U, sul ydryl, and hydroxyl groups. T eir chemotherapeutic and cytotoxic e ects are
TARABINEPFS, DEPOCYT, others) directly related to the alkylation o reactive amine, oxygen, or phosphate groups on
• Dacarbazine (DTIC; DTIC-DOME) DNA (see Figure 45-1). T e N7 atom o guanine is particularly susceptible to the
ormation o a covalent bond with bi unctional alkylating agents and may represent
• Dactinomycin (actinomycin D; COSMEGEN) the key target that determines their biological e ects (see Figure 45-2). Other atoms
• Daunorubicin (daunomycin, rubidomycin; in the purine and pyrimidine bases o DNA, including N1 and N3 o the adenine
CERUBIDINE, others) ring, N3 o cytosine, and O6 o guanine, react with these agents, as do the amino
(continues) and sul ydryl groups o proteins and the sul ydryl groups o glutathione.
(Continued)
626
Cancer Chemotherapy and Cytotoxic Agents CHAPTER 4 5
MECHANISMS OF ACTION AND RESISTANCE OF ALKYLATING AGENTS AND DRUGS INCLUDED IN THIS
PLATINUM COORDINATION COMPLEXES (SEE TABLE 45-1) CHAPTER (Cont.)
MECHANISMS OF MECHANISMS OF • Decitabine (2′-deoxy-5-azacytidine)
CLASSIFICATION DRUG ACTION RESISTANCE
• Docetaxel (TAXOTERE)
Nitrogen Mustards Mechlorethamine HCl Form highly reactive Overexpression of • Doxorubicin (ADRIAMYCIN)
Cyclophosphamide carbonium ion nucleotide excision
Ifosfamide intermediates that repair (NER) pathway • Epirubicin (ELLENCE, others)
Melphalan alkylate reactive Mutations of p53 • Estramustine (EMCYT)
Chlorambucil amines, oxygens, and DNA repair by O6-alkyl,
Bendamustine phosphates on DNA methyl guanine • Etoposide (VP-16-213; VEPESID, others)
(Figures 45-1 through methyltransferase • Floxuridine (FUdR, fuorodeoxyuridine;
45-4) which leads to (MGMT) FUDR, others)
cell death Activated
intermediates of • Fludarabine phosphate (FLUDARA,
cyclophosphamide OFORTA)
can be degraded • Gemcitabine (2′,2′-difuorodeoxycytidine;
by aldehyde dFdC, GEMZAR)
dehydrogenase,
glutathione transferase, • High-dose methotrexate with leucovorin
and other pathways rescue (HDM-L)
(see Figure 45-4) • Hydroxyurea (HU; HYDREA, DROXIA,
See Side Bar
others)
MECHANISMS OF
RESISTANCE TO • Idarubicin (IDAMYCINPFS)
ALKYLATING AGENTS • I os amide (IFEX,others)
Ethyleneimines and Altretamine Cytotoxic mechanism Overexpression of NER • Irinotecan (CPT-11; CAMPTOSAR, others)
Methylmelamines (hexamethylendiamine) of altretamine is pathway • Ixabepilone (IXEMPRA)
Thiotepa unknown (it has no Mutations of p53
alkylating activity DNA repair by MGMT • L-asparaginase (L-ASP; ELSPAR)
in vitro but is See Side Bar • Leucovorin ( olinicacid, citrovorum actor,
demethylated in liver MECHANISMS OF 5- ormyltetrahydro olate, N5- ormyl FH4)
microsomes to form RESISTANCE TO
formaldehyde) ALKYLATING AGENTS • Lometrexol
Thiotepa and its • Lomustine (CCNU; CeeNU)
primary metabolite
(TEPA) form DNA • Mechlorethamine HCl (MUSTARGEN)
cross-links • Melphalan (ALKERAN)
Alkyl Sulfonates Busulfan Alkylate DNA Overexpression of NER • Methotrexate (amethopterin; RHEUMA-
through the release of pathway TREX,TREXALL, others)
methyl radicals (see Mutations of p53 • Mitomycin (mitomycin-C; MUTAMYCIN,
Figures 45-1 and 45-3) DNA repair by MGMT
others)
See Side Bar
MECHANISMS OF • Mitotane (o,p’-DDD)
RESISTANCE TO • Mitoxantrone (NOVANTRONE, others)
ALKYLATING AGENTS
• Nab-paclitaxel (ABRAXANE)
Nitrosoureas Carmustine (BCNU) Exert their cytotoxicity Overexpression of NER • Nelarabine
Lomustine (CCNU) through the pathway
Semustine spontaneous Mutations of p53
(6-methoxy-arabinosyl-guanine)
(methyl-CCNU) breakdown to an DNA repair by MGMT • Oxaliplatin (ELOXATIN)
Streptozocin alkylating intermediate, See Side Bar • Paclitaxel (TAXOL, others)
(streptozotocin) the 2-chloroethyl MECHANISMS OF
diazonium ion, a RESISTANCE TO • Pegaspargase (PEG-l -Asparaginase;
strong electrophile, ALKYLATING AGENTS ONCASPAR)
that can alkylate • Pemetrexed (MTA; ALIMTA)
guanine, cytidine,
and adenine bases, • Pentostatin (2’-deoxyco ormycin)
leading to interstrand • Pralatrexate (FOLOTYN)
or intrastrand cross-
linking of DNA (see • Procarbazine (MATULANE)
Figures 45-1, 45-3, • Raltitrexed (TOMUDEX)
and 45-5) (continues)
(Continued)
627
SECTION VIII Chemotherapy of Neoplastic Diseases
L-AS PARAGINAS E
RNA
(tra ns fe r, me s s e nge r, ribos oma l) De a mina te s a s pa ra gine
P ROTEIN TYROS INE
KINAS E INHIBITORS, Inhibits prote in synthe s is
ANTIBODIES
EP OTHILONES
Block a ctivitie s of s igna ling pa thways Prote ins TAXANES
VINCA ALKALOIDS
ESTRAMUSTINE
Enzyme s Micro-
tubule s Inhibit function of microtubule s
FIGURE 45-1 Summary o the mechanisms and sites o action o some chemotherapeutic agents use ul in neoplastic disease.
A Ac tivatio n
S P HAS E
δ+ δ- S P ECIFIC DRUGS
CH2 CH2 Cl + CH2 cytos ine a ra binos ide,
H3 C N H3 C N Cl hydroxyure a , topois ome ra s e
CH2 CH2 Cl CH2
S inhibitors
CH2 CH2 Cl
G1
B Nucle o philic attack o f S P HAS E S P ECIFIC
uns table aziridine ring by e le c tro n do no r S ELF-LIMITING
che ckpoints 6-me rca ptopurine ,
(–S H of prote in, –N– of prote in or DNA ba s e ,
G1 me thotrexa te
=O of DNA ba s e or phos pha te ) G2 G2
CH2 CH2 Cl
(Continued)
633
SECTION VIII Chemotherapy of Neoplastic Diseases
(Continued)
634
Cancer Chemotherapy and Cytotoxic Agents CHAPTER 4 5
Pemetrexed (MTA) Inhibits DHFR, and is readily converted See Side Bar MECHANISMS OF
to polyglutamates, which more potently RESISTANCE TO ANTIMETABOLITES
inhibit glycinamide ribonucleotide
ormyltrans erase (GART) and thymidylate
synthase (TS) (see Figures 45-1 and 45-6)
Pralatrexate Exert their primary inhibitory e ects on TS See Side Bar MECHANISMS OF
Raltitrexed (see Figure 45-6) RESISTANCE TO ANTIMETABOLITES
Lometrexol Primary inhibitory e ects are on GART to See Side Bar MECHANISMS OF
block early steps in purine biosynthesis (see RESISTANCE TO ANTIMETABOLITES
Figure 45-6)
Pyrimidine 5-Fluorouracil (5-FU) Enzymatically converted in cells to the See Side Bar MECHANISMS OF
Analogs Floxuridine (FUdR, f uorodeoxyuridine) nucleotide orms (see Figure 45-7); RESISTANCE TO ANTIMETABOLITES
Capecitabine FUTP is incorporated into RNA, FdUTP is
incorporated into DNA, and FdUMP inhibits
TS (see Figures 45-1, 45-7, and 45-8)
Cytarabine (cytosine arabinoside, Ara-C) Enzymatically converted in cells to its See Side Bar MECHANISMS OF
active orm, the 5′-monophosphate RESISTANCE TO ANTIMETABOLITES
ribonucleotide (Ara-CMP), by deoxycytidine
kinase (dCK); Ara-CMP is phosphorylated
to orm Ara-CDP and Ara-CTP, which inhibit
DNA polymerase, thus blocking replication
and repair synthesis, and elongation (see
Figures 45-1 and 45-3)
(Continued)
635
SECTION VIII Chemotherapy of Neoplastic Diseases
Gemcitabine (2′,2′-di uorodeoxyuridine) Converted to di uorodeoxycytidine di- See Side Bar MECHANISMS OF
and triphosphates (dFdCDP and dFdCTP) RESISTANCE TO ANTIMETABOLITES
which inhibit DNA synthesis by multiple
mechanisms including incorporation o
dFdCTP into DNA and subsequent DNA
strand termination (see Figure 45-1)
Purine Analogs 6-Mercaptopurine (6-MP) Converted by hypoxanthine guanine See Side Bar MECHANISMS OF
6-Thioguanine (6-TG) phosphoribosyl trans erase (HGPRT) into RESISTANCE TO ANTIMETABOLITES
the corresponding ribonucleotides (6-MP
to 6-thioGMP and 6-TG to T-IMP)
T-IMP inhibits the synthesis o ribosyl-
5-phosphate and is also converted to
6-thioGMP
6-thioGMP is incorporated into DNA
causing strand breaks and base mispairing
(see Figures 45-1 and 45-3)
Fludarabine phosphate Phosphorylated by dCKto the active See Side Bar MECHANISMS OF
triphosphate derivative, which inhibits DNA RESISTANCE TO ANTIMETABOLITES
polymerase, DNA primase, DNA ligase,
and ribonucleotide reductase (RNR), and
becomes incorporated into DNA and RNA;
chain termination occurs when incorporated
into DNA (see Figure 45-1); incorporation
into RNA inhibits RNA unction, RNA
processing, and mRNA translation
Cladribine (2-chlorodeoxyadenosine, A ter phosphorylation by dCKto cladribine See Side Bar MECHANISMS OF
2-CdA) triphosphate, it is incorporated into DNA RESISTANCE TO ANTIMETABOLITES
producing DNA strand breaks, depleting
NAD and ATP, and leading to apoptosis (see
Figure 45-1); it is a potent inhibitor o RNR
636
Cancer Chemotherapy and Cytotoxic Agents CHAPTER 4 5
A Thymidylate s ynthe s is
P RP P GAR AICAR
+ + +
a s pa rtate N-10 formyl GAR FH4 Glu n
FH4 Glu n tra ns formyla s e
AICAR IMP
+ +
N-10 formyl AICAR FH4 Glu n
FH4 Glu n tra ns formyla s e
FIGURE 45-6 Sites o action o methotrexate and its polyglutamates. AICAR, aminoimidazole carboxamide; dUMP, deoxy-
uridine monophosphate; FH2Glu n, dihydro olate polyglutamate; FH4Glu n, tetrahydro olate polyglutamate; GAR, glycinamide
ribonucleotide; IMP, inosine monophosphate; PRPP, 5-phosphoribosyl-1-pyrophosphate; TMP, thymidine monophosphate.
637
SECTION VIII Chemotherapy of Neoplastic Diseases
5
FUR FUMP FUDP FUTP RNA
1
1 Uridine phos phoryla s e
Dihydro 5-FU 3 2 Thymidine phos phoryla s e
3 P hos phoribosyl tra ns fe ra se
7 (P RP P )
5-FU 6 4 Thymidine kina s e
inhibitor of 5 Uridine kina s e
thymidyla te
syntha s e
6 Ribonucle otide re ducta s e
7 Dihydropyrimidine de hydroge na s e
2
4
FUdR FdUMP FdUDP FdUTP DNA
FIGURE 45-7 Activation pathways or 5- uorouracil (5-FU) and 5- oxuridine (FUR). FdUDP, uorodeoxyuridine diphosphate; FdUMP, uorode-
oxyuridine monophosphate; FdUTP, uorodeoxyuridine triphosphate; FUDP, oxuridine diphosphate; FUdR, uorodeoxyuridine; FUMP, oxuridine
monophosphate; FUTP, oxuridine triphosphate; PRPP, 5-phosphoribosyl-1-pyrophosphate.
MECHANISMS OF FdUMP
RESISTANCE TO dUMP dTMP dTTP
ANTIMETABOLITES
• Acquired resistance to methotrexate a ects thymidyla te
each known step in methotrexate action: syntha s e
» Impaired transport o methotrexate N5-10 me thyle ne FH2 Glu n
into cells FH4 Glu n
» Production o altered orms o DHFR Othe r a ctions of 5-FU nucle otide s :
that have decreased a nity or the • Inhibition of RNA proce s s ing
(M X-PGs) in both normal and tumor cells. T ese M X-PGs constitute an intra-
MECHANISMS OF
cellular storage orm o olates and olate analogs, and dramatically increase inhibi-
RESISTANCE TO
tory potency o the analog or additional sites, including thymidylate synthase ( S)
and 2 early enzymes in the purine biosynthetic pathway (see Figure 45-6). Finally, ANTIMETABOLITES (Cont.)
the dihydro olic acid polyglutamates that accumulate in cells behind the blocked » High levels o the degradative enzymes
DHFR reaction also act as inhibitors o S and other enzymes (see Figure 45-6). dihydrouracil dehydrogenase and
As with most antimetabolites, methotrexate is only partially selective or tumor thymidine phosphorylase
cells and kills rapidly dividing normal cells, such as those o the intestinal epithe- » Insu icient concentrations o 5,
lium and bone marrow. Folate antagonists kill cells during the S phase o the cell 10-methylenetetrahydro olate, thus
cycle (see Figure 45-3) and are most e ective when cells are proli erating rapidly. preventing ormation o maximal
levels o the inhibited ternarycomplex
b. What is the rationale or the use o leucovorin?
withTS
o unction as a co actor in one-carbon trans er reactions, olate must rst be
• Resistance to Ara-Chas been attributed to
reduced by DHFR to FH 4.
the ollowing:
Introduction o high-dose methotrexate regimens with “rescue” o host toxicity
» Reduced in uxthrough nucleoside
by the reduced olate, leucovorin ( olinic acid, citrovorum actor, 5- ormyl tetra-
carriers (eg, hENT1 transporter
hydro olate, N5- ormyl FH 4), extends the e ectiveness o this drug to treat both
mutation)
systemic and CNS lymphomas, osteogenic sarcoma, and leukemias. T e admin-
istration o leucovorin within 24 hours a er high-dose in usions o methotrexate » Reduced activities o catabolicenzymes
allows the use o regimens that produce cytotoxic concentrations o drug in the (deoxycytidine kinase [dCK] is the rate-
CSF and protects against leukemic meningitis. T e toxic e ects o methotrexate limiting activating enzyme)
are rapidly terminated by administering leucovorin which repletes the intracellu- » Increased activities o anabolic
lar pool o FH 4 co actors. enzymes
c. How might pharmacogenetics a ect the response o this patient to anti olate » Cytidine deaminase which converts
treatment? Ara-Cto nontoxicAraU
T e C677 substitution in methylenetetrahydro olate reductase (M HFR) reduces » dCMPdeaminase which converts
the activity o the enzyme that generates methylenetetrahydro olate, the co actor Ara-CMPto inactive Ara-UMP
or S (see Figure 45-6), and thereby increases methotrexate toxicity, especially » 5′ nucleotidase which degrades
GI toxicity (see Chapter 7 in Goodman & Gilman’s T e Pharmacological Basis of Ara-CMP
T erapeutics, 12th Edition or a more comprehensive description o the pharma- • Gemcitabine resistance is ound in tumors
cogenetics o methotrexate). T e presence o this polymorphism in leukemic cells with lowlevels o dCKand high levels o
con ers increased sensitivity to methotrexate and might also modulate the toxicity cytidine deaminase.
and therapeutic e ect o pemetrexed, a predominant S inhibitor. Likewise, poly-
• The most common mechanismo 6-MP
morphisms in the promoter region o S govern the translation e ciency o this
resistance is de ciencyor complete lacko
message and, by governing the intracellular levels o S in both normal and tumor
the activating enzyme, HGPRT,or increased
cells, modulate the response and toxicity o both anti olates and f uoropyrimidines
alkaline phosphate activity; other mecha-
such as 5-f uorouracil. Other common polymorphisms that a ect methotrexate
nisms or resistance include the ollowing:
pharmacotherapy include those in the genes that code or DHFR and proline trans-
ormylases (see Chapter 7 in Goodman & Gilman’s T e Pharmacological Basis of » Decreased drug uptake
T erapeutics, 12th Edition). » Increased ef uxdue to one o several
active transporters
d. How do other olate antagonists di er rom methotrexate in their mechanism o
action other important properties? » Alteration in allostericinhibition o
ribosylamine 5-phosphate synthase
Pemetrexed and its polyglutamates have a somewhat di erent spectrum o biochem-
ical actions. Like methotrexate, pemetrexed inhibits DHFR, but as a polyglutamate, » Impaired recognition o DNAbreaks and
it even more potently inhibits glycinamide ribonucleotide ormyltrans erase (GAR ) mismatches due to loss o a component
and thymidylate synthase ( S). Unlike methotrexate, it produces little change in the (MSH6) o MMR
pool o reduced olates, indicating that the distal sites o inhibition ( S and GAR ) • Resistance to udarabine is associated
predominate. Its pattern o deoxynucleotide depletion, as studied in cell lines, also with the ollowing:
di ers rom methotrexate, as it causes a greater all in thymidine triphosphate ( P) » Decreased activityo dCK(the enzyme
than in other triphosphates. Like methotrexate, it induces p53 and cell-cycle arrest, that phosphorylates and thereby
but this e ect does not seem to depend on downstream induction o p21. Pralatrex- activates the drug)
ate is more e ectively taken up and polyglutamated than methotrexate.
» Increased drug ef ux
New olate antagonists that are better substrates or the reduced olate carrier have
» Increased ribonucleotide reductase
been identi ed. In e orts to bypass the obligatory membrane transport system and
(RNR) activity
(continues)
(Continued)
639
SECTION VIII Chemotherapy of Neoplastic Diseases
CASE 45 4
A 58-year-o d man is prescribed topica 5-FU to treat precancerous skin esions on his
ace and arms
a. What is the mechanism o action o 5-FU?
5-FU is an analog o thymine. It is enzymatically converted in cells to a nucleotide,
f oxuridine monophosphate (FUMP), by one o several pathways (see Figure 45-7).
FUMP can then ollow several di erent pathways (see Figure 45-7). One pathway
leads to the ormation o the triphosphate FU P, which is incorporated into RNA.
5-FU incorporation into RNA is one mechanism o cytotoxicity as the result o
major e ects on both the processing and unctions o RNA.
In an alternative reaction sequence crucial or antineoplastic activity, FUMP is
reduced to FUDP by RNR to the deoxynucleotide level and then to FdUMP, a
potent inhibitor o thymidylate synthesis ( S; see Figures 45-7 and 45-8). S is
required or the physiological conversion o dUMP to d MP, which is phosphory-
lated to d P and incorporated into DNA (see Figure 45-8). T us, blocking S
prevents DNA synthesis (see Figure 45-1) and is another mechanism o cytotoxic-
ity. In 5-FU–treated cells, both f uorodeoxyuridine triphosphate (FdU P) and
deoxyuridine triphosphate (dU P) (the substrate that accumulates behind the
blocked S reaction) incorporate into DNA in place o the depleted physiological
d P (see Figure 45-7). T e signi cance o the incorporation o FdU P and dU P
into DNA is unclear. Presumably, the incorporation o deoxyuridylate and/or f uo-
rodeoxyuridylate into DNA would call into action the excision-repair process. T is
process may result in DNA strand breakage because DNA repair requires d P, but
this substrate is lacking as a result o S inhibition.
T e olate co actor, N5,10 methylene tetrahydro olate, and FdUMP orm a cova-
lently bound ternary complex with S (see Figure 45-8). T is inhibited complex
resembles the transition state ormed during the enzymatic conversion o dUMP
to thymidylate. T e physiological complex o S- olate-dUMP progresses to the
synthesis o thymidylate by trans er o the methylene group and 2 hydrogen atoms
rom olate to dUMP, but this reaction is blocked in the inhibited complex o S-
FdUMP- olate by the stability o the f uorine carbon bond on FdUMP; sustained
inhibition o the enzyme results.
5-FU also may be converted by thymidine phosphorylase to the deoxyriboside f uo-
rodeoxyuridine (FUdR) and then by thymidine kinase to FdUMP (see Figure 45-7).
T ese complex metabolic pathways or the generation o FdUMP may be bypassed
through administration o f oxuridine (f uorodeoxyuridine; FUdR), which is converted
directly to FdUMP by thymidine kinase (FUdR rarely is used in clinical practice).
b. When used to treat tumors, what are the mechanisms o resistance to the
f uoropyrimidines?
Resistance to the cytotoxic e ects o 5-FU or FUdR has been ascribed to loss or
decreased activity o the enzymes necessary or activation o 5-FU, ampli cation o
(Continued)
640
Cancer Chemotherapy and Cytotoxic Agents CHAPTER 4 5
S, mutation o S to a orm that is not inhibited by FdUMP, and high levels o the
degradative enzymes dihydrouracil dehydrogenase and thymidine phosphorylase.
S levels are controlled by an autoregulatory eedback mechanism wherein the
unbound enzyme interacts with and inhibits the translational e ciency o its own
mRNA, which provides or the rapid S modulation needed or cellular division.
When S is bound to FdUMP, inhibition o translation is relieved, and levels o ree
S rise. T is may be an important mechanism by which malignant cells become
insensitive to the e ects o 5-FU.
Some malignant cells appear to have insu icient concentrations o N 5,10 methy-
lene tetrahydro olate, and thus cannot orm maximal levels o the inhibited
ternary complex with S. Addition o exogenous olate in the orm o N5- ormyl
FH 4 (leucovorin) increases ormation o the complex and enhances responses to
5-FU in clinical trials.
c. What are the important toxicities when the f uoropyrimidines are used to
treat tumors?
T e earliest untoward symptoms during a course o therapy are anorexia and nau-
sea, ollowed by stomatitis and diarrhea, which constitute reliable warning signs
that a su cient dose has been administered. Mucosal ulcerations occur throughout
the GI tract and may lead to ulminant diarrhea, shock, and death, particularly in
patients who are dihydropyrimidine dehydrogenase de cient.
5-FU is inactivated by reduction o the pyrimidine ring in a reaction carried out
by dihydropyrimidine dehydrogenase (DPD), which is ound in the liver, intestinal
mucosa, tumor cells, and other tissues. Inherited de ciency o this enzyme leads to
greatly increased sensitivity to the drug (see Figure 45-7). T e rare individual who
totally lacks this enzyme may experience pro ound drug toxicity ollowing conven-
tional doses o the drug. DPD de ciency can be detected either by enzymatic or
molecular assays using peripheral white blood cells or by determining the plasma
ratio o 5-FU to its metabolite, 5-f uoro-5,6-dihydrouracil.
Myelosuppression is also a major toxicity. Loss o hair, occasionally progressing to
total alopecia, nail changes, dermatitis, and increased pigmentation and atrophy
o the skin may be encountered. Hand- oot syndrome, a particularly prominent
adverse e ect o capecitabine (an orally administered prodrug o 5-FU), consists
o erythema, desquamation, pain, and sensitivity to touch o the palms and soles.
Acute chest pain with evidence o ischemia in the electrocardiogram may result
rom coronary artery vasospasms during or shortly a er 5-FU in usion.
T e signi cant risk o toxicity with f uoropyrimidines emphasizes the need or very
skill ul supervision by physicians amiliar with the action and possible hazards.
CASE 45 5
A 32-year-o d woman is being treated with 6-MP or her eukemia
a. What is the mechanism o action o 6-mercaptopurine?
6-MP is a purine analog. 6-MP and a related 6-thiopurine, 6-thioguanine (6- G),
unction as analogs o the natural purines, hypoxanthine and guanine. T e sub-
stitution o sul ur or oxygen on C6 o the purine ring creates compounds that
are readily transported into cells, including activated malignant cells. Nucleotides
ormed rom 6-MP and 6- G inhibit de novo purine synthesis and also become
incorporated into nucleic acids (see Figure 45-1). Both 6- G and 6-MP are excel-
lent substrates or hypoxanthine guanine phosphoribosyl trans erase (HGPR )
and are converted in a single step to the ribonucleotides 6-thioguanosine-5′-
monophosphate (6-thioGMP) and 6-thioinosine-5′-monophosphate ( -IMP),
respectively. Because -IMP is a poor substrate or guanylyl kinase, the enzyme
that converts guanosine monophosphate (GMP) to guanosine diphosphate (GDP),
-IMP accumulates intracellularly and in a second step is converted to 6- GMP.
(Continued)
641
SECTION VIII Chemotherapy of Neoplastic Diseases
MECHANISMS OF ACTION AND RESISTANCE OF CYTOTOXIC NAURAL PRODUCTS (SEE TABLE 45-4)
CLASSIFICATION DRUG MECHANISMS OF ACTION MECHANISMS OF RESISTANCE
Microtubule-Damaging Vinblastine sul ate Bind to β tubulin blocking its polymerization See Side Bar MECHANISMS OF
Agents—Vinca Alkaloids Vinorelbine with α tubulin into microtubules, thus RESISTANCE TO CYTOTOXIC
Vincristine sul ate preventing mitotic spindle ormation which NATURAL PRODUCTS
blocks cells in mitosis leading to apoptosis (see
Figures 45-1 and 45-3)
Microtubule-Damaging Paclitaxel Bind to β tubulin site (di erent than the vinca See Side Bar MECHANISMS OF
Agents—Taxanes Nab-paclitaxel alkaloids) and promote rather than inhibit RESISTANCETO CYTOTOXIC
Docetaxel microtubule ormation causing aberrant NATURAL PRODUCTS
microtubule structures away rom the centriole
and arrest in mitosis (see Figures 45-1 and 45-3)
(Continued)
642
Cancer Chemotherapy and Cytotoxic Agents CHAPTER 4 5
Microtubule-Damaging Ixabepilone Bind to β tubulin (at a site distinct rom taxanes) See Side Bar MECHANISMS OF
Agents—Epothilones and trigger microtubule nucleation at multiple RESISTANCE TO CYTOTOXIC
sites away rom the centriole (see Figure 45-1) NATURAL PRODUCTS
Topoisomerase inhibitors— Topotecan Bind and stabilize the normally transient DNA- See Side Bar MECHANISMS OF
Camptothecin Analogs Irinotecan (CPT-11) topoisomerase I cleavable complex, inhibiting RESISTANCETO CYTOTOXIC
religation and resulting in single-stranded DNA NATURAL PRODUCTS
strand breaks (reversible) and double-stranded
DNA strand breaks (irreversible)
(see Figure 45-1)
Topoisomerase inhibitors— Etoposide (VP-16-213) Form a ternary complex with topoisomerase II See Side Bar MECHANISMS OF
Epipodophyllotoxins Teniposide (VM-26) and DNA that prevents resealing o the strand RESISTANCETO CYTOTOXIC
break; the enzyme remains bound to the ree NATURAL PRODUCTS
end o the broken DNA strand, leading to an
accumulation o DNA breaks and cell death (see
Figure 45-1)
643
SECTION VIII Chemotherapy of Neoplastic Diseases
645
SECTION VIII Chemotherapy of Neoplastic Diseases
MECHANISMS OF TABLE 45-5 Miscellaneous Agents (some of these agents are covered in Chapter 46)
RESISTANCE TO CYTOTOXIC TYPE OF AGENT NONPROPRIETARY NAMES DISEASE
NATURAL PRODUCTS (Cont.)
Substituted urea Hydroxyurea Chronic myelogenous
• Resistance to mitomycin has been ascribed leukemia; polycythemia vera;
to the ollowing: essential thrombocytosis
» De cient activation Di erentiating agents Tretinoin, arsenic trioxide Acute promyelocytic leukemia
» Intracellular inactivation o the
reduced quinone Histone deacetylase inhibitor Cutaneous T-cell lymphoma
(vorinostat)
» P-glycoprotein–mediated drug ef ux
Protein tyrosine kinase Imatinib Chronic myelogenous
inhibitors leukemia; GI stromal tumors
(GIST); hypereosinophilia
syndrome
Biological response modi ers Inter eron-al a, interleukin-2 Hairy cell leukemia; Kaposi’s
sarcoma; melanoma;
carcinoid; renal cell; non-
Hodgkin’s lymphoma;
mycosis ungoides; chronic
myelogenous leukemia
646
Cancer Chemotherapy and Cytotoxic Agents CHAPTER 4 5
radicals. T ese can generate both hydrogen peroxide and hydroxyl radicals, which
attack DNA and oxidize DNA bases.
Bleomycin is a member o unique group o DNA-cleaving antibiotics which are
ermentation products o Streptomyces verticillus. Bleomycin’s cytotoxicity results
rom its ability to cause oxidative damage to the deoxyribose o thymidylate and
other nucleotides, leading to single- and double-stranded breaks in DNA. T e bleo-
mycin molecule is a glycopeptide that contains a metal-binding cage that is bound
to either Fe2+ or Cu 2+. In the presence o O2 and a reducing agent the metal–drug
complex becomes activated and unctions as a errous oxidase, trans erring elec-
trons rom Fe2+ to molecular oxygen to produce oxygen radicals. Bleomycin binds
to DNA, and the activated complex generates ree radicals that are responsible or
abstraction o a proton at the 3′ position o the deoxyribose backbone o the DNA
chain, opening the deoxyribose ring and generating a strand break in DNA.
Vinblastine is a vinca alkaloid derived rom the Madagascar periwinkle plant,
Catharanthus roseus. Other vinca alkaloids with antitumor activity include vincris-
tine, vindesine, and vinorelbine. T e vincas bind speci cally to β tubulin and block
its polymerization with α tubulin into microtubules, thus preventing the ormation
o mitotic spindles. In the absence o an intact mitotic spindle, duplicated chromo-
somes cannot align along the division plate. T ey disperse throughout the cyto-
plasm (exploded mitosis) or may clump in unusual groupings, such as balls or stars.
Cells are blocked in mitosis and undergo changes characteristic o apoptosis.
Dacarbazine (D IC) is a triazene alkylating agent. It is metabolically activated
by hepatic CYPs through an N-demethylation reaction. In the target cell, spon-
taneous cleavage o the metabolite, methyl-triazeno-imidazole-carboxamide
(M IC), yields an alkylating moiety, a methyl diazonium ion. T is reactive species
incorporates methyl groups into DNA. For a detailed description o DNA alkylation
reactions, re er to Case 45-1a.
b. What is the rationale or using combinations o cytotoxic drugs such as the
ABVD regimen compared to single-agent therapies?
Most cytotoxic drugs are used in combination with other cytotoxic agents with
di erent mechanisms o action to enhance tumor cell killing and to avoid the
development o resistance. Drugs in combination can negate the e ects o a resis-
tance mechanism speci c or a single agent, and they may be synergistic because
o their biochemical interactions. Ideally, drug combinations should not overlap in
their major toxicities.
KEY CONCEPTS
Cytotoxic antineop astic agents are structura y and mechanistica y diverse
T e e cacy o many cytotoxic agents depends on intact ce cyc e checkpoint
regu ation and apoptotic mechanisms
Rapid y dividing ce s (inc uding norma ce s such as GI epithe ia ce s and
bone marrow ce s) are typica y more sensitive to the e ects o cytotoxic agents
Common acute toxicities o cytotoxic agents inc ude GI damage and
mye osuppression
Mye osuppression can ead to increased risk o opportunistic in ections and
b eeding disorders
DNA modi ying agents are typica y mutagenic and carcinogenic, resu ting
in increased risk o eukemias and other cancers months or years o owing
treatment
Cytotoxic agents can cause chronic damage to critica organs, inc uding the kid-
ney, iver, and heart
Most cytotoxic chemotherapeutic agents are etotoxic
(Continued)
647
SECTION VIII Chemotherapy of Neoplastic Diseases
SUMMARY QUIZ
QUESTION 45-2 When administered prior to 5-FU, this agent enhances the activation
o and antitumor activity by increasing poo s o PRPP
a Leucovorin
b Oxa ip atin
c Methotrexate
d Cytarabine (Ara-C)
e F uxuridine
QUESTION 45-3 An enzyme derived rom Escherichia coli that deprives eukemia ce s
o a required amino acid is
a pentostatin
b l -asparaginase (l -ASP)
c deoxycytidine kinase (dCK)
d trabectedin
e asparagine synthase
QUESTION 45-4 Pac itaxe and the other taxanes have a centra ro e in the therapy
o ovarian, breast, ung, GI, genitourinary, and head and neck cancers T e cytotoxic
e ect o the taxanes in tumor ce s is the resu t o
a inhibition o microtubu e ormation
b inhibition o microtubu e disassemb y
c enhancement o microtubu e disassemb y
d inhibition o topoisomerase I
e inhibition o topoisomerase II
648
Cancer Chemotherapy and Cytotoxic Agents CHAPTER 4 5
QUESTION 45-2 Answer is c. A number o agents have been combined with 5-FU in
attempts to enhance cytotoxic activity through biochemica modu ation Methotrexate,
by inhibiting purine synthesis and increasing ce u ar poo s o PRPP (see Figure 45-6),
enhances the activation o 5-FU (see Figure 45-7), and increases antitumor activity o
5-FU when given prior to but not o owing 5-FU
Some ma ignant ce s appear to have insu cient concentrations o N 5,10 methy-
ene tetrahydro o ate, and thus cannot orm maxima eve s o the inhibited ternary
comp ex with S Addition o exogenous o ate in the orm o N5- ormy FH 4
( eucovorin) increases ormation o the comp ex and enhances responses to 5-FU
(see Figure 45-8)
T e combination o cisp atin and 5-FU has yie ded impressive responses in
tumors o the upper aerodigestive tract, but the mo ecu ar basis o their interaction is
not we understood Oxa ip atin, which downregu ates S expression, is common y
used with 5-FU
Perhaps the most c inica y important interaction is the enhancement o irradiation
by uoropyrimidines, the mechanistic basis or which is unc ear 5-FU with simu tane-
ous irradiation cures ana cancer and enhances oca tumor contro in head and neck,
cervica , recta , gastroesophagea , and pancreatic cancers
649
SECTION VIII Chemotherapy of Neoplastic Diseases
with other agents, inc uding methotrexate, doxorubicin, vincristine, and prednisone or
the treatment o ALL and or high-grade ymphomas Resistance arises through induc-
tion o asparagine synthetase in tumor ce s
l -ASP toxicities resu t rom its antigenicity as a oreign protein and its inhibition
o protein synthesis Hypersensitivity reactions, inc uding urticaria and u -b own
anaphy axis, occur in 5-20% o patients and may be ata T ese reactions usua y are
hera ded by the ear ier appearance o circu ating neutra izing antibody and acce erated
enzyme c earance rom p asma In these patients, pegaspargase (a preparation in which
the enzyme is conjugated to 5000-Da units o monomethoxy po yethy ene g yco ) is a
sa e and e ective a ternative T e so-ca ed “si ent” enzyme inactivation by antibodies
occurs in a higher percentage o patients than overt hypersensitivity and may be associ-
ated with a negative c inica outcome, especia y in high-risk ALL patients
QUESTION 45-4 Answer is b. Pac itaxe and other taxanes (nab-pac itaxe and
docetaxe ) bind speci ca y to the β tubu in subunit o microtubu es and antagonize
the disassemb y o this key cytoske eta protein, with the resu t that bund es o micro-
tubu es and aberrant structures derived rom microtubu es appear in the mitotic phase
o the ce cyc e Arrest in mitosis o ows Drugs that b ock ce cyc e progression prior
to mitosis antagonize the toxic e ects o taxanes Resistance to taxanes is associated in
some cancer ce s with increased expression o the mdr-1 gene and its product, P-g y-
coprotein; other resistant ce s have β tubu in mutations (these atter ce s may disp ay
heightened sensitivity to vinca a ka oids) T e taxanes pre erentia y bind to the βII
tubu in subunit o microtubu es; there ore, ce s may become resistant by upregu ating
the βIII iso orm o tubu in
T e vinca a ka oids and co chicine derivatives di er rom the taxanes in that they
bind to a di erent site on β tubu in site and inhibit microtubu e ormation rather than
inhibit disassemb y
Estramustine binds to β tubu in and microtubu e-associated proteins, causing
microtubu e disassemb y and inhibition o mitosis
Ixabepi one and other members o the epothi ones c ass resemb e taxanes in that
they bind to β tubu in and trigger microtubu e nuc eation at mu tip e sites away rom
the centrio e T is chaotic microtubu e stabi ization triggers ce cyc e arrest at the
G2-M inter ace and apoptosis Epothi ones bind to a site distinct rom that o taxanes
In vitro studies suggest that ixabepi one is ess susceptib e to P-g ycoprotein-mediated
mu tidrug resistance when compared to taxanes Mechanisms imp icated in epothi one
resistance inc ude mutation o the β tubu in binding site and up-regu ation o iso orms
o β tubu in
QUESTION 45-5 Answer is c. T e camptothecins bind to and stabi ize the norma y
transient DNA-topoisomerase I c eavab e comp ex
T e DNA topoisomerases are nuc ear enzymes that reduce torsiona stress in
supercoi ed DNA, a owing se ected regions o DNA to become su cient y untang ed
and re axed to permit rep ication, repair, and transcription wo c asses o topoisom-
erase (I and II) mediate DNA strand breakage and resea ing, and both have become
the target o cancer chemotherapies Camptothecin ana ogs inhibit the unction o
topoisomerase I, whi e a number o di erent chemica entities (eg, anthracyc ines,
epipodophy otoxins, acridines) inhibit topoisomerase II opoisomerase I binds cova-
ent y to doub e-stranded DNA through a reversib e transesteri cation reaction T is
reaction yie ds an intermediate comp ex in which the tyrosine o the enzyme is bound
to the 3′-phosphate end o the DNA strand, creating a sing e-strand DNA break T is
“c eavab e comp ex” a ows or re axation o the DNA torsiona strain, either by passage
o the intact sing e-strand through the nick or by ree rotation o the DNA about the
nonc eaved strand Once the DNA torsiona strain has been re ieved, the topoisomer-
ase I resea s the c eavage and dissociates rom the new y re axed doub e he ix
(Continued)
650
Cancer Chemotherapy and Cytotoxic Agents CHAPTER 4 5
Ethyleneimines and Altretamine Palliative treatment or See Side Bar TOXICITIES OF Peripheral and central
Methylmelamines (hexamethylendiamine) persistent or recurrent ALKYLATING DRUGS neurotoxicity (ataxia,
ovarian cancer ollowing Main toxicities are depression, con usion,
cisplatin-based myelosuppression and drowsiness, hallucinations,
combination therapy neurotoxicity dizziness, and vertigo)
Nausea and vomiting also Peripheral blood counts and
are common side e ects a neurological examination
and may be dose-limiting should be per ormed prior to
Renal dys unction may the initiation o each course
necessitate discontinuing o therapy
the drug Severe, li e-threatening
orthostatic hypotension may
develop in patients who
receive monoamine oxidase
(MAO) inhibitors concurrently
with altretamine
Thiotepa Primarily used or high- See Side Bar TOXICITIES OF May cause neurotoxic
dose chemotherapy ALKYLATING DRUGS symptoms, including coma and
regimens seizures in high-dose regimens
Alkyl Sul onates Busul an See Table 45-1 See Side Bar TOXICITIES OF Pulmonary brosis, GI mucosal
ALKYLATING DRUGS damage, and hepatic veno-
Major toxic e ects occlusive disease (VOD) are
are related to important toxicities with high-
myelosuppression dose regimens
Occasionally, patients VOD and hepatotoxicity is
experience nausea, increased by coadministration
vomiting, and diarrhea with drugs that inhibit CYPs
Long-term use leads Anticonvulsants must be used
to impotence, sterility, concomitantly to protect
amenorrhea, and etal against acute CNS toxicities,
mal ormation including tonic-clonic seizures,
which may occur several hours
a ter each dose
(Continued)
651
SECTION VIII Chemotherapy of Neoplastic Diseases
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Nitrosoureas Carmustine (BCNU) See Table 45-1 and See Side Bar TOXICITIES OF With the exception o
Lomustine (CCNU) text o Chapter 61 o ALKYLATING DRUGS streptozocin, nitrosoureas
Semustine (methyl-CCNU) Goodman &Gilman’s The With streptozocin, cause pro ound and delayed
Streptozocin (streptozotocin) Pharmacological Basis of nausea is requent and myelosuppression with
Therapeutics, 12th Edition mild, reversible renal or recovery 4-6 weeks a ter a
or uses o speci c agents hepatic toxicity occurs in single dose
Carmustine, lomustine, approximately two-thirds Renal ailure with long-term
and semustine are highly o cases (renal toxicity treatment
lipophilic, readily cross the may be cumulative), and Highly carcinogenic and
blood-brain barrier and hematological toxicity mutagenic
are used to treat brain occurs in 20% o patients BCNU in high doses with bone
tumors marrow rescue produces
Streptozocin is used hepatic VOD, pulmonary
exclusively in the brosis, renal ailure, and
treatment o human secondary leukemia
pancreatic islet cell
carcinoma and
malignant carcinoid
tumors
Triazenes Dacarbazine (DTIC) See Table 45-1 and See Side Bar TOXICITIES OF Temozolomide is administered
Temozolomide text o Chapter 61 o ALKYLATING DRUGS cyclically, and hematological
Goodman &Gilman’s The DTIC induces nausea monitoring is necessary to
Pharmacological Basis of and vomiting in >90% o guide dosing adjustments
Therapeutics, 12th Edition patients
or uses o speci c agents Myelosuppression is mild
Primary indication and readily reversible
or dacarbazine is within 1-2 weeks
in the combination A u-like syndrome
chemotherapy o consisting o chills, ever,
Hodgkin’s disease; malaise, and myalgias
modestly e ective against may occur
malignant melanoma and Hepatotoxicity,
adult sarcomas alopecia, acial ushing,
Temozolomide is neurotoxicity, and
the standard agent dermatological reactions
in combination with are less common
radiation therapy or
patients with malignant
glioma and astrocytoma
Methylhydrazines Procarbazine See Table 45-1 and See Side Bar TOXICITIES OF Augments sedative e ects;
text o Chapter 61 o ALKYLATING DRUGS concomitant use o CNS
Goodman &Gilman’s The Most common toxic depressants should be
Pharmacological Basis of e ects include leukopenia avoided
Therapeutics, 12th Edition and thrombocytopenia A weak MAO inhibitor
or uses o speci c agents GI symptoms such as Has disul ram-like action,
Currently employed or mild nausea and vomiting EtOH ingestion should be
second-line therapy in occur in most patients; avoided
malignant brain tumors; diarrhea and rash are Highly carcinogenic,
is rarely used in current noted in 5-10% o cases mutagenic, and teratogenic,
practice and is associated with a
5-10% risk o acute leukemia
in combination with other
agents or radiation
Causes in ertility, particularly
in males
(Continued)
652
Cancer Chemotherapy and Cytotoxic Agents CHAPTER 4 5
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Platinum Coordination Cisplatin See Table 45-1 and See Side Bar TOXICITIES OF Cisplatin-induced
Complexes Carboplatin (CBDCA) text o Chapter 61 o ALKYLATING DRUGS nephrotoxicity; to prevent
Oxaliplatin Goodman &Gilman’s The Marked nausea and renal toxicity with cisplatin,
Pharmacological Basis of vomiting occur in almost it is important to establish
Therapeutics, 12th Edition all patients and usually can a chloride diuresis by the
or uses o speci c agents be controlled with 5-HT3 in usion o 1-2 L o normal
Oxaliplatin exhibits antagonists, NK1-receptor saline prior to treatment
a range o antitumor antagonists, and high- Ami ostine is a thiophosphate
activity (colorectal and dose corticosteroids cytoprotective agent that
gastric cancer) that di ers Electrolyte disturbances, reduces renal toxicity
rom other platinum including hypo- Ototoxicity
agents, perhaps due magnesemia, Anaphylactic-like reactions
to its MMR- and HMG- hypocalcemia, Aluminum reacts with and
independent e ects hypokalemia, and inactivates cisplatin; the
hypophosphatemia drug should not come in
are common; routine contact with needles or other
monitoring o plasma Mg 2+ in usion equipment that
recommended contain aluminum during its
Ototoxicity preparation or administration
Anaphylactic-like reactions Dose-limiting toxicity
Carboplatin is relatively o carboplatin is
well tolerated, causing myelosuppression
less nausea, neurotoxicity, Dose-limiting toxicity o
ototoxicity, and oxaliplatin is a peripheral
nephrotoxicity than neuropathy
cisplatin Platinum agents cause
leukemia and pulmonary
brosis months to years a ter
administration
Folic Acid Analogs Methotrexate(amethopterin) See Table 45-3 and Primary toxicities o Myelosuppression can
(Anti olates) High-dose methotrexate text o Chapter 61 o anti olates a ect the bone increase risk or spontaneous
with leucovorin rescue Goodman &Gilman’s The marrow and the intestinal hemorrhage or li e-
(HDM-L) Pharmacological Basis of epithelium and usually threatening in ection, and
Trimetrexate Therapeutics, 12th Edition resolve within 10-14 days may require prophylactic
Pemetrexed or uses o speci c agents Pemetrexed is also trans usion o platelets and
Pralatrexate Methotrexate is also used associated with a broad-spectrum antibiotics i
Raltitrexed to treat psoriasis and prominent erythematous ebrile
Lometrexol rheumatoid arthritis (see and pruritic rash in 40% Prolonged myelosuppression
Chapter 23) o patients which can may occur in patients
be diminished with with compromised renal
dexamethasone unction and requires
Additional toxicities dosage adjustment based on
include alopecia, creatinine clearance
dermatitis, an allergic
interstitial pneumonitis,
nephrotoxicity (a ter
high-dose therapy),
de ective oogenesis or
spermatogenesis, abortion,
and teratogenesis
(Continued)
653
SECTION VIII Chemotherapy of Neoplastic Diseases
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Pyrimidine Analogs 5-Fluorouracil (5-FU) See Table 45-3 and Anorexia and nausea, Mucosal ulcerations
Floxuridine (FUdR, text o Chapter 61 o ollowed by stomatitis throughout the GI tract may
uorodeoxyuridine) Goodman &Gilman’s The and diarrhea constitute lead to ulminant diarrhea,
Capecitabine Pharmacological Basis of reliable warning signs that shock, and death, particularly
Therapeutics, 12th Edition a suf cient dose has been in patients who are DPD
or uses o speci c agents administered de cient
5-FU is rarely used as a Alopecia, nail changes, Myelosuppression (more o ten
single agent dermatitis, and increased with bolus regimens)
5-FU also is a potent pigmentation and atrophy Hand- oot syndrome
radiation sensitizer o the skin may occur (more o ten with in usional
5-FU is used topically or regimens)
premalignant keratoses Coronary vasospasm with
o the skin and multiple 5-FU in usion
super cial basal cell The signi cant risk o toxicity
carcinoma with uoropyrimidines
emphasizes the need or
very skill ul supervision by
physicians amiliar with the
action and possible hazards
Cytarabine (cytosine See Table 45-3 and Acute, severe leukopenia, A ter high-dose Ara-C (1-2
arabinoside, Ara-C) text o Chapter 61 o thrombocytopenia, and weeks) dyspnea, ever, and
Goodman &Gilman’s The anemia with striking pulmonary in ltrates may
Pharmacological Basis of megaloblastic changes occur, which may be atal in
Therapeutics, 12th Edition GI disturbances, stomatitis, 10-20% o patients
or uses o speci c agents conjunctivitis, reversible Intrathecal Ara-C (especially
hepatic enzyme with systemic high-dose
elevations, noncardiogenic methotrexate) or high-dose
pulmonary edema, and systemic Ara-C may cause
dermatitis CNS toxicity including ataxia
and slurred speech, seizures,
delirium, myelopathy, or coma,
especially in patients >40 years
o age and/or patients with
poor renal unction
Azacytidine (5-azacytidine) See Table 45-3 and Myelosuppression and Severe nausea and vomiting
Decitabine text o Chapter 61 o mild GI symptoms when given intravenously in
(2′-deoxy-5-azacytidine) Goodman &Gilman’s The large doses
Pharmacological Basis of
Therapeutics, 12th Edition
or uses o speci c agents
(Continued)
654
Cancer Chemotherapy and Cytotoxic Agents CHAPTER 4 5
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Purine Analogs 6-Mercaptopurine (6-MP) See Table 45-3 and Myelosuppression Myelosuppression may be
6-Thioguanine (6-TG) text o Chapter 61 o (develops more gradually severe and prolonged in
Goodman &Gilman’s The than with olic acid patients with a polymorphism
Pharmacological Basis of antagonists) a ecting TPMT
Therapeutics, 12th Edition Anorexia, nausea, or Predisposes to opportunistic
or uses o speci c agents vomiting in ~25% o in ection such as reactivation
The combination o adults, but stomatitis and o hepatitis B, ungal in ection,
methotrexate and 6-MP diarrhea are rare and Pneumocystis pneumonia
appears to be synergistic Jaundice and hepatic and an increased incidence o
6-MP is also used or enzyme elevations occur squamous cell malignancies o
Crohn’s disease (see in up to one-third o adult the skin
Chapter 23) patients treated with 6-MP;
usually resolves upon
discontinuation o therapy
Fludarabine phosphate See Table 45-3 and Myelosuppression (World Depletion o CD4+ T cells
text o Chapter 61 o Health Organization grade Predisposes to opportunistic
Goodman &Gilman’s The 3 or 4) in about hal o in ections
Pharmacological Basis of patients Tumor lysis syndrome
Therapeutics, 12th Edition Nausea and vomiting (relatively in requent)
or uses o speci c agents in a minor raction; Altered mental status, seizures,
Also used as an in requently chills and optic neuritis, and coma at
immunosuppressant ever, malaise, anorexia, higher doses and in older
in nonmyeloablative peripheral neuropathy, patients
allogeneic bone marrow and weakness Auto-immune events (acute
transplantation, where hemolytic anemia or pure
it suppresses the host red cell aplasia, prolonged
response and may cytopenias)
encourage alloreactive Myelodysplasia and acute
donor T cells leukemias may arise as late
complications
Clo arabine (2-chloro-2′- See Table 45-3 and Major toxicity is Clinical syndrome o
uoro-arabinosyladenine) text o Chapter 61 o myelosuppression hypotension, tachyphemia,
Goodman &Gilman’s The Elevated hepatic enzymes pulmonary edema, organ
Pharmacological Basis of and increased bilirubin dys unction, ever, are all
Therapeutics, 12th Edition Nausea, vomiting, suggestive o capillary leak
or uses o speci c agents and diarrhea syndrome and cytokine
Hypokalemia and release; evidence o capillary
hypophosphatemia leak should lead to immediate
discontinuation o the drug
Nelarabine (6-methoxy- See Table 45-3 and Myelosuppression Frequent, serious neurological
arabinosyl-guanine) text o Chapter 61 o and liver unction test sequelae such as seizures,
Goodman &Gilman’s The abnormalities delirium, somnolence,
Pharmacological Basis of peripheral neuropathy, or
Therapeutics, 12th Edition Guillain-Barré syndrome;
or uses o speci c agents neurological side e ects may
not be reversible
(Continued)
655
SECTION VIII Chemotherapy of Neoplastic Diseases
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Pentostatin See Table 45-3 and Myelosuppression, GI Immunosuppression may
(2′-deoxyco ormycin) text o Chapter 61 o symptoms, skin rashes, and persist or several years a ter
Goodman &Gilman’s The abnormal liver unction discontinuation
Pharmacological Basis of studies Major renal and neurological
Therapeutics, 12th Edition Neutropenic ever and complications are
or uses o speci c agents opportunistic in ections encountered with high doses
may occur Severe or even atal
pulmonary toxicity may
occur in combination with
udarabine phosphate
Microtubule- Vinblastine sul ate See Table 45-4 and Mild myelosuppression Syndrome o inappropriate
Damaging Agents— Vinorelbine text o Chapter 61 o and mild neurotoxicity secretion o antidiuretic
Vinca Alkaloids Vincristine sul ate Goodman &Gilman’s The GI disturbances including hormone has been reported
Pharmacological Basis of nausea, vomiting, anorexia, with vinblastine, less
Therapeutics, 12th Edition and diarrhea may occur commonly with vincristine
or uses o speci c agents Severe constipation Extravasation during injection
with vincristine may be may lead to cellulitis and
prevented by a prophylaxis phlebitis
with laxatives and bulk-
orming agents
Alopecia occurs in
~20% o patients given
vincristine, however,
it is always reversible,
requently without
cessation o therapy
Vinorelbine may cause
allergic reactions and mild,
reversible changes in liver
enzymes
Microtubule-Damaging Paclitaxel See Table 45-4 and Myelosuppression A ter treatment with paclitaxel,
Agents—Taxanes Nab-paclitaxel text o Chapter 61 o Peripheral neuropathy myalgias or several days are
Docetaxel Goodman &Gilman’s The with paclitaxel is dose- common
Pharmacological Basis of limiting; with high-dose Mucositis is common in 72-
Therapeutics, 12th Edition schedules or prolonged or 96-hour in usions and in
or uses o speci c agents use, a stocking-glove the weekly schedule with
sensory neuropathy can paclitaxel
be disabling Asymptomatic bradycardia
Hypersensitivity reactions and occasional silent
in patients receiving ventricular tachycardia can
paclitaxel in usions o short occur with paclitaxel
duration (1-6 h) are largely With multiple cycles o
averted by pretreatment docetaxel therapy, progressive
with dexamethasone, uid retention can occur
diphenhydramine, and leading to peripheral edema,
histamine H2 receptor pleural and peritoneal
antagonists uid, and pulmonary
Higher rates o peripheral edema in extreme cases;
neuropathy with nab- dexamethasone can prevent
paclitaxel compared this
to paclitaxel but rarely
hypersensitivity reaction
Docetaxel causes
greater neutropenia
than paclitaxel but less
peripheral neuropathy
and less requent
hypersensitivity
(Continued)
656
Cancer Chemotherapy and Cytotoxic Agents CHAPTER 4 5
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Microtubule- Estramustine See text o Chapter 61 o Myelosuppression Possesses estrogenic side
Damaging Goodman &Gilman’s The e ects (gynecomastia,
Agents—Estramustine Pharmacological Basis of impotence, elevated risk
Therapeutics, 12th Edition o thrombosis, and uid
or uses o speci c agents retention), hypercalcemia,
acute attacks o porphyria,
impaired glucose tolerance,
and hypersensitivity reactions,
including angioedema
Topoisomerase Topotecan See Table 45-4 and Dose-limiting toxicity o Severe neutropenia and ebrile
inhibitors— Irinotecan (CPT-11) text o Chapter 61 o topotecan with all dosing neutropenia (which may
Camptothecin Goodman &Gilman’s The schedules is neutropenia, be atal with concomitant
Analogs Pharmacological Basis of with or without diarrhea)
Therapeutics, 12th Edition thrombocytopenia, and Inhibition o
or uses o speci c agents GI side e ects such as acetylcholinesterase activity
mucositis and diarrhea in by irinotecan may occur
some patients within the rst 24 h
Less common but mild causing a cholinergic
topotecan-related syndrome (acute diarrhea,
toxicities include nausea diaphoresis, hypersalivation,
and vomiting, elevated abdominal cramps, visual
liver transaminases, ever, accommodation disturbances,
atigue, and rash lacrimation, rhinorrhea,
Dose-limiting toxicity asymptomatic bradycardia)
with irinotecan is delayed which can be treated
diarrhea which can be with atropine
reduced by treatment
with loperamide (see
Chapter 33)
Common but mild toxicities
with irinotecan include
nausea and vomiting,
atigue, vasodilation or
skin ushing, mucositis,
elevation in liver
transaminases, and alopecia
657
SECTION VIII Chemotherapy of Neoplastic Diseases
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Anticancer Dactinomycin See Table 45-4 and Anorexia, nausea, and Severe injury may occur
Antibiotics— (actinomycin D) text o Chapter 61 o vomiting as a result o local drug
Actinomycins Goodman &Gilman’s The Hematopoietic suppression extravasation
Pharmacological Basis of with pancytopenia
Therapeutics, 12th Edition Proctitis, diarrhea, glossitis,
or uses o speci c agents cheilitis, and ulcerations
o the oral mucosa are
common
Dermatological
mani estations (alopecia,
erythema, desquamation,
and increased in ammation
and pigmentation) in areas
previously or concomitantly
subjected to X-ray radiation
Anticancer Doxorubicin (ADRIAMYCIN) See Table 45-4 and Myelosuppression, Cardiac toxicity (acute and
Antibiotics— Daunorubicin (daunomycin, text o Chapter 61 o stomatitis, alopecia, GI chronic) characterized by
Anthracyclines and rubidomycin) Goodman &Gilman’s The disturbances, and rash are tachycardia, arrhythmias,
Anthracenediones Idarubicin Pharmacological Basis of common toxicities dyspnea, hypotension,
Epirubicin Therapeutics, 12th Edition Mitoxantrone causes less pericardial e usion, and
Valrubicin or uses o speci c agents cardiac toxicity, nausea, congestive heart ailure poorly
Mitoxantrone vomiting, and alopecia responsive to digitalis; chronic
than does doxorubicin cardiomyopathy is cumulative
Erythematous streaking dose-related and can occur
near the site o in usion years a ter treatment;
(“ADRIAMYCIN are”) is concomitant administration o
a benign local allergic dexrazoxane may avert later
reaction and should cardiotoxicity
not be con used with
extravasation
Anticancer Bleomycin See Table 26-4 and Skin toxicities, including Pulmonary toxicity (1-5% o
Antibiotics— text o Chapter 61 o hyperpigmentation, patients), which begins with
Bleomycin Goodman &Gilman’s The hyperkeratosis, erythema, a dry cough, ne rales, and
Pharmacological Basis of ulceration, and rarely di use basilar in ltrates on
Therapeutics, 12th Edition Raynaud’s phenomenon X-ray and may progress to li e-
or uses o speci c agents Other toxicities include threatening pulmonary brosis
hyperthermia, headache, (~1% die); risk o pulmonary
nausea and vomiting, and toxicity is related to total dose
a peculiar acute ulminant
reaction in ~1% patients
with lymphomas or
testicular cancer
Anticancer Mitomycin (mitomycin-C) See Table 45-4 and Myelosuppression, A hemolytic uremic syndrome
Antibiotics— text o Chapter 61 o characterized by (hemolysis, neurological
Mitomycin Goodman &Gilman’s The marked leukopenia and abnormalities, interstitial
Pharmacological Basis of thrombocytopenia pneumonia, and glomerular
Therapeutics, 12th Edition damage resulting in renal
or uses o speci c agents ailure) believed to result rom
drug-induced endothelial
damage; toxicity increases
with dose (28% renal ailure
in total high dose); early
recognition and immediate
discontinuation o drug is
needed to minimize toxicity
Interstitial pulmonary brosis
Heart ailure, especially in
combination with doxorubicin
(Continued)
658
Cancer Chemotherapy and Cytotoxic Agents CHAPTER 4 5
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Trabectedin Trabectedin Approved outside Mild myelosuppression Signi cant hepatic enzyme
the United States or elevations and atigue in one-
second-line treatment third o patients, but with
o so t tissue sarcomas dexamethasone pretreatment
and ovarian cancer transaminase increases are
in combination with less pronounced and rapidly
doxorubicin reversed
Rhabdomyolysis (rarely)
Enzymes L-asparaginase (L-ASP See Table 45-4 and Toxicities resulting rom Hypersensitivity reactions to
Pegaspargase text o Chapter 61 o inhibition o protein L-ASP, including urticaria and
(PEG-L-asparaginase) Goodman &Gilman’s The synthesis in normal tissues ull-blown anaphylaxis, occur
Pharmacological Basis of (eg, hyperglycemia due to in 5-20% o patients and may
Therapeutics, 12th Edition insulin de ciency, clotting be atal; pegaspargase is a
or uses o speci c agents abnormalities due to sa e and e ective alternative
de cient clotting actors, in patients who show
hypertriglyceridemia hypersensitivity to L-ASP
due to e ects on “Silent”enzyme inactivation by
lipoprotein production, antibodies occurs in a higher
hypoalbuminemia) percentage o patients than
overt hypersensitivity and may
be associated with a negative
clinical outcome, especially in
high-risk ALL patients
Pancreatitis
Dysregulated coagulation
(thrombosis and hemorrhage)
Mitotane Mitotane (o,p′-DDD) Adrenal cortex cancer Anorexia and nausea in Because o drug-induced
most patients, somnolence adrenal cortex damage,
and lethargy in ~34%, and adrenocorticosteroid
dermatitis in 15-20% replacement therapy is
necessary
Hydroxyurea (HU) Hydroxyurea (HU) See Table 45-5 and Myelosuppression, which Potent teratogen; should
text o Chapter 61 o is rapidly reversible with not be used in women with
Goodman &Gilman’s The drug discontinuation childbearing potential
Pharmacological Basis of Desquamative
Therapeutics, 12th Edition interstitial pneumonitis,
or uses o speci c agents GI disturbances, and
dermatological reactions
(including increased
pigmentation and pain ul
leg ulcers)
Di erentiating Tretinoin (all-trans retinoic See Table 45-5 and Dry skin, cheilitis, “Di erentiation syndrome”
Agents—Retinoids acid, ATRA) text o Chapter 61 o reversible hepatic enzyme or “retinoic acid syndrome”
Goodman &Gilman’s The abnormalities, bone caused by an outpouring
Pharmacological Basis of tenderness, pseudotumor o cytokines and mature-
Therapeutics, 12th Edition cerebri, hypercalcemia, appearing neutrophils o
or uses o speci c agents and hyperlipidemia leukemic origin results in
a syndrome o respiratory
distress, ever, pulmonary
in ltrates pleural and
pericardial e usions, and
mental status changes that
a ect 15-20% o patients and
may have a atal outcome;
mitigated by dexamethasone
pretreatment
(Continued)
659
SECTION VIII Chemotherapy of Neoplastic Diseases
TOXICITIES
CLASS AND UNIQUE; CLINICALLY
SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Di erentiating Arsenic trioxide (ATO) See Table 45-5 and Reversible side e ects Di erentiation syndrome
Agents—Arsenic text o Chapter 61 o include hyperglycemia, similar to ATRA in 10% o
Trioxide Goodman &Gilman’s The hepatic enzyme elevations, patients which is reversed by
Pharmacological Basis of atigue, dysesthesias, and oxygen, corticosteroids, and
Therapeutics, 12th Edition light-headedness temporary discontinuation
or uses o speci c agents o ATO
Prolongation o QTc interval in
40% o patients (torsades de
pointes is rare); monitor serum
electrolytes, treat hypokalemia,
and avoid using ATO with
other QT-prolonging drugs
(see Chapter 18)
Di erentiating Vorinostat (suberoylanilide See Table 45-5 and Fatigue, nausea, diarrhea, Deep venous thrombosis and
Agents—HDAC hydroxamic acid, SAHA) text o Chapter 61 o and thrombocytopenia pulmonary embolism with
Inhibitors Romidepsin (depsipeptide) Goodman &Gilman’s The vorinostat
Pharmacological Basis of Prolongation o QTc interval
Therapeutics, 12th Edition with vorinostat, requiring
or uses o speci c agents caution when used in patients
with underlying cardiac
disease, care ul monitoring
o the QTc interval, and
correction o electrolyte
(K+, Mg ++) abnormalities, and
avoidance o use with other
QT-prolonging drugs (see
Chapter 18)
660
CHAPTER
661
SECTION VIII Chemotherapy of Neoplastic Diseases
(Continued)
662
Targeted Anticancer Therapies CHAPTER 4 6
MECHANISM OF MECHANISM OF
DRUG CLASS DRUG ACTION RESISTANCE
Thalidomide and Thalidomide Multiple
Its Derivatives Lenalidomide immunomodulatory
(Immunomodulatory mechanisms (see
analogs, IMiDs) Figure 46-1)
663
SECTION VIII Chemotherapy of Neoplastic Diseases
MECHANISM OF MECHANISM OF
DRUG CLASS DRUG ACTION RESISTANCE
Glucocorticoids Prednisone Binds to speci c
Dexamethasone physiological
receptors that
translocate to the
nucleus and induce
antiproli erative and
apoptotic responses
in sensitive cells (see
Chapter 29)
664
Targeted Anticancer Therapies CHAPTER 4 6
MECHANISM OF MECHANISM OF
DRUG CLASS DRUG ACTION RESISTANCE
Gonadotropin- Cetrorelix Antagonize GnRH
Releasing Hormone Ganirelix receptors on pituitary
(GnRH) Antagonists Abarelix gonadotropin-
Degarelix producing cells,
causing inhibition
o testosterone
production in Leydig
cells without causing
the initial testosterone
f are caused by GnRH
agonists
CASE 46 1
A 34-year-old man is diagnosed with Philadelphia chromosome-positive (Ph +) chronic
myelogenous leukemia (CML).
a. What is the molecular mechanism that causes this orm o cancer?
A single molecular event, in this case the 9:22 chromosomal translocation which
results in the Philadelphia chromosome (Ph +), leads to expression o the Abelson
protooncogene kinase ABL used to BCR (breakpoint cluster region), yielding a
(Continued)
665
SECTION VIII Chemotherapy of Neoplastic Diseases
T c e ll IGF1R
ce ll Othe r TK re ce ptors
me mbra ne
NK c e ll
pro duc tio n IL-2
and INF-γ
+ D
func tio nality P I3K Ra s
NK Ce ll s tre s s
e ne rgy de ple tion
Anti-apo pto s is a mino a cid s ta tus
c e ll g rowth A
Akt mTORC2
Tumo r A1/Bfl-1
c e ll NFκ-B
IL-6 Ra pa mycins
FKBP 12
MAP K
Adhe s io n mTORC1
Ang io g e ne s is
IL-6
IL-6 S DF-1α prolife ra tion
IGFL bFGF S 6K1 4EBP
VEGF TNFα
B
Capillary tra ns la tion tra ns la tion s urviva l
e ndo the lium a utopha gy me ta bolis m prolife ra tion
Bo ne marrow s tro ma
C me ta bolis m
FIGURE 46-1 Schematic overview o proposed mechanisms o antimy- FIGURE 46-2 Insulin-like growth actor 1 receptor (IGF-1R)
eloma activity o thalidomide and its derivatives. Some biological hallmarks and other tyrosine kinase (TK) growth actor receptors sig-
o the malignant phenotype are indicated in the boxes. The proposed sites nal through multiple pathways. A key pathway is regulated
o action or thalidomide (letters inside circles) are hypothesized to also by phosphatidylinositol-3 kinase (PI3K) and its downstream
be operative or thalidomide derivatives. A. Direct anti–multiple myeloma partner, the mammalian target o rapamycin (mTOR). Rapamy-
(MM) e ect on tumor cells, including G1 growth arrest and/or apoptosis, cins complex with FKBPP12 to inhibit the mTORC1 complex.
even against MM cells resistant to conventional therapy. This is due to the mTORC2 remains una ected and responds by upregulating
disruption o the antiapoptotic e ect o BCL-2 amily members, blocking Akt, driving signals through the inhibited mTORC1. The various
NF-κB signaling, and inhibition o the production o interleukin-6 (IL-6). B. downstream outputs o the 2 complexes are shown. Phosphor-
Inhibition o MM-cell adhesion to bone marrow stromal cells partially due ylation o 4EBP by mTOR inhibits the capacity o 4EBP to inhibit
to the reduction o IL-6 release. C. Decreased angiogenesis due to the inhi- ei -4E and slow metabolism. 4EBP, eukaryotic initiation actor
bition o cytokine and growth actor production and release. D. Enhanced 4e (ei -4E) binding protein; FKBP12, the immunophilin target
T-cell production o cytokines, such as IL-2 and inter eron-γ (IFN-γ), that (binding protein) or tacrolimus (FK506); S6K1, S6 kinase 1.
increase the number and cytotoxic unctionality o natural killer (NK) cells.
VEGF, vascular endothelial growth actor.
constitutively activated protein tyrosine kinase, BCR-ABL, and then the malignant
phenotype. T is is the most common mechanism causing CML.
b. What is the rst-line treatment or CML and what is the rationale or this
pharmacotherapy?
Imatinib and the related compounds dasatinib and nilotinib induce clinical and
molecular remissions in more than 90% o CML patients in the chronic phase o
disease. T ese agents target the BCR-ABL tyrosine kinase and inhibit its activity.
c. What are the mechanisms o resistance to imatinib pharmacotherapy o CML?
Resistance to the tyrosine kinase inhibitors arises rom point mutations in 3 sepa-
rate segments o the BCR-ABL kinase domain. T e contact points between imatinib
and the enzyme become sites o mutations in drug-resistant leukemic cells; these
mutations prevent tight binding o the drug and lock the enzyme in its open con g-
uration, in which it has access to substrate. Most such mutations hold the enzyme
in its open and enzymatically active con rmation. T e most common resistance
mutations a ect amino acids 255 and 315, both o which serve as contact points
(Continued)
666
Targeted Anticancer Therapies CHAPTER 4 6
TABLE 46-1 Monoclonal Antibodies Approved for Hematopoietic and Solid Tumors
ANTIGEN AND TUMOR RADIOISOTOPE-BASED
CELL TARGETS ANTIGEN FUNCTION NAKED ANTIBODIES ANTIBODIES TOXIN-BASED ANTIBODIES
Antigen: CD20
Antigen: CD52
Tumor type: B-cell CLL and Unknown Alemtuzumab (humanized) None None
T-cell lymphoma
Antigen: CD33
Antigen: HER2/neu
(ErbB2)
Tumor type: breast cancer Tyrosine kinase Trastuzumab (humanized) None None
Antigen: VEGF
CLL, chronic lymphocytic leukemia; EGFR, epidermal growth actor receptor; NSCLC, non-small cell lung cancer; VEGF, vascular endothelial
growth actor.
CH3 CH3
N N
O CH3 O CH3
CYP2D6
(CYP 2B6, CYP 2C9,
CYP 2C19, CYP 3A)
S ULT1A1
OH
Tamoxife n 4-hydroxy-tamoxife n
CYP3A4/5
(CYP 2C9 + othe r CYP3A4/5 S ulfa te
CYP s ) me ta bolite s
CH3 CH3
N N
O H O H
S ULT1A1
CYP2D6
OH
N-de s me thyl-tamoxife n Endoxife n
DHEA
s ulfa te
Chole s te rol
17 α 17, 20
Pre gne nolone 17-hydroxypre gne nolone De hydroe pia ndros te rone
(DHEA)
17 α 17, 20
Proge s te rone 17-hydroxyproge s te rone Andros te ne dione
A
21 21 17βR
Es trone
17, 20
17βR
De oxycorticos te rone 11-de oxycortis ol Te s to s te ro ne A
a bira te rone Es tradio l
11β 11β 5α R
18
Aldo s te ro ne
FIGURE 46-4 Steroid synthesis pathways. The enclosed shaded area contains the pathways used by the adrenal glands and gonads. Enzymes
are shown next to their respective biochemical pathways, inhibitors are shown in boxes with T-shaped arrows pointing at the enzymes they
inhibit. 11β, 11β-hydroxylase; 17,20, C-17,20-lyase (also CYP17); 17α, 17α-hydroxylase (CYP17); 17βR, 17β-reductase; 18, aldosterone synthase; 21,
21-hydroxylase; 3β, 3β-hydroxysteroid dehydrogenase; 5αR, 5α-reductase; A, aromatase.
668
Targeted Anticancer Therapies CHAPTER 4 6
d. What other cancers and diseases are e ectively treated with imatinib?
Imatinib has e cacy in diseases in which the ABL, kit, or PDGFR protein kinases
have dominant roles in driving the proli eration o the tumor, re ecting the pres-
ence o a mutation that results in constitutive activation o the kinase, either by
usion with another protein or via point mutations. T us, imatinib shows remark-
able therapeutic bene ts in patients with chronic-phase CML (BCR-ABL), GIS
(kit mutation-positive gastrointestinal stromal tumor), chronic myelomonocytic
leukemia (EV 6-PDGFR translocation), hypereosinophilia syndrome (FIP1L1-
PDGFR), and dermato brosarcoma protuberans (constitutive production o the
ligand or PDGFR). It is the agent o choice or GIS patients with metastatic dis-
ease and as adjuvant therapy o c-kit-positive GIS . GIS biology is particularly
instructive, as patients with an exon 11 mutation o kit have a signi cantly higher
partial response rate (72%) than those with no detectable kit mutations (9%).
e. What are the common and important side e ects o therapy with imatinib,
dasatinib, and nilotinib?
Imatinib, dasatinib, and nilotinib cause GI distress (diarrhea, nausea, and vomit-
ing), but these symptoms usually are easily controlled. All 3 drugs promote uid
retention, which may lead to dependent edema, and periorbital swelling. Dasatinib
may cause pleural e usions. Nilotinib may prolong the Q interval, and should
be used with caution in patients with underlying heart disease or arrhythmias,
although ventricular arrhythmias have not been reported. Signi cant myelosup-
pression occurs in requently but may require trans usion support, dose reduction,
or discontinuation o the drug. All 3 drugs in this class can be associated with hepa-
totoxicity. Most nonhematological adverse reactions are sel -limited and respond
to dose adjustments. Af er the adverse reactions such as edema, myelosuppression,
or GI symptoms have been resolved, the drug may be reinitiated and titrated back
to e ective doses.
CASE 46 2
In a number o epithelial cancers, the epidermal growth actor receptor (EGFR) is
overexpressed or is activated by mutations.
a. What role does the EGFR play in these epithelial cancers?
T e EGFR belongs to the ErbB amily o transmembrane receptor tyrosine kinases.
EGFR, also known as ErbB1 or HER1, is essential or the growth and di erentia-
tion o epithelial cells. Ligand binding to the extracellular domain o EGFR amily
members causes receptor dimerization and stimulates the protein tyrosine kinase
activity o the intracellular domain, resulting in autophosphorylation o several
yr residues in the C-terminal domain. Recognition o the phosphotyrosines by
other proteins initiates protein-protein interactions that result in stimulation o a
variety o signaling pathways, including MAPK, PI3K/Akt, and S A pathways (see
Figures 46-2 and 46-5). In epithelial cancers, overexpression (or mutational activa-
tions) o the EGFR is a common nding and, to some extent, creates a dependence
on EGFR signaling in these tumors.
b. What drugs are available to target the EGFR in epithelial cancers?
wo separate classes o drugs that target the EGFR pathway have become important
agents in the therapy o solid tumors. T e EGFR tyrosine kinase inhibitors erlotinib
and ge tinib bind to the kinase domain and block the enzymatic unction o EGFR.
T e monoclonal antibodies cetuximab and panitumumab (see able 46-1) bind
speci cally to the extracellular domain o EGFR. T ey inhibit EGFR-dependent
signaling through inhibition o ligand-dependent activation and receptor dimeriza-
tion, downregulation o EGFR expression, and induction o antibody-dependent
cell-mediated cytotoxicity.
(Continued)
669
SECTION VIII Chemotherapy of Neoplastic Diseases
EGF PDGF
IGF-1 TGF β
RAS
PI3K
RAF S MADS
AKT
MEK
TRANS CRIPTION
S uppre s s io n pro life ratio n
o f apo pto s is ang io g e ne s is
me tas tas is
FIGURE 46-5 Growth actor signaling. Binding o agonist ligands to growth actor receptors
causes receptor dimerization and activation o cytosolic protein kinase domains, leading to
activation o multiple signaling pathways. Shown here are the RAS/MAPK/ ERK, PI3K, and SMAD
pathways, each o which is activated by receptors or cross-talk rom adjacent pathways. Their
signals regulate proli eration, metabolism, survival, and the synthesis o other growth actors,
such as the vascular endothelial growth actor (VEGF).
(Continued)
670
Targeted Anticancer Therapies CHAPTER 4 6
Alemtuzumab ADCC; CDC; apoptosis Escalating doses o 3, 10, 30 mg/m 2 IV In usion-related toxicity, T-cell depletion
three times/week ollowed by 30 mg/ with increased in ection; hematopoietic
m 2 three times/week or 4-12 weeks suppression; pancytopenia
Trastuzumab ADCC; apoptosis; inhibition o arrest Loading dose o 4-mg/kg in usion Cardiomyopathy; in usion-related
HER2 signaling with G1 arrest ollowed by 2 mg/kg weekly toxicity
Cetuximab Inhibition o EGFR signaling; Loading dose o 400-mg/kg in usion In usion-related toxicity; skin rash in 75%
apoptosis; ADCC ollowed by 250 mg/kg weekly
Bevacizumab Inhibition o angiogenesis/ 5 mg/kg IVevery 14 days until Hypertension; pulmonary hemorrhage;
neovascularization disease progression GI per oration; proteinuria; congestive
heart ailure
Denileukin diftitox Targeted diphtheria toxin with 9-18 µg/kg/day IV or the rst 5 days Fever; arthralgia; asthenia; hypotension
inhibition o protein synthesis every 3 weeks
Gemtuzumab Double-strand DNA breaks and Two doses o 9 mg/m 2 IVseparated In usion-related toxicity; hematopoietic
ozogamicin apoptosis by 14 days suppression; mucosal hepatic (VOD);
skin toxicity
90
Y ibritumomab Targeted radiotherapy 0.4 mCi/kg IV Hematological toxicity; myelodysplasia
tiuxetan
131
I tositumomab Targeted radiotherapy Patient-speci c dosimetry Hematological toxicity; myelodysplasia
ADCC, antibody-dependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity; EGFR, epidermal growth actor receptor;
intravenous; VOD, veno-occlusive disease.
671
SECTION VIII Chemotherapy of Neoplastic Diseases
CASE 46 3
A 58-year-old woman is diagnosed with metastatic Her2/neu-positive (Her2+)
breast cancer.
a. What is Her2/neu and how does this patient’s Her2/neu-positive status a ect her
prognosis and the available therapeutic options?
T irty percent o breast cancers overexpress the HER2/neu (ErbB2) receptor due to
gene ampli cation on chromosome 17. Ampli cation o the receptor is associated
with lower response rates to hormonal therapies and to most cytotoxic drugs, with
the exception o anthracyclines. Patients with HER2/neu-ampli ed tumors have
higher recurrence rates af er standard adjuvant therapy and poorer overall survival,
as compared to patients with HER2-nonampli ed tumors. T e internal domain o
the HER2/neu glycoprotein encodes a tyrosine kinase that activates downstream
signaling, enhances metastatic potential, and inhibits apoptosis.
Both antibodies (trastuzumab) and small molecules (lapatinib and others in clinical
trial) have striking antitumor e ects in patients with Her2-positive breast cancer,
and have become essential therapeutic agents in combination with cytotoxic
chemotherapy or this aggressive malignancy.
Currently, trastuzumab is approved or HER2/neu-overexpressing metastatic breast
cancer, in combination with paclitaxel as initial treatment or as monotherapy ol-
lowing chemotherapy relapse. rastuzumab synergizes with other cytotoxic agents
in HER2/neu-overexpressing cancers. Lapatinib is FDA-approved or HER2-ampli-
ed, trastuzumab-re ractory breast cancer, in combination with the uoropyrimi-
dine analog, capecitabine (see Chapter 45). As a small molecule, lapatinib crosses
the blood-brain barrier more readily than inhibitor antibodies and has produced
anecdotal responses in patients with brain metastases and decreased the incidence
o brain metastases in its phase III trial.
b. What are the mechanisms o action o the ErbB2-targeted agents?
rastuzumab exerts its antitumor e ects through several putative mechanisms o
action: inhibition o homo- or heterodimerization o receptor, thereby preventing
receptor kinase activation and downstream signaling; initiation o Fcγ-receptor-
mediated antibody-dependent cellular cytotoxicity; and blockade o the angioge-
netic e ects o HER2 signaling.
Small molecules can inhibit receptor tyrosine kinase activity o ErbB2 (HER2/neu)
and have antitumor activity in patients who have developed progressive disease
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672
Targeted Anticancer Therapies CHAPTER 4 6
on trastuzumab. Lapatinib and other pan-HER inhibitors block both ErbB1 and
ErbB2 and bind to an internal site on the receptor (usually the A P-binding
pocket), compared to the external binding site o trastuzumab. Lapatinib also
inhibits a truncated orm o the HER2 receptor that lacks a trastuzumab-binding
domain. T ese di erences may account or the activity o lapatinib in trastuzumab-
resistant patients.
c. What other types o cancers express HER2/neu?
HER2/neu expression is also ound in subsets o patients with gastric, esophageal,
lung, and other solid tumors, but clinical studies o the e ects o trastuzumab in
these tumors have not yet been completed.
d. What are the important toxicities o the HER2/neu-targeted agents?
T e in usional e ects o trastuzumab are typical o other monoclonal antibodies
and include ever, chills, nausea, dyspnea, and rashes. Premedication with diphen-
hydramine and acetaminophen is indicated.
T e most serious toxicity o trastuzumab is cardiac ailure (see able 46-2); reasons
or cardiotoxicity are poorly understood, although the HER2 antigen is highly
expressed in the developing heart during embryogenesis, and HER2 knockout mice
ail to survive because o cardiomyopathy. Cardiac ailure is a potentially disabling
or atal side e ect unless it is recognized early and the drug is discontinued. Be ore
initializing therapy, baseline electrocardiogram and cardiac ejection raction mea-
surement should be obtained to rule out underlying heart disease, and patients
deserve care ul clinical ollow-up thereaf er or signs or symptoms o congestive
heart ailure, such as cough, weight gain, or edema. When trastuzumab is used as a
single agent, less than 5% o patients will experience a decrease in lef -ventricular
ejection raction, and 1% will have clinical signs o congestive ailure. However, lef -
ventricular dys unction occurs in up to 20% o patients who received the antibody
in combination with doxorubicin and cyclophosphamide. T e risk o cardiac toxic-
ity is greatly reduced with taxane–trastuzumab combinations.
Lapatinib toxicities include mild diarrhea, cramping, and exacerbation o gas-
troesophageal re ux. When lapatinib is combined with capecitabine, diarrhea
becomes a signi cant side e ect in one-third o patients. Lapatinib’s inhibition o
ErbB1 (EGFR) causes an acne orm rash in one-third o patients; the rash can be
e ectively controlled in most cases with topical or oral antibiotics and topical ben-
zoyl peroxide gel.
Unlike trastuzumab, lapatinib has not produced a clear signal o cardiac toxicity.
Nonetheless, because it targets ErbB2, lapatinib should be used with caution in
combination with other cardiotoxic drugs and with care ul surveillance in patients
who have underlying heart disease.
CASE 46 4
Angiogenesis is an essential property o many solid tumors, and the target o a number
o anticancer drugs. One clinically important angiogenic pathway involves vascular
endothelial growth actor (VEGF) and its cognate receptors.
a. What is VEGF and how is it important in tumor growth and survival?
Cancer cells secrete angiogenic actors that induce the ormation o new blood
vessels and guarantee the ow o nutrients to the tumor cells. Angiogenic actors
secreted by tumors include VEGF (vascular endothelial growth actor), FGF ( bro-
blast growth actor), GF-β (trans orming growth actor β), and PDGF (platelet-
derived growth actor). Multiple tumor types overexpress these angiogenic actors.
T e best studied o the angiogenic actors is VEGF. VEGF initiates endothelial cell
proli eration when it binds to a member o the VEGF receptor (VEGFR) amily, a
group o highly homologous receptors with intracellular tyrosine kinase domains
(Continued)
673
SECTION VIII Chemotherapy of Neoplastic Diseases
that includes VEGFR1 (FL 1), VEGFR2 (KDR), and VEGFR3 (FL 4). T e bind-
ing o VEGF to its receptor activates the intracellular VEGFR tyrosine kinase
activity and initiates mitogenic and antiapoptotic signaling pathways within the
endothelial cell.
b. What agents target the VEGF pathway and what are their mechanisms o action?
Antibodies targeting VEGF, such as bevacizumab, sterically hinder the interaction
o VEGF with its receptor. As an alternative to VEGF antibody therapy, the inves-
tigational drug a ibercept (VEGF rap), a recombinant molecule that utilizes the
VEGFR1-binding domain to sequester VEGF, acts as a “soluble decoy receptor” or
VEGF. Alternatively, the propagation o proangiogenic signals can be abrogated
by the inhibition o the tyrosine kinase activity o VEGFR. T ree small molecules
(pazopanib, sora enib, and sunitinib) that inhibit the kinase unction o VEGFR-2
have been approved or clinical use.
c. What kinds o tumors are e ectively treated with agents that target the VEGF
pathway?
As a single agent, bevacizumab delays progression o renal-cell cancer, and, in com-
bination with cytotoxic chemotherapy, e ectively treats lung, colorectal, and breast
cancers. Bevacizumab is also approved as a single agent ollowing prior therapy or
glioblastoma.
Sunitinib competitively inhibits the binding o A P to the tyrosine kinase domain
on the VEGFR-2, and also inhibits other protein tyrosine kinases (FL 3, PDGFR-α,
PDGFR-β, RE , CSF-1R, and c-KI ). Sunitinib has activity in metastatic renal-
cell cancer, producing a higher response rate (31%) and a longer progression- ree
survival than any other approved antiangiogenic drug. Sunitinib also is approved
or treatment o advanced renal-cell carcinoma and GIS that have developed resis-
tance to imatinib as a consequence o c-KI mutations.
Sora enib, like sunitinib, targets multiple protein tyrosine kinases (VEGFR1,
VEGFR2, VEGFR3, PDGFR-β, c-KI , FL -3, and b-RAF). Sora enib is the only
drug currently approved or treatment o hepatocellular carcinoma. It is also gener-
ally the pre erred rst-line therapy in metastatic renal-cell cancer.
d. What are the important toxicities o the agents that target the VEGF pathway?
T e main toxicities o bevacizumab (see able 46-2) are shared by all antiangio-
genic inhibitors, including sunitinib and sora enib. Speci cally, patients taking this
class o antiangiogenic agents can experience bleeding, hypertension, proteinuria,
and uncommonly, arterial thromboembolic events and intestinal per oration. How-
ever, because sunitinib is a multitargeted tyrosine kinase inhibitor, it has a broader
side e ect pro le than bevacizumab.
A prominent concern with this class o agents is the potential or vessel injury
and bleeding. Bevacizumab is contraindicated or patients who have a history o
hemoptysis, brain metastasis, or a bleeding diathsis, but in appropriately selected
patients, the rate o li e-threatening pulmonary hemorrhage is less than 2%. T e
sa ety o operating on patients treated with bevacizumab continues to be a major
concern because o the risk o bleeding and poor wound healing; elective surgery
should be delayed or at least 4 weeks rom the last dose o antibody, and treatment
should not be resumed or at least 4 weeks af er surgery.
Other toxicity characteristics o antiangiogenic drugs include hypertension and
proteinuria. A majority o patients receiving bevacizumab require antihyperten-
sive therapy, particularly those receiving higher doses and more prolonged treat-
ment. T e mechanism driving this hypertension is still unclear but may relate, in
part, to decreased endothelial nitric oxide production. T e blood pressure o all
patients on bevacizumab should be care ully monitored and antihypertensives used
when appropriate. Case reports describe patients with poorly controlled hyperten-
sion developing a reversible posterior leukoencephalopathy during bevacizumab
(Continued)
674
Targeted Anticancer Therapies CHAPTER 4 6
CASE 46 5
A 47-year-old patient diagnosed with renal cancer is being treated with temsirolimus, a
congener o rapamycin (sirolimus).
a. What is the mechanism o action o rapamycin and its congeners?
T e rapamycins inhibit an enzyme complex, m ORC1, which occupies a downstream
position in the PI3 kinase pathway (see Figure 46-2). m OR orms the m ORC1
complex with a member o the FK506-binding protein amily, FKBP12. Among other
actions, m ORC1 phosphorylates S6 kinase and also relieves the inhibitory e ect o
4EBP on initiation actor el -4E, thereby promoting protein synthesis and metabolism.
T e antitumor actions o the rapamycins result rom their binding to FKBP12 and
inhibition o m ORC1. Rapamycin and its congeners have immunosuppressant
e ects, inhibit cell-cycle progression and angiogenesis, and promote apoptosis.
b. What are the toxicities o the rapamycins?
T e rapamycin analogs have very similar patterns o toxicity. T e most promi-
nent side e ects are a mild maculopapular rash, mucositis, anemia, and atigue,
each occurring in 30 to 50% o patients. A minority o patients will develop leu-
kopenia or thrombocytopenia with progressive cycles o treatment, and these
e ects are reversed i therapy is discontinued. Less common side e ects include
hyperglycemia, hypertriglyceridemia, and, rarely, pulmonary in ltrates and inter-
stitial lung disease. Pulmonary in ltrates emerge in 8% o patients receiving evero-
limus and in a smaller percentage o those treated with temsirolimus. In patients
showing minor radiological changes, but without symptoms, drug administration
may be continued. I symptoms such as cough or shortness o breath develop or
radiological changes progress, the drug should be discontinued. Prednisone may
hasten the resolution o radiological changes and symptoms.
(Continued)
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SECTION VIII Chemotherapy of Neoplastic Diseases
CASE 46 6
A 50-year-old woman has a small lump in one o her breasts removed. T e pathology
indicates it is an estrogen receptor-positive (ER+) breast cancer. Her oncologist starts
her on a course o tamoxi en.
a. What is the mechanism o action o tamoxi en in breast cancer and in noncan-
cerous tissues?
amoxi en is classi ed as a selective estrogen receptor modulator (SERM)
(see Chapter 28). SERMs bind to the ER and exert either estrogenic or anties-
trogenic e ects, depending on the speci c organ. amoxi en citrate is the most
widely studied antiestrogenic treatment in breast cancer. T e recent decline in
breast cancer mortality in Western countries is believed to be partly due to the
common use o tamoxi en, especially in the adjuvant setting. However, in addi-
tion to its estrogen antagonist e ects in breast cancer, tamoxi en also exerts
estrogenic agonist e ects on nonbreast tissues, thus in uencing the overall ther-
apeutic index o the drug.
amoxi en is a competitive inhibitor o estradiol binding to the estrogen receptor
(ER), o which there are 2 subtypes: ERα and ERβ. T e 2 ER subtypes have di erent
tissue distributions and can either homo- or heterodimerize. Binding o estradiol
and SERMs to the estrogen-binding sites o the ERs initiates a change in con orma-
tion o the ER, dissociation o the ER rom heat-shock proteins, and inhibition o
ER dimerization. Dimerization acilitates the binding o the ER to speci c DNA
estrogen-response elements (EREs) in the vicinity o estrogen-regulated genes.
Coregulator proteins interact with the receptor to act as corepressors or coactiva-
tors o gene expression. Di erences in tissue distribution o ER subtypes, the unc-
tion o coregulator proteins, and the various transcriptional activating actors likely
explain the variability o response to tamoxi en in hormone receptor–positive (ER+)
breast cancer and its agonist and antagonist activities in noncancerous tissues.
Other organs displaying agonist e ects o tamoxi en include the uterine endome-
trium (endometrial hypertrophy, vaginal bleeding, and endometrial cancer), the
coagulation system (thromboembolism), bone metabolism (increase in bone min-
eral density [BMD]), and liver (alterations o blood lipid pro le).
Metabolism o tamoxi en is complex (see Figure 46-3) and principally involves
CYPs 3A4/5, and 2D6 in the ormation o N-desmethyl tamoxi en, and CYP2D6
to orm 4-hydroxytamoxi en, a more potent metabolite. Both metabolites can be
urther converted to 4-hydroxy-N-desmethyltamoxi en, which retains high a nity
or the ER.
b. What are the clinical uses o tamoxi en?
amoxi en has become a standard agent as a result o its anticancer activity and
good tolerability pro le. amoxi en is prescribed or the prevention o breast cancer
in high-risk patients, or the adjuvant therapy o early-stage breast cancer ollowing
primary tumor excision, and or the therapy o advanced (metastatic) breast cancer
(see able 46-3). It prevents the development o breast cancer in women at high risk
based on a strong amily history, prior nonmalignant breast pathology, or inheri-
tance o the BRCA1 or BRCA2 genes.
(Continued)
676
Targeted Anticancer Therapies CHAPTER 4 6
TABLE 46-3 Clinical Uses for Anti-Estrogen Therapy in ER+ Breast Cancer
DISEASE SETTING
DRUG ADJUVANT premen ADJUVANT postmen METASTATIC premen METASTATIC postmen
Tamoxi en Yes (5 yr) Yes (be ore AI or 2-5 yr) Yes Yes
Premen, premenopausal; Postmen, postmenopausal; AI, aromatase inhibitor; PD, progressive disease; TAM, tamoxi en; ER, estrogen receptor.
c. What are selective estrogen receptor downregulators (SERDs) and how do they
di er rom SERMs like tamoxi en?
SERDs, also termed “pure anti-estrogens,” include ulvestrant and a host o agents in
experimental trials. SERDs, unlike SERMs, are devoid o any estrogen agonist activ-
ity. Fulvestrant is a steroidal antiestrogen that binds to the ER with an a nity more
than 100 times that o tamoxi en. T e drug inhibits the binding o estrogen but also
alters the receptor structure such that the receptor is targeted or proteasomal degra-
dation; ulvestrant also may inhibit receptor dimerization. Unlike tamoxi en, which
stabilizes or even increases ER expression, ulvestrant reduces the number o ER
molecules in cells, both in vitro and in vivo; as a consequence o this ER downregu-
lation, the drug abolishes ER-mediated transcription o estrogen-dependent genes.
Whereas tamoxi en is used in both premenopausal and postmenopausal women
with breast cancer at early and late stages, ulvestrant is reserved or use in premeno-
pausal women with metastatic breast cancer (see able 46-3).
d. What are the mechanisms by which tumors develop resistance to tamoxi en?
Despite its bene ts, initial or acquired resistance to tamoxi en requently occurs.
Polymorphisms in CYP2D6 that reduce its activity lead to lower plasma levels o
4-OH tamoxi en, a potent metabolite (see Figure 46-3), and are associated with
higher risks o disease relapse and a lower incidence o hot ashes. CYP2D6 is also
responsible or the activation o tamoxi en to its active metabolite endoxi en (see
Figure 46-3).
Cross-talk between the ER and HER2/neu pathway also has been implicated in
tamoxi en resistance. T e paired box 2 gene product (PAX2) has been identi ed as
a crucial mediator o ER repression o ErbB2 by tamoxi en. Interactions between
PAX2 and the ER coactivator AIB-1/SRC-3 determine tamoxi en response in breast
cancer cells.
e. What are the toxicities and bene cial e ects that this woman is likely to experi-
ence while on tamoxi en?
T e common adverse reactions to tamoxi en include vasomotor symptoms (hot
ashes), atrophy o the lining o the vagina, hair loss, nausea, and vomiting. T ese
may occur in less than or equal to 25% o patients and rarely are su ciently severe
to require discontinuation o therapy. Menstrual irregularities, vaginal bleeding and
discharge, pruritus vulvae, and dermatitis occur with increasing severity in post-
menopausal women.
amoxi en also increases the incidence o endometrial cancer by 2- to 3- old, par-
ticularly in postmenopausal women who receive 20 mg/d or 2 years or more. In
general, tamoxi en-associated endometrial cancers are reported as low-grade and
(Continued)
677
SECTION VIII Chemotherapy of Neoplastic Diseases
CASE 46 7
An 84-year-old gentleman has metastatic prostate cancer with symptoms that include
bone pain. His oncologist recommends that he receive hormone therapy.
a. What is hormone therapy?
T e growth o a number o cancers is hormone-dependent or regulated by
hormones. Hormone analogs and antagonists are used or the treatment o both
breast and prostate cancer, as well as several other cancers (see able 46-4). T ese
molecules interrupt the stimulatory axis created by systemic pools o androgens
and estrogens, inhibit hormone production or binding to receptors, and ultimately
(Continued)
678
Targeted Anticancer Therapies CHAPTER 4 6
block the complex expression o genes that promotes tumor growth and survival.
T ese drugs have proven e ective in extending survival and delaying or preventing
tumor recurrence in breast cancer and prostate cancer.
b. What is the goal o hormone therapy in treating metastatic prostate cancer?
Localized prostate cancer requently is curable with surgery or radiation therapy.
However, when distant metastases are present, hormone therapy is the primary
treatment. Standard approaches either reduce the concentration o endogenous
androgens or inhibit their e ects. Androgen deprivation therapy (AD ) is the
standard rst-line treatment. AD is accomplished via surgical castration (bilat-
eral orchiectomy) or medical castration (using gonadotropin-releasing hormone
[GnRH] agonists or antagonists). Other hormone therapy approaches are used in
second-line treatment and include antiandrogens, estrogens, and inhibitors o ste-
roidogenesis (see able 46-4).
AD is considered palliative, not curative, treatment. AD can alleviate cancer-
related symptoms, produce objective responses, and normalize serum prostate
speci c antigen (PSA) in more than 90% o patients. AD provides important
quality-o -li e bene ts, including reduction o bone pain and reduction o rates o
pathological racture, spinal cord compression, and ureteral obstruction. It also
prolongs survival.
c. T is patient will receive androgen deprivation therapy (AD ) using a synthetic
GnRH analog, leuprolide. What is the mechanism o action o GnRH agonists?
T e biosynthesis o androgens, primarily in the testes and adrenals, is described
in Chapter 28, and the regulation o Leydig cell synthetic activity by the hypo-
thalamic–pituitary axis is considered there as well. In the United States, the most
common orm o AD involves chemical suppression o the pituitary gland
(Continued)
679
SECTION VIII Chemotherapy of Neoplastic Diseases
with GnRH agonists. Synthetic GnRH analogs have greater receptor a nity and
reduced susceptibility to enzymatic degradation than the naturally occurring
GnRH molecule and are 100- old more potent. GnRH (also termed luteinizing hor-
mone–releasing hormone, LHRH) agonists bind to GnRH receptors on pituitary
gonadotropin-producing cells, causing an initial release o both LH and FSH and a
subsequent increase in testosterone production rom testicular Leydig cells. Af er
~1 week o therapy, GnRH receptors are downregulated on the gonadotropin-pro-
ducing cells, causing a decline in the pituitary response. T e all in serum LH leads
to a decrease in testosterone production to castrate levels within 3 to 4 weeks o the
rst treatment. Subsequent treatments maintain testosterone at castrate levels.
d. During the rst ew days o treatment with leuprolide, the patient com-
plains that his bone pain has worsened. What is causing this worsening o his
symptoms?
During the rst ew days o therapy with a GnRH agonist, there is transient rise in
LH, and the resultant testosterone surge may induce an acute stimulation o prostate
cancer growth and a “ are” o symptoms rom metastatic deposits. Patients may
experience an increase in bone pain or obstructive bladder symptoms lasting or
2 to 3 weeks. T e are phenomenon can be e ectively counteracted with concurrent
administration o 2 to 4 weeks o oral antiandrogen therapy (ie, combined androgen
blockade), which may inhibit the action o the increased serum testosterone levels.
Combined androgen blockade (CAB) requires administration o AD with an
antiandrogen. T e theoretical advantage is that the GnRH agonist will deplete
testicular androgens, while the antiandrogen component competes at the receptor
with residual androgens made by the adrenal glands. CAB provides maximal relie
o androgen stimulation. Numerous large trials have compared CAB with AD
monotherapy, with variable results. Several meta-analyses o these trials suggest a
bene t or CAB in 5-year survival but not at earlier time points. oxicity and costs
associated with CAB are higher than with AD alone.
GnRH antagonists have been developed to suppress testosterone while avoiding
the are phenomenon o GnRH agonists. Other than avoidance o the initial are,
GnRH antagonist therapy o ers no apparent advantage compared with GnRH
agonists. T e rst available GnRH antagonist, abarelix, rapidly achieves medical
castration. However, local reactions and anaphylaxis have discouraged its clinical
acceptance and have led to its withdrawal rom the market. A second GnRH antag-
onist, degarelix, is not associated with systemic allergic reactions and is approved
or prostate cancer in the United States.
e. Af er several months o treatment with leuprolide, the oncologist adds an addi-
tional agent, abiraterone to urther reduce growth o the patient’s tumor. What is
the rationale or adding this agent?
In the castrate state, androgen receptor (AR) signaling, despite low steroid lev-
els, supports continued prostate cancer growth. AR signaling may occur due to
androgens produced rom nongonadal sources, AR gene mutations, or AR gene
ampli cation. Nongonadal sources o androgens include the adrenal glands and the
prostate cancer cells themselves (see Figure 46-4). Androstenedione, produced by
the adrenal glands, is converted to testosterone in peripheral tissues and tumors.
Intratumoral de novo androgen synthesis also may provide su cient androgen or
AR-driven cell proli eration.
Abiraterone is an irreversible inhibitor o both 17α-hydroxylase and C-17,20-lyase
CYP17 activity (see Figure 46-4). T e parent compound, abiraterone acetate, is
orally bioavailable and has been well tolerated in castration-resistant prostate
cancer patients as secondary hormone therapy in phase I and II studies. With
continuous administration, abiraterone increases AC H levels, resulting in miner-
alocorticoid excess. Glucocorticoids, such as prednisone, are administered to com-
pensate or inhibition o adrenal steroidogenesis.
680
Targeted Anticancer Therapies CHAPTER 4 6
KEY CONCEPTS
argeted anticancer therapies are designed to block the oncogenic pathways
that cause speci c cancers.
T e e cacy and speci city o targeted anticancer therapies depends on the
expression o the molecular target in cancer cells.
Resistance to targeted therapy can develop because o mutations in the molecu-
lar target, decreased expression o the target, alterations in target pathways, as
well as changes in drug e ux and metabolism.
Dif erent agents (eg, antibodies and small molecule inhibitors) directed at the
same molecular target can have very dif erent spectra o antitumor activity.
T e growth and survival o many cancers, particularly breast and prostate can-
cer, are hormone-dependent or regulated by hormones; hormone therapy can
extend survival and delay or prevent tumor recurrence in many patients.
argeted anticancer therapies are o en used in combination with cytolytic
anticancer agents to achieve higher response rates.
SUMMARY QUIZ
QUESTION 46-4 Which o the ollowing agents kills multiple myeloma (MM) cells by
indirectly preventing the transcriptional activity o NF-κB?
a. T alidomide
b. Lenalidomide
c. Bortezomib
d. Sora enib
e. Sirolimus
681
SECTION VIII Chemotherapy of Neoplastic Diseases
Monoclonal Cetuximab See Table 46-1 See Table 46-2 See Table 46-2
Antibodies— Panitumumab Cetuximab is used or Rash and dermatological Rare but serious adverse
Growth Factor Trastuzumab squamous cell carcinoma o toxicities are common e ects with cetuximab and
Receptors (EGFR, the head and neck (HNSCC), with cetuximab and panitumumab include interstitial
HER2/neu, VEGFRs, EGFR-positive metastatic panitumumab; headache lung disease, hypomagnesemia,
PDGFR) Antibodies colorectal cancer, and in and diarrhea may also occur cardiopulmonary arrest, and
combination with other anaphylactoid reactions
agents or other metastatic The most serious toxicity o
colon cancers trastuzumab is cardiac ailure;
Trastuzumab is used or patients should be evaluated
HER2/neu-ampli ed breast be ore therapy and a terward
cancer or changes in le t ventricular
unction
(Continued)
683
SECTION VIII Chemotherapy of Neoplastic Diseases
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Monoclonal Bevacizumab See Table 46-1 See Table 46-2 See Table 46-2
Antibodies— Ranibizumab Bevacizumab is used in Potential or vessel injury, Bevacizumab is associated with
Growth Factor highly vascularized tumors, bleeding, and poor wound arterial thromboembolic events
(VEGF) Antibodies including renal-cell, lung, healing ollowing surgery and GI per oration
colorectal, and breast Hypertension (a majority Bevacizumab is contraindicated
cancers, and glioblastoma o patients require in patients who have a history
Bevacizumab restores antihypertensive therapy) o hemoptysis, brain metastasis,
hearing in patients with and proteinuria (usually or a bleeding diathesis; elective
progressive dea ness due to asymptomatic) surgery should be delayed or at
neuro bromatosis type 2– least 4 weeks rom the last dose o
related tumors antibody, and treatment should
Ranibizumab is used to treat not be resumed or at least 4
wet macular degeneration weeks a ter surgery
(see Chapter 47)
Monoclonal Rituximab See Table 46-1 See Table 46-2 See Table 46-2
Antibodies—CD20 131
I-Tositumomab Rituximab is used as a single The radioimmunoconjugates Rituximab in usion reactions
Antibodies 90
Y-Ibritumomab agent or relapsed indolent cause antibody-related can be li e-threatening, but
tiuxetan lymphomas and with hypersensitivity, bone with pretreatment are usually
O atumumab chemotherapy or di use marrow suppression, and mild and limited to ever,
large B-cell lymphoma and secondary leukemias chills, throat itching, urticaria,
other indolent B-cell non- O atumumab’s primary and mild hypotension; severe
Hodgkin lymphomas (NHLs) toxicities consist o mucocutaneous skin reactions,
Rituximab is also used or immunosuppression and including Stevens-Johnson
autoimmune diseases, opportunistic in ection, syndrome are rare
including rheumatologic hypersensitivity reactions May cause reactivation o
disease, thrombotic during antibody in usion, hepatitis B virus or rarely, JC virus;
thrombocytopenic purpura, and myelosuppression should not be administered to
autoimmune hemolytic patients with active in ection
anemias, cryoglobulin- Hypogammaglobulinemia and
induced renal disease and autoimmune syndromes may
multiple sclerosis occur 1-5 months ollowing
O atumumab is approved treatment with rituximab
or treating patients with
chronic lymphocytic
leukemia (CLL)
Monoclonal Alemtuzumab See Table 46-1 See Table 46-2 See Table 46-2
Antibodies—CD52 Used to treat B- and T-cell Acute in usion reactions and CD4+ T-cell counts may remain
Antibodies low-grade lymphomas serious myelosuppression, pro oundly depleted or 1 year
and CLL (all blood lineages) with Alemtuzumab does not combine
signi cant risk o ungal, well with chemotherapy in
viral, and other opportunistic standard regimens because
in ections; patients should o signi cant in ectious
receive antibiotic and complications
antiviral prophylaxis and
be monitored or signs and
symptoms o CMVand other
in ections
Monoclonal Gemtuzumab See Table 46-1 See Table 46-2 See Table 46-2
Antibodies—CD33 ozogamicin Currently is approved in Myelosuppression in all Causes a syndrome that
Antibodies patients >60 years with AML patients, hepatocellular resembles hepatic venoocclusive
in rst relapse damage in 30-40% o disease when patients
patients subsequently undergo
myeloablative therapy or
when ollowing, high-dose
chemotherapy
Prolonged myelosuppression,
particularly delayed recovery o
platelet counts
(Continued)
684
Targeted Anticancer Therapies CHAPTER 4 6
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Thalidomide and Thalidomide See Table 45-5 Sedation and constipation Thalidomide-related peripheral
its Derivatives Lenalidomide Used in newly diagnosed are common with sensory neuropathy (10-30% o
(Immunomodulatory and heavily pretreated thalidomide, but not with patients); long-standing sensory
analogs, IMiDs) relapsed/re ractory multiple lenalidomide loss may not reverse and caution
myeloma (MM) patients Lenalidomide causes is advised in patients with
Lenalidomide also used signi cant leukopenia in preexisting neuropathy
in 5q − myelodysplastic 20% o patients Rarely, lenalidomide causes
syndrome (MDS) and CLL Thromboembolic risk hepatotoxicity and renal
increases with both dys unction
thalidomide and CLL patients taking lenalidomide
lenalidomide should receive pretreatment
hydration and allopurinol to
avoid the consequences o tumor
swelling and tumor lysis
Thalidomide is teratogenic, but
lenalidomide is not
mTOR Inhibitors Rapamycin See Table 45-5 [in previous Mild maculopapular rash, Pulmonary in ltrates and
Temsirolimus chapter] mucositis, anemia, and interstitial lung disease; i
Everolimus Used or renal-cell cancer atigue, each occurring in symptoms such as cough or
and may also be use ul in 30-50% o patients shortness o breath develop or
mantle cell lymphomas and Leukopenia or radiological changes progress, the
other cancers thrombocytopenia with drug should be discontinued
progressive cycles o
treatment in some patients
Interleukin-2 (IL-2) Aldesleukin See Table 45-5 Most patients develop a Most signi cant toxicity with
Receptor Agonists Denileukin di titox Aldesleukin used or pruritic skin rash over most aldesleukin is capillary leak
metastatic renal-cell cancer o the body syndrome which can be li e-
and metastatic melanoma See Table 46-2 or denileukin threatening, but reversible with
Denileukin di titox used di titox toxicities discontinuation o therapy;
or recurrent/re ractory patients should have good
cutaneous T-cell lymphomas hepatic and renal unction be ore
starting therapy
Typical signi cant toxicities with
denileukin di titox include acute
hypersensitivity reactions, vascular
leak syndrome, and constitutional
toxicities (see also Table 46-2)
Colony-Stimulating See Chapter 25 Used as supportive therapy See Chapter 25 See Chapter 25
Factors to restore hematopoiesis
ollowing high-dose and
combination therapies
(see Chapter 25)
(Continued)
685
SECTION VIII Chemotherapy of Neoplastic Diseases
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Glucocorticoids Prednisone See Table 46-4 See Chapter 29 See Chapter 29
Dexamethasone Used as cytotoxic agents
in the treatment o acute
leukemia in children and
malignant lymphoma in
children and adults
Used to control autoimmune
hemolytic anemia and
thrombocytopenia
associated with CLL
Used with radiotherapy to
reduce edema related to
tumors in critical areas such
as the brain and spinal cord
Estrogens and See Chapter 28 See Table 46-4 See Chapter 28 High-dose therapy has signi cant
Androgens Used in hormone- risk o thromboembolism (see
dependent neoplasms Chapter 28)
such as breast and prostate
cancers
Antiestrogens— Tamoxi en See Table 46-4 Vasomotor symptoms (hot Increased risk o thromboembolic
Selective Toremi ene Used or prevention o breast f ashes), atrophy o the lining events
Estrogen-Receptor Raloxi ene cancer in high-risk patients, o the vagina, hair loss, nausea, Increased risk o endometrial
Modulators (SERMs) or the adjuvant therapy o and vomiting cancer
early-stage breast cancer, and Menstrual irregularities,
or the therapy o advanced vaginal bleeding and
breast cancer (estrogen discharge, pruritus vulvae, and
receptor-positive [ER+] dermatitis are more severe in
cancers are most responsive) postmenopausal women
Antiestrogens— Anastrozole See Table 46-4 Vaginal bleeding, vaginal Lower risk o estrogen-
Aromatase (CYP19) Letrozole Adjuvant hormonal therapy discharge, hot f ashes, but related toxicities (including
Inhibitors Exemestane in postmenopausal women lower requency o such side thromboembolism, endometrial
with early-stage breast e ects than tamoxi en cancer) than tamoxi en, but
cancer and as treatment or greater risk o musculoskeletal
advanced breast cancer (ER+ disorders and ractures
and PR+)
(Continued)
686
Targeted Anticancer Therapies CHAPTER 4 6
TOXICITIES
CLASS AND
SUBCLASSES NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
Gonadotropin- GnRH See Table 46-4 Vasomotor f ashing, loss Cause an initial release o LH and
Releasing Hormone Leuprolide Used or rst-line androgen o libido, impotence, FSH resulting in a testosterone
(GnRH) Agonists Buserelin deprivation therapy (ADT) gynecomastia, atigue, surge that may cause an acute
Na arelin as palliative treatment to anemia, weight gain, stimulation o prostate cancer
Histrelin alleviate cancer-related decreased insulin sensitivity, growth and a “f are”o symptoms
Triptorelin symptoms (eg, bone pain), altered lipid pro les, rom metastatic deposits; the
Goserelin produce objective responses, osteoporosis and ractures, f are phenomenon can be
and normalize serum and loss o muscle mass counteracted with concurrent
prostate-speci c antigen administration o antiandrogen
(PSA) in patients with therapy (known as combined
metastatic prostate cancer androgen blockade [CAB])
Antiandrogens— Cyproterone Megestrol Most commonly used as Cause more gynecomastia, Cyproterone is associated with
Steroidal secondary hormone therapy mastodynia, and liver toxicity
in prostate cancer or in CAB hepatotoxicity but less
Cyproterone has in erior vasomotor f ashing, and loss
e cacy compared with o bone mineral density than
other orms o ADT GnRH agonists
Antiandrogens— Flutamide See Table 46-4 Flutamide causes diarrhea, Flutamide is associated with risk
Nonsteroidal Bicalutamide Used as secondary hormone breast tenderness, and o hepatotoxicity
Nilutamide therapy (in combination with nipple tenderness; less Nilutamide is associated rarely
other agents) or in CAB commonly, nausea, vomiting, with interstitial pneumonitis
Nilutamide causes mild
nausea, alcohol intolerance
(5-20%), and diminished
ocular adaptation to
darkness (25-40%)
Estrogens See Chapter 28 See Table 46-4 Impotence, loss o libido, Increased risk o myocardial
High-dose estrogen is and lethargy in arctions, strokes, and
used in patients with pulmonary emboli; increased
prostate cancer to reduce mortality
testosterone to castrate
levels via negative eedback
on the hypothalamic–
pituitary axis
Estrogen may also exert a
cytotoxic e ect on prostate
cancer cells
Inhibitors o Ketoconazole Used to reduce nongonadal Ketoconazole causes Glucocorticoids are administered
Steroidogenesis Abiraterone (eg, adrenal and tumor) signi cant diarrhea and to compensate or inhibition o
androgen synthesis in hepatic enzyme elevations adrenal steroidogenesis
castration-resistant prostate Abiraterone increases
cancer ACTH levels, resulting in
mineralocorticoid excess
687
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SECTION
689
CHAPTER
47 Ocular Pharmacology
T is chapter will be most use ul a er having a basic understanding o the material
DRUGS INCLUDED IN THIS
in Chapter 64, Ocular Pharmacology in Goodman & Gilman’s T e Pharmacological
CHAPTERa Basis of T erapeutics, 12th Edition In addition to the material presented here, the
• Abobotulinumtoxin A(DYSPORT) 12th Edition contains:
• Acetylcholine (MIOCHOL-E) • A detailed description o the anatomy o the eye and extraocular structures
• Apraclonidine (IOPIDINE) • able 64-1 Autonomic Pharmacology o the Eye and Related Structures
• Atropine (ATROPINE-CARE, ISOPTOATROPINE) • able 64-8 Vitreous Substitutes
• Azelastine (OPTIVAR) • T e mechanism o action o vitamin A in retinal physiology and vision
• Bepotastine (BEPREVE) • Figure 64-7 Structural ormula or β-carotene and structural ormulas or the vita-
• Betaxolol (BETOPTIC, others) min A amily o retinoids
• Bevacizumab (AVASTIN) • able 64-9 Ophthalmic E ects o Selected Vitamin De ciencies and Zinc De ciency
• Bimatoprost (LUMIGAN, LATISSE) • Figure 64-8 Major steps in photoreceptor signaling
• Brimonidine (ALPHAGAN, others)
LEARNING OBJECTIVES
• Brinzolamide (AZOPT)
Understand the principles o using drugs to treat ophthalmic disorders
• Brom enac(XIBROM)
• Carbachol (MIOSTAT,ISOPTOCARBACHOL, Know the ocular toxicities o systemic drugs
others) Know the mechanisms o action, clinical uses, and toxicities o ophthalmic
• Carteolol (OCCUPRES, others) drugs
• Chondroitin sul ate (VISCOAT) Describe how ophthalmic drugs administered topically can cause systemic side
• Cromolyn sodium(CROLOM, others) e ects
• Cyanoacrylate tissue adhesive (ISODENT, Understand the pathophysiology o glaucoma and the role o pharmacotherapy
DERMABOND, HISTOACRYL) in its management
• Cyclopentolate (CYCYLOGYL, others)
• Cyclosporin A(RESTASIS) MECHANISMS OF ACTION OF DRUGS FOR OPHTHALMIC USE
• Dexamethasone (DEXASOL, others) DRUG CLASS DRUG MECHANISM OF ACTION
• Diclo enac(VOLTAREN, others) Autonomic Agents Dipive rin Prodrug that is converted to
• Di uprednate (DUREZOL) epinephrine by esterases in the
cornea see Table 47 4, Figure 47 1,
• Dipive rin (PROPINE, others) and Chapter 7)
• Dorzolamide (TRUSOPT,others)
Apraclonidine Selective α2 adrenergic agonist see
• Echothiophate (PHOSPHOLINEIODIDE) Brimonidine Table 47 4 and Figure 47 1)
• Emedastine di umarate (EMADINE)
Acetylcholine Cholinergic agonist see Table 47 4,
• Epinastine (ELESTAT) Carbachol Figure 47 1, and Chapter 6)
• Fibrinogen glue (TISSEEL, EVICEL) Pilocarpine
• Fluocinolone ophthalmicimplant (RETISERT) Echothiophate Organophosphate
• Fluorescein sodium acetylcholinesterase inhibitor see
Table 47 4, Figure 47 1, and Chapter 6)
• Fluorometholone (FML, others)
• Fluorouracil Atropine Muscarinic antagonist see
Scopolamine Table 47 4, Figure 47 1, and
• Flurbipro en (OCUFEN, others) Homatropine Chapter 6)
• Homatropine (ISOPTOHOMATROPINE, others) Cyclopentolate
Tropicamide
• Hyaluronate (HEALON, others)
• Hydroxyamphetamine + topicamide Phenylephrine Sympathomimetic agent see
(PAREMYD) Naphazoline Table 47 4, Figure 47 1, and
(continues) Tetrahydrozoline Chapter 7)
(Continued)
690
Ocular Pharmacology CHAPTER 4 7
Cipro oxacin hydrochloride 0.3% solution; 0.3% ointment H, D RCD Conjunctivitis, keratitis,
(CILOXAN, others) keratoconjunctivitis,
corneal ulcers, blepharitis,
blepharoconjunctivitis,
meibomianitis, dacryocystitis
Gentamicin sul ate GARAMYCIN, 0.3% solution; 0.3% ointment H Conjunctivitis, blepharitis, keratitis,
GENOPTIC, GENT-AK, keratoconjunctivitis, corneal
GENTACIDIN, OTHERS) ulcers, blepharoconjunctivitis,
meibomianitis, dacryocystitis
Sul acetamide sodium BLEPH-10, 1%, 10%, 15%, and 30% solution; H, BD Conjunctivitis, other super cial
CETAMIDE, ISOPTO CETAMIDE, 10% ointment ocular in ections
others)
Tobramycin sul ate c TOBREX, 0.3% solution; 0.3% ointment H External in ections o the eye and
AKTOB, DEFY, others) its adnexa
a
For speci c in ormation on dosing, ormulation, and trade names, re er to the Physicians’Desk Reference for Ophthalmic Medicines, which is
published annually. bPolymyxin B is ormulated or delivery to the eye in combination with bacitracin, neomycin, gramicidin, oxytetracycline,
or trimethoprim. See Chapters 38 41 or urther discussion o these antibacterial agents. cTobramycin is ormulated or delivery to the eye in
combination with dexamethasone or loteprednol etabonate. H, hypersensitivity; BD, blood dyscrasia; D RCD, drug related corneal deposits.
Tri uridine VIROPTIC, others) Topical 1% solution) PK, H Herpes simplex keratitis and
keratoconjunctivitis
Valacyclovir VALTREX) Oral 500 and 1000 mg tablets) Herpes simplex keratitisa
Herpes zoster ophthalmicusa
Famciclovir FAMVIR) Oral 125 , 250 , and 500 mg Herpes simplex keratitisa
tablets) Herpes zoster ophthalmicusa
693
SECTION IX Special Systems Pharmacology
Amphotericin Ba 0.1 0.5% typically 0.15%) topical Yeast and ungal keratitis and
solution endophthalmitis
0.8 1 mg subconjunctival Yeast and ungal endophthalmitis
5 µg intravitreal injection Yeast and ungal endophthalmitis
Intravenous Yeast and ungal endophthalmitis
Imidazoles
Of label use. Only natamycin NATACYN) is commercially available and labeled or ophthalmic use.
a
All other anti ungal drugs are not labeled or ophthalmic use and must be ormulated or the given
method o administration. For urther dosing in ormation, re er to the Physicians’Desk Reference for
Ophthalmic Medicines. For additional discussion o these anti ungal agents, see Chapter 43.
Iris
Ce rvica l
sympa the tic
ne rve
Cilia ry
ga nglion
Optic Pa ra -
ne rve sympa the tic
fibe rs of
Optic oculomotor
cha s m ne rve
b
Optic S upe rior
tra ct ce rvica l
sympa the tic
ga nglion
La te ra l
ge nicula te Infe rior
body cilio-s pina l
a sympa the tic
Optic ce nte r
ra dia tion
Vis ua l
cortex Edinge r-We s tpha l Hypotha la mic
nucle i a nd sympa the tic
Motor ce nte r nucle i of Pe rlia ce nte r
in occipita l cortex
FIGURE 47-1 Autonomic innervation o the eye by the sympathetic a) and parasympathetic
b) nervous systems. (Adapted with permission from Wybar KC, Kerr-Muir M. Baillière Concise Medical
Textbooks, Ophthalmology, 3rd ed. Baillière Tindall, New York, 1984. Copyright © Elsevier.)
694
Ocular Pharmacology CHAPTER 4 7
Carbachol MIOSTAT, ISOPTO CARBACHOL, 0.01 3% solution Miosis in surgery Corneal edema, miosis, induced
others) Glaucomaa myopia, decreased vision, brow
ache, retinal detachment
Pilocarpine ISOPTO CARPINE, PILOCAR, 0.5%, 1%, 2%, 4%, and 6% Glaucoma Same as or carbachol
PILAGAN, PILOPINE HS, PILOPTIC, PILOSTAT, solution; 4% gel
others)
Anticholinesterase agents
Muscarinic antagonists
Atropine ATROPINE-CARE, ISOPTO 0.5%, 1%, and 2% solution; Cycloplegia, mydriasis,b Photosensitivity, blurred vision
ATROPINE) 1% ointment Cycloplegic retinoscopy,a
Dilated unduscopic exam
Sympathomimetic agents
695
SECTION IX Special Systems Pharmacology
Ri abutin Iridocyclitis
CASE 47 1
A 48-year-old man with a 10-year history o congestive heart ailure ollowing an acute
myocardial in arction is treated with timolol eye drops or increased intraocular pressure
(IOP) A er using the eye drops or 1 week the patient notices increased atigue and
shortness o breath
a. What kind of drug in timolol?
imolol is a nonselective β adrenergic receptor antagonist (see Chapter 7). Its
adverse systemic e ects are bradycardia, negative cardiac inotropy, and decreased
cardiac output. T ese e ects would worsen this patient’s congestive heart ailure.
b. How is the timolol associated with a worsening of this patient’s heart failure
when the drug is being administered as drops to the eye?
All ophthalmic medications are potentially absorbed into the systemic circula-
tion (see Figure 47-2; able 47-5), so undesirable systemic side e ects may occur.
opically administered drugs may undergo systemic distribution primarily by nasal
mucosal absorption and possibly by local ocular distribution by transcorneal/
transconjunctival absorption. Following transcorneal absorption, the aqueous
humor accumulates the drug, which then is distributed to intraocular structures
as well as potentially to the systemic circulation via the trabecular meshwork
pathway (see Figures 47-2 and 47-3).
(Continued)
696
Ocular Pharmacology CHAPTER 4 7
TEARS
CONJUNCTIVA
CORNEA S CLERA
AQUEOUS
HUMOR
IRIS CILIARY
BODY
SYSTEMIC CIRCULATION
FIGURE 47-2 Possible absorption pathways o an ophthalmic drug ollowing topical application
to the eye. Solid black arrows represent the corneal route; dashed blue arrows represent the
conjunctival/scleral route; the black dashed arrow represents the nasolacrimal absorption
pathway. (Adapted with permission from Chien DS et al. Curr Eye Res. 1990;9:1051–1059. Copyright ©
Taylor &Francis Group, http://www.informaworld.com.)
Subconjunctival, sub Tenon’s, Prompt or sustained, depending Anterior segment in ections, Local toxicity, tissue injury, globe
and retrobulbar injections on ormulation posterior uveitis, cystoid macular per oration, optic nerve trauma,
edema central retinal artery and/or vein
occlusion, direct retinal drug toxicity
with inadvertent globe per oration,
ocular muscle trauma, prolonged
drug ef ect
Intraocular intracameral) Prompt Anterior segment surgery, Corneal toxicity, intraocular toxicity,
injections in ections relatively short duration o action
Intravitreal injection or device Absorption circumvented, Endophthalmitis, retinitis, age Retinal toxicity
immediate local ef ect, potential related macular degeneration
sustained ef ect
697
SECTION IX Special Systems Pharmacology
La crima l ca na liculi
Ope ning of
na s ola crima l duct
CASE 47 2
A 17-year-old girl is brought to the emergency room a er ingesting Jimson weed
Her main complaint is the bright lights that are an irritation to her eyes Her pupils
are dilated
a. What is Jimson weed?
Jimson weed is commonly ound in backyards and vacant lots. Its seeds contain
belladonna alkaloids including atropine (see Chapters 3 and 6). T e seeds are
ingested to attain the CNS e ects o atropine including mild hallucinations.
b. Why do antimuscarinic substances cause mydriasis?
T e autonomic innervation o the eye by the sympathetic and parasympathetic
nervous systems is shown in Figure 47-1. T e e ect o cholinergic agents on the
pupil is constriction (miosis) (see able 47-6). T us, the e ect o an anticholin-
ergic agent such as atropine would be dilation (mydriasis). For urther explanation
see Chapter 6.
Topically applied ophthalmic drugs unless otherwise noted. a This percentage o pilocarpine is not commercially available and usually is
prepared by the physician administering the test or by a pharmacist. This test also requires that no prior manipulation o the cornea ie,
tonometry or measuring intraocular pressure or testing corneal sensation) be done so that the normal integrity o the corneal barrier is intact.
Normal pupils will not respond to this weak dilution o pilocarpine; however, an Adie’s pupil mani ests a denervation supersensitivity and is,
there ore, pharmacodynamically responsive to this dilute cholinergic agonist.
698
Ocular Pharmacology CHAPTER 4 7
CASE 47-3
A 53-year-old man has been told by his ophthalmologist that his intraocular pressure is
increased and that he will need to be treated or glaucoma
a. What is the pathophysiology of glaucoma?
T e peripheral anterior chamber angle is an important anatomical structure or
di erentiating 2 orms o glaucoma: open-angle glaucoma, which is by ar the most
common orm o glaucoma in the United States, and angle-closure glaucoma (see
Figure 47-4). Current medical therapy o open-angle glaucoma is aimed at decreas-
ing aqueous humor production and/or increasing aqueous outf ow. T e pre erred
management or angle-closure glaucoma is surgical iridectomy, by either laser
or incision, but short-term medical management may be necessary to reduce the
acute intraocular pressure (IOP) elevation and to clear the cornea prior to surgery.
Long-term IOP reduction may be necessary, especially i the peripheral iris has
permanently covered the trabecular meshwork.
(Continued)
cilia ry proce s s
cilia ry mus cle Ciliary
cilia ry e pithe lium bo dy
pa rs pla na
FIGURE 47-4 A. Anatomy o the eye. B. Enlargement o the anterior segment, revealing the
cornea, angle structures, lens, and ciliary body. (Adapted with permission from Riordan-Eva P.
Anatomy and embryology of the eye. In, Vaughan &Asbury’s General Ophthalmology, 17th ed.
[Riordan-Eva P, Whitcher JP, eds.] McGraw-Hill, New York, 2008. Copyright © 2008 by The McGraw-Hill
Companies, Inc. All rights reserved.)
699
SECTION IX Special Systems Pharmacology
CASE 47 4
A 60-year-old man wakes up with a crusty discharge in both eyes His ophthalmologist
diagnoses blepharitis
a. What is blepharitis?
Blepharitis is a common bilateral inf ammatory process o the eyelids characterized
by irritation and burning, usually associated with a Staphylococcus spp. in ection.
Local hygiene is the mainstay o therapy; topical antibiotics requently are used,
usually in gel, drop, or ointment orm, particularly when the disease is accompa-
nied by conjunctivitis and keratitis.
Conjunctivitis is an inf ammatory process o the conjunctiva that varies in sever-
ity rom mild hyperemia to severe purulent discharge. T e more common causes o
conjunctivitis include viruses, allergies, environmental irritants, contact lenses, and
chemicals. T e less common causes include other in ectious pathogens, immune-
mediated reactions, associated systemic diseases, and tumors o the conjunctiva
or eyelid.
Keratitis, or corneal inf ammation, can occur at any level o the cornea (eg, epi-
thelium, subepithelium, stroma, and endothelium). It can be due to nonin ectious
or in ectious causes. Numerous microbial agents have been identi ed as causes o
in ectious keratitis, including bacteria, viruses, ungi, spirochetes, cysts, and tro-
phozoites. Severe in ections with tissue loss (corneal ulcers) generally are treated
more aggressively than in ections without tissue loss (corneal in ltrates).
T e mild, small, more peripheral in ections usually are not cultured, and the eyes
are treated with broad-spectrum topical antibiotics. In more severe, central, or larger
in ections, corneal scrapings or smears, cultures, and sensitivities are per ormed,
and the patient is immediately started on intensive hourly, around-the-clock topi-
cal antibiotic therapy. T e goal o treatment is to eradicate the in ection and reduce
the amount o corneal scarring and the chance o corneal per oration and severe
decreased vision or blindness. T e initial medication selection and dosage are
adjusted according to the clinical response, and culture and sensitivity results.
b. What are the treatment options with this patient?
able 47-1 shows the topical antibacterial agents available or ophthalmic use. See
Chapters 38, 39, 40, and 41 or additional details about speci c agents.
700
Ocular Pharmacology CHAPTER 4 7
CASE 47-5
A 33-year-old woman has developed a herpes simplex in ection o her cornea
(viral keratitis)
a. What is the pathophysiology of viral infections of the eye?
Viral keratitis, an in ection o the cornea that may involve either the epithelium or
stroma, is most commonly caused by herpes simplex type I and varicella zoster viruses.
Less common viral etiologies include herpes simplex type II, Epstein-Barr virus, and
cytomegalovirus (CMV). opical antiviral agents are indicated or the treatment o
epithelial disease due to herpes simplex in ection. When treating viral keratitis topi-
cally, there is a very narrow margin between the therapeutic topical antiviral activity
and the toxic e ect on the cornea; hence, patients must be ollowed very closely.
b. What treatment options are available for this patient?
T e various antiviral drugs currently used in ophthalmology are summarized in
able 47-2 (see Chapter 44 or additional details about speci c agents).
T e primary indications or the use o antiviral drugs in ophthalmology are viral
keratitis, herpes zoster ophthalmicus, and retinitis. T ere currently are no antivi-
ral agents or the treatment o viral conjunctivitis caused by adenoviruses, which
usually has a sel -limited course and typically is treated by symptomatic relie
o irritation.
opical glucocorticoids are contraindicated in herpetic epithelial keratitis due to
active viral replication. In contrast, or herpetic disci orm keratitis, which predomi-
nantly is presumed to involve a cell-mediated immune reaction, topical glucocorti-
coids accelerate recovery.
CASE 47 6
A 43-year-old woman who has been receiving chemotherapy or colon cancer is diag-
nosed with a ungal keratitis
a. What treatment is available for this patient?
T e only currently available topical ophthalmic anti ungal preparation is a poly-
ene, natamycin (NA ACYN). Other anti ungal agents may be extemporaneously
compounded or topical, subconjunctival, or intravitreal routes o administration
(see able 47-3). T e pharmacology and structures o speci c anti ungal agents are
given in Chapter 43.
As with systemic ungal in ections, the incidence o ophthalmic ungal in ections
has risen with the growing number o immunocompromised hosts. Ophthalmic
indications or anti ungal medications include ungal keratitis, scleritis, endo-
phthalmitis, mucormycosis, and canaliculitis. Risk actors or ungal keratitis
include trauma, chronic ocular sur ace disease, contact lens wear, and immunosup-
pression (including topical steroid use). In 2005 to 2006, there was a worldwide
epidemic o Fusarium ungal keratitis related to a speci c contact lens solution,
which resolved when it was removed rom the market. When ungal in ection is
suspected, samples o the a ected tissues are obtained or smears, cultures, and sen-
sitivities, and this in ormation is used to guide drug selection.
KEY CONCEPTS
T e eye is relatively secluded rom systemic access by blood-retinal, blood-
aqueous, and blood-vitreous barriers; as a consequence, the eye exhibits some
unusual pharmacodynamics and pharmacokinetic properties
opically administered drugs may undergo systemic distribution primarily by
nasal mucosal absorption and possibly by local ocular distribution by transcor-
neal/transconjunctival absorption
(Continued)
701
SECTION IX Special Systems Pharmacology
Drug absorption rom the nasal mucosa avoids rst-pass metabolism by the
liver, and consequently, signi cant systemic side e ects may be caused by topical
medications
Individual variation may be an important consideration or ocular drug distri-
bution due to drug-melanin binding to melanocytes in the iris
Classical pharmacokinetic theory based on studies o systemically administered
drugs does not ully apply to all ophthalmic drugs administered topically or locally
A er topical instillation o a drug, the rate and extent o absorption are deter-
mined by the time the drug remains in the cul-de-sac and precorneal tear lm,
elimination by nasolacrimal drainage, drug binding to tear proteins, drug metab-
olism by tear and tissue proteins, and di usion across the cornea and conjunctiva
Several drug ormulations prolong the time a drug remains on the sur ace o
the eye and thus acilitate drug absorption
Appropriate selection o an antimicrobial and route o administration is
dependent on the patient’s symptoms, the clinical examination, and the
culture/sensitivity results
SUMMARY QUIZ
QUESTION 47-1 A 42-year-old man with a seizure disorder has developed glaucoma
It is possible that he has developed glaucoma rom the use o
a phenytoin
b topiramate
c carbamazepine
d lamotrigine
e valproic acid
QUESTION 47-3 A 53-year-old woman with type 2 diabetes has noticed that her blood
sugar has been dif cult to regulate a er she started using glucocorticoid eye drops It is
likely that the glucocorticoid is being absorbed into the systemic circulation rom the
a nasal mucosa
b drops that spill rom the eye and enter her oral cavity
c lens
d vitreous humor
e canal o Schlemm
QUESTION 47-4 A 42-year-old man with glaucoma is treated with the α2 adrenergic
receptor agonist apraclonidine Despite being a derivative o clonidine, apraclonidine
does not cause systemic hypotension because it is
a tightly bound to plasma proteins
b metabolized rapidly by the liver
c highly ionized at physiological pH
d not absorbed rom the eye
e rapidly excreted by the kidney
702
Ocular Pharmacology CHAPTER 4 7
QUESTION 47-5 A 48-year-old man experiences a bluish haze and light sensitivity
when he takes which o the ollowing medications?
a etracycline
b Amoxicillin
c Metoprolol
d Ibupro en
e adala l
QUESTION 47-7 Vitamin A plays an essential role in the unction o the retina Vitamin A
de ciency inter eres with
a tear production
b vision in dim light
c color distinction
d peripheral vision
e vision in bright light
Atropine Mydriasis, cycloplegia Photosensitivity and Side ef ects and toxicity are
Scopolamine blurred vision generally related to systemic
Homatropine absorption see Chapter 6)
(Continued)
704
Ocular Pharmacology CHAPTER 4 7
TOXICITIES
Class and Subclasses Names Clinical Uses Common Unique; Clinically Important
Naphazoline Decongestant
Tetrahydozoline
Prostaglandin Latanoprost Used to treat glaucoma Blurred vision, burning, See Chapter 22
Analogs Travoprost stinging, conjunctival
Brimatoprost hyperemia, dry eyes
Carbonic Anhydrase Dorzolamide Used to treat glaucoma Side ef ects and toxicity are
Inhibitors Brinzolamide generally related to systemic
absorption see Chapter 15)
Ophthalmic Dexamethasone Treatment o ocular Side ef ects and toxicity Development o cataracts,
Glucocorticoids Prednisolone in ammatory diseases are generally related to secondary in ections,
Fluorometolone systemic absorption see secondary open angle
Loteprednol Chapter 29) glaucoma
Rimexolone
Di uprednate
Nonsteroidal Anti Flurbipro en Used to treat ocular Side ef ects and toxicity Occasionally associated with
in ammatory Agents Ketorolac in ammation are generally related to corneal per oration
Diclo enac systemic absorption see
Brom enac Chapter 22)
Nepa enac
Antihistamines and Emedastine di umarate Used to treat allergic Side ef ects and toxicity
Mast Cell Stabilizers Cromolyn sodium conjunctivitis are generally related to
Lodoxamide tromethamine systemic absorption see
Pemirolast Chapter 21)
Nedocromil
Olopatadine
Ketoti en umarate
Bepotastine
Azelastine
Epinastine
TOXICITIES
Class and Subclasses Names Clinical Uses Common Unique; Clinically Important
Agents Used in Onabotulinumtoxin A Used in the treatment Double vision, lid droop
the Treatment o Abobotulinumtoxin A o strabismus and Potentially li e threatening
Strabismus and blepharospasm distant spread o toxin see
Blepharospasm Chapter 6)
Agents Used to Vertepor n Approved or photodynamic Headache, injection site Temporary photosensitivity
Treat Macular therapy o the exudative reactions, and visual o the skin and eyes
Degeneration orm o age related macular disturbances Patients must avoid direct
degeneration ARMD) sunlight or bright indoor
lights or 5 days
Pegaptanib Treatment o neovascular Side ef ects are related to Monitor patients or increase
wet) ARMD the intravitreal injection IOP and endophthalmitis
Rare cases o anaphylaxis
Wetting Agents and Tyloxapol Arti cial tears and ophthalmic Localized burning and
Tear Substitutes Carboxy methylcellulose lubricants used or the irritation
Hydroxylethyl cellulose management o dry eyes
Hydroxypropyl cellulose
Hydroxypropyl
methyl cellulose
Methylcellulose
706
CHAPTER
Dermatological Pharmacology 48
T is chapter will be most use ul a er having a basic understanding o the material in
DRUGS INCLUDED IN THIS
Chapter 65, Dermatological Pharmacology in Goodman & Gilman’s T e Pharmacological
Basis of T erapeutics, 12th Edition. In addition to the material presented here, the CHAPTERa
12th Edition contains: • Acitretin (SORIATANE)
• A detailed description o the structures o the skin and their pharmacological • Adalimumab (HUMIRA)
implications • Adapalene (DIFFERIN)
• A discussion o antimicrobial therapy o skin disorders • Ale acept (AMEVIVE)
• A discussion o the use o cytotoxic and immunosuppressive drugs in the treatment • Alitretinoin (9-cis-retinoicacid)
o skin disorders (PANRETIN)
• ables 65-4 and 65-5 which are a listing o topical and systemic retinoids, respectively • Aminolevulinicacid (ALA, LEVULAN
• Chemical structures o drugs used to treat dermatological disorders KERASTICK)
• Azathioprine (IMURAN, others)
LEARNING OBJECTIVES
• Azelaicacid (AZELEX,FINACEA)
Understand how drugs are absorbed through the skin.
• Benzyl alcohol
Know the mechanisms o action, therapeutic uses, and toxicities o topical and
• Bexarotene (TARGRETIN)
systemic drugs used to treat dermatological disorders.
• Bleomycin (BLENOXANE)
Know the principles o photochemotherapy o dermatological disorders.
• Calcipotriene (DOVONEX,others)
Know the science behind the use o sunscreen agents.
• Capsaicin (ZOSTRIX,CAPSIN)
MECHANISMS OF ACTION • Carmustine (BICNU)
DRUG CLASS DRUG MECHANISM OF ACTION • Chloroquine (ARALEN, others)
• Crotamiton (EURAX)
Glucocorticoids Triamcinolone acetonide See Chapter 29
Triamcinolone hexacetonide • Cyclophosphamide
Numerous other agents • Cyclosporine (NEORAL, GENGRAF, others)
(Table 48 7)
• Dapsone (diaminodiphenylsul one, DDS)
Retinoids Tretinoin Exert their e ect on gene expression • Denileukin Di titox(ONTAK)
Isotretinoin by activating 2 amilies o receptors:
Acitretin retinoic acid receptors (RARs) and • Doxorubicin (DOXIL, CAELYX)
Tazarotene retinoid X receptors (RXRs) • Ealizumab (RAPTIVA)
Bexarotene Bexarotene selectively binds RXRs
Adapalene • Etanercept (ENBREL)
Alitretinoin • Finasteride (PROPECIA, others)
Vitamin Analogs Calcipotriene Vitamin D analog exerts its e ects • Fluorouracil (CARAC, others)
through the vitamin D receptor • Hydroquinone (TRI-LUMA)
(VDR); upon binding the VDR, the
drug receptor complex associates • Hydroxychloroquine (PLAQUENIL, others)
with RXR α and binds to vitamin D • Imiquimod (ALDARA)
response elements on DNA
• In iximab (REMICADE)
Photochemotherapeutic Methoxsalen Methoxsalen ollowed by ultraviolet • Isotretinoin(13-cis-retinoicacid)(ACCUTANE)
Drugs (PUVA, Table 48 4) radiation between 320 340 nm
• Ivermectin (STOMECTOL)
(UVA) results in 2 photoreactions:
Type I reactions involve the oxygen • Lindane
independent photoaddition o the • Malathion (OVIDE)
psoralen to pyrimidine bases in
DNA; Type II reactions are oxygen • Mechlorethamine (MUSTARGEN)
dependent and involve the trans er o • Mequinol (SOLAGE, in combination with
energy to molecular oxygen, creating tretinoin and vitamin C)
reactive oxygen species (Table 48 4) (continues)
(continued)
707
SECTION IX Special Systems Pharmacology
(Continued)
708
Dermatological Pharmacology CHAPTER 4 8
La nge rha ns ce ll
EFALIZUMAB ALEFACEP T
ICAM-1 LF3A
CD80/CD86 MHC
LFA1CD2CD28 Ag
CD4
TCR
CD3
CD45RO +
T ce ll
FIGURE 48-1 Mechanisms o action o selected biological agents in psoriasis. Newer biological agents
can inter ere with one or more steps in the pathogenesis o psoriasis, resulting in clinical improvement.
See text in Chapter 65, Dermatological Pharmacology in Goodman &Gilman’s The Pharmacological Basis
of Therapeutics, 12th Edition or details. ICAM 1, intercellular adhesion molecule 1; LFA, lymphocyte
unction–associated antigen; MHC, major histocompatibility complex; TCR, T cell receptor.
710
Dermatological Pharmacology CHAPTER 4 8
Ke ra tinocyte
Cytokine a ctiva tion Epide rmis
s e cre tion
Migra tion Migra tion
through a ffe re nt Che mokine
lympha tics s e cre tion
Clona l expa ns ion
De rmis Antige n
pre s e nta tion
De rmis
CD45RO +
CD45RA+ CLA+
CD45RO +
CLA– Lymph node CLA+ Blood
FIGURE 48-2 Immunopathogenesis o psoriasis. Psoriasis is a prototypical inf ammatory skin disorder in which speci c T cell populations are
stimulated by as yet unde ned antigen(s) presented by antigen presenting cells. The T cells release proinf ammatory cytokines, such as tumor
necrosis actor α (TNF α) and inter eron γ (IFN γ), that induce keratinocyte and endothelial cell proli eration. APC, antigen presenting cell; CLA,
cutaneous lymphocyte associated antigen.
CASE 48 1
A 70-year-old woman has developed an in ection rom scratching an area on her leg.
Despite her physician’s recommendation or an oral antibiotic, she wishes to have a
“cream” to put on it.
a. What is the process o absorption o the antibiotic through the skin?
Passage through the outermost layer is the rate-limiting step or percutaneous
absorption. Figure 48-3 shows the structure and layers o the skin, and Figure 48-4
shows the compartments o skin as they relate to cutaneous drug delivery. T e
mechanisms o percutaneous absorption are shown in the Side Bar MECHANISMS
OF PERCU ANEOUS ABSORP ION.
b. What are the important considerations when applying a drug to the skin?
T e important considerations when applying a drug to the skin are shown in
able 48-1. In addition, the ollowing considerations should be taken into account:
dosage, under-application o a drug because o cost considerations o en occurs
when large amounts o skin are treated or a long time; regional anatomical
variation, drug penetration is higher on the ace, intertriginous areas, and
perineum due to stratum corneum thickness (see Figures 48-3 and 48-4). Skin sites
that are naturally occluded by apposing sur aces, such as the axillae, groin, and
in ramammary areas, are vulnerable to drug-related atrophy rom potent topical
glucocorticoids; altered barrier function in disease, in many dermatological diseases,
the stratum corneum is abnormal and barrier unction is compromised. In these
(Continued)
711
SECTION IX Special Systems Pharmacology
Solubilizing medium >31% water (up to 80%) <25% water Contains water soluble May be aqueous or
polyethylene glycols alcoholic
Advantages or patient Spreads and removes Spreads easily Nonstaining Low residue on scalp
easily Slows water evaporation Greaseless
No greasy eel Gives a cooling e ect Clear appearance
Locations on body Most locations Avoid intertriginous areas Foams well or scalp and Solutions and oams are
other hairy locations well accepted on scalp
De s mos ome
FIGURE 48-3 Structure o the epidermis. The epidermis matures progressively rom the stratum basale (SB) to the stra
tum spinosum (SS), stratum granulosum (SG), and stratum corneum (SC). Important structural and metabolic proteins
are produced at speci ic layers o the epidermis. (Reproduced with permission from Wolff Ket al (eds). Fitzpatrick’s
Dermatology in General Medicine, 7th ed. McGraw-Hill, Inc., 2008. Figure 45-2.)
Ve hicle
re s e rvoir
S tr. corne um Re s e rvior Ba rrie r
~20 mm function function
Binding
Via ble e pide rmis
~100 mm
Re s orption
Cuta ne ous
va s cula ture
Binding Lymph
De rmis ve s s e ls
~1200 mm
Pe rme a tion
Hypode rmis
FIGURE 48-4 Cutaneous drug delivery. Diagrammatic representation o the 3 compartments o the skin as they
relate to drug delivery: sur ace, stratum (Str.), and viable tissues. A ter application o drugs to the sur ace, evaporation,
structural, and compositional alterations, which determine the bioavailability o drugs, occur in the applied ormula
tion. The stratum corneum limits di usion o compounds into the viable skin and body. A ter absorption, compounds
either bind targets in viable tissues or di use within the viable tissue or into the cutaneous vasculature, where
they may be carried to internal cells and organs. (Reproduced with permission from Wolff Ket al (eds). Fitzpatrick’s
Dermatology in General Medicine, 7th ed. McGraw-Hill, Inc., 2008. Figure 215-1.)
713
SECTION IX Special Systems Pharmacology
Components LFA 3 and Fc IgG1 Complementarity IgG1 p75 TNF receptor and Variable region o
determining region Fc IgG1 mouse monoclonal
o mouse monoclonal antibody on
antibody on human IgG1
human IgG1
Method o IM SC SC SC IV
administration
Dosing or 15 mg weekly × 12 0.7 mg/kg rst week, 80 mg loading dose, 50 mg twice weekly × 3, 5 mg/kg at weeks 0, 2,
psoriasis weeks, stop 12 weeks, then 1 mg/kg weekly then 40 mg biweekly months then 50 mg and 6, then every 6 8
then repeat weekly weeks
FDA indications Moderate severe Moderate severe Moderate severe Moderate severe Severe psoriasis;
psoriasis psoriasis psoriasis; moderate psoriasis; moderate moderate severe
severe psoriatic arthritis; severe psoriatic arthritis; psoriatic arthritis;
adult and juvenile adult and juvenile adult rheumatoid
rheumatoid arthritis; rheumatoid arthritis; arthritis; ankylosing
ankylosing spondylitis; ankylosing spondylitis spondylitis; ulcerative
Crohn’s disease colitis; Crohn’s disease
Pregnancy B C B B B
category
CASE 48 2
A 35-year-old man has the diagnosis o psoriasis. He is being treated with
methotrexate.
a. What is psoriasis?
Psoriasis is a disorder o T 1 cell-mediated immunity (see Figure 48-2), with the
epidermal changes being secondary to the e ect o released cytokines.
b. Why is methotrexate e cacious in the treatment o psoriasis?
T e antimetabolite methotrexate is a olic acid analog that competitively inhibits
dihydro olate reductase (see Chapter 45). Methotrexate has been used or moderate
to severe psoriasis since 1951. It suppresses immunocompetent cells in the skin, and
it also decreases the expression o cutaneous lymphocyte-associated antigen (CLA)–
positive cells and endothelial cell E-selectin, which may account or its ef cacy.
c. What adverse e ects o methotrexate might limit its use?
Doses o methotrexate must be decreased or patients with impaired renal
clearance. Methotrexate should never be co-administered with trimethoprim–
sul amethoxazole, probenecid, salicylates, or other drugs that can compete with
it or protein binding and thereby raise plasma concentrations to levels that may
result in bone marrow suppression. Fatalities have occurred because o concur-
rent treatment with methotrexate and nonsteroidal anti-in ammatory agents.
Methotrexate exerts signi cant antiproli erative e ects on the bone marrow; there-
ore, a complete blood count should be monitored serially. Physicians administer-
ing methotrexate should be amiliar with the use o olinic acid (leucovorin) to
rescue patients with hematological crises caused by methotrexate-induced bone
marrow suppression. Care ul monitoring o liver unction tests is necessary but
may not be adequate to identi y early hepatic brosis in patients receiving chronic
methotrexate therapy. Methotrexate-induced hepatic brosis may occur more com-
monly in patients with psoriasis than in those with rheumatoid arthritis. Conse-
quently, liver biopsy is recommended when the cumulative dose reaches 1 to 1.5 g.
A baseline liver biopsy also is recommended or patients with increased potential
risk or hepatic brosis, such as a history o alcohol abuse or in ection with hepa-
titis B or C. Patients with signi cantly abnormal liver unction tests, symptomatic
liver disease, or evidence o hepatic brosis should not use this drug. Many clini-
cians routinely administer olic acid along with methotrexate to ameliorate side
e ects; this does not reduce ef cacy o the methotrexate. Pregnancy and lactation
are absolute contraindications to methotrexate use.
d. What other therapeutic options are available or this patient?
Biological agents (see Chapter 23) are compounds derived rom living organisms
that target speci c mediators o immunological reactions. Classes o biologicals
include recombinant cytokines, interleukins, growth actors, antibodies, and usion
proteins. Currently, 5 biological agents are approved or the treatment o psoriasis
(see able 48-3). Biological therapies modi y the immune response in psoriasis
through (1) reduction o pathogenic cells, (2) inhibition o -cell activation,
(3) immune deviation ( rom a T 1 to a T 2 immune response), and (4) blockade o
the activity o in ammatory cytokines.
(Continued)
715
SECTION IX Special Systems Pharmacology
Method o drug administration Oral Topical cream or solution o a To isolated plasma within
Topical lotion prodrug (aminolevulinic acid or photopheresis device
Bath water methylaminolevulinate)
Activating wavelength UVA2 (320 340 nm) 417 nm and 630 nm UVA2 (320 340 nm)
Adverse ef ects (chronic) Photoaging Potential scarring Loss o venous access a ter
Nonmelanoma skin cancer repeated venipuncture
Melanomaa
Cataractsa
T e appeal o biological agents in the treatment o psoriasis is that they speci cally
target the activities o lymphocytes and cytokines that mediate in ammation
versus traditional systemic therapies that are broadly immunosuppressive or
cytotoxic. hus, the use o these agents theoretically should result in ewer
toxicities and side e ects.
When evaluating the ef cacy o biological agents, it is important to understand the
standard measurement o ef cacy in psoriasis treatment, the Psoriasis Area and
Severity Index (PASI). T e PASI quanti es the extent and severity o skin involve-
ment in di erent body regions as a score rom 0 (no lesions) to 72 (severe disease).
o gain FDA approval or the treatment o psoriasis, a biological agent must decrease
the PASI by 75%. Although such quanti cation is an essential element in controlled
clinical trials, many patients in practice may gain clinically signi cant bene t rom
biological treatment without achieving this degree o PASI improvement.
CASE 48 3
Prior to his treatment with methotrexate, the patient in Case 48-2 was treated with
photochemotherapy.
a. What is photochemotherapy?
Phototherapy and photochemotherapy are treatment methods in which UV or
visible radiation is used to induce a therapeutic response either alone or in the
presence o a photosensitizing drug. o be e ective, the incident radiation must
(Continued)
716
Dermatological Pharmacology CHAPTER 4 8
b. What are the potential toxicities o phototherapy and photochemotherapy and SYSTEMIC Tetracycline
how should patients be monitored? Doxycycline
Minocycline
Patients treated with these modalities should be monitored or concomitant use o Trimethoprim
other potential photosensitizing medications be ore initiation o therapy. Such drugs sul amethoxazole
include phenothiazines, thiazides, sul onamides, nonsteroidal anti-in ammatory
agents, sul onylureas, tetracyclines, and benzodiazepines.
T e major side e ects o PUVA are listed in able 48-4. Phototoxicity is character-
ized by erythema, edema, blistering, and pruritus. Ocular toxicity can be prevented
by wearing UVA-blocking glasses the day o treatment. T e risk o nonmelanoma
skin cancer is dose-dependent, with the greatest risk in those receiving more than
250 treatments. A possible association o melanoma and extensive exposure to
PUVA has been reported; however, several other studies have ailed to con rm this
association. As skin cancer may not develop or decades a er exposure, annual skin
examinations should be continued or years a er completion o PUVA.
CASE 48 4
A 17-year-old boy with nonin ammatory acne is treated with a topical retinoid
preparation.
a. What is acne?
Acne is believed to result rom a combination o sebaceous gland hyperplasia, ol-
licular hyperkeratosis, Propionibacterium acnes colonization, and in ammation.
T ough incompletely understood mechanisms, topical retinoids correct abnormal
ollicular keratinization, reduce P. acnes counts, and reduce in ammation, thereby
making them the cornerstone o acne therapy. opical retinoids are rst-line agents
or nonin ammatory (comedonal) acne and o en are combined with other agents
in the management o in ammatory acne.
b. What is the mechanism o action o retinoids?
Retinoids exert their e ects on gene expression by activating 2 amilies o receptors—
retinoic acid receptors (RARs) and retinoid X receptors (RXRs)—that are members
o the steroid receptor super amily.
Unique therapeutic e ects can be produced by targeting speci c retinoid receptors.
For example, retinoids that target RARs predominantly a ect cellular di erentia-
tion and proli eration, whereas retinoids that target RXRs predominantly induce
apoptosis. Hence, tretinoin, adapalene, and tazarotene, which target RARs, are used
in acne, psoriasis, and photoaging (disorders o di erentiation and proli eration),
whereas bexarotene and alitretinoin, which target RXRs, are used in mycosis un-
goides and Kaposi sarcoma (to induce apoptosis o malignant cells).
c. What retinoid preparations are available or this patient?
opical and systemic retinoids are shown in ables 65-4 and 65-5, respectively, in
Goodman and Gilman’s T e Pharmacological Basis of T erapeutics, 12th Edition.
(Continued)
717
SECTION IX Special Systems Pharmacology
CASE 48 5
A 53-year-old woman has widespread tinea corporis in ection in her skin that is causing
irritation and itching. Her physician has prescribed oral uconazole.
a. What preparations are available or the treatment o cutaneous ungal in ections?
able 48-5 shows the recommendations or cutaneous anti ungal therapy.
(Continued)
718
Dermatological Pharmacology CHAPTER 4 8
SUNSCREEN AGENTS
ULTRAVIOLET A (UVA) SUNSCREEN AGENTS ULTRAVIOLET B (UVB) SUNSCREEN AGENTS
Avobenzone (Parsol 1789) p Aminobenzoic acid (PABA) esters (padimate O)
Oxybenzone Cinnamates (octinoxate)
Titanium dioxide Octocrylene
Zinc oxide Salicylates (octisalate)
Ecamsule (MEXORYL SX)
CASE 48 6
A 23-year-old woman is planning a beach vacation. She asks you or advice on
sunscreen agents.
a. What are sunscreens?
Photoprotection rom the acute and chronic e ects o sun exposure is readily avail-
able with sunscreens. T e major active ingredients o available sunscreens include
chemical agents that absorb incident solar radiation in the UVB and/or UVA ranges
and physical agents that contain particulate materials that can block or re ect inci-
dent energy and reduce its transmission to the skin (see the able SUNSCREEN
AGEN S). Many o the sunscreens available are mixtures o organic chemical
absorbers and particulate physical substances. Ideal sunscreens provide a broad
spectrum o protection and are ormulations that are photostable and remain intact
or sustained periods on the skin. T ey also should be nonirritating, invisible, and
nonstaining to clothing. No single sunscreen ingredient possesses all these desir-
able properties, but many are quite e ective nonetheless.
T e major measurement o sunscreen photoprotection is the sun protection actor
(SPF), which de nes a ratio o the minimal dose o incident sunlight that will produce
erythema or redness (sunburn) on skin with the sunscreen in place (protected) and
the dose that evokes the same reaction on skin without the sunscreen (unprotected).
T e SPF provides valuable in ormation regarding UVB protection but is useless in
documenting UVA ef cacy. In 2007, the FDA proposed a consumer- riendly rating
system or UVA products consisting o 1 to 4 stars representing low, medium, high, and
highest UVA protection available in an O C sunscreen product as an indicator o the
product’s ability to prevent tanning. T e test proposed to determine UVA rating is anal-
ogous to the SPF test used to determine the e ectiveness o UVB sunscreen products.
Except or total sun avoidance, sunscreens are the best single method o protection
rom UV-induced damage to the skin.
719
SECTION IX Special Systems Pharmacology
CASE 48 7
A 65-year-old woman has a complaint o itching on her arms and legs. Physical exami-
nation shows that she has broken skin on her legs rom scratching.
a. What are the common causes o itching?
T e term pruritus is derived rom the Latin prurire, which means “to itch.” Pruritus
is a symptom unique to skin that occurs in a multitude o dermatological disorders,
including dry skin or xerosis, atopic eczema, urticaria, and in estations. Itching also
may be a sign o internal disorders, including malignant neoplasms, chronic renal
ailure, and hepatobiliary disease. In addition to treating the underlying disorder,
a general approach to the treatment o pruritus can be made by classi ying pruritus
into one o our clinical categories (see able 48-6).
b. What agents are available or itching when there is no obvious cause?
Agents use ul in treating pruritus are listed in able 48-6.
KEY CONCEPTS
Drugs can be applied to the skin to directly treat disorders o the skin or to
deliver drugs to other tissues.
E ective and sa e use o topical agents requires appreciation o the physical and
physiological variables that in uence the interactions o drugs and the skin,
impacting absorption and transport.
(Continued)
720
Dermatological Pharmacology CHAPTER 4 8
T ere is a superf cial capillary plexus between the epidermis and dermis that
is the site o the majority o the systemic absorption o cutaneous drugs (see
Figure 48-4).
Passage through the outermost layer o skin (stratum corneum) is the rate-limiting
step or percutaneous absorption.
T e unique therapeutic e ects o retinoids can be produced by targeting specif c
retinoid receptors (RXR and RAR).
Except or total sun avoidance, sunscreens are the best single method o
protection rom UV-induced damage to the skin.
Cytotoxic and immunosuppressive drugs are used in dermatology or immuno-
logically mediated diseases such as psoriasis, autoimmune blistering diseases,
and leukocytoclastic vasculitis (see able 48-8).
Biological therapies modi y the immune response in patients with
psoriasis through (1) reduction o pathogenic cells, (2) inhibition o -cell
activation, (3) immune deviation ( rom a T 1 to a T 2 immune response),
and (4) blockade o the activity o in ammatory cytokines (see able 48-3 and
Figures 48-2 and 48-1).
SUMMARY QUIZ
QUESTION 48-1 T e rate-limiting step in the absorption o drugs through the skin
is passage through the
a. dermis.
b. epidermis.
c. stratum corneum.
d. hypodermis.
e. sweat glands.
QUESTION 48-2 A 35-year-old man has a ungal in ection o his toenails. A systemic
anti ungal preparation, griseo ulvin, is prescribed because
a. topical anti ungal preparations are irritating.
b. topical anti ungal agents are expensive.
c. systemic anti ungal agents produce high drug concentrations in the nails.
d. systemic anti ungal agents have no adverse e ects.
e. topical anti ungal preparation are easily washed o the nails.
QUESTION 48-3 A 23-year-old woman with recalcitrant acne is being treated with an
oral dose o isotretinoin. She should be warned against
a. getting pregnant.
b. sun exposure.
c. close contact with her 1-year-old child.
d. ying in an airplane.
e. eating broccoli.
d. cognitive unction.
e. visual unction.
QUESTION 48-5 A 76-year-old man has severe eczema on his legs or which a potent
glucocorticoid ointment is prescribed. He should be warned not to use an occlusive
dressing as it may result in
a. blistering.
b. decreased kidney unction.
c. behavioral changes.
d. suppression o the hypothalamic-pituitary-adrenal axis.
e. breakdown o the glucocorticoid.
722
Dermatological Pharmacology CHAPTER 4 8
723
SECTION IX Special Systems Pharmacology
Retinoids Tretinoin Tretinoin, adapalene, and Topical retinoids Systemic retinoids are
Isotretinoin tazarotene, which target may cause erythema highly teratogenic and their
Acitretin RARs, are used to treat acne, desquamation, use is contraindicated in
Tazarotene psoriasis, and photoaging burning, stinging, and women who are pregnant,
Bexarotene Bexarotene and alitretinoin, photosensitivity contemplating pregnancy,
Adapalene which target RXRs are used Serum lipid elevation is or breast eeding
Alitretinoin to treat mycosis ungoides a common laboratory The use o topical retinoids
and Kapposi sarcoma abnormality o systemic should be avoided during
Acitretin Is used to treat the retinoids pregnancy
cutaneous mani estations o Systemic retinoids may
psoriasis also cause cheilitis, xerosis,
Isotretinoin is approved or cutaneous photosensitivity,
the treatment o recalcitrant photophobia, myalgia,
and nodular acne vulgaris nail ragility, and
increased susceptibility to
staphylococcal in ections
Vitamin Analogs Calcipotriene Vitamin D analog used in the Perilesional irritation and Hypercalcemia and
treatment o psoriasis mild photosensitivity hypercalcuria with high
doses
(Continued)
724
Dermatological Pharmacology CHAPTER 4 8
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Photochemotherapeutic PUVA Approved or the treatment Erythema, blistering, and See Table 48 4
Drugs Methoxsalen o vitiligo and psoriasis pruritus (see Table 48 4)
Antimicrobial Agents Various antibacterial, Treatment o cutaneous See Chapters 38, 39, 40, See Chapters 38, 39, 40, 41,
anti ungal, and antiviral in ections (see Chapters 38, 41, 43, and 44 43, and 44
agents 39, 40, 41, 43, and 44) (See
Table 48 5 or anti ungal
agents
Agents Used to Treat Permethrin Treatment o scabies and Irritation and burning
In estations lice in estations in in ants ≥2
months o age
Antimalarial Agents Chloroquine Used in the treatment See Chapter 35 See Chapter 35
Hydroxychloroquine o cutaneous lupus
Quinacrine erythematosus, cutaneous
dermatomyositis, porphyria
cutanea tarda, and
sarcoidosis
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Alkylating Agents Cyclophosphamide Used or the treatment o See Chapter 45 See Chapter 45
Mechlorethamine cutaneous T cell lymphoma
Carmustine
Other Immunosuppressive Mycophenolate mo etil Used to treat inf ammatory See Chapter 23 See Chapter 23
and Anti inf ammatory and autoimmune diseases in
Agents dermatology
Biological Agents and Ale acept Treatment o psoriasis See Table 48 3 and See Table 48 3 and
Tumor Necrosis Factor E alizumab Inf iximab is a mouse human Chapter 23 Chapter 23
(TNF) Inhibitors Etanercept chimeric IgG1 monoclonal
Inf iximab antibody
Adalimumab Etanercept is a ully human
TNF receptor usion protein
Adalimumab is a human
IgG1 monoclonal antibody
Agent Used or Treatment Denileukin di tox Used to treat advanced Pain, ever, chills, nausea, Hypersensitivity reaction
o Cutaneous T Cell cutaneous T cell lymphoma vomiting, and diarrhea (hypotension, back pain,
Lymphoma (see Chapter 46) dyspnea, and chest pain)
Capillary leak syndrome
(edema, hypoalbuminemia,
and hypotension)
(see Chapter 46)
Sunscreens Various chemicals (see Used to provide protection Local irritation and skin
Table SUNSCREEN AGENTS) against ultraviolet radiation sensitivity
Drugs or Androgenic Minoxidil Used to treat hair loss Allergic and contact See Chapter 15
Alopecia dermatitis
Finasteride Used to treat hair loss Decreased libido, Pregnant women should
erectile dys unction, and not be exposed to
ejaculation disorder nasteride
See Chapter 28
(Continued)
726
Dermatological Pharmacology CHAPTER 4 8
TOXICITIES
UNIQUE; CLINICALLY
CLASS AND SUBCLASSES NAMES CLINICAL USES COMMON IMPORTANT
Agents Used to Treat Hydroquinone Used to treat hormonally or Dermatitis and ochronosis Monobenzone may
Hyperpigmentation Monobenzone light induced pigmentation cause permanent
Azelaic within the epidermis hypopigmentation
Mequinol
Podophyllin Treatment o anogenital Irritation and ulcerative Should not be used during
warts local reactions pregnancy
727
PREFACE
INDEX
Page numbers o owed by “ ,” “t,” or “b” indicate gures, tab es, or boxes respective y.
728
Adrenergic neuron b ocking agents, abeta o , 126t, 128t, 146t g ucocorticoids, genera princip es, 464b
antihypertensives, 277t, 286t eva butero , 125t, 143t hydrocortisone, 390t, 403t, 460t, 464, 464
guanadre , 277t, 287t evobetaxo o , 126t, 145t mechanisms o action, 459t, 462 , 464
reserpine, 277t, 286t evobuno o , 125t, 144t names and preparations, 460t–461t
Adrenergic pharmaco ogy, 139t isdexam etamine, 120t, 141t physio ogic unctions and pharmaco ogic
acebuto o , 126t, 128t, 146t mechanisms o action, 119t–120t, 123 e ects, 462t–463t
a butero , 125t, 127, 135, 137, 143t mephentermine, 119t, 139t potencies and equiva ent doses, 463t
a uzosin, 119t, 140t metabo ism, 123 rheumatoid arthritis, 463–465
α1 adrenergic receptor antagonists, 119t, metaprotereno , 125t, 143t therapeutic uses, 463b
121–124, 123 , 140t metaramino , 119t, 139t toxicities, 464b
α1-se ective adrenergic receptor methamphetamine, 120t, 141t Adrenocortica suppressants, mitotane, 679t
agonists, 119t, 122 , 123 , 139t methy dopa, 119t, 140t cancer, 644t, 659t
α2 adrenergic receptor antagonists, 120t, methy phenidate, 120t, 141t pharmaco ogy, 459t, 469t
123 , 141t metiprano o , 125t, 144t Adrenocortico ytic agents, 459t
α2-se ective adrenergic receptor metopro o , 126t, 127–129, 128t, 145t Adrenocorticotropic hormone (AC H)
agonists, 119t, 122 , 123 , midodrine, 119t, 139t ana og, 459t, 461 , 468t
124–125, 139t–140t moda ni , 120t, 142t cosyntropin, 459t, 461 , 468t
α adrenergic receptor agonists, 83t–84t, nado o , 125t, 128t, 144t mechanisms o action, 459t, 461
93, 94, 123 , 136, 137 naphazo ine, 120t, 142t Adriamycin. See Doxorubicin
α receptor antagonists, additiona , 120t, nebivo o , 126t, 128t, 146t Adverse drug events, 56–57, 57t
123 , 141t norepinephrine, 118t, 135, 137, 139t Adverse e ects, 5b, 9–12. See also speci c
amphetamine, 120t, 135–136, 137, 141t oxymetazo ine, 120t, 136, 137, 142t drugs and drug classes
aprac onidine, 119t, 140t pemo ine, 120t, 141t speci city, 9
ar ormotero , 125t, 144t penbuto o , 128t A nity (KA), 6b, 8
ateno o , 126t, 128t, 146t phenoxybenzamine, 120t, 136, 137, 141t competitive antagonists, 7b, 16, 17
betaxo o , 126t, 128t, 145t phento amine, 120t, 141t A atoxin B1, 41t, 60–62, 61
β1-se ective adrenergic receptor antago- pheny ephrine, 119t, 139t hepatitis B rom, 61
nists, 123 , 128t, 145t–146t pindo o , 126t, 128t, 145t A rican-American heart ai ure therapy, 306,
β2-se ective adrenergic receptor agonists, pirbutero , 125t, 143t 306b, 309, 310
123 , 127, 143t–144t prazosin, 119t, 121–124, 123 , 140t Agonism, quanti cation, 7
β adrenergic receptor agonists, procatero , 125t, 143t Agonists, 3b, 8. See also speci c types
123 , 142t proprano o , 125t, 128t, 136, 138, 144t a osteric (a otropic), 4b, 5 , 8
β adrenergic receptor antagonists propy hexedrine, 120t, 142t u , 4b, 4 , 7b, 9
with additiona cardiovascu ar e ects, pseudoephedrine, 120t, 142t inverse, 4, 4b, 4 , 9
123 , 128t, 146t ritodrine, 125t, 144t partia , 4b, 4 , 7b, 9
or heart ai ure, 129–130, 286t, 302t, 304, sa metero , 125t, 143t primary, 3b, 8
311t (See also Heart ai ure) serotonin, norepinephrine, and dopamine Akathisia, 172t
mechanisms o action, 302t reuptake inhibitors, 147t A bumin, 22b
nonse ective, 123 , 128t, 144t–145t sibutramine, 147t A butero
third-generation, 123 , 129t, 146t si odosin, 119t, 140t pharmaco ogy, 125t, 127, 135, 137, 143t
vasodi ating, 126 sympathomimetic agonists, misc., 120t, pu monary, 389t, 402t
bisopro o , 126t, 128t, 145t 123 , 141t–142t A c ometasone dipropionate, 460t. See also
bito tero , 125t, 143t synthesis, storage, and re ease, 122 Corticosteroids
brimonidine, 119t, 140t tamsu osin, 119t, 140t A coho . See Ethano
bucindo o , 126t, 146t terazosin, 119t, 140t A coho dehydrogenase (ALDH), 178
bunazosin, 120t, 141t terbuta ine, 125t, 143t disu ram on, 187
carteo o , 125t, 128t, 144t timo o , 126t, 128t, 145t genetic variants, 189, 190
carvedi o , 126t, 128t, 129, 146t transporters, catecho amine p asma A coho ism
catecho amine metabo ism, 121 membrane, 124t detoxi cation, 257
ce ipro o , 126t, 128t, 146t urapidi , 120t, 141t eta e ects, 182b, 187
c assi cation, 123 xy ometazo ine, 120t, 142t negative rein orcement, 265, 266
c onidine, 119t, 124–125, 139t yohimbine, 120t, 141t neurochemica system impacts, 185t
dexmedetomidine, 119t, 139t Adrenergic receptors, 122 physio ogica system e ects, 183,
dexmethy phenidate, 120t, 141t Adrenocortica steroid biosynthesis inhibitors 183t–185t, 189, 190
dobutamine, 125t, 142t, 308t aminog utethimide, 459t, 469t treatment, 186, 256–257, 256t
doxazosin, 119t, 140t etomidate, 459t, 469t A coho ism drugs, 177t, 186–187,
epinephrine, 118t, 139t ketoconazo e, 459t, 469t 186t, 193t
esmo o , 126t, 128t, 146t mechanisms o action, 459t acamprosate, 177t, 186–187, 186t,
enotero , 125t, 143t metyrapone, 459t, 466, 469t 193t, 257
ormotero , 125t, 144t Adrenocortica steroids, 468t. See also Cor- disu ram, 177t, 178 , 186–187, 186t,
guanabenz, 119t, 140t ticosteroids; G ucocorticoids; 193t, 257
guan acine, 119t, 140t speci c agents ethano and methano metabo ism, 178
indoramin, 120t, 141t adrena insu ciency, 461 , 465, 467, 468 na me ene, 177t, 193t
isoetharine, 125t, 143t conjunctivitis, bacteria , 466 na trexone, 177t, 186–187, 186t,
isoprotereno , 125t, 142t Crohn’s disease, 465 203, 257
ketanserin, 120t, 133t, 141t Cushing’s syndrome, 465–466 A coho withdrawa syndrome, 256, 256t
729
A des eukin procarbazine, 629t, 652t A osteric agonists, 4b, 5 , 8
anticancer, 663t, 682, 683, 685t toxicities, 632b–633b, 652t A osteric antagonists, 4b, 9
immunostimu ant, 381t, 388t uses, 629t A osteric site, 8
A dicarb, 100t, 115t nitrogen mustards, 627t, 651t A otropic agonists, 4b, 5 , 8
A dosterone antagonists. See K+-sparing activation, in vivo, 631, 631 A otropic antagonists, 4b, 9
diuretics, minera ocorticoid bendamustine, 627t, 651t A otropic site, 8
antagonists ch orambuci , 627t, 651t A -trans retinoic acid (A RA), 645t,
A dosterone receptor antagonists, 269t, 271t, cyc ophosphamide, 627t, 631 , 646t, 659t
272 , 285t 632t, 651t A motriptan, 130t, 147t
ep erenone, 269t, 280–281, 285t, i os amide, 627t, 632t, 651t A og iptin, 471t, 472 , 479t
302t, 311t mechanisms o action, 626, 627t, 628, A opecia, androgenic, 710t, 726t
heart ai ure, 302t, 307, 311t 628b, 630 nasteride, 710t, 726t
ep erenone, 302t, 311t mechanisms o resistance, 627t, minoxidi , 710t, 726t
mechanisms o action, 302t 632–633, 632b A osetron, 498t, 505, 506, 508t
spirono actone, 302t, 307, 311t mech orethamine HC , 627t, 651t antidiarrhea , 505, 506
spirono actone, 269t, 285t, 302t, me pha an, 627t, 632t, 651t pharmaco ogy, 130t, 147t
307, 311t toxicities, 632b–633b, 632t, 651t 1α-Hydroxycho eca ci ero , 481t, 488t
A e acept, 376t, 386t uses, 629t 1α-Hydroxy ase, 482 , 486, 487
dermato ogic, 709t, 710 , 714t, 726t nitrosoureas, 652t 5α-Reductase inhibitors, 442t, 458t
immunotherapy, 376t, 386t carmustine, 632t, 652t dutasteride, 442t, 458t
psoriasis, 709t, 710 omustine, 652t nasteride, 442t, 456, 457, 458t
A emtuzumab mechanisms o action, 627t, α1-Acid g ycoprotein, 22b
anticancer, 662t, 667t, 671t, 684t 628b, 630 α1 Adrenergic receptor antagonists, 119t,
immunotherapy, 376t, 378, 386t mechanisms o resistance, 627t, 121–124, 140t
A endronate, 481t, 488t 632–633, 632b antihypertensives, 277t
A entani , 195t, 208t semustine, 652t doxazosin, 277t, 286t
A uzosin, 119t, 140t streptozocin, 652t prazosin, 277t, 286t
A iskiren, 273t, 282, 283, 286t toxicities, 632b–633b, 652t terazosin, 277t, 286t
A itretinoin, 707t, 724t uses, 629t c assi cation, 123
A ka ine urine, 20b, 21–22, 39 p atinum coordination comp exes, 628t, mechanisms o action, 119t, 123
A ka oids, natura , 99t 633–635, 653t pharmaco ogy, 140t
A ky ating agents, 626–635, 627t–628t, carbop atin, 628t, 629t, 632t, 653t prazosin, 121–124, 123
651t–653t. See also speci c types ce cyc e speci city, 630 α1-Se ective adrenergic receptor agonists,
and agents cisp atin, 628t, 629t, 632t, 653t 119t, 124–125, 139t
activation, in vivo, 631, 631 mechanisms o action, 628b–629b, 628t, c assi cation, 123
a ky su onates, 627t, 651t 630 , 633 c onidine, 124–125
busu an, 627t, 632t, 651t mechanisms o resistance, 628t, 632b, mechanisms o action, 119t, 123
mechanisms o action, 627t, 634–635 pharmaco ogy, 122 , 139t
628b–629b, 630 oxa ip atin, 628t, 629t, 653t α2 Adrenergic receptor agonists
mechanisms o resistance, 627t, toxicities, 632b–633b, 632t, c assi cation, 123
632–633, 632b 633–634, 653t mechanisms o action, 119t
toxicities, 632b–633b, 632t, 651t uses, 629t, 653t α2 Adrenergic receptor antagonists, 120t,
ce cyc e speci city, 630 toxicities, 631–632, 632b–633b 123 , 141t
dermato ogic, 708t, 724t, 726 dose- imiting, 631, 632t antihypertensives, 277t, 286t
carmustine, 708t, 724t, 726t triazenes, 652t c onidine, 277t, 286t
cyc ophosphamide, 708t, 724t, 726t dacarbazine, 628t, 629t, 630 , guanabenz, 277t, 286t
mech orethamine, 708t, 724t, 726t 645–647, 652t guan acine, 277t, 286t
DNA repair mechanisms, 629b mechanisms o action, 628b, c assi cation, 123
ethy eneimines and methy me amines, 628t, 630 pharmaco ogy, 141t
627t, 651t mechanisms o resistance, 628t, α2-Se ective adrenergic receptor agonists,
a tretamine (hexamethy endiamine), 632–633, 632b 119t, 124–125, 139t–140t
627t, 651t temozo omide, 652t c assi cation, 123
mechanisms o action, 627t, toxicities, 632b–633b, 652t mechanisms o action, 119t, 122 , 139
628b–629b, 630 uses, 629t pharmaco ogy, 122 , 139t–140t
mechanisms o resistance, 627t, A ky Su onates, 627t, 651t α Adrenergic receptor agonists, 123 ,
632–633, 632b busu an, 627t, 632t, 651t 136, 137
thiotepa, 627t, 632t, 651t mechanisms o action, 627t, air ow resistance, 136, 137
toxicities, 632b–633b, 632t, 651t 628b–629b, 630 c assi cation, 123
mechanisms o action, 626, 627t–628t, mechanisms o resistance, 627t, pharmaco ogy, 83t–84t, 93, 94
628, 628b–629b, 630 632–633, 632b α Adrenergic receptor antagonists, 120t,
mechanisms o resistance, 627t–628t, toxicities, 632b–633b, 632t, 651t 123 , 141t
632–633, 632b uses, 629t c assi cation, 123
methy hydrazines, 629t, 652t A ergic reactions, 46t. See also speci c drugs mechanisms o action, 120t
mechanisms o action, 628b–629b, and drug classes pharmaco ogy, 141t
628t, 630 case study, 3–6 α-G ucosidase inhibitors, 471t, 479t
mechanisms o resistance, 628t, urticaria, H 1 antihistamines or, 351, 352 acarbose, 471t, 479t
632–633, 632b A opurino , 369t, 370–372, 373t mechanisms o action, 471t
730
α-G ucosidase inhibitors (Cont.) on protein synthesis, 559, 560 Androgen deprivation therapy, 679–680
mig ito , 471t, 479t with rena dys unction, 562 Androgenic a opecia, 710t, 726t
vog ibose, 471t, 479t resistance, 559–560, 559b nasteride, 710t, 726t
A prazo am, 92, 176t, 180, 191t, 192t streptomycin, 567t minoxidi , 710t, 726t
addiction, 257–258, 257t tobramycin, 566t Androgen receptor antagonists, 442t, 458t
withdrawa syndrome, 257–258, 257t Amino evu inic acid photodynamic bica utamide, 442t, 458t
A tep ase, 323t, 329–330, 329 , 333t therapy, 708t, 725t utamide, 442t, 454, 456, 457,
A tretamine, 627t, 651t Amiodarone, 312t, 321t 458t, 679t
mechanisms o action, 627t, e ectrophysio ogic actions, 317t ni utamide, 442t, 458t
628b–629b, 630 iodine-induced hypothyroidism, 435t, Androgens, 442t, 452–454, 458t
mechanisms o resistance, 627t, 438, 439 anticancer, 664t, 679t, 686t
632–633, 632b ventricu ar bri ation, 316 biosynthesis, 679
toxicities, 632b–633b, 651t ventricu ar tachycardia, 318 drugs against (See Antiandrogens)
A vimopan, 498t, 507t Amitripty ine, 150t, 152–154, 152 , 168, 169, structures, 453
A zheimer’s disease, 245–246, 246 173t, 205t testosterone, 442t, 458t
acety cho ine de ciency, 246, 250–252 Am odipine testosterone bucca tab et, 442t, 458t
A zheimer’s disease drugs, 239t, 245–248, antihypertensive, 277t, 282, 287t, 294 testosterone cypionate, 442t, 458t
247t, 253t myocardia ischemia, 290t, 294–295, 298, testosterone enanthate, 442t, 458t
behaviora , 247–248 299, 300t testosterone ge , 442t, 458t
cognitive, 246–247, 247t Amobarbita , 177t, 181t, 192t testosterone patch, 442t, 458t
donepezi , 239t, 246, 247t, 250–252, 253t Amoxapine, 150t, 173t testosterone undecanoate, 442t, 458t
ga antamine, 239t, 246, 247t, 253t Amoxici in, 552t, 555t Anemia
memantine, 239t, 246–247, 251, 252, 253t or duodena u cer, 492, 494t mega ob astic, 417–418, 537–540
rivastigmine, 239t, 246, 247t, 253t Amphetamine, 120t, 135–136, 137, 141t. pernicious, 417–418
tacrine, 239t, 247t, 253t See also speci c types Anesthesia, genera , 211–214
Amanita muscaria, 97, 100 a ertness, 135–136, 137 anesthetic state, components, 211b
Amanita phalloides, 97 toxidrome, 53t rst time, 211–212
Amantadine Amphotericin B, 530t, 534, 535t, 588t, genera princip es, 211–212, 212b
anti-in uenza, 601t, 602t, 604 , 589–590 inducing agents, 212 , 213–214, 213 ,
612–613, 620t adverse e ects, 590 213t (See also Anesthetic agents,
adverse e ects, 613 ormu ations and pharmacokinetics, parentera )
in uenza A prophy axis, 612 589–590, 589t, 596t mechanisms, 211b, 212–213
mechanisms o action and resistance, mechanisms o action, 588t, 589 , 590 types, 212
602t, 604 613 mechanisms o resistance, 588t Anesthesia, spina , 217–219
Parkinson’s disease, 239t, 242t, 245, 253t pharmacokinetic properties, 589t Anesthetic adjuncts
Ambenonium ch oride, 97 , 100t, 104–105, uses, 596t ana gesics, 211t, 217, 223t
105 , 106 , 114t Amphotericin B (C-AMB), 588t, 589–590, benzodiazepines, 211t, 216–217, 223t
Ambrisentan, pu monary, 391t, 398–400, 589 , 589t, 595, 596, 596t dexmedetomidine, 211t, 223t
399 , 404t Amphotericin B co oida dispersion neuromuscu ar b ocking agents,
Amcinonide, 460t. See also (C-ABCD), 588t, 589–590, 589 , 211t, 223t
Corticosteroids 589t, 596t Anesthetic agents, 210–224
Amebic co itis, 532–533 Amphotericin B ipid comp ex (ABLC), 588t, endotrachea intubation, 216–217
paromomycin, 531t, 532–533, 535t 589–590, 589 , 589t, 596t mechanisms o action, 210t–211t
Amethopterin. See Methotrexate Amphotericin B iposoma (L-AMB), 588t, Anesthetic agents, inha ationa , 222t–223t
Amikacin, 559–566, 559b, 567t 589–590, 589 , 589t, 596t b ood:gas partition coe cient, 215–216,
Ami oride, 269t, 284t Ampici in, 552t, 555t 215 , 215t, 220, 221
Aminocyc ito s, 569t, 576t Amprenavir, 601t, 603t, 608 , 609 , 622t choices, 214
Aminog utethimide, 459t, 469t Amy in agonists CO2 absorbent, 220, 221
Aminog ycosides, 559–567 mechanisms o action, 471t des urane, 210t, 215t, 220, 221, 223t
amikacin, 565, 566, 567t pram intide, 471t, 479t en urane, 210t, 215t, 223t
+ β- actam antibiotics, 559, 560 Amyotrophic atera sc erosis (ALS), 239t, ha othane, 210t, 215t, 222t
dosing 249, 253t iso urane, 210t, 215t, 222t
maintenance, 562 bac o en, 239t, 249, 253t minimum a veo ar concentration (MAC),
schedu e, 515, 560–561, 561 dantro ene, 239t, 249, 253t 215, 215t
gentamicin, 566t ri uzo e, 239t, 249, 251, 252, 253t nitrous oxide, 210t, 215t, 223t
kanamycin, 567t tizanidine, 239t, 249, 253t pharmacokinetics, 215, 215t
mechanisms o action, 559b Anakinra potencies, 215, 215t
monitoring, p asma concentrations, immunotherapy, 376t, 386t sevo urane, 210t, 215t, 223t
561–562, 563, 564–565 rheumatoid arthritis, 368t speed o induction, 215–216, 215t, 216
neomycin, 567t Ana gesic anesthetic adjuncts, 211t, uptake, 215t, 216, 216
nephrotoxicity, 563–564 217, 223t xenon, 211t, 215t, 223t
neti micin, 567t Anandamide, 263 Anesthetic agents, oca , 224t
ototoxocity, 562–563 Anaphy axis, 56 administration
penetration, intrace u ar, 564–566 Anastrozo e, 442t, 458t routes, 217b, 219
penici in inactivation, 565, 566 anticancer, 664t, 677t, 679t, 686t spina , 217–219
postantibiotic e ect, 564, 565 mechanisms o action, 442t, 664t, 678 a ergic reactions, 217, 220, 221
731
articaine, 224t isinopri , 273t, 281, 282, 285t angina, 293t
benzocaine, 224t mechanisms o action, 273t, 274–276, 275 atria bri ation, 315, 316
bupivacaine, 224t moexipri , 273t, 285t cardiac action potentia , 312 , 313
Ch oroprocaine, 224t perindopri , 273t, 285t c ass IA (sodium channe b ockers), 312t,
cocaine, 224t quinapri , 273t, 285t 320t–321t
dibucaine, 224t ramipri , 273t, 285t disopyramide, 312t, 317t, 321t
dyc onine, 224t structure, 275 procainamide, 312t, 316, 317t, 320t
epinephrine in, 217 trando apri , 273t, 285t quinidine, 312t, 317t, 320t
end artery tissues and gangrene, 220, Angiotensin II (Ang II), e ects, 274 c ass IB (sodium channe b ockers),
221–222 Angiotensin II (Ang II) receptor 312t, 321t
idocaine, 224t antagonists, 270t idocaine, 312t, 316, 317t, 319, 320, 321t
mechanisms o action, 217, 218 Angiotensin (A 1) receptor b ockers (ARBs), mexi etine, 312t, 317t, 321t
mepivacaine, 224t 270t, 273t, 285t c ass IC (sodium channe b ockers),
pramoxine, 224t candesartan ci exeti , 273t, 285t 312t, 321t
pri ocaine, 224t diabetics, 274 ecainide, 312t, 317t, 321t
procaine, 224t heart ai ure, 273t, 274, 279, 280, 285t, propa enone, 312t, 317t, 321t
proparacaine, 224t 301t, 310t c ass II (β adrenergic receptor
ropivacaine, 224t ibupro en on, 282, 283 antagonists), 312t, 317t, 321t
su te (methy paraben) in, 220, 221 irbesartan, 273t, 285t esmo o , 312t, 321t
tetracaine, 224t osartan, 273t, 285t proprano o , 312t, 317t, 321t
uses, 217b o mesartan medoxomi , 273t, 285t sota o , 312t, 317t, 321t
on vo tage-gated Na+ channe s, 217 structure, 275 c ass III, 312t, 317t, 321t–322t
Anesthetic agents, parentera , 222t te misartan, 273t, 285t amiodarone, 312t, 316, 317t, 318, 321t
context-sensitive ha -time, va sartan, 273t, 280, 282, 283, 285t do eti ide, 312t, 317t, 322t
214, 214 Anidu a ungin, 588t, 589 , 598t dronedarone, 312t, 317t, 321t
di erences, 213t, 214 Anima testing, 8 ibuti ide, 312t, 317t, 322t
etomidate, 210t, 213t, 214 , 222t Antacids, 490t, 496t sota o , 312t, 321t
ospropo o , 210t, 222t Antagonism, 4b, 5 , 8–9. See also c ass IV (Ca2+ channe b ockers,
on GABAA receptor, 219–220, 221 speci c receptors nondihydropyridine), 312t, 322t
ketamine, 210t, 213t, 214 , 217, 222t a osteric (a otropic), 4b, 9 di tiazem, 312t, 315, 317t, 322t
methohexita , 210t, 213t, 222t chemica , 4b, 9, 48b verapami , 312t, 317t, 322t
pharmacokinetics, 212 , 213–214 dispositiona , 48b drug–drug interactions, 319, 320
pharmaco ogica properties, 213t drug–drug interaction, 48b e ectrophysio ogic actions, 317t
propo o , 210t, 213t, 214 , 220, mechanisms, 4b, 5 inhibitor concentration, 513–514, 514
221, 222t receptor, 48b ong Q and torsade de pointes,
sodium thiopenta , 210t, 213t, 214 , 222t Antagonists, 4b, 5 , 8–9. See also speci c drugs 313–315, 314t, 315b
termination and redistribution, 220, 221 competitive, 4b, 5b, 5 , 7b, 16, 17 magnesium su ate, 317t, 322t
use, 213 unctiona , 4b mechanistic approach, 314t
Anesthetic state, 211b noncompetitive, 4b, 5 Na+-K+-A Pase inhibitors, 312t, 322t
Angina, 290t. See also Myocardia Anthe minthics, 536–541. See also digoxin, 312t, 317t, 319, 320, 322t
ischemia He minth in ection drugs paroxysma ventricu ar tachycardia
Angina drugs Anthracenedione derivative immunostimu- (PSV ), 314t, 318
myocardia ischemia (See Myocardia ants, mitoxantrone, 382t, 388t premature ventricu ar beats, 314t
ischemia drugs) Anthracyc ines and anthracenediones, post-MI, 314t, 319, 320
non-myocardia ischemia conditions, 643t, 658t tachyarrhythmia mechanisms, 313b
293t–294t daunorubicin, 630 , 643t, 645b, 658t ventricu ar bri ation, 314t, 316
Angioedema. See also speci c drugs doxorubicin, 630 , 643t, 645–647, Antibiotics. See Antimicrobia agents
ACE inhibitors, 279 645b, 658t Antibiotics, anticancer, 630 , 643t, 658t
Angiogenesis, 673 epirubicin, 630 , 643t, 645b, 658t actinomycins, dactinomycin, 630 ,
Angiotensin-converting enzyme (ACE) idarubicin, 630 , 643t, 645b, 658t 643t, 658t
inhibitors, 270t, 273t, 285t mechanisms o action, 630 , 643t anthracyc ines and anthracenediones,
acute MI, 279 mechanisms o resistance, 643t, 645b 643t, 658t
adverse e ects, 276 mitoxantrone, 630 , 643t, 645b, 658t daunorubicin, 630 , 643t, 645b, 658t
angioedema, 279 uses, 644t, 658t doxorubicin, 630 , 643t, 645–647,
benzapri , 273t, 285t va rubicin, 630 , 643t, 645b, 658t 645b, 658t
captopri , 273t, 279, 285t Antiandrogens, targeted anticancer epirubicin, 630 , 643t, 645b, 658t
cautions, 274–276 nonsteroida , 665t, 679t, 687t idarubicin, 630 , 643t, 645b, 658t
diabetics, 274 bica utamide, 665t, 687t mechanisms o action, 630 , 643t
ena apri , 273t, 274–276, utamide, 665t, 679t, 687t mechanisms o resistance, 643t, 645b
275 , 285t ni utamide, 665t, 687t mitoxantrone, 630 , 643t, 645b, 658t
ena apri at, 273t, 285t steroida , 665t, 687t uses, 644t, 658t
osinopri , 273t, 285t cyproterone, 665t, 687t va rubicin, 630 , 643t, 645b, 658t
heart ai ure, 272 , 276 , 279, 285t, megestro , 665t, 687t b eomycin, 630 , 643t, 645b, 658t
303–304, 310t Antiarrhythmic drugs, 312–322 mechanisms o action, 643t
mechanisms o action, 270t, 273t, adenosine receptor agonists, 312t, 322t mechanisms o resistance, 643t,
274–276, 275 , 301t adenosine, 312t, 317t, 318, 322t 645b–646b
732
Antibiotics, anticancer (Cont.) mood e evation, 152–153, 152 Antidiarrhea agents, 498t, 508t
mitomycin, 630 , 643t, 646b, 658t phases o treatment, 153–154 a osetron, 498t, 505, 506, 508t
uses, 644t, 658t sites o actions, 152 bismuth, 498t, 508t
Anticho inergic toxidrome, 53t structures, dosing, and adverse e ects, carboxymethy ce u ose, 498t, 508t
Anticho inesterase agents, 89 155t–156t cho estyramine, 498t, 508t
Anticho inesterase insecticides, 102, 102b, therapeutic ag, 153 c onidine, 498t, 508t
103 , 103t, 104 . See also Antidepressants, atypica , 150t, di enoxin + atropine, 498t, 508t
speci c types 156t, 174t diphenoxy ate + atropine, 498t,
antidotes, 40t, 65t, 102 atomoxetine, 150t, 174t 500, 508t
pra idoxime, 41t, 42t, 65t, bupropion, 150t, 174t operamide, 209t, 498t, 500–501, 508t
100t, 102 mianserin, 150t, 174t mechanisms o action, 498t
Anticoagu ants. See also speci c drugs and mirtazapine, 150t, 174t octreotide, 498t, 508t
drug classes ne azodone, 150t, 174t Antidiarrhea agents, opioid, 209t
indications, 325t reboxetine, 150t, 174t di enoxin, 209t
monitoring, 325, 325t, 330b structures, dosings, and adverse diphenoxy ate (+ atropine), 209t, 498t,
toxicities, 325 e ects, 156t 500, 508t
Anticoagu ants, ora trazodone, 150t, 174t operamide, 209t, 498t, 500–501, 508t
direct actor Xa inhibitors, Antidepressants, tricyc ic ( CAs) mechanisms o action, 195t
323t, 333t adverse e ects, 154 Antidotes, 42t, 65t. See also speci c poisons
apixaban, 323t, 328, 331, 333t e der y, 71, 72, 75 Antiemetics. See Antinauseants and
mechanisms o action, 323t pain target and site o action, 205t antiemetics
rivaroxaban, 323t, 328, 333t sites o actions, 152 Antiestrogens, targeted anticancer
direct thrombin inhibitors, 333t Antidiabetic agents, ora aromatase inhibitors, 664t, 679t, 686t
dabigatran etexi ate, 323t, 328, 333t α-g ucosidase inhibitors, 471t, 479t anastrozo e, 664t, 677t, 679t, 686t
mechanisms o action, 323t acarbose, 471t, 479t exemestane, 664t, 677t, 679t, 686t
vitamin K antagonist, 333t mechanisms o action, 471t etrozo e, 664t, 677t, 679t, 686t
mechanisms o action, 323t mig ito , 471t, 479t se ective estrogen-receptor
war arin (See War arin) vog ibose, 471t, 479t downregu ators, 664t
Anticoagu ants, parentera amy in agonists u vestrant, 664t, 677t, 686t
activated protein C, 333t mechanisms o action, 471t se ective estrogen-receptor modu ators,
drotrecogin a a, 323t, 333t pram intide, 471t, 479t 664t, 686t
mechanisms o action, 323t biguanides, met ormin, 470t, 479t mechanisms o resistance, 664t
direct thrombin inhibitors, 323t, 333t bi e acid sequestrants, 471t, 479t ra oxi ene, 664t, 686t
argatroban, 323t, 330, 331, 333t co eseve am, 471t, 479t tamoxi en, 664t, 667 , 676–678, 677t,
biva irudin, 323t, 333t mechanisms o action, 471t 679t, 686t
desirudin, 333t dipeptidy peptidase-4 inhibitors, 471t, toremi ene, 664t, 677t, 679t, 686t
mechanisms o action, 323t 472 , 476, 479t uses, 677t, 686t
heparinoid, 323t, 325, 333t a og iptin, 471t, 472 , 479t Anti o ates. See Fo ic acid ana ogs
ardeparin, 323t, 325, 333t mechanisms o action, 471t, 472 (anti o ates)
da teparin, 323t, 325, 333t saxag iptin, 471t, 472 , 479t Anti unga agents, 588–599
enoxaparin, 323t, 325, 333t sitag iptin, 471t, 472 , 479t amphotericin B, 588t, 589–590, 589 , 596t
ondaparinux, 323t, 325, 333t vi dag iptin, 471t, 472 , 479t adverse e ects, 590
heparin, 323t, 325, 327 , 333t drug deve opment, 6–9 amphotericin B (C-AMB), 595, 596, 596t
ovenox, 325–326, 326 GLP-1 agonists, 471t, 472 , 476, 479t amphotericin B co oida dispersion
ow-mo ecu ar-weight heparins, 323t, exenatide, 471t, 472 , 479t (C-ABCD), 596t
324–325, 325 , 333t irag utide, 471t, 472 , 479t amphotericin B ipid comp ex
mechanisms o action, 323t mechanisms o action, 471t, 472 (ABLC), 596t
nadroparin, 323t, 325, 333t insu in secretagogues, nonsu ony urea, amphotericin B iposoma
tinzaparin, 323t, 325, 333t 470t, 472 , 479t (L-AMB), 596t
Anticonvu sants. See also speci c drugs and nateg inide, 470t, 472 , 479t mechanisms o action, 588t, 589 , 590
drug classes repag inide, 470t, 472 , 479t mechanisms o resistance, 588t
pain target and site o action, 205t insu in secretagogues, su ony urea, 470t, pharmacokinetic properties, 589t
Anticonvu sants, ma aria, 151t, 175t 472 , 479t butena ne, 599t
carbamazepine, 151t, 164–165, 175t adverse e ects, 475 cic opirox o amine, 598t
amotrigine, 151t, 165, 175t g ic azide, 470t, 472 , 479t dermato ogic, 708t, 721, 722, 725t
va proic acid, 151t, 164–165, 169, g imepiride, 470t, 472 , 477, echinocandins, 588t, 589 , 598t
173, 175t 478, 479t anidu a ungin, 598t
Antidepressants, 155t–156t g ipizide, 470t, 472 , 479t caspo ungin, 588t, 589 , 593, 593 , 598t
actions and e ects, 152–154, 152 g yburide, 470t, 472 , 479t mechanisms o action, 588t, 593, 593
adverse e ects, 154 mechanisms o action, 470t, 477, 478 mica ungin, 598t
disposition, 158t mechanisms o action, 470t–471t ucytosine, 588t, 589 , 595, 596, 596t
drug-re ated deaths, 51t thiazo idinediones, 470t, 475–476, 479t griseo u vin, 588t, 593–596, 598t, 721, 722
e der y, 71, 72, 75 adverse e ects, 476 ha progin, 598t
initia treatment phase, 153 mechanisms o action, 470t imidazo es and triazo es, 588t, 589 ,
ong-term e ects, 153 piog itazone, 470t, 475–476, 479t 590, 597t
maintenance phase, 154 rosig itazone, 470t, 475–476, 479t CYP interactions, 590, 590t
733
drug interactions, 590t–592t β adrenergic receptor antagonists, 277t, mechanisms o action and resistance,
uconazo e, 588t, 590, 595, 596, 286t (See also β adrenergic recep- 602t, 604
597t, 719 tor antagonists) ose tamivir, 601t, 602t, 604 , 620t
itraconazo e, 597t Ca channe b ockers, L-type, 270t,
2+
rimantadine, 601t, 602t, 604 , 620t
posaconazo e, 597t 277t, 287t (See also Ca2+ channe zanamivir, 601t, 602t, 604 , 620t
voriconazo e, 588t, 589 , 590t–592t, b ockers) Antima aria s agents, dermato ogic
592–593, 595, 596, 597t dihydropyridines, 277t, 282, 287t, 290t, (See Ma aria chemotherapy,
imidazo es and triazo es, topica , 588t, 300t, 306 (See also Ca2+ channe dermato ogic agents)
597t–598t b ockers, L-type, dihydropyridine) Antimetabo ites, 635–642, 635t–636t,
butoconazo e, 597t edema, 282 653t–656t
c otrimazo e, 597t mechanisms o action, 277t dermato ogic, 708t, 724t, 725t
econazo e, 597t nondihydropyridines, 277t, 278, 287t 5- uorouraci , 708t, 724t, 725t
ketoconazo e, 598t (See also Ca2+ channe b ockers, azathioprine, 708t, 724t, 725t
miconazo e, 594, 597t L-type, nondihydropyridine) methotrexate, 708t, 715, 721–722, Anti-
oxiconazo e, 598t choice, 270, 270t unga agents 724t, 725t
sertaconazo e, 598t c assi cation, 270t o ic acid ana ogs, 635t, 653t
su conazo e, 598t diabetes with, 273–274 high-dose methotrexate with eucovo-
terconazo e, 597t direct renin inhibitors/ rin rescue, 635t, 638–640, 653t
tioconazo e, 597t vasodi ators, 270t ometrexo , 635t, 653t
mechanisms and sites o action, diuretics, 268t–270t, 269–272, 283t–285t mechanisms and sites o action, 635t
588t, 589 (See also Diuretics) mechanisms o resistance, 635t,
na i ne, 589 , 599t ibupro en on, 282, 283 638b, 640
nystatin, 599t mechanisms o action, 270t methotrexate, 635t, 653t
ophtha mic, 694t, 701 nephrons, 270b pemetrexed, 635t, 653t
terbina ne, 588t, 589 , 596, 598t pregnancy, 277–278, 278 pharmacogenetics, 637 , 639
to na ate, 598t renin-angiotensin system inhibitors, pra atrexate, 635t, 653t
undecy enic acid, 599t 270t, 273t, 274–276, 274 , 275 , ra titrexed, 635t, 653t
Whit e d’s ointment, 599t 279, 281–282, 285t (See also toxicities, 653t
Antig ucocorticoids Renin-angiotensin system (RAS) trimetrexate, 635t, 653t
mechanisms o action, 459t inhibitors) uses, 637t
mi epristone, 459t, 469t treatment a gorithm, 275 , 276 mechanisms o action, 653t–656t
Antihepatitis agents, 600t–602t, 620t vasodi ators mechanisms o resistance, 638b–640b,
ade ovir dipivoxi , 600t, 602t, 620t arteria , 278t, 287t (See also 653t–656t
entecavir, 600t, 602t, 620t Vasodi ators, arteria ) purine ana ogs, 636t, 641–642, 655t–656t
hepatitis B, entecavir, 618, 619 arteria and venous, nitroprusside, 6-mercaptopurine, 630 , 636t,
hepatitis C, ribavirin-pegy ated inter- Anti unga agents 278t, 287t 641–642, 655t
eron, 613–614, 617, 618 Antihypertensive drugs, sympatho ytics, 6-thioguanine, 630 , 636t, 655t
inter erons, 600t–602t, 606 , 620t 270t, 277t c adribine, 630 , 636t, 655t
amivudine, 600t, 602t, 607 , 620t adrenergic neuron b ocking agents, Anti- c o arabine, 636t, 655t
mechanisms o action and unga agents 277t, 286t udarabine phosphate, 630 ,
resistance, 602t guanadre , 277t, 287t 636t, 655t
peginter erons, 601t reserpine, 277t, 286t mechanisms o action, 630 , 636t,
Antiherpes agents, 600t–602t, 605–608, 619t centra y acting adrenergic agents 641–642
acyc ovir, 600t–601t, 604 –605 , methy dopa, 277t, 286t mechanisms o resistance, 636t,
605–608, 605t, 617–618, 619t α2 adrenergic receptor antagonists, 277t, 639b–640b
cido ovir, 600t, 601t, 605, 619t 286t ne arabine, 636t, 655t
docosano , 600t c onidine, 277t, 286t pentostatin, 636t, 656t
omivirsen, 600t, 602t, 609, 619t guanabenz, 277t, 286t toxicities, 642, 655t–656t
oscarnet, 600t, 602t, 604 , 605, 609–612, guan acine, 277t, 286t uses, 637t, 655t–656t
617, 618, 619t mechanisms o action, 277t pyrimidine ana ogs, 635t–636t, 640–641
gancic ovir, 600t, 602t, 604 , 605, 605 , α1 adrenergic receptor antagonists, 277t 5- uorouraci (5-FU), 630 , 635t,
609, 617, 618, 619t doxazosin, 277t, 286t 638b–639b, 638 , 640–641
idoxuridine, 600t, 602t, prazosin, 277t, 286t azacytidine, 636t
605–606, 619t terazosin, 277t, 286t capecitabine, 630 , 635t, 638
mechanisms o action and resistance, β adrenergic receptor antagonists, cytarabine (Ara-C), 630 , 635t, 639b,
601t–602t, 606–607, 606 oxazosin, 277t 648, 649
pencic ovir, 600t, 602t, 604 , 605, 605 , Anti-IgE monoc ona antibodies, decitabine, 636t
608, 619t oma izumab, 390t, 397, 404t oxuridine (FUdR), 630 , 635t,
tri uridine, 601t, 602t, 606, 619t Anti-in ectives. See Antimicrobia agents 638b–639b, 638
va acyc ovir, 601t, 605, 608 Anti-in ammatories, dermato ogic. See gemcitabine, 630 , 636t, 639b
va gancic ovir, 601t Immunosuppressants and anti- mechanisms and sites o action, 630 ,
Antihistamines. See Histamine receptor in ammatories, dermato ogic 635t–636t, 638 , 640
antagonists Anti-in uenza agents, 601t, 602t, Anti unga mechanisms o resistance, 635t–636t,
Antihypertensive drugs, 269–270. See also agents 604 , 620t 639b, 640–641
speci c drugs and drug classes amantadine, 601t, 602t, 604 , uses, 637t
Ang II receptor antagonists, 270t 612–613, 620t uses, 637t
734
Antimicrobia , ocu ar, topica , 692t–693t tic opidine, 323t, 332t choice, 227b
Antimicrobia agents. See also speci c drugs irreversib e, COX-1 inhibitors dosage, 227b
and drug classes aspirin, 323t, 324–325, 332t, e bamate, 226t, 237t
dermato ogic, 708t, 725t 371, 372 gabapentin, 225t, 237t
antibacteria s, 708t, 725t mechanisms o action, 323t, 358 genera princip es, 227b
anti unga s, 708t, 721, 722, 725t sites o action, 325 hepatic microsoma enzyme
retapamu in, 708t, 725t Antipro i erative/antimetabo ic agents, interactions, 227t
mechanisms o action, 2b 375t, 385t. See under Bio ogica iminosti benes, 225t, 236t
Antimicrobia therapy princip es, 512–519. immunosuppressants carbamazepine, 225t, 226 ,
See also speci c drugs azathioprine, 368t, 375t, 380, 385t 232–235, 236t
and disorders evero imus, 375t, 385t oxcarbazepine, 225t, 236t
area under the curve, 514, 515 MPA, 375t, 385t acosamide, 226t, 237t
barrier penetration, 512–513, 513 mycopheno ate mo eti , 375t, 383, amotrigine, 225t, 232, 237t
b ood-brain, 512 (See also B ood-brain 384, 385t Lennox-Gastaut syndrome, 232
barrier (BBB)) siro imus, 375t, 377 , 383, 384, 385t evetiracetam, 225t, 234–235, 237t
b ood-CSF, 24b, 28 , 94 Anti-protozoa drugs, 530–535. See also mechanisms o action, 225t, 225t–226t,
β- actam antibiotic resistance, 516–517 Protozoa drugs 226 –227
c assi cation, 512b Antipsychotics Ca channe b ockers, -type, 225t,
2+
combination therapy, 517b, 518 adverse e ects, 172t 225t–226t, 227 , 230–231
disease progression time ine, 516, 516 e der y, 77b, 168, 169, 171 GABAA receptor synaptic transmission,
dosing schedu e nonpsychotic disorders, 163b 225t, 225t–226t, 226
on concentration-time pro e, Antipsychotics, atypica , 151t, Na+ channe inactivation, 225t,
514, 515 160t–161t, 175t 225t–226t, 226
resistance suppression, 515 aripiprazo e, 151t, 170t, 175t pregaba in, 225t, 237t
drug and dose regimen choice, microbia chemica structures, dosages, and ru namide, 226t, 237t
aboratory, 513–514, 514 maintenance, 160t–161t succinimides, 225t, 236t
drug penetration, 512–513, 512b metabo ism, 170t ethosuximide, 225t, 230–231, 234,
ef ux pumps, 515b, 517 o anzapine, 151t, 165, 168, 170t, 235, 236t
empiric therapy, 516 , 518–519 171–172, 175t methsuximide, 225t, 236t
endocarditis risk and prophy axis, potencies, 162t tiagabine, 226t, 237t
515b, 516 quetiapine, 151t, 171t, 175t topiramate, 226t, 235, 236, 237t,
HIV combination therapy, 518, 519 risperidone, 151t, 168, 169, 171t, 175t 702, 703
indices, most important, 514, 515 Antipsychotics, typica , 151t, 160t, 175t va proic acid, 225t, 231–232, 234,
inhibitory sigmoid Emax curve, 513, 513 , asenapine, 151t, 170t, 175t 235, 236t
514, 514 chemica structures, dosages, and with amotrigine, 235
peak p asma concentration, 514, 515, maintenance, 160t zonisamide, 226t, 237t
515 , 519 c ozapine, 151t, 167–169, 170t, 172, 175t Antispasmodics, bowe , 498t, 508t
postantibiotic e ect, 515 droperido , 151t, 175t dicyc omine, 498t, 508t
pre-surgery prophy axis, 515b, 516 ha operido , 151t, 159, 163 , 171t, 175t g ycopyrro ate, 498t, 508t
resistance, 515b, 517 i operidone, 151t, 170t, 175t hyoscyamine, 498t, 508t
wound in ection prophy axis, oxapine, 151t, 175t mechanisms o action, 498t
514b, 516 metabo ism, 170t methscopo amine, 498t, 508t
Antinauseants and antiemetics, 498t, 508t mo indone, 151t, 175t Antispasticity agents, cho inergic,
aprepitant, 498t, 502t, 508t pa iperidone, 151t, 170t, 175t 106t, 117t
choice, 501, 501 potencies, 162t Antithymocyte g obu in (A G), 376t, 377 ,
c assi cation, 501, 502t receptor occupancy and c inica 377t, 378, 385t
dronabino , 498t, 502, 502t, 508t response, 163 Antithyroid agents, 431t, 439t–440t.
mechanisms o action, 498t sertindo e, 151t, 175t See also T yroid and
nabi one, 498t, 502, 508t ziprasidone, 151t, 171t, 175t antithyroid drugs
ondansetron, 498t, 501, 502t, 505, Antipsychotics, typica , phenothiazines, carbimazo e, 431t, 440t
506, 508t 150t, 174t compounds, 435t
Antip ate et agents ch orpromazine, 150t, 171t, 174t methimazo e, 431t, 435–436, 438,
GPIIb/IIIa, 323t, 324–325, 332t uphenazine, 150t, 174t 439, 440t
abciximab, 323t, 324–325, perphenazine, 150t, 174t propy thiouraci , 431t, 439t
331–332, 332t tri uoperazine, 150t, 174t Anti-thyroid hormone
epti batide, 323t, 324–325, 332t Antirigidity agents, cho inergic, compounds, 435t
mechanisms o action, 323t 106t, 117t Anti- NF reagents, 376t, 386t.
tiro ban, 323t, 324–325, 332t Antiseizure drugs, 225–235 See also under Bio ogica
indications, 324t acetazo amide, 225t, 237t immunosuppressants
irreversib e, ADP receptor antagonists, adverse e ects, 227b, 227t ada imumab, 368t, 376t, 381, 383,
323t, 332t agents and princip es, 227b, 228 384, 386t
c opidogre , 323t, 324, 325, 325t, barbiturates, phenobarbita , 225t, 236t certo izumab pego , 376t, 381, 386t
331–332, 332t benzodiazepines, 225t, 237t etanercept, 376t, 380, 386t
mechanisms o action, 323t c onazepam, 225t, 237t go imumab, 376t, 386t
prasugre , 323t, 324, 325, 325t, 332t c orazepate, 225t, 237t in iximab, 368t, 376t, 380, 381, 386t
735
Antitussives, 209t, 391t, 404t nevirapine, 601t, 603t, 608 , 610 , Ar ormotero
benzonatate, 209t, 210t, 391t, 404t 615, 622t pharmaco ogy, 125t, 144t
mechanisms o action, 196t structures, 610 pu monary, 390t, 402t
opioid nuc eoside reverse transcriptase inhibitors Argatroban, 323t, 330, 331, 333t
codeine, 209t, 391t, 404t (NR Is), 601t, 603t, 607 , 608 , 621t Arginine vasopressin, 423t, 424 , 429t
dextromethorphan, 391t, 404t abacavir, 601t, 603t, 607 , 608 , 621t Aripiprazo e, 130t, 148t, 151t, 170t, 175t
O C cough medicines, young adverse e ects, 615 adverse e ects, 163
chi dren, 350 didanosine, 601t, 603t, 607 , 608 , 621t mania prophy axis, 165
Antivira agents, 600–624 emtricitabine, 601t, 603t, 607 , mechanisms o action, 162–163
antihepatitis agents, 600t–602t, 620t 608 , 621t Aromatase inhibitors, 664t, 679t, 686t
ade ovir dipivoxi , 600t, 602t, 620t HIV, 614–615 anastrozo e, 664t, 677t, 679t, 686t
entecavir, 600t, 602t, 620t amivudine, 601t, 602t, 607 , 621t exemestane, 664t, 677t, 679t, 686t
inter erons, 600t–602t, 606 , 620t mechanisms o action and resistance, etrozo e, 664t, 677t, 679t, 686t
amivudine, 600t, 602t, 607 , 620t 602t–603t, 604 , 608 , 614–615 Arrhythmia drugs. See Antiarrhythmic drugs
mechanisms o action and stavudine, 601t, 603t, 607 , 608 , 621t Arrhythmias, cardiac, angina drugs, 293t
resistance, 602t structures, 607 Arsenic, 41t, 43t, 63, 64, 66t
peginter erons, 601t teno ovir disoproxi , 601t–603t, 607 , Arsenic trioxide (A O), 630 , 645t, 646t, 660t
antiherpes, 600t–602t, 605–608, 619t 608 , 621t Artemether, 520t, 529t
acyc ovir, 600t, 601t, 604 , 605–608, za citabine, 601t, 621t Artemether- ume antrine, 520t, 521,
605 , 605t, 617, 618, 619t zidovudine, 601t, 602t, 607 , 527, 529t
cido ovir, 600t, 601t, 605, 619t 608 , 621t Artemisinin-based combination therapies
docosano , 600t ophtha mic, 693t, 701 (AC s), 521
omivirsen, 600t, 602t, 609, 619t other Artemisinin, 520t, 529t
oscarnet, 600t, 602t, 604 , 605, imiquimod, 601t, 602t, 621t artemether, 520t, 529t
609–612, 617, 618, 619t ribavirin, 601t, 602t, 620t artemether- ume antrine, 520t, 521,
gancic ovir, 600t, 602t, 604 , 605, 605 , te bivudine, 601t, 602t, 607 , 608 , 620t 527, 529t
609, 617, 618, 619t teno ovir disoproxi , 601t–603t, artesunate, 520t, 529t
idoxuridine, 600t, 602t, 605–606, 619t 607 , 608 dihydroartemisinin, 520t, 529t
mechanisms o action and resistance, protease inhibitors, 601t, 603t, 608 , 609 , Artesunate, 520t, 529t
601t–602t, 606–607, 606 621t–622t Arthritis. See also Rheumatoid arthritis
pencic ovir, 600t, 602t, 604 , 605, 605 , amprenavir, 601t, 603t, 608 , NSAIDs or, 366–368 (See also Nonste-
608, 619t 609 , 622t roida anti-in ammatory drugs
tri uridine, 601t, 602t, 606, 619t atazanavir, 601t, 603t, 608 , 609 , 622t (NSAIDs))
va acyc ovir, 601t, 605, 608 darunavir, 601t, 603t, 608 , 609 , 622t Articaine, 224t
va gancic ovir, 601t indinavir, 601t, 603t, 608 , 609 , 621t ASA. See Aspirin
anti-in uenza, 601t, 602t, 604 , 620t opinavir, 601t, 603t, 615, 622t Asenapine, 151t, 170t, 175t
amantadine, 601t, 602t, 604 , mechanisms o action and resistance, Aspergillus avus, 60, 61
612–613, 620t 603t, 608 , 609 Aspirin, 357t, 358 , 360t, 365–366, 371, 372
mechanisms o action and resistance, ne navir, 601t, 603t, 608 , 609 , 622t antip ate et, 323t, 324–325, 332t
602t, 604 ritonavir, 601t, 603t, 608 , 609 , COX-1 inhibitors or NSAIDs with,
ose tamivir, 601t, 602t, 604 , 620t 615–619, 622t 365–366
rimantadine, 601t, 602t, 604 , 620t saquinavir, 601t, 603t, 608 , 609 , 621t pain target and site o action, 205t
zanamivir, 601t, 602t, 604 , 620t tipranavir, 601t, 603t, 608 , 609 , 622t pregnancy, 365
entry inhibitors, 601t, 603t, 608 , 611 , virus rep ication stages and targets, 612t prophy axis, dai y, 365
616, 623t Anxio ytics toxidrome, 53t
en uvirtide, 601t, 603t, 608 , 611 , benzodiazepine, 174t (See also Association rate (k+1), 6b
616, 623t Benzodiazepines) Asthma, 393–397, 396
maraviroc, 601t, 603t, 608 , 611 , 623t buspirone, 150t, 174t mi d, 393–394 (See also
mechanisms o action and Apixaban, 323t, 328, 331, 333t Pu monary drugs)
resistance, 603t APLs, universa , g atiramer acetate, severe, 393–398
amcic ovir, 605, 608 382t, 388t symptoms and pathophysio ogy, 393
integrase inhibitor Apomorphine, 130t, 148t A 1 receptor b ockers. See Angiotensin (A 1)
mechanisms o action and Parkinson’s disease, 239t, 242t, 253t receptor b ockers (ARBs)
resistance, 603t Apparent dissociation constant (Kapp), 7b Atazanavir, 601t, 603t, 608 , 609 , 622t
ra tegravir, 601t, 603t, 611 , 623t Aprac onidine CP3A4 metabo ism, 617
mechanisms o action and resistance, b ood-brain barrier, 702, 703 Ateno o
601t–603t ophtha mic, 690t, 695t, 702, 703, 704t myocardia ischemia, 300t
non-nuc eoside reverse transcriptase pharmaco ogy, 119t, 140t pharmaco ogy, 126t, 128t, 146t
inhibitors (NNR Is), 601t, 603t, Aprepitant, 498t, 502t, 508t Atomoxetine, 150t, 174t
608 , 610 , 623t Aprotinin, 347t Atorvastatin, 334t, 343t
de avirdine, 601t, 603t, 608 , 610 , 623t aP , 330b Atovaquone, 520t, 529t
e avirenz, 601t, 603t, 608 , 610 , 623t Arachidonic acid metabo ism, 358 Atovaquone-proguani , or ma aria
etravirine, 601t, 603t, 608 , cyc ooxygenase pathway, 358 chemoprophy axis, 521–522, 522t, 526
610 , 623t ipoxygenase pathways, 358 , 359 chemotherapy, 520t, 527, 529t
mechanisms o action and resistance, Ardeparin, 323t, 325, 333t A P inhibitors. See Protein tyrosine
603t, 608 , 610 Area under the curve (AUC), 514, 515 kinase inhibitors
736
Atracurium, 106t, 107t, 116t adverse e ects, 182 antiseizure, 225t, 237t
Atria bri ation, 315, 316. See also amobarbita , 177t, 181t, 192t c onazepam, 225t, 237t
Antiarrhythmic drugs butabarbita , 177t, 181t, 192t c orazepate, 225t, 237t
ab ation, 314t, 316 mechanisms o action, 180–181 anxio ytic, 174t
antiarrhythmics, 314t mephobarbita , 177t, 181t, 192t categories, e imination-based, 178b
competitive amateur ath ete, 316 methohexita , 177t, 192t ch ordiazepoxide, 176t, 191t, 192t
DC cardioversion, 314t, 316 overdose treatment, 189, 190 c onazepam, 176t, 191t, 192t
digoxin, 319, 320 pentobarbita , 177t, 181t, 192t c orazepate, 176t, 191t, 192t
uncomp icated, drugs, 315 pharmaco ogic properties and uses, 181t dependence and withdrawa , 180
war arin, 327 phenobarbita , 177t, 181t, 189, 190, 192t, diazepam, 176t, 191t, 192t, 214
Atria utter, antiarrhythmics, 314t 225t, 236t drug-re ated deaths, 51t
Atria natriuretic peptide, 269t secobarbita , 177t, 180, 192t e der y, 71, 77b
carperitide, 269t, 284t structures, 181t estazo am, 176t, 191t, 192t
nesiritide, 269t, 280, 284t thiopenta , 177t, 181t, 192t, 214 urazepam, 176t, 180, 191t, 192t
Atria tachycardia, antiarrhythmics, 314t to erance and physica dependence, with hepatic cirrhosis, 189, 190
Atropine, 40t, 65t, 96t, 101–102, 181–182 hypnotics choice, 189, 190, 191t
101t, 112t toxidrome, 53t orazepam, 176t, 189, 190, 191t, 192t
adverse e ects, 80–82, 112t trade names, 181t metabo ic re ationships
e ects, dose in, 101t Baroreceptor re ex, e der y, 77b among, 188
mechanisms o action, 96t Barrier penetration, 512–513, 513 midazo am, 176t, 191t, 192t, 214
ophtha mic, 690t, 695t, 704t b ood-brain, 512 (See also B ood-brain overdose treatment, umazeni , 41t, 42t,
uses, 112t barrier (BBB)) 65t, 177t, 179–180, 192t
Autonomic gang ia drugs, 106t b ood-CSF, 24b, 28 , 94 oxazepam, 176t, 189, 190, 191t, 192t
Autonomic gang ionic b ockade, 107t Basa gang ia quazepam, 176t, 191t, 192t
Autonomic nervous system, 80–85, 92 Huntington’s disease, 248, 248 sedative-hypnotics, 176t, 178b, 180,
anatomy, 81 Parkinson’s disease, 240–241, 241 189–190, 191t–192t
e ector organs, 83t–84t Basi iximab, 376t, 386t temazepam, 176t, 191t, 192t
gang ionic b ockade, 107t BCNU. See Carmustine (BCNU) toxidrome, 53t
parasympathetic, 82 , 85, 92, 107t BCRP transporter, 24t triazo am, 176t, 191t, 192t
periphera divisions, 80, 85b Bec omethasone dipropionate, 390t, 403t Benzonatate
somatic motor and e erent nerves, Beers Criteria, 69–70, 78b antitussive, 209t, 210t, 391t, 404t
82 , 92 Be atacept, 381t, 387t mechanisms o action, 391t
sympathetic, 82 , 85, 92, 107t Belladonna atropa toxidrome, 53t Benzoy ecgonine, 262
AV noda reentrant tachycardia (PSV ) anti- Be adonna, 101–102 Benztropine mesy ate, 96t, 114t
arrhythmics, 314t Bendamustine, 627t, 651t Benzy a coho , dermato ogic, 708t, 725t
Azacytidine (5-azacytidine), 636t, 654t activation, in vivo, 631, 631 Bepotastine, ophtha mic, 691t, 705t
mechanisms and sites o action, 630 , mechanisms o action, 626, 627t, 628, Best Pharmaceutica s or Chi dren Act o
636t, 638 , 640 628b, 630 2002 (BPCA), 71b
mechanisms o resistance, 636t mechanisms o resistance, 627t, 11β-Hydroxysteroid dehydrogenase, 464 ,
toxicities, 637t, 654t 632–633, 632b 467, 468
uses, 637t, 654t toxicities, 632b–633b, 651t β B ockers. See β adrenergic receptor
Azathioprine uses, 629t antagonists
dermato ogic, 708t, 724t, 725t Bendro umethiazide, 269t, 284t Betamethasone preparations, 460t. See also
idiosyncratic reaction, 504 Benzapri , 273t, 285t Corticosteroids
immunotherapy, 368t, 375t, 380, 385t Benznidazo e, 530t–531t, 535t Betaxo o , 126t, 128t, 145t
in ammatory bowe disease, 498t, Benzo[a]pyrene, 41t, 63–65 ophtha mic, 691t, 695t, 704t
502–503, 503 , 509t Benzocaine, 224t β1-Se ective adrenergic receptor
metabo ism, 502–503, 503 Benzodiazepine antagonists, 128t, 145t–146t
rheumatoid arthritis, 368t, 375t, addiction, 257–258, 257t mechanisms o action, 123 , 126t
380, 385t withdrawa syndrome, 257–258, 257t pharmaco ogy and pharmacokinetics,
u cerative co itis, 502–503, Benzodiazepine receptor agonists, 177t, 192t 123 , 128t, 145t–146t
506, 507 eszopic one, 177t, 192t β2 Adrenergic receptor agonists, ong-
Aze aic, 710t, 727t za ep on, 177t, 192t acting pu monary, 390t, 402t
Aze astine, 347t, 355t zo pidem, 177t, 178–179, 192t adverse e ects, 392b, 398
ophtha mic, 691t, 705t Benzodiazepine receptor antagonists, 192t ar ormotero , 390t, 402t
Azithromycin, 568t, 570 , 576t, 692t umazeni , 41t, 42t, 65t, 177t, asthma, 393–394, 396–397, 402
Az oci in, 552t 179–180, 192t adverse e ects, 392b
Aztreonam, 549t, 553, 558t Benzodiazepines, 191t–192t bronchodi ation, indirect
a coho withdrawa , 256–257 actions, 391b
B a prazo am, 176t, 180, 191t, 192t, mechanisms o action, 390t, 391 , 394
Baci us Ca mette-Guerin (BCG), 381t, 387t 257–258, 257t COPD, 395
Bacitracin, 569t, 573, 577t, 692t amyotrophic atera sc erosis, 249 ormotero , 390t, 402t
Bac o en, 239t, 249, 253t anesthetic adjuncts, 211t, 216–217, 223t indacatero , 390t, 402t
Bactrim a ergy, 56–57 anticonvu sants, 190 mechanisms o action, 390t, 391b,
Ba sa azide, 357t, 498t, 503 , 509t antidote, umazeni , 42t, 65t, 177t, 391 , 394
Barbiturates, 177t, 180–182, 181t, 192t 179–180 sa metero , 390t, 402t
737
β2 Adrenergic receptor agonists, short-acting, mechanisms o action, 301t etanercept, 376t, 380, 386t
pu monary, 389t, 401, 402t metopro o , 301t, 303–304, 306, 310t go imumab, 376t, 386t
adverse e ects, 392b β Ce , pancreatic, 471 , 472 , 473 in iximab, 368t, 376t, 380,
a butero , 389t, 402t β-Lactam antibiotics, 549–558. See also 381, 386t
asthma, 393–394 speci c agents and drug classes dermato ogic, 709t, 714t, 715–716, 726t
eva butero , 389t, 402t + aminog ycosides, 559, 560 ada imumab, 709t, 714t, 722, 723, 726t
mechanisms o actions, 389t, 391b, amoxici in-c avu anic acid, 555, 558t a e acept, 709t, 710 , 714t, 726t
391 , 394 aztreonam, 549t, 553, 558t e a izumab, 709t, 710 , 714t, 726t
metaprotereno , 389t, 402t β- actamase inhibitors, 549t, 553, 558t etanercept, 709t, 714t, 726t
pirbutero , 389t, 402t carbapenems, 549t, 553 in iximab, 709t, 714t, 726t
terbuta ine, 389t, 402t cepha osporins, 549t, 550b, 553–555, disease-modi ying anti-rheumatic drugs
β2-Se ective adrenergic receptor agonists, 556t–558t (See also abatacept, 368t, 381t, 387t
127, 143t–144t Cepha osporins) ada imumab, 368t
adverse e ects, 127 c avu anic acid, 555, 558t anakinra, 368t
a butero , 125t, 127, 135, 137, 143t doripenem, 558t certo izumab, 368t
mechanisms o action, 123 , 125t, 127 ef ux pumps, 551 go imumab, 368t
pharmaco ogy and pharmacokinetics, enzyme c asses, 550b in iximab, 368t, 376t, 380, 386t
123 , 128t, 143t–144t ertapenem, 558t rituximab, 368t
β Adrenergic receptor agonists, 123 , 142t imipenem, 558t IL-1 inhibitors, 376t, 386t
with additiona cardiovascu ar e ects, imipenem-ci astatin, 554–555 anakinra, 376t, 386t
123 , 128t, 146t mechanisms o action, 549t canakinumab, 376t, 386t
adverse e ects, 128–129 meropenem, 558t ri onacept, 376t, 386t
antihypertensive, 286t penici ins, 549t, 550–556, 555t–556t LFA-1 & LFA-3 inhibitors
doxazosin, 277t (See also Penici ins) a e acept, 376t, 386t
c assi cation, 123 resistance, 516–517, 549t, 550b e a izumab, 376t, 386t
e der y, 77b on Staphylococcus aureus, 550 monoc ona antibody, anti-CD3,
heart ai ure, 311t β-Lactamase, 517, 519 muromonab-CD3, 376t,
dobutamine, 302t, 307–308, 308t, 311t β-Lactamase inhibitors, 549t, 553, 558t 378, 385t
dopamine, 302t, 307–308, 308t, 311t c avu anic acid, 558t monoc ona antibody, anti-CD25, 376t,
mechanisms o action, 302t, 307–308 resistance, 549t 379, 386t
or heart ai ure, 129–130, 286t, 302t, su bactam, 558t basi iximab, 376t, 386t
304, 311t tazobactam, 558t dac izumab, 376t, 386t
intrinsic sympathomimetic activity, β-Lactam enzyme c asses, 550b monoc ona antibody, anti-CD52,
15, 16 Bethanecho , 95t, 99t, 112t a emtuzumab, 376t, 378, 386t
mechanisms o action, 125t, mechanisms o action, 95t po yc ona antibodies, immune
127–128, 128t pharmaco ogy, 99t, 112t g obu in preparations, 376t, 377 ,
metopro o Bevacizumab, 662t, 671t, 674–675, 684t 377t–378t, 378, 385t
heart ai ure, 306, 309, 310 Bexarotene, 707t, 724t Biotrans ormation, 20b, 28b
myocardia ischemia, 300t Beza brate, 335t, 344t Biotrans orming enzymes, 29b, 29t
pharmaco ogy, 126t, 127–129, 128t, 145t Bica utamide, 442t, 458t, 665t, 679t, 687t Bipo ar disorder, 164–166
myocardia ischemia, 289t, 291 , BiDi , 306, 306b Bisacody , 498t, 508t
292–294, 300t Biguanides, 470t, 479t Bismuth, 490t, 496t, 498t, 508t
ateno o , 300t Bi e acid–binding resins (sequestrants), 334t, Bisopro o
with nitrates, 294 339, 340, 343t heart ai ure, 301t, 309, 310, 310t
proprano o , 300t cho estyramine, 334t, 342–343, 343t pharmaco ogy, 126t, 128t, 145t
timo o , 300t co eseve am, 334t, 340, 343t, 471t, 479t Bisphosphonates, 481t, 488t
nonse ective, 123 , 128t, 144t–145t co estipo , 334t, 342–343, 343t adverse e ects, 485, 487, 488t
mechanisms o action, 125t–126t diabetes me itus, 471t, 479t a endronate, 481t, 488t
pharmaco ogy and pharmacokinetics, mechanisms o action, 334t, 471t etidronate sodium, 481t, 488t
123 , 128t, 144t–145t Bimatoprost, ophtha mic, 691t, 705t or hyperca cemia, 481t, 485, 488t
ophtha mic, 690t–691t, 695t, 700 Binding, 20 pamidronate, 481t, 488t
pharmacokinetics, 128t in vitro studies, 8 zo edronate, 481t, 485, 488t
pharmaco ogy, 123 , 128t, 142t p asma protein, 22b ibandronate, 481t, 485, 488t
pheochromocytoma, 136, 137 chi dren, 68b jaw osteonecrosis rom, 481t, 485, 488t
third-generation, 123 , 129t, 146t e der y, 74b, 75t mechanisms o action, 481t
mechanisms o action, 126t tissue, 22b–23b or Paget disease, 481t, 488t
pharmaco ogy, 123 , 146t e der y, 75t pamidronate, 481t, 488t
vasodi ating, 129t Bioavai abi ity, 20b, 33b. See also speci c risedronate, 481t, 488t
vasodi ating, 126 drugs and drug classes ti udronate, 481t, 488t
β Adrenergic receptor antagonists e der y, 73b, 73 , 73t–74t zo edronate, 481t, 485, 488t
antiarrhythmic, 312t, 317t, 321t in ant, ora drug, 72, 74 Bito tero , 125t, 143t
esmo o , 312t, 321t vo ume o distribution, 30, 33b, 34b Biva irudin, 323t, 333t
proprano o , 312t, 317t, 321t Bio ogica immunosuppressants, 385t–386t B eomycin, 643t, 658t
sota o , 312t, 317t, 321t anti- NF reagents, 376t, 386t dermato ogic, 709t, 724t, 726t
heart ai ure, 286t, 304, 310t ada imumab, 368t, 376t, 381, 383, mechanisms o action, 630 , 643t, 647
bisopro o , 301t, 309, 310, 310t 384, 386t mechanisms o resistance, 645b
carvedi o , 301t, 309, 310, 310t certo izumab pego , 376t, 381, 386t B epharitis, 700
738
B epharospasm agents, 692t, 706t carboxymethy ce u ose, 498t, 508t Bradykinin, 347t
abobotu inumtoxin A, 692t, 706t cho estyramine, 498t, 508t Bradykinin antagonists
onabotu inumtoxin A, 692t, 706t c onidine, 498t, 508t ka ikrein inhibitors, 347t
B ood-brain barrier (BBB), 24b, 28 di enoxin + atropine, 498t, 508t kinin receptor antagonists, 347t, 355t
drug di usion, 94 diphenoxy ate + atropine, 498t, Brain. See also speci c agents and disorders
e der y, 74b 500, 508t signa transduction, 88
in ants, 68b operamide, 209t, 498t, 500–501, 508t Brater’s a gorithm, 275 , 276 , 283
penetration, 512 mechanisms o action, 498t Breast cancer. See also Cancer chemotherapy
pH on di usion, 19–20, 19b–20b, 19 , 20 , octreotide, 498t, 508t and cytotoxics; speci c agents
35, 37–38, 90 antinauseants and antiemetics, 498t, 508t ER+, 676–679
B ood coagu ation reactions, 325–326, 326 aprepitant, 498t, 502t, 508t Her2/neu-positive, 672
B ood-CSF barrier, 24b, 28 , 94 choice, 501, 501 tamoxi en, 442t, 451, 456, 457, 458t, 664t,
B ood:gas partition coe cient, 215–216, c assi cation, 501, 502t 667 , 676–678, 677
215 , 215t, 220, 221 dronabino , 498t, 502, 502t, 508t Breast eeding, FDA drug ru es, 72b
BNP, human recombinant. See mechanisms o action, 498t Brimonidine, ophtha mic, 690t, 695t, 704t
Nesiritide (BNP) nabi one, 498t, 502, 508t Brinzo amide, ophtha mic, 691t, 705t
Bone remode ing cyc e, 482 , 485 ondansetron, 498t, 501, 502t, 505, Brom enac, 357t, 373t
Bone turnover disorder drugs, 480–489 506, 508t ophtha mic, 691t, 705t
bisphosphonates, 481t, 488t antispasmodics, 498t, 508t Brimonidine, 119t, 140t
a endronate, 481t, 488t dicyc omine, 498t, 508t Bromocriptine, 422t, 426, 428t
etidronate sodium, 481t, 488t g ycopyrro ate, 498t, 508t Parkinson’s disease, 242t
ibandronate, 481t, 485, 488t hyoscyamine, 498t, 508t pharmaco ogy, 130t, 148t
mechanisms o action, 481t mechanisms o action, 498t Brompheniramine ma eate, 346t, 354t
pamidronate, 481t, 488t methscopo amine, 498t, 508t BSEP transporter, 23t, 24t, 25t, 38
risedronate, 481t, 488t in ammatory bowe disease, Bucindo o , 126t, 146t
ti udronate, 481t, 488t 498t–499t, 509t Budesonide, 381, 460t. See also
zo edronate, 481t, 485, 488t ada imumab, 499t, 509t Corticosteroids
hormones azathioprine, 498t, 502–503, 503 , 509t Crohn’s disease, 465
ca citonin, 480t, 483–484, 483 , ba sa azide, 498t, 503 , 509t in ammatory bowe disease, 498t, 509t
486, 487 budesonide, 498t, 509t pu monary, 390t, 402, 403t, 460t
teriparatide, 480t certo izumab pego , 499t, 509t Bumetanide, 269t, 282, 283, 284t
hyperca cemia, 483–484 cyc osporine, 499t, 509t Bunazosin, 120t, 141t
mechanisms o action, 480t–481t in iximab, 499t, 509t Bupivacaine, 224t
monoc ona antibody, denosumab, mechanisms o action, 498t–499t Buprenorphine, 194t, 195t, 200t, 203, 209t
481t, 488t mesa amine, 498t, 503 , 509t or opioid addiction, 261–262
phosphate binders, 481t, 484, 488t methotrexate, 499t, 509t or opioid dependence, 203
anthanum carbonate, 481t, 484, 488t nata izumab, 499t, 509t Buprenorphine/na oxone, 261–262
mechanisms o action, 481t, 488t o sa azine, 498t, 503 , 506, 507, 509t Bupropion, 150t, 174t
rena osteodystrophy, 482 , 484 su asa azine, 381, 498t, 502, 503 , 505, or smoking, 259
seve amer hydroch oride, 481t, 484, 488t 507, 509t Busere in, 664t, 687t
rena osteodystrophy, 482 , 484 axatives, 498t, 507t–508t Buspirone, 130t, 133t, 136, 138, 147t, 150t, 174t
vitamin D and ana ogs, 481t, 482 , bisacody , 498t, 508t Busu an, 627t, 632t, 651t
484, 488t bowe e ects, 500t mechanisms o action, 627t, 628b–629b, 630
1α-hydroxycho eca ci ero , 481t, 488t c assi cation, 500t mechanisms o resistance, 627t,
22-oxaca citro parica cito , 481t, 488t docusate sodium, 498t, 508t 632–633, 632b
ca cipotrio , 481t, 488t actu ose, 497t, 505, 506–507, 507t toxicities, 632b–633b, 632t, 651t
ca citrio , 481t, 482 , 488t magnesium citrate, 497t, 507t uses, 629t
dihydrotachystero , 481b magnesium hydroxide, 497t, 507t Butabarbita , 177t, 181t, 192t
doxerca ci ero , 481b magnesium su ate, 497t, 507t Butena ne, 599t
ergoca ci ero , 481t, 488t mechanisms o action, 498b, 498t, 499 Butoconazo e, 588t, 597t
intestina bypass surgery, 486, 487 po yethy ene g yco , 497t, 507t Butorphano , 194t, 195t, 200t, 203, 209t
parica cito , 481t, 488t sa ine, 497t, 507t
therapeutic uses, 481b sodium phosphate, 497t, 507t C
Bortezomib, 663t, 681, 682–683, 685t opioid antagonists Ca2+ channe b ockers
Bosentan, 391t, 398–400, 399 , 404t a vimopan, 498t, 507t adverse e ects, 295
Botu inum toxins, 106t, 117t mechanisms o action, 498t contraindications, 295
abotu inum toxin A, 692t, 706t methy na trexone, 498t, 499, 505, toxidrome, 53t
onabotu inum toxin A, 106t, 117t, 506, 507t Ca channe b ockers, L-type, 270t, 277t, 287t
2+
739
Ca2+ channe b ockers, L-type, dihydropyridine Candesartan ci exeti , 273t, 285t Carisoprodo , 177t, 193t
antihypertensive, 277t, 282, 287t, 290t, 300t Candidiasis Carmustine (BCNU), 627t, 652t
am odipine, 277t, 282, 287t, 290t, esophagea , 589 , 590t–592t, 594–596 degradation, 631
294–295, 298, 299, 300t ora , 467, 468 dermato ogic, 708t, 724t, 726t
c evidipine, 277t, 287t, 290t, 300t vagina , 594 mechanisms o action, 627t, 628b, 630
e odipine, 277t, 287t, 290t, 300t Cannabinoid receptors, 263, 358 mechanisms o resistance, 627t,
isradipine, 277t, 287t, 290t, 300t Cannabis, 263 632–633, 632b
nicardipine, 277t, 287t Capecitabine, 635t, 654t toxicities, 631 , 632t, 652t
ni edipine, 277t, 287t, 290t, 300t mechanisms o action, 630 , 635t, 638 uses, 629t
niso dipine, 277t, 287t, 290t, 300t uses, 637t, 654t Carteo o , 125t, 128t, 144t
heart ai ure, 290t, 300t, 306 Capreomycin, 579t, 587t ophtha mic, 691t, 695t, 704t
nimodipine, 290t, 300t Capsaicin, 710t, 727t Carvedi o
Ca channe b ockers, L-type,
2+
Captopri , 273t, 279, 285t heart ai ure, 301t, 309, 310, 310t
nondihydropyridine Carbacho , 95t, 99t, 112t MI patients, 279
antiarrhythmic, 312t, 315, 317t, 322t mechanisms o action, 95t pharmaco ogy, 126t, 128t, 129, 146t
di tiazem, 312t, 315, 317t, 322t ophtha mic, 690t, 695t, 704t Caspo ungin, 588t, 589 , 593, 593 , 598t
verapami , 312t, 317t, 322t pharmaco ogy, 99t, 112t Catecho amines. See also speci c
antihypertensive, 277t, 287t Carbamate insecticides, 100t, 102, 115t types and drugs
di tiazem, 277t, 278, 287t, 290t, 300t atropine or, 42t, 65t (See also Atropine) endogenous, 118t, 139t
verapami , 277t, 287t, 290t, 300t, 306 Carbamazepine metabo ism, 121
Ca2+ channe s, 86, 87 , 89t a coho withdrawa , 257 transporters, p asma membrane, 124t
-type, antiseizure drugs on, 225t, anticonvu sants, 151t, 164–165, 175t Catecho -O-methy trans erase (COM ),
225t–226t, 227 , 230–231 antiseizure, 225t, 226 , 232–235, 236t 240 , 243, 250, 251
Cabergo ine, 130t, 148t, 422t, 426, 428t or g ossopharyngea and trigemina neu- evodopa metabo ism, 243, 243 , 244
Cadmium, 41t, 43t, 65t ra gias, 233 Catecho -O-methy trans erase (COM )
Ca cimimetics. See Cinaca cet Huntington’s disease, 248 inhibitors, 238t, 242t, 244, 244
Ca cineurin, 383–384 or ightning-type pain, 233 CBDCA. See Carbop atin (CBDCA)
Ca cipotriene, 707t, 724t Carbapenems, 549t, 553 CCNU. See Lomustine (CCNU)
Ca cipotrio , 481t, 488t Carbary , 100t, 115t Ce ac or, 556t
Ca citonin, 480t, 483–484, 483 , 486, 487 Carbenici in, 552t, 556t Ce adroxi , 556t
hyperca cemia, 480t, 481t, 483–484, Carbidopa, 238t, 244 Ce dinir, 557t
483 , 488t Carbidopa/ evodopa, 238t, 242, 250, Ce ditoren pivoxi , 557t
Paget disease, 481t, 488t 251, 252t Ce epime, 558t
P H in, 483 Carbimazo e, 431t, 440t Ce xime, 557t
regu ation, 486, 487 Carbinoxamine, 346t, 353t Ce metazo e, 557t
Ca citrio , 481t, 482 , 488t Carbon dioxide gas, therapeutic, 211t, 223t Ce operazone, 557t
Ca cium sensor mimetics. See Cinaca cet Carbonic anhydrase inhibitors Ce otaxime, 557t
Camptothecin ana ogs, 643t, 657t antihypertensive, 268t, 271t, 272 , 283t Ce otetan, 556t
irinotecan, 630 , 643t, 644b–645b, 649– acetazo amide, 268t, 283t Ce oxitin, 556t
651, 657t brinzo amide, 283t Ce podoxime proxeti , 557t
mechanisms o action, 630 , 643t, dich orphenamide, 268t Ce prozi , 556t
649–651 dorzo amide, 283t Ce azidime, 553, 557t
mechanisms o resistance, 643t, methazo amide, 268t Ce ibuten, 557t
644b–645b ophtha mic, 691t, 705t Ce izoxime, 557t
topotecan, 630 , 643t, 644b–645b, brinzo amide, 691t, 705t Ce riaxone, 554, 555, 557t
649–651, 657t dorzo amide, 691t, 705t Ce uroxime, 556t
toxicities, 657t Carbop atin (CBDCA), 628t, 653t Ce uroxime axeti , 556t
uses, 644t, 657t mechanisms o action, 628b–629b, 628t, Ce ecoxib, 357t, 358 , 363t, 371,
Canakinumab, 376t, 386t 630 , 633 372, 373t
Cancer chemotherapy and cytotoxics, mechanisms o resistance, 628t, 632b, cardiovascu ar risk, 357, 365b,
626–660. See also speci c drugs 634–635 371, 372
and drug classes toxicities, 632b–633b, 632t, 633–634, 653t Ce ipro o , 126t, 128t, 146t
a ky ating agents, 626–635, 627t–628t, uses, 629t, 653t Centra y acting adrenergic agents,
651t–653t (See also A ky ating Carboxymethy ce u ose, 498t, 508t antihypertensive
agents) ophtha mic, 692t, 706t α2 adrenergic receptor antagonists,
antimetabo ites, 635–642, 635t–636t, Carcinogens, 43t, 60–62, 60 , 61 . See also 277t, 286t
653t–656t speci c types c onidine, 277t, 286t
ce cyc e speci city, 630 a atoxin B1, 41t, 60–62, 61 guanabenz, 277t, 286t
cytotoxic natura products, 630 , initiation and promotion, 60, 60 guan acine, 277t, 286t
642t–644t, 645–647 Cardiac action potentia , 312 , 313 methy dopa, 277t, 286t
cytotoxics with diverse mechanisms o Cardiac arrhythmias, drugs. See Centra nervous system (CNS), 92
action, 644t–646t, 659t–660t (See Antiarrhythmic drugs distribution, 24b
also Cytotoxics with diverse mech- Cardiovascu ar disease risk drugs, 91–92 (See also speci c drugs)
anisms o action) assessment, 335–336, 338 neurotransmitters, 86b, 91–92, 91t
targeted, 661–687 (See also argeted anti- LDL-C treatment guide ines, 336, 336t Ce adroxi , 556t
cancer therapies) prevention guide ines, 335, 335b, 338 Cepha exin, 556t
740
Cepha osporins, 553–555, 556t–558t Chlamydia, cyc oserine, 579t, 587t carbacho , 95t, 99t, 112t
mechanisms o action, 549t Ch ora hydrate, 177t, 193t carbamate insecticides, 100t, 102
mechanisms o resistance, Ch orambuci , 629t carbary , 100t, 115t
549t, 550b Ch oramphenico , 568t, 569 , 571, 576t, 692t cevime ine, 95t, 112t
Cepha osporins, rst-generation, 556t Ch ordiazepoxide, 176t, 191t, 192t ch orpyri os, 100t, 103t, 115t
ce adroxi , 556t Ch oride channe s, 86 cho ine acety trans erase, 97
cepha exin, 556t 2-Ch oro-2'- uoro-arabinosy adenine. See cho ine esters, 99t
cephazo in, 556t C o arabine (2-ch oro-2'- cho inergic crisis, 105
Cepha osporins, ourth-generation, ce epime, uoro-arabinosy adenine) cisatracurium, 106t, 107t, 117t
558t 2-Ch orodeoxyadenosine (2-CdA. See cyc opento ate hydroch oride, 96t, 114t
Cepha osporins, second-generation, C adribine dantro ene, 106t, 117t
556t–557t Ch orophy in, 62 dari enacin, 96t, 101t, 113t
ce ac or, 556t Ch oroprocaine, 224t diazinon, 100t, 103t, 115t
ce metazo e, 557t Ch oroquine dicyc omine hydroch oride, 96t, 113t
ce otetan, 556t dermato ogic, 708t, 725t donepezi , 100t, 115t
ce oxitin, 556t ma aria chemotherapy, 521t, 522t, doxacurium, 106t, 107t, 117t
ce prozi , 556t 523–524, 526, 529t edrophonium, 100t, 104–105, 104 , 114t
ce uroxime, 556t P. alciparum resistance, 523–524, 523 esoterodine, 96t, 101t, 113t
ce uroxime axeti , 556t toxicities, 524 avoxate, 96t
oracarbe , 557t Ch oroquine/hydroxych oroquine, 521t, 522t, ga antamine, 100t, 115t
Cepha osporins, third-generation, 553, 554, 523–524, 526, 529t g ycopyrro ate, 96t, 113t
555, 557t Ch oroquine phosphate, 522t homatropine hydrobromide, 96t, 114t
ce dinir, 557t Ch orothiazide, 269t, 284t ipratropium, 96t
ce ditoren pivoxi , 557t Ch orpheniramine, 346t, 354t jimson weed, 101–102, 101t
ce xime, 557t Ch orpromazine, 150t, 171t, 174t mecamy amine, 106t, 117t
ce operazone, 557t Ch orpyri os, 100t, 103t, 115t mechanisms o action
ce otaxime, 557t Ch ortha idone, 269t, 284t muscarinic agonists, 95t
ce podoxime proxeti , 557t Cho estero absorption inhibitors muscarinic antagonists, 96t
ce azidime, 553, 557t ezetimibe, 335t, 344t, 350 methacho ine, 99t, 112t
ce ibuten, 557t ezetimibe/simvastatin, 344t, 350 methscopo amine bromide, 96t, 114t
ce izoxime, 557t Cho estero eve c assi cation, 337t mivacurium, 106t, 107t, 117t
ce riaxone, 554, 555, 557t Cho estyramine muscarinic acety cho ine receptors,
Cephazo in, 556t antidiarrhea , 498t, 508t 98t–99t
Certo izumab (pego ) on drug absorption, 342–343 muscarinic receptor antagonists, 99t, 100,
Crohn’s disease, 381 Cho ine acety trans erase (ChA ), 97 101b, 101t
immunotherapy, 376t, 381, 386t Cho ine esters, 99t muscarinic receptors, 97
in ammatory bowe disease, 499t, 509t Cho inergic antagonists, pu monary mushrooms, 97, 100
rheumatoid arthritis, 368t muscarinic, 390t, 401–402, 403t. neostigmine bromide, 100t, 114t
Cetirizine, 347t, 348, 348b, 351–352, 355t See also speci c drugs and neostigmine methy su ate, 100t, 114t
chi dren, 351, 352 drug classes neuroe ector junction, 97
motion sickness, 352 adverse e ects, 395 neuromuscu ar b ocking agents
pregnancy and actation, 348, 348b, asthma, severe, 397 c assi cation, 107t
351–352 COPD, 394–395 mechanisms, 106t
Cetrore ix, 423t, 429t, 665t, 686t ipratropium bromide, 390t, 402, 403t nicotine gum or ozenge, 106t, 108,
Cetuximab, 662t, 667t, 669–672, 683t mechanisms o action, 390t 108b, 117t
Cevime ine, 95t, 112t tiotropium bromide, 390t, 401–402, 403t nicotine nasa spray or vapor inha er,
Channe s, ion, 3. See also speci c types Cho inergic crisis, 105 106t, 108, 108b, 117t
Che ators, heavy meta , 66t. See also Cho inergic pharmaco ogy, 95–116. nicotine transderma patch, 106t, 108,
speci c agents See also speci c drugs and 108b, 117t
Chemica antagonism, 4b, 9, 48b drug classes nicotinic acety cho ine receptors, 98t
Chemotherapy, cancer. See Cancer acety cho ine, 95t, 97 , 99t, 112t onabotu inum toxin A, 106t, 117t
chemotherapy and cytotoxics; acety cho ine receptors, 97 organophosphates, 100t, 102, 102b,
speci c drugs and drug classes acety cho inesterase, 97 103t, 104
Chi dren. See also speci c drugs and disorders acety cho inesterase inhibitors, 100t oxybutynin, 96t, 99t, 100, 101b, 101t, 113t
gray baby syndrome, 68 a dicarb, 100t, 115t Panaeolus, 97
in ant ora drug bioavai abi ity, 72, 74 a ka oids, natura , 99t pancuronium, 97 , 105 , 106 , 106t,
kernicterus, 68 Amanita muscaria, 97, 100 107t, 116t
medication sa ety and FDA, 71b–72b Amanita phalloides, 97 physostigmine sa icy ate, 100t, 102, 114t
morphine ambenonium ch oride, 97 , 100t, pi ocarpine, 95t, 99t, 112t
in ant dosing, 72, 74 104–105, 105 , 106 , 114t pi ocarpine hydroch oride, 95t, 99t, 112t
metabo ism, 68 atracurium, 106t, 107t, 116t pipecuronium, 97 , 105 , 106 , 106t,
Chi dren, pharmacokinetics atropine, 96t, 101–102, 101t, 112t 107t, 116t
absorption, 67b autonomic gang ionic b ockade, 107t pra idoxime, 41t, 42t, 65t, 100t, 102, 116t
distribution, 68b be adonna, 101–102 propoxur, 100t, 115t
excretion, 69b benztropine mesy ate, 96t, 114t Psilocybe, 97
metabo ism, 70b bethanecho , 95t, 99t, 112t psi ocybin, 97
741
pyridostigmine bromide, 100t, 114t mechanisms o resistance, 628t, 632b, C oxaci in, 551, 552t, 554, 555, 555t
rimabotu inum toxin B, 106t, 117t 634–635 C ozapine, 130t, 147t, 151t, 167–169, 170t,
rivastigmine, 100t, 115t toxicities, 632b–633b, 632t, 633–634 172, 175t
rocuronium, 97 , 105 , 106 , 106t, uses, 629t, 632t, 653t CO2 absorbent, 220, 221
107t, 117t Cita opram, 130t, 146t, 150t, 174t Cocaethy ene, 265, 266
sarin, 100t, 103t, 115t Citrovorum actor, 406t, 416, Cocaine
scopo amine, 96t, 112t 417–418, 420t addiction, 262–263
so i enacin, 96t, 101t, 113t C adribine (2-ch orodeoxyadenosine, drug-re ated deaths, 51t
soman, 100t, 103t, 116t 2-CdA), 630 , 636t, 655t ethano with, 265, 266
succiny cho ine, 97 , 105 , 107t, 108, 116t mechanisms o action, 630 , 636t, oca anesthetic, 224t
summary tab e, 112t–117t 641–642 toxidrome, 53t
tabun, 100t, 103t, 116t mechanisms o resistance, 636t withdrawa , 263, 263t
tiotropium, 96t, 113t C arithromycin, 568t, 570 , 571, 576t Cockcro -Gau t equation, 76b
to terodine, 96t, 101t, 113t duodena u cer, 492, 494t Codeine, 195t, 200t, 206, 208, 208t
trihexyphenidy hydroch oride, peptic u cer disease, 571 antitussive, 209t, 391t, 404t
96t, 114t toxicities, 571 Co chicine, 369t, 370, 373t
trimethaphan, 106t, 117t C audication, 295b Co d medicines. See also speci c drugs and
tropicamide, 96t, 114t C audication treatment, 295b ingredients
trospium ch oride, 96t, 101t, 113t C avu anic acid, 549t, 553, 558t a coho with, 366
varenic ine, 106t, 117t C - channe s, 86 O C, young chi dren, 350
vecuronium, 97 , 105 , 106 , 106t, 107t, C earance (CL), 33b, 35, 35b–36b, 36 , 39 Co eseve am, 471t, 479t
108, 116t e der y, 75b, 76 , 76t–77t, 77 on drug absorption, 343
Cho inergic toxidrome, 53t rst-order kinetics, 36b Co estipo , on drug absorption, 342–343
Cho inesterase inhibitor, 89 in ants and chi dren, 69b Co itis, amebic, 532–533
Cho inesterase reactivators, 41t, 42t, 65t, 102, p asma concentration-time curves, paromomycin, 531t, 532–533, 535t
104 , 116t 36b, 37 Co itis, u cerative
Chondroitin su ate, ophtha mic, 692t, 706t C emastine umarate, 346t, 353t azathioprine, 502–503, 503 , 506, 507
Choriogonadotropin a a, 423t, 427, C evidipine su asa azine, 381, 502
428, 430t antihypertensive, 277t, 287t thiopurine methy trans erase, 502–503,
Chromium, 41t, 43t, 66t myocardia ischemia, 290t, 300t 503 , 506, 507
Chronic mye ogenous eukemia, Ph+, C indamycin, 568t, 574, 575, 576t Co ony-stimu ating actors, 663t, 685t.
664–669 C obetaso propionate, 460t. See also See also speci c types
rst- ine treatment, 665–666 Corticosteroids Combination therapy, antimicrobia ,
mo ecu ar mechanism, 665–666 C ocorto one propionate, 460t. See also 517b, 518
Chronic obstructive pu monary disease Corticosteroids Combined androgen b ockade, 680
(COPD), 394–395 C o arabine (2-ch oro-2'- uoro-arabinosy - Competitive antagonists, 4b, 5b, 5 , 16, 17
pathophysio ogy, 394 adenine), 630 , 636t, 655t a nity, 7b
treatments, 394–395 (See also mechanisms o action, 630 , 636t, Competitive neuromuscu ar b ocking
Pu monary drugs) 641–642 agents, 97 , 105 , 106 , 106t, 107t,
Chronic rena ai ure, diuresis, 282, 283 mechanisms o resistance, 636t 116t–117t
Chy omicrons, metabo ic pathways, 335 uses, 637t Concentration–response (curve), 6b, 6
Cic esonide, 460t. See also Corticosteroids C o azimine, 579t, 583, 587t quanta , 11 , 12
pu monary, 390t, 403t C o brate, 335t, 344t Concentration–time curves, p asma,
Cic opirox o amine, 598t C omethiazo e, 177t, 193t 36b, 37
Cido ovir, 600t, 601t, 605, 619t, 693t C omiphene, 442t, 452, 455–457, 458t dose administration schedu e, 514, 515
Cigarette addiction. See Smoking C omipramine, 150t, 173t e der y, 73
Ci astatin, 554–555 C onazepam, 176t, 191t, 192t Conduction abnorma ities
Ci ostazo , 295b amyotrophic atera sc erosis, 249 angina drugs, 293t
Cimetidine antiseizure, 225t, 237t arrhythmia drugs (See Antiarrhythmic
gastric acid disease, 491, 494, 495 C onidine drugs)
structure, 492 antidiarrhea , 498t, 508t Congestive heart ai ure. See Heart ai ure
to erance, 491, 494, 495 antihypertensive, 277t, 286t Conivaptan, 279t, 281, 288t
Cinaca cet, 481t, 486, 487, 488t or opioid addiction, 261 Conjugated equine estrogens, 441t, 445t
hyperparathyroidism, 481t, 488t pharmaco ogy, 119t, 124–125, 139t Conjugated estrogen + medroxyprogesterone
hypoca cemia, 481t, 488t C opidogre , 323t, 324, 325, 325t, acetate, 441t
Cinchonism, 524 331–332, 332t Conjugation, phase 2, 28–29, 28b, 33 ,
Cipro brate, 335t, 344t bioactivation, 22, 28, 325t 35, 39
Cipro oxacin, 544, 544 , 545, 548t, 692t dosing, 22, 28 neonata , 70b
Cisapride, 133t patient-to-patient variabi ity, Conjugation reactions, drug metabo ism, 32t
bowe disorders, 497t, 504, 506, 507t 331–332 Conjunctivitis, 700
nausea and vomiting, 504, 506 drug interactions, 28 adrenocortica steroids in, 466
postmarketing survei ance, 47–48 mechanisms o action, 323t, 330, 331 Constipation
Cisatracurium, 106t, 107t, 117t C orazepate, 176t, 191t, 192t uid vo ume, 499, 499
Cisp atin, 628t, 653t antiseizure, 225t, 237t axatives, 498b, 498t, 499, 499 ,
mechanisms o action, 628b–629b, 628t, C otrimazo e, 588t, 597t 507t–508t
630 , 633 C otting cascade, 325–326, 326 rom morphine, 92
742
Context-sensitive ha -time, anesthetic, Costimu atory b ockade, 380b, 380 toxicities, 631 , 632b–633b, 632t, 651t
214, 214 Cosyntropin, 459t, 461 , 468t dermato ogic, 708t, 724t, 726t
Contraceptives, ora , 448–450, 458t Cough, 400 mechanisms o action, 626, 627t, 628,
brand names and ormu ations, 443t–444t Cough medicines. See Antitussives 628b, 630
desogestre , 443t COX-1/2 inhibitors mechanisms o resistance, 627t,
drospirenone, 441t, 443t, 444t aspirin, 323t, 324–325, 332t 632–633, 632b
emergency, 452 COX-1 inhibitors or NSAIDs with, rheumatoid arthritis, 368t
ethiny estradio ormu ations, 441t, 365–366 toxicities, 631–632, 631 , 632b–633b,
443t–444t, 457t irreversib e 632t, 651t
evonorgestre , 443t, 444t aspirin, 357t, 358 , 360t, 365–366, uses, 629t
mechanisms o action, 441t, 441t–442t 371, 372 Cyc oserine
migraine history, 455, 456–457 mechanisms o action, 357t, 358 Mycobacterium avium comp ex,
norethindrone, 441t, 443t, 444t COX-1 inhibitors 579t, 587t
norgestre , 443t, 444t mechanisms o action, 323t, 357t, 358 tubercu osis, 579t, 587t
options, 448–450 se ective, 357t, 358 Cyc osporine, 368t, 375t, 377 , 380,
progesterone, 450 u cers rom, 492 382–383, 385t
progestin-on y, 450, 458t COX-2 inhibitors dermato ogic, 708t, 724t, 726t
risks and adverse e ects, 450–451 mechanisms o action, 358 in ammatory bowe disease, 499t, 509t
u iprista , 442t, 444t, 452, 458t pain target and site o action, 205t mechanisms o action, 375t, 382–383
Copper supp ement, 406t, 419t se ective ophtha mic, 691t, 705t
Cornea in ammation, 700 cardiovascu ar hazard, 357, 365b, rheumatoid arthritis, 368t, 376t, 385t
Coronary heart disease, risk actors, 371, 372 CYP (cytochrome P-450 super ami y), 29b,
335, 335b ce ecoxib, 357t, 358 , 363t, 371, 29t, 30, 30b–31b, 33
Corticore in, 459t, 461 , 468t 372, 373t antiseizure drug interactions, 227t
Corticosteroids, 468t. See also speci c agents etoricoxib, 363t drug–drug interactions, 30b
carbohydrate and protein metabo ism, umiracoxib, 363t genes, 30b
467, 468 menstrua cramping, 364 genetic po ymorphisms, 27t, 28, 31b
Crohn’s disease, 465 parecoxib, 363t imidazo e and triazo e interactions,
dexamethasone suppression test, 465–466 risks, 357 590, 590t
dose tapering, 465 Creatine c earance, oading dose, 34 induction, 31b
genera princip es, 464b Crohn’s disease agents, 381 reaction cata ysis, 30b, 32t
mechanisms o action, 459t, 462 ada imumab, 381 SSRIs on, 133
names and preparations, 460t–461t adrenocortica steroids, 465 CYP2C9, 27t, 30b–31b, 595, 596
physio ogic unctions and pharmaco ogic azathioprine, 503–504 azo e anti unga s on, 590, 590t
e ects, 462t–463t budesonide, 465 po ymorphisms, 10t, 12–14, 13
potencies and equiva ent doses, 463t certo izumab, 381 CYP2C19, 27t, 30b–31b, 595, 596
rheumatoid arthritis, 463–465 in iximab, 381, 503 c opidogre bioactivation, 22, 28, 325t,
therapeutic uses, 463b prednisone, 465, 467, 468 331–332
toxicities, 464b su asa azine, 381, 498t, 502, 503 , 505, isoniazid on, 582, 585, 586
Corticosteroids, inha ed pu monary, 507, 509t isoniazid + phenytoin on, 585, 586
390t, 403t Cromo yn sodium, ophtha mic, 691t, 705t prasugre bioactivation, 325t
adverse e ects, 393b, 397–398 Crotamiton, 708t, 725t CYP2D6, 27t, 30b–31b
asthma, 393–397 Cryptosporidia uoxetine, 157
bec omethasone dipropionate, 390t, 403t diarrhea, 532 isoniazid on, 582, 585, 586
bioavai abi ity, 467, 468 nitazoxanide, 530t, 532, 535t paroxetine, 157
budesonide, 390t, 402, 403t, 460t Cupric su ate, 406t, 419t SSRIs on, 133
candidiasis, ora , 467, 468 Cushing’s syndrome, 466 CYP2E, isoniazid on, 582
cic esonide, 390t, 403t, 460t Cutaneous -ce ymphoma agents, CYP3A4, 27t, 30b–31b, 595, 596
COPD, 395 709t, 727t atazanavir metabo ism by, 617
uniso ide, 390t, 403t, 460t Cyanoacry ate, ophtha mic, 692t, 706t azo e anti unga s on, 590, 590t
uticasone, 390t, 403t Cyanocoba amin, 406t, 414–415, isoniazid on, 582, 585, 586
mechanisms o action, 390t, 392 , 393 417–418, 420t opinavir metabo ism, 618, 619
mometasone, 390t, 403t, 461t Cyc ic nuc eotide–gated nonspeci c cation macro ides, 572
triamcino one, 390t, 403t, 461t channe inhibitors, 269t quinupristin/da opristin, 572, 575
Corticosteroids, systemic pu monary, carperitide, 269t, 284t ritonavir on, 617–619
390t, 403t nesiritide, 269t, 280, 284t St. John’s wort on, 619
hydrocortisone, 390t, 403t, 460t, 464, 464 Cyc izine, 346t, 350, 352, 354t, 502t CYP3A5, 27t, 30b–31b
mechanisms o action, 390t, 392 , 393 Cyc ooxygenase-1 (COX-1), 324, 324 , CYP3A7, 27t, 30b–31b
methy predniso one, 390t, 403t, 460t–461t 325 , 358 Cyproheptadine, 346t, 354t
predniso one, 390t, 403t, 461t Cyc opento ate, ophtha mic, 690t, 695t, 705t Cyproterone, 665t, 687t
Corticotropin-re easing hormone (CRH), Cyc opento ate hydroch oride, 96t, 114t Cytarabine (cytosine arabinoside, Ara-C),
459t, 461 , 468t Cyc ophosphamide, 627t, 631 , 635t, 648, 649, 654t
corticore in, 459t, 461 , 468t 632t, 651t mechanisms o action, 630 , 635t
mechanisms o action, 459t, 461 activation, in vivo, 631, 631 mechanisms o resistance, 635t, 639b
Cortiso , 11β-hydroxysteroid dehydrogenase cancer chemotherapy, 626, 628–633 toxicities, 637t, 654t
on, 464 , 467, 468 metabo ism, 631 uses, 637t, 654t
743
Cytochrome P-450 super ami y. See CYP mechanisms o action, 630 , 643t, hydroxych oroquine, 708t, 725t
(cytochrome P-450 645–647 quinacrine, 708t, 725t
super ami y) mechanisms o resistance, 645b antimetabo ites, 708t, 724t, 725t
Cytokine–ce interactions, 408 DDAVP, 279t, 288t 5- uorouraci (FU), 708t, 724t, 725t
Cytokines, recombinant, 381t. See also Deaths, drug-re ated, 51, 51t. See also azathioprine, 708t, 724t, 725t
speci c agents speci c drugs methotrexate, 708t, 715, 721–722,
a des eukin, 381t Decitabine (2'-deoxy-5-azacytidine), 724t, 725t
inter eron-α-2b, 381t 636t, 654t antimicrobia agents, 708t, 725t
inter eron-β-1a, 381t, 382 mechanisms and sites o action, 630 , antibacteria s, 708t, 725t
inter eron-β-1b, 381t, 382 636t, 638 , 640 anti unga s, 708t, 721, 722, 725t
inter eron-γ-1b, 381t mechanisms o resistance, 636t retapamu in, 708t, 725t
Cytotoxic natura products, 630 , 642t–644t, toxicities, 637t, 654t bio ogic agents, 709t, 714t, 715–716, 726t
645–647 uses, 637t, 654t ada imumab, 709t, 714t, 722, 723, 726t
Cytotoxics De erasirox, 41t, 65t a e acept, 709t, 710 , 714t, 726t
cancer (See Cancer chemotherapy and De eroxamine, 40t, 42t, 55, 65t e a izumab, 709t, 710 , 714t, 726t
cytotoxics; speci c drugs and drug Degare ix, 665t, 686t etanercept, 709t, 714t, 726t
classes) Dihydroartemisinin, 520t, 529t in iximab, 709t, 714t, 726t
natura products (See Natura products, De avirdine, 601t, 603t, 608 , 610 ca cineurin inhibitors, 708t, 724t, 726t
cytotoxic) mechanisms o action and resistance, cyc osporine, 708t, 724t, 726t
Cytotoxics with diverse mechanisms o 603t, 608 , 610 pimecro imus, 708t, 724t, 726t
action, 644t–646t, 659t–660t structure, 610 tacro imus, 708t, 724t, 726t
adrenocortica suppressants, mitotane, De irium tremens, 256t capsaicin, 710t, 727t
644t, 659t, 679t Δ-9- HC, 265, 266 cutaneous -ce ymphoma agents, deni-
di erentiating agents Deni eukin di itox eukin di itox, 709t, 727t
arsenic trioxide, 630 , 645t, anticancer, 663t, 671t, 685t g ucocorticoids, 707t, 722, 723, 724t
646t, 660t cutaneous -ce ymphoma agents, 709t, adverse e ects, 723, 724t
HDAC inhibitors, 645t, 660t 727t potency, 723t
romidepsin, 645t, 660t Denosumab, 481t, 488t triamcino one acetonide, 707t,
vorinostat, 645t, 646t, 660t 2'-Deoxy-5-azacytidine. See Decitabine 723t, 724t
retinoids, 645t, 646t, 659t (2'-deoxy-5-azacytidine) triamcino one hexacetonide, 707t,
substitutes urea, hydroxyurea, 630 , 645t, 2'Deoxyco ormycin, 636t, 637t, 723t, 724t
646t, 659t 641–642, 656t H 1 b ockers
Dependence, 264, 266. See also Addiction; rst-generation, 718t
D Opioid addiction; speci c drugs second-generation, 718t
Dabigatran etexi ate, 323t, 328, 333t barbiturates, 181–182 H 2 b ockers, 718t
Dacarbazine (D IC), 628t, 629t, 630 , benzodiazepines, 180 hyperpigmentation, 710t, 727t
645–647, 652t opioid, buprenorphine or, 203 aze aic, 710t, 727t
mechanisms o action, 628b, 628t, Depo arizing neuromuscu ar b ocking hydroquinone, 710t, 727t
630 , 647 agents, 97 , 105 , 107t, 108, 116t mequino , 710t, 727t
mechanisms o resistance, 628t, Depression monobenzone, 710t, 727t
632–633, 632b drug-induced immunosuppressives and anti-in amma-
toxicities, 632b–633b, 652t acute, 92 tories, other, 709t, 724t, 726t
uses, 629t hyperexcitabi ity a er, 89–90, 94 b eomycin, 709t, 724t, 726t
Dac izumab, 376t, 386t drugs (See Antidepressants) dapsone, 709t, 724t, 726t
Dactinomycin, 630 , 643t, 658t Depsipeptide, 645t, 660t doxorubicin, 709t, 726t
Da teparin, 323t, 325, 333t Derma absorption. See Skin absorption imiquimod, 709t, 724t, 726t
Dantro ene Derma administration mycopheno ate mo eti , 709t, 724t, 726t
amyotrophic atera sc erosis, 239t, e der y, 74t tha idomide, 709t, 724t, 726t
249, 253t Dermato ogic disorders vinb astine, 709t, 724t, 726t
pharmaco ogy, 106t, 117t eczema, 720, 722, 723 in estation agents, 708t, 725t
Dapsone impetigo, 714 benzy a coho , 708t, 725t
dermato ogic, 709t, 724t, 726t pruritus, 720, 720t crotamiton, 708t, 725t
eprosy, 579t, 581 , 583–586, 587t psoriasis, 709t, 710 , 715–716 ivermectin, 708t, 725t
Daptomycin, 569t, 570 , 573, pyoderma, 714 indane, 708t, 725t
575, 577t tinea corporis, 719 ma athion, 708t, 725t
dosing schedu e, 515 topica administration, 714–715 permethrin, 708t, 725t
mechanisms o action, 569t, 573 Dermato ogic therapies, 707–727 percutaneous absorption, 710t,
Darbepoetin a a, 405t, 406–409, 418t a ky ating agents, 708t, 724t, 726 711–715, 711t, 713 (See also Skin
Dari enacin, 96t, 101t, 113t carmustine, 708t, 724t, 726t absorption)
Darunavir, 601t, 603t, 608 , 609 , 622t cyc ophosphamide, 708t, 724t, 726t photochemotherapeutic, 707t,
Dasatinib mech orethamine, 708t, 724t, 726t 716t, 725t
anticancer, 661t, 668, 683t androgenic a opecia, 710t, 726t methoxsa en, 707t, 716t, 725t
mechanisms o resistance, 668 nasteride, 710t, 726t photopheresis, 716t
pharmacodynamics, 15 minoxidi , 710t, 726t PUVA, 716–717, 716t, 725t
Daunorubicin, 643t, 658t antima aria agents, 708t, 725t trioxsa en, 716t
ch oroquine, 708t, 725t photodynamic therapy, 708t, 716t, 725t
744
Dermato ogic therapies (Cont.) Diazoxide sitag iptin, 471t, 472 , 479t
amino evu inic acid, 708t, 725t hypertension and edema, 278t, 287t vi dag iptan, 471t, 472 , 479t
methy amino evu inate, 708t, 725t hypog ycemia, 471t, 472 , 476, 479t Dimenhydrinate, 346t, 353t
podophy in, 727t Dibucaine, 224t Diphenhydramine, 19–22, 40t, 42t, 65t
rate- imiting step, 721, 722 Dic o enac, 357t, 362t, 371, 372, 373t adverse e ects, 89–90, 347
retinoids, 707t, 717–718, 717b, 724t ophtha mic, 691t, 705t or a ergic reaction, ood, 349–350
acitretin, 707t, 724t Dic oxaci in, 551, 552t, 554, 555, 555t antidote use, 42t, 65t
adapa ene, 707t, 724t Dicyc omine (hydroch oride) antihistamine, 3–6
a itretinoin, 707t, 724t bowe antispasmodic, 498t, 508t e der y, 69
bexarotene, 707t, 724t pharmaco ogy, 96t, 113t H 1 receptor antagonist, 3–6, 346t,
isotretinoin, 707t, 721, 722, 724t Didanosine, 601t, 603t, 607 , 608 , 621t 347–350
pregnancy warning, 721, 722, 724t mechanisms o action and resistance, ipid membrane di usion,
tazarotene, 707t, 724t 603t, 607 , 608 19–20, 20
tretinoin, 707t, 724t structure, 607 mechanisms o action, 346t, 347
sunscreens, 710t, 719b, 726t Di enoxin, 209t motion sickness, 350
vitamin ana ogs, ca cipotriene, 707t, 724t Di enoxin + atropine, 498t, 508t pharmacodynamics, 3–6
Des urane, 210t, 215t, 220, 221, 223t Di erentiating agents pharmacokinetics, 19–22
Desiccated thyroid, 431t, 439t arsenic trioxide, 630 , 645t, 646t, 660t pregnancy, 352
Desipramine, 150t, 173t HDAC inhibitors, 645t, 660t toxidrome, 53t
Desirudin, 333t romidepsin, 645t, 660t Diphenoxy ate, 209t
Des oratadine, 347t, 355t vorinostat, 645t, 646t, 660t Diphenoxy ate + atropine, 498t, 500, 508t
Des ore in, 664t retinoids, 645t, 646t, 659t Diphyllobothrium latum, 537–540
Desmopressin (DDAVP), 279t, 288t Di usion. See also B ood-brain barrier Dipive rin, ophtha mic, 690t, 695t, 704t
Desonide, 460t. See also Corticosteroids (BBB); B ood-CSF barrier Direct actor Xa inhibitors, 323t, 333t
Desven a axine, 130t, 147t, 150t, 174t aci itated, 19b, 19 apixaban, 323t, 328, 331, 333t
Detoxi cation. See Addiction; speci c drugs ionized mo ecu es, 19b, 19 mechanisms o action, 323t
Dexamethasone, 460t. See also ipid membrane, 19–20, 20 rivaroxaban, 323t, 328, 333t
Corticosteroids nonionized mo ecu es, 19–20, 19b–20b, Direct renin inhibitors, 270t, 273t, 286t
anticancer, 664t, 686t 19 , 20 , 35, 37–38 a iskiren, 273t, 282, 283, 286t
ophtha mic, 691t, 705t passive, 19b, 19 mechanisms o action, 273t
Dexamethasone suppression test, 465–466 Di orasone diacetate, 460t. See also structure, 275
Dex ansoprazo e, 490t, 496t Corticosteroids Direct renin inhibitors/vasodi ators, 270t
Dexmedetomidine Di unisa , 357t, 360t, 373t Direct thrombin inhibitors, 323t, 333t
anesthetic adjunct, 211t, 223t 2',2'-Di uorodeoxyuridine. See Gemcitabine argatroban, 323t, 330, 331, 333t
pharmaco ogy, 119t, 139t Di uprednate biva irudin, 323t, 333t
Dexmethy phenidate, 120t, 141t ophtha mic, 691t, 705t dabigatran etexi ate, 323t, 328, 333t
Dexpantheno , 498t, 507t Digoxin desirudin, 333t
Dextromethorphan, 209t, 210t, 391t, 404t antiarrhythmic, 312t, 317t, 319, mechanisms o action, 323t
Diabetes me itus 320, 322t Disease mode s, 7
antihypertensives, 273–274 atria bri ation, 319, 320 Disease-modi ying anti-rheumatic drugs
diagnostic criteria, 473, 473t e ectrophysio ogic actions, 317t (DMARDs), 368b, 368t, 379–380
drugs promoting, 477t heart ai ure, 301t, 306, 307, 308t, 311t bio ogica s
g ucocorticoids, 467, 468 maintenance dose, steady state, abatacept, 368t
hypertension with, 273–274 30–31, 34 ada imumab, 368t
type 1, 473–474 (See also Insu in) pharmacokinetics, 30–34 anakinra, 368t
type 2, 473t, 474–476, 475 (See also Anti- pharmaco ogy, 308t certo izumab, 368t
diabetic agents, ora ) therapeutic index, 31, 306 go imumab, 368t
Diabetes me itus pharmacotheapy, toxicity, 306, 309, 310 in iximab, 368t, 376t, 380, 386t
470–479 vo ume o distribution, 30 rituximab, 368t
antidiabetic drugs (See Antidiabetic Dihydrotachystero , 481b rheumatoid arthritis, 368b, 368t, 379–380
agents, ora ) Dihydrotestosterone, 449 sma mo ecu es
comprehensive care, 473, 473 Diisopropy uorophosphate (DFP), 103t, 104 azathioprine, 368t, 375t, 380, 385t
drug deve opment, 6–9 Di tiazem cyc ophosphamide, 368t
hemog obin A1c, 473, 474t, 475–476 antiarrhythmic, 312t, 315, 317t, 322t cyc osporine, 368t, 376t, 380, 385t
insu in, 470–474 antihypertensive, 277t, 278, 287t hydroxych oroquine, 368t
therapeutic goa s, 473, 474t e ectrophysio ogic actions, 317t e unomide, 368t
Dia ysis disequi ibrium syndrome, 283t myocardia ischemia, 290t, 300t methotrexate, 368b, 368t, 380
Diarrhea Dimenhydrinate, 352 minocyc ine, 368t
causes, 499b Dimercapro , 41t, 42t, 66t su asa azine, 368t
drugs, 498t, 508t (See also Antidiarrhea Dimercaptosuccinic acid (DMSA), 41t, 66t Disease progression time ine, antimicrobia
agents) Dimethoxymethamphetamine (DOM), 266 therapy, 516, 516
Giardia intestinalis, 500–501 Dipeptidy peptidase-4 (DPP-4) inhibitors, Disopyramide
Diazepam, 176t, 191t, 192t 471t, 472 , 476, 479t antiarrhythmic, 312t, 317t, 321t
context-sensitive ha -time, 214 A og iptin, 471t, 472 , 479t e ectrophysio ogic actions, 317t
e der y, 71 mechanisms o action, 471t, 472 Dispositiona antagonism, 48b
Diazinon, 100t, 103t, 115t saxag iptin, 471t, 472 , 479t Dissociation rate (k-1), 6b
745
Distribution, 20 , 21b. See also speci c drugs methyc othiazide, 269t, 284t ropiniro e, 130t, 148t
and drugs classes meto azone, 269t, 284t rotigotine, 130t, 148t
chi dren, 68b po ythiazide, 269t, 284t serotonin, norepinephrine, and dopamine
CNS, 24b quinethazone, 269t, 284t reuptake inhibitors, 147t
de nition, 21b trich ormethiazide, 269t, 284t serotonin synthesis and inactivation, 131
e der y, 74b, 75t treatment a gorithm, 275 , 276 sibutramine, 147t
phases, 21b DMSA, 41t, 66t Dopaminergic (DA) receptor agonists,
poisoning, 52 DNA 130t, 148t
rate, 20 , 36b–37b, 37 drug binding, 2b Dopaminergic (DA) receptor antagonists,
tissue, 21b repair mechanisms, 629b 130t, 148t
transmembrane, weak e ectro ytes, 19–20, DNase (dornase a a), muco ytic, 390t, 404t Dopaminergic termina , 138–139, 138
19b–20b, 19 , 20 , 35, 37–38 DNA virus rep icative cyc es, 604 Dopexamine, 118t, 139t
Disu ram, 177t, 178 , 186–187, 186t, Dobutamine, 125t, 142t Doripenem, 558t
193t, 257 heart ai ure, 302t, 307–308, 308t, 311t Dornase a a, muco ytic, 390t, 404t
Diuretics, 268t–269t, 269–272, 270t, mechanisms o action, 307–308 Dorzo amide, ophtha mic, 691t, 705t
283t–285t. See also speci c types Docetaxe , 642t, 648–650, 656t Dose. See also speci c drugs and drug classes
atria natriuretic peptide, 269t mechanisms o action, 630 , 642t, e ective vs. etha , 44
carperitide, 269t, 284t 648–650 Dose-dependent reactions, 46t
nesiritide, 269t, 280, 284t mechanisms o resistance, 642t, 644b Dose-response curves (re ationship), 4 –7 ,
carbonic anhydrase inhibitors, 268t, 271t, toxicities, 656t 6b, 6 , 8–9, 44 , 45
272 , 283t uses, 644t, 656t graded vs. quanta , 45
acetazo amide, 268t, 283t Docosano , 600t toxicity, 44 , 45
brinzo amide, 283t Docusate sodium, 498t, 508t Dosing interva , 31, 38b–39b
dich orphenamide, 268t Do eti ide Dosing rate, 31, 35b, 38, 38b, 38 , 39
dorzo amide, 283t antiarrhythmic, 312t, 317t, 322t Dosing schedu e. See also speci c agents
methazo amide, 268t e ectrophysio ogic actions, 317t on concentration-time pro e, 514, 515
c assi cation, 270t, 272 Do asetron, 130t, 147t resistance suppression, 515
excretory and rena hemodynamic DOM, 266 Doxacurium, 106t, 107t, 117t
e ects, 271t Domperidone, 497t, 507t Doxapram, 391t, 404t
heart ai ure, 284t–285t, 301t, 304, 311t Donepezi Doxazosin
ibupro en on, 282, 283 A zheimer’s disease, 239t, 246, 247t, antihypertensive, 277t, 286t
K+-sparing, minera ocorticoid antago- 250–252, 253t pharmaco ogy, 119t, 140t
nists, 269t, 271t, 272 , 285t pharmaco ogy, 100t, 115t Doxepin, 150t, 173t, 346t, 353t
ep erenone, 269t, 280–281, 285t Dopamine (DA), 118t, 139t Doxerca ci ero , 481b
spirono actone, 269t, 285t, 307 derivatives, 118t, 139t Doxorubicin, 643t, 645–647, 658t
K+-sparing, Na+-channe inhibitors, 269t, heart ai ure, 302t, 307–308, dermato ogic, 709t, 726t
271t, 272 , 284t 308t, 311t mechanisms o action, 630 , 643t,
ami oride, 269t, 284t Parkinson’s disease, 240–241, 241 645–647
triamterene, 269t, 282, 283, 284t postsynaptic e ect, 136–137, mechanisms o resistance, 645b
oop, 269t, 271t, 272 , 284t 138–139, 138 Doxycyc ine, 568t, 569 , 571, 574, 575, 576t
bumetanide, 269t, 282, 283, 284t storage and re ease, 122 ma aria chemoprophy axis, 522t
ethacrynic acid, 269t, 284t synthesis, 122 , 239, 240 mechanisms o action, 568t, 571
urosemide, 269t, 280, 284t, 306 Dopamine (DA) agonists, endocrine, MRSA in ections, 571
torsemide, 269t, 284t 422t, 428t DPP-4. See Dipeptidy peptidase-4
mechanisms and sites o action, bromocriptine, 422t, 426, 428t (DPP-4) inhibitors
268t–269t, 270b–271b, 270t, cabergo ine, 422t, 426, 428t Dronabino
271t, 272 pro actin-secreting pituitary or anorexia, 266
nephrons, 270b adenoma, 426 antidiarrhea , 498t, 502, 502t, 508t
NSAIDs and resistance, 274b quinago ide, 422t, 426, 428t or nausea and vomiting, 502, 502t
osmotic, 268t, 271t, 283t Dopamine (DA) receptors, 122 chemotherapy-re ated, 265, 266
g ycerin, 268t, 283t Dopaminergic pharmaco ogy Dronedarone
isosorbide, 268t, 283t apomorphine, 130t, 148t antiarrhythmic, 312t, 317t, 321t
mannito , 268t, 283t aripiprazo e, 130t, 148t, 162–163, 165 e ectrophysio ogic actions, 317t
urea, 268t, 283t bromocriptine, 130t, 148t Droperido , 151t, 175t
renin re ease pathways, 272 cabergo ine, 130t, 148t Drospirenone, 441t, 443t, 444t, 446t
resistance, 274b dopamine, 118t, 139t Drotrecogin a a, 323t, 333t
therapy, 274b dopamine derivatives, 118t, 139t Drugabi ity, 7
thiazide/thiazide- ike, 269t, 271, 271t, dopaminergic receptor agonists, 130t, Drug addiction. See Addiction, drug; Opioid
272 , 284t 148t, 422t, 426, 428t pharmaco ogy; speci c drugs
bendro umethiazide, 269t, 284t dopaminergic receptor antagonists, Drug approva process, FDA, 44 , 45t,
ch orothiazide, 269t, 284t 130t, 148t 46–48, 46t
ch ortha idone, 269t, 284t dopexamine, 118t, 139t Drug deve opment, 6–9
hydroch orothiazide, 269t, 271, eno dopam, 118t, 139t Drug–drug interactions, 48. See also speci c
273–274, 282, 283, 284t mechanisms o action, 130t drugs and drug classes
hydro umethiazide, 269t, 284t pergo ide, 130t, 148t on absorption, 48t
indapamide, 269t, 284t pramipexo e, 130t, 148t acetaminophen, 48
746
Drug–drug interactions (Cont.) mu tip e-agent therapy, 339 distribution and vo ume o distribution,
additive, 48b nicotinic acid, 335t, 343t 74b, 75t
antiarrhythmics, 319, 320 mechanisms o action, 335t excretion, 76b, 78t
c assi cation and description, 48b, 48t niacin, 335t, 340, 341, 342, 343t rst-pass c earance, 73t–74t
CYP, 30b pregnancy risk, 340 ha - i e, 77
on drug metabo ism, 48, 48b, 48t vytorin, 339, 340 metabo ism, 73t–74t, 75b
Drug interactions, 47 . See also speci c drugs Dystonia, acute, 172t p asma concentration–time curves, 73 , 73t
and drug classes E ectro ytes, weak
Drug overdose, 63, 64 E p asma–gastric juice partitioning,
Drug penetration, 512–513, 512b Ebastine, 347t, 355t 19b–20b, 20 , 21–22
Drug receptor, 2b, 3t. See also Receptor, drug; Echinocandins, 588t, 589 , 598t transmembrane distribution, 19–20,
speci c drugs and receptors anidu a ungin, 598t 19b–20b, 19 , 20 , 35, 37–38
Drug-receptor comp ex (LR), 6b caspo ungin, 588t, 589 , 593, 593 , 598t E etriptan, 130t, 147t
Drug-receptor comp ex con ormationa mechanisms o action, 588t, 593, 593 11β-hydroxysteroid dehydrogenase, 464 ,
change (LR*), 6b mica ungin, 598t 467, 468
Drug–receptor interactions, 3b–5b, 4 , 6b Echothiophate, ophtha mic, 690t, 695t, 704t E imination, 35b. See also C earance;
Drug-re ated deaths, agents, 51t Econazo e, 588t, 597t speci c drugs
Drug target, 2b Eczema, 720, 722, 723 rst-order kinetics, 36b
Drug testing, new drug, 44 , 45, 45t Edema drugs poisoning, 52
D IC. See Dacarbazine (D IC) diuretics (See Diuretics) E imination t1/2, 34b, 37 , 39b
Du oxetine, 130t, 147t, 150t, 174t to vaptan, 279t, 281, 288t e der y, 77
Duodena u cers Edrophonium, 100t, 104–105, 104 , 114t E trombopag, 406t, 419t
proton pump inhibitor + c arithromycin + ED A CaNa2, 41t, 42t, 63, 64, 66t Emedastine di umarate
metronidazo e or amoxici in, 492, E a izumab ophtha mic, 691t, 705t
494t, 495, 571 dermato ogic, 709t, 710 , 714t, 726t Emesis. See Antinauseants and antiemetics
proton pump inhibitors, 492, 493, immunotherapy, 376t, 386t Emetic stimu i, 501, 501
494t, 495 psoriasis, 709t, 710 Empiric therapy. See also speci c drugs and
Duration o action, 36 E avirenz, 601t, 603t, 623t disorders
Dutasteride, 442t, 458t mechanisms o action and resistance, antimicrobia , 516 , 518–519
Dyc onine, 224t 603t, 608 , 610 Emtricitabine, 601t, 603t, 621t
Dys ipidemia structure, 610 mechanisms o action and resistance,
c assi cation, 337t E ective concentration, ha -maxima (EC50), 603t, 607 , 608
high-risk, 335b, 337t 6 , 7b, 9 structure, 607
LDL-C treatment guide ines, 336t E ective dose, 44 Ena apri , 273t, 274–276, 275 , 285t
Dys ipidemia drugs, 334–344 vs. etha dose, 44 Ena apri at, 273t, 285t
bi e acid–binding resins, 334t, 339, median (ED50), 44 , 45 Endocannabinoids, 358
340, 343t E ector organs, autonomic, 83t–84t Endocarditis risk and prophy axis, 515b, 516
cho estyramine, 334t, 342–343, 343t E ector tone Endocrine pancreas and pharmacotherapy,
co eseve am, 334t, 340, 343t parasympathetic, 107t insu in
co estipo , 334t, 342–343, 343t sympathetic, 107t secretion regu ation, 470t, 472
mechanisms o action, 334t E erent nerves, autonomic nervous system, 82 signa ing pathways, 470t, 471
cho estero absorption inhibitor E cacious, 7b Endothe in-1 receptor antagonists,
ezetimibe, 335t, 344t, 350 E cacy pu monary, 391t, 404t
ezetimibe/simvastatin, 344t, 350 u , 4b, 4 adverse e ects, 400
bric acid, 335t, 339, 344t re ative, 7b, 7 , 9 ambrisentan, 391t, 398–400, 399 , 404t
beza brate, 335t, 344t Ef ux pumps, 515b, 517 bosentan, 391t, 398–400, 399 , 404t
cipro brate, 335t, 344t antimicrobia agent, 516b mechanisms o action, 391t
c o brate, 335t, 344t resistance, 515b, 517 pu monary artery hypertension,
eno brate, 335t, 341, 342, 344t Ef ux transporters, 24b 398–400, 399
gem brozi , 335t, 344t b ood-brain and b ood-CSF barriers, Endotrachea intubation, neuromuscu ar
HMG-CoA reductase inhibitors, 24b, 28 b ocking drugs, 216. See also
334t, 343t E ornithine, 530t, 535t Neuromuscu ar b ocking agents
adverse e ects, 338 EGFR (ErbB1), 667t En urane, 210t, 215t, 223t
atorvastatin, 334t, 343t E der y, 68–69, 72, 75 En uvirtide, 601t, 603t, 608 , 611 , 616, 623t
choice, 342, 343 benzodiazepines, 71, 77b adverse e ects, 616
uvastatin sodium, 334t, 343t diphenhydramine, 40t, 65t, 69 HIV, 617–618
ovastatin, 334t, 341, 342, 343t drug response, 77b mechanisms o action and resistance,
mechanisms o action, 334t, 337 inappropriate medications, 603t, 608 , 611 , 616
other drugs with, 339 69–70, 78b Eno ic acid derivatives
pitavastatin ca cium, 334t, 343t NSAIDs, 68–69, 72, 75 me oxicam, 357t, 363t, 373t
pravastatin ca cium, 334t, 343t optimizing drug regimens, 77b nabumetone, 357t, 363t, 373t
pregnancy risks, 340 therapeutic window, 11 , 12, 12 piroxicam, 357t, 363t, 373t
rosuvastatin ca cium, 334t, 338, 343t tricyc ic antidepressants, 72, 75 Enoxaparin, 323t, 325, 333t
simvastatin, 334t, 343t E der y pharmacokinetics Entacapone
LDL-C treatment guide ines, 336t absorption and bioavai abi ity, 73b, 73 , antivira , 600t, 602t, 620t
mechanisms o action, 334t–335t 73t–74t Parkinson’s disease, 238t, 242t,
or metabo ic syndrome, 339–340 c earance, 75b, 76 , 76t–77t, 77 244 , 251, 252t
747
Enteric nervous system, 82–83 Epoprosteno estropipate, 441t, 445t
Entecavir adverse e ects, 400 ethiny estradio , 441t, 457t
antihepatitis, 600t, 602t, 620t pu monary, 391t, 398–400, 399 , 404t gonadotropin secretion, 447
HIV + chronic HBV, 618, 619 Epothi ones, 643t, 644b, 650, 657t hormone rep acement therapy, 441t–442t,
Enterobius in ection, 536, 539, 540 Epti batide, 323t, 324–325, 332t 445t–446t, 446–448, 455–457, 458t
Entry inhibitors, 601t, 603t, 608 , 611 , Equi ibration, 20 , 36b–37b, 37 evonorgestre , 443t, 444t, 446t
616, 623t Equi ibrative transport, membrane mechanisms o action, 441t–442t
en uvirtide, 601t, 603t, 608 , 611 , transporters, 23b ora contraceptives, 441t–444t, 448–450
616, 623t Equi ibrium association constant (KA), 6b, 8 (See also Contraceptives, ora )
maraviroc, 601t, 603t, 608 , Equi ibrium dissociation constant (KD), 6b, se ective estrogen receptor modu ators,
611 , 623t 8, 16, 17 442t, 458t
mechanisms o action and resistance, 603t ErbB2-targeted agents, 672–673 ra oxi ene, 442t, 458t
Environmenta toxicity. See oxicity, ER+ breast cancer, 676–679 tamoxi en, 442t, 451, 456, 457,
c inica and environmenta Ergoca ci ero , 481t, 488t 458t, 667
Enzymes. See also speci c types Ergot a ka oids and derivatives, 120t, toremi ene, 442t, 458t
biotrans orming, 29b, 29t 141t, 147t synthetic conjugated estrogens, 441t
intrace u ar, 3t Er otinib, 661t, 670–672, 683t Estrogen synthesis inhibitors, 442t, 458t
transmembrane, 3t Ertapenem, 558t anastrozo e, 442t, 458t, 664t, 678
xenobiotic metabo izing, 29b, 29t Erythromycin, 568t, 570 , 576t exemestane, 442t, 458t
Epiderma growth actor receptor (EGFR), in bowe disorders, 497t, 507t ormestane, 442t, 458t
epithe ia cancers, 669 Erythropoietin (EPO), 407t, 408 etrozo e, 442t, 458t
Epiderma growth actor receptor (EGFR) Escherichia coli, cyc oserine, 579t, 587t Estropipate, 441t, 445t
targeting agents, 669–671 Escita opram, 130t, 146t Eszopic one, 177t, 192t
adverse e ects, 671 Esmo o Etanercept
cetuximab, 662t, 669–672, 683t antiarrhythmic, 312t, 321t dermato ogic, 709t, 714t, 726t
c asses, 669 pharmaco ogy, 126t, 128t, 146t immunotherapy, 376t, 380, 386t
epithe ia cancers treated, 670–671 Esomeprazo e, 490t, 495, 496t Ethacrynic acid, 269t, 284t
er otinib, 661t, 670–672, 683t Estazo am, 176t, 191t, 192t Ethambuto
ge tinib, 661t, 670–672, 683t Estradio cypionate, 441t, 457t Mycobacterium avium comp ex,
mechanisms o resistance, 672 Estradio + drospirenone, 441t, 444t, 457t 578t, 583, 587t
Epidermis, 713 Estradio micronized, 441t, 457t tubercu osis, 578t, 583, 587t
Epi epsy Estradio nonmicronized, 441t, 457t Ethano . See also A coho ism
drug choice, 227b Estradio + norethindrone, 441t, 443t, 444t, abstention, 183
ear y diagnosis and treatment, 228 446t, 457t with acetaminophen, 366
genera princip es, 227b Estradio , testosterone e ects, 449 a coho dehydrogenase 2*2, 178 ,
pharmacotherapy (See Antiseizure drugs) Estradio transderma /topica ge , 441t, 189, 190
seizure c assi cation, 228, 229t 445t, 457t antidote, 42t, 50, 65t
treatment princip es, 227b, 228 Estradio vagina ring/vagina tab ets, 441t, cocaine with, 265, 266
Epinastine, ophtha mic, 691t, 705t 445t, 457t coronary heart disease protection,
Epinephrine (E) Estradio va erate, 441t, 457t 182–183
adverse e ects, 217 Estramustine, 630 , 643t, 650, 657t drug-re ated deaths, 51t
or a ergic reactions, 349–350 Estrogen antagonists, 442t, 458t eta a coho syndrome, 182b, 187
anaphy axis, 56 c omiphene, 442t, 452, 455–457, 458t metabo ism, 49 , 178
end artery tissues, gangrene, u vestrant, 442t, 458t metronidazo e with, 533, 534
220, 221–222 mechanisms o action, 442t neurochemica system impacts, 185t
in oca anesthetics, 217 Estrogen esteri ed esters, 441t physio ogica system e ects, 183,
metabo ism, 121 Estrogen receptor, 448 183t–185t, 189, 190
pharmaco ogy, 118t, 139t Estrogens, 441t, 457t poisoning, 41t, 49 , 65t
synthesis, storage, and re ease, 122 anticancer, 664t, 665t, 679t, 686t, 687t teratogenic e ects, 182b, 187
Epinephrine (E) receptors, 122 biosynthetic pathways, 446 toxicity, 41t, 65t
Epipodophy otoxins, 643t, 657t conjugated equine estrogens, 441t, 445t Ethiny estradio , 441t, 457t
etoposide, 630 , 643t, 645b, 657t conjugated estrogen + medroxyprogester- Ethionamide, 579t, 587t
mechanisms o action, 630 , 643t one acetate, 441t Ethosuximide, 225t, 230–231, 234,
mechanisms o resistance, 643t, 645b drospirenone, 441t, 443t, 444t, 446t 235, 236t
teniposide, 630 , 643t, 645b, 657t estradio cypionate, 441t, 457t Ethy ene g yco antidote
toxicities, 657t estradio + drospirenone, 441t, 444t, 457t ethano , 65t
uses, 644t, 657t estradio micronized, 441t, 457t omepizo e, 42t, 65t, 178
Epirubicin, 643t, 658t estradio nonmicronized, 441t, 457t Ethy eneimines and methy me anines,
mechanisms o action, 630 , 643t, estradio + norethindrone, 441t, 443t, 627t, 651t
645–647 444t, 446t, 457t a tretamine, 627t, 651t
mechanisms o resistance, 645b estradio transderma /topica ge , 441t, mechanisms o action, 627t,
Epithe ia cancers, EGFR overexpression/ 445t, 457t 628b–629b, 630
activation, 669–672 estradio vagina ring/vagina tab ets, mechanisms o resistance, 627t,
Ep erenone, 269t, 280–281, 441t, 445t, 457t 632–633, 632b
285t, 302t, 311t estradio va erate, 441t, 457t thiotepa, 627t, 632t, 651t
Epoetin a a, 405t, 406–409, 418t estrogen esteri ed esters, 441t toxicities, 632b–633b, 632t, 651t
748
Etidronate sodium, 481t, 488t Fe odipine mechanisms o resistance, 638b–639b,
Etodo ac, 357t, 361t, 373t antihypertensive, 277t, 287t 640–641
Etomidate, 459t, 469t myocardia ischemia, 290t, 300t toxicities, 637t, 641, 654t
anesthetic, 210t, 213t, 214 , 222t Fenamates uses, 637t, 654t
context-sensitive ha -time, 214 u enamic acid, 362t, 373t FL -3 igand (FL), 407t, 408
parentera anesthetic, 210t, 213t, 222t mec o enamate, 357t, 362t, 373t F uconazo e, 588t, 589 , 590, 597t
sedative-hypnotic, 177t, 193t me enamic acid, 357t, 362t, 373t adverse e ects, 719
Etoposide (VP-16-213), 643t, 657t Feno brate, 335t, 341, 342, 344t ormu ations and actions, 597t
mechanisms o action, 630 , 643t Feno dopam mechanisms o action and resistance,
mechanisms o resistance, 643t, 645b hypertension and edema, 278t, 287t 588t, 590
toxicities, 657t pharmaco ogy, 118t, 139t tinea corporis, 719
uses, 644t, 657t Fenotero , 125t, 143t war arin interaction, 595, 596
Etoricoxib, 363t Fentany F ucytosine, 588t, 589 , 595, 596, 596t
Etravirine, 601t, 603t, 608 , 610 , 623t heroin with, 260 F udarabine phosphate, 630 , 636t, 655t
mechanisms o action and resistance, pharmaco ogy, 194t, 195t, 203, mechanisms o action, 630 , 636t,
603t, 608 , 610 205–207, 208t 641–642
structure, 610 Ferrous aspartate, 406t, 413–414, 419t mechanisms o resistance, 636t,
Evero imus Ferrous umarate, 406t, 413–414, 419t 638b–640b
anticancer, 663t, 685t Ferrous g uconate, 406t, 413–414, 419t toxicities, 642
immunotherapy, 375t, 385t Ferrous sa ts, 406t, 413–414, 419t uses, 637t
Excitatory postsynaptic potentia (EPSP), Ferrous succinate, 406t, 413–414, 419t F udrocortisone acetate, 460t
autonomic, 106 Ferrous su ate, 406t, 413–414, 419t F umazeni , 41t, 42t, 65t, 177t, 179–180, 192t
Excretion, 20 Ferti ity agents, 442t, 452, 455–457, 458t F u medicines. See also speci c agents and
chi dren, 69b Ferumoxyto , 406t, 419t ingredients
e der y, 76b, 78t Fesoterodine, 96t, 101t, 113t a coho with, 366
pH, 20b Feta a coho syndrome, 182b F uniso ide, 460t. See also Corticosteroids
weak acid, 36, 39 Fexo enadine, 347t, 355t pu monary, 390t, 403t
Exemestane Fibric acid ( brates), 335t, 339, 344t F uocino one, ophtha mic, 691t, 705t
anticancer, 664t, 677t, 679t, 686t beza brate, 335t, 344t F uocino one acetonide, 460t
estrogen synthesis inhibitor, 442t, 458t cipro brate, 335t, 344t F uocinonide, 460t
Exenatide, 471t, 472 , 479t c o brate, 335t, 344t F uorodeoxyuridine. See F oxuridine
Exercise-induced angina, 290t, 291 eno brate, 335t, 341, 342, 344t (FUdR, uorodeoxyuridine)
Exertiona angina, 290t, 291 gem brozi , 335t, 344t F uorometho one, 460t
Expectorants, 390t, 404t Fibrin c ot ormation, 325–326, 326 F uorometho one acetate, 460t
Eye Fibrino ysis, 329, 329 F uorometo one, ophtha mic, 691t, 705t
anatomy, 699 Fibrino ytics, tPA, 323t, 333t 5-F uorouraci , 635t, 640–641, 654t
autonomic innervation, 694 a tep ase, 323t, 329–330, 329 , 333t activation pathways, 638
Eythropoiesis-stimu ating agents (ESAs), mechanisms o action, 323t agents combined with, 648, 649
405t, 418t retep ase, 323t, 333t dermato ogic, 708t, 724t, 725t
darbepoetin a a, 405t, 406–409, 418t tenectep ase, 323t, 333t mechanisms and sites o action, 630 ,
epoetin a a, 405t, 406–409, 418t Fibrogen ge , ophtha mic, 692t, 706t 635t, 638 , 640
indications, 406–409 Fi grastim. See G-CSF ( grastim) mechanisms o resistance, 635t,
iron de ciency rom, 409 Finasteride, 442t, 456, 457, 458t 638b–639b, 640–641
mechanisms o action, 405t androgenic a opecia, 710t, 726t ophtha mic, 691t, 705t
toxicities and hazards, 409 First-pass e ect, 20b, 35, 36–37 topica , precancerous skin esions,
e der y, 73t–74t 640–641
F nitrog ycerin and nitrates, 22, toxicities, 637t, 641, 654t
Faci itated di usion, 19b, 19 291, 299 uses, 637t, 654t
Faci itated transport, 23b Fish tapeworm, 537–540 F uoxetine
Factor Xa inhibitors, direct, 323t, 333t 5-ASA, 498t, 503 , 509t on CYP2D6, 157
apixaban, 323t, 328, 331, 333t 5-F uorouraci (5-FU), 635t, 640–641, 654t. Huntington’s disease, 248
mechanisms o action, 323t See also 5-F uorouraci pharmaco ogy, dopaminergic and seroto-
rivaroxaban, 323t, 328, 333t 5-LOX inhibitors, 390t, 403t nergic, 130t, 131–133, 131 , 133t,
Famcic ovir, 605, 608 5α-reductase inhibitors, 442t, 458t 146t
Famotidine dutasteride, 442t, 458t psychopharmaco ogy, 150t, 157, 174t
gastric acid disease, 490t, 496t nasteride, 442t, 456, 457, 458t F uphenazine, 150t, 174t
structure, 492 FK506-binding protein-12 (FKBP-12), F urandreno ide, 460t. See also
FDA 383, 384 Corticosteroids
chi dren, 71b–72b F avoxate, 96t F urazepam, 176t, 180, 191t, 192t
drug approva process, 44 , 45t, F ecainide F urbipro en, ophtha mic, 691t, 705t
46–48, 46t antiarrhythmic, 312t, 317t, 321t F utamide
pregnancy and breast eeding, 72b e ectrophysio ogic actions, 317t androgen receptor antagonist action, 442t,
FDA Sa ety and Innovation Act o F oxuridine (FUdR, uorodeoxyuridine), 454, 456, 457, 458t, 679t
2012, 72b 635t, 640–641, 654t anticancer, targeted, 665t, 679t, 687t
Febuxostat, 369t, 370, 374t mechanisms and sites o action, 630 , prostate cancer, 442t, 454, 456, 457, 679t
Fe bamate, 226t, 237t 635t, 638 , 640 F uticasone, 390t, 403t
749
F uvastatin (sodium), 334t, 343t neonata , 70b prostag andin ana og, misoprosto , 490t,
F uvoxamine, 130t, 146t, 150t, 174t Funga in ections. See also speci c types 493, 494, 495, 496t
Fo ate de ciency, 412 , 413b, 414–415 agents (See Anti unga agents) proton pump inhibitors, 490t, 491 , 492,
pregnancy, 416, 417 aspergi osis, invasive, 595, 596 493 , 496t
trimethoprim-su amethoxazo e, candidiasis dex ansoprazo e, 490t, 496t
543, 543 esophagea , 589 , 590t–592t, esomeprazo e, 490t, 495, 496t
Fo ate metabo ism, 543 594–596 gastroesophagea re ux disease,
Fo ic acid ana ogs (anti o ates), 635t, 653t ora , 467, 468 492, 493
Fo ic acid and derivatives, 406t, 412 , vagina , 594 iron de ciency rom, 495
415b, 420t coccidioida meningitis, 590, 592t–593t, ansoprazo e, 490t, 493 , 496t
absorption and distribution, 412 595, 596 mechanisms o action, 490t, 491 , 495
de ciency, 412 , 413b, 414–415 cryptococca meningitis, omeprazo e, 490t, 493 , 496t
o ic acid, 406t, 412 , 414–417, 414b, 595, 596 pantoprazo e, 490t, 493 , 496t
415b, 420t eye, 701 rabeprazo e, 490t, 493 , 496t
o inic acid, 406t, 416, 417–418, 420t mucormycoses, 589–590 structures, 493
genera princip es, 414b onychomycosis, 595–596, 721, 722 or u cers, 492, 493, 494t, 495
mechanisms o action, 406t tinea, 593–594 vitamin B12 absorption, 492
vitamin B12 interactions, 410b, 412 Furosemide, 269t, 280, 284t, 304t Gastric emptying, neonates and in ants, 67b
Fo ic acid de ciency, 412 , 413b, 414–415 Gastric secretion, regu ation, 491
pregnancy, 416, 417 G Gastroesophagea re ux disease (GERD),
Fo inic acid, 406t, 416, 417–418, 420t GABA 400. See also Pu monary drugs
Fo ic e-stimu ating hormone (FSH), on GABAA receptor, 226 cimetidine, 491
423t, 429t metabo ism, antiseizure drugs, 225t–226t, management guide ines, 493
o itropin α, 423t, 430t 226b, 226 pregnancy, 494, 495
o itropin β, 423t, 430t GABAA receptor proton pump inhibitors, 492
menotropin, 423t, 429t anesthetics on, 219–221 treatments, 400
uro o itropin, 423t, 429t antiseizure drugs on, 225t, G-CSF ( grastim), 405t, 407t, 408 ,
Fo itropin α, 423t, 430t 225t–226t, 226 409–410, 416, 417, 418t
Fo itropin β, 423t, 430t binding sites, 178 indications, 409–410, 416, 417
Fomepizo e, 41t, 42t, 65t, 178 umazeni , 179 mechanisms o action, 405t, 407t
Fomivirsen, 600t, 619t GABA on, 226 sites o action, 408
antiherpes, 600t, 602t, 609, 619t sedative-hypnotics on, 178 , 179 G-CSF, pegy ated recombinant
CMV retinitis, 609 Gabapentin, 205t, 225t, 237t (peg grastim), 405t, 407t, 408 ,
mechanisms o action and Ga antamine 409–410, 418t
resistance, 602t A zheimer’s disease, 239t, 246, Ge tinib, 661t, 670–672, 683t
Fondaparinux, 323t, 325, 333t 247t, 253t Gemcitabine, 630 , 636t, 654t
Formestane, 442t, 458t pharmaco ogy, 100t, 115t mechanisms and sites o action, 630 ,
Formotero Gancic ovir, 600t, 619t 636t, 638 , 640
pharmaco ogy, 125t, 144t antiherpes, 600t, 602t, 604 , 605, 605 , mechanisms o resistance, 635t, 639b
pu monary, 390t, 402t 609, 617, 618, 619t toxicities, 637t, 654t
Forward rate (k+1), 6b CMV retinitis, 609, 617, 618 uses, 637t, 654t
Foscarnet, 600t, 609–612, 619t herpes simp ex virus, 605 Gem brozi , 335t, 344t
adverse e ects, 612, 617, 618 mechanisms o action and resistance, Gemtuzumab ozogamicin, 662t, 667t,
antiherpes, 600t, 602t, 604 , 605, 609–612, 602t, 604 , 605 672t, 684t
617, 618, 619t Gang ionic b ocking drugs, 106t, 117t Genetic po ymorphisms
CMV retinitis, 609–612 Gang ionic stimu ating agents, nicotine, 106t, CYP, 27t, 28, 31b
herpes simp ex virus, 605 108, 108b, 117t drug response, 10t, 12–14, 13
mechanisms o action and resistance, Ganire ix, 423t, 429t, 665t, 687t Genotoxic e ects, 46t
602t, 604 , 610–612 Gases, therapeutic, 211t, 223t–224t. Gentamicin, 559–566, 559b, 566t
Fosinopri , 273t, 285t See also speci c agents Giardia intestinalis, 500–501
Fosphenytoin, 225t, 236t carbon dioxide, 211t, 223t Giardiasis, 531–532
Fospropo o , 210t, 222t he ium, 211t, 224t diarrhea, 500–501
Fractiona occupancy ( ), 7b, 8 nitric oxide, 211t, 223t metronidazo e, 530t, 532–533, 535t
Frovatriptan, 130t, 147t oxygen, 211t, 223t G argine. See also Diabetes me itus
FUdR. See F oxuridine (FUdR, Gastric acid disease drugs, 490–496 vs. ispro, 478
uorodeoxyuridine) antacids, 490t, 496t G atiramer acetate, 382t
Fu agonists, 4b, 4 , 7b, 9 bismuth, 490t, 496t G aucoma, 699–700, 699
Fu e cacy, 4b, 4 cytoprotective agents, sucra ate, G ic azide, 470t, 472 , 479t
Fu vestrant, 442t, 458t 490t, 496t G imepiride, 470t, 472 , 477, 478, 479t
anticancer, 664t, 677t, 686t H1 receptor antagonists, 490t, 491 , 496t G imepiride + met ormin, 477, 478
estrogen antagonist, 442t, 458t cimetidine, 491, 492t, 494, 495 G ipizide, 470t, 472 , 479t
Fumagi in, 530t, 535t amotidine, 490t, 492 , 496t GLP-1 agonists, 471t, 472 , 476, 479t
Functiona antagonists, 4b mechanisms o action, 490t, 491 exenatide, 471t, 472 , 479t
Functiona iron de ciency, 409 nizatidine, 490t, 492 , 496t irag utide, 471t, 472 , 479t
Functiona ization, phase 1, 28b, 33 , ranitidine, 490t, 492 , 496t mechanisms o action, 471t, 472
35, 38 to erance, 491, 494, 495 G ucocorticoid receptors, 462
750
G ucocorticoids. See also speci c drugs and des ore in, 664t Guanabenz
drug classes GnRH, 664t, 680, 687t antihypertensive, 277t, 286t
anticancer, targeted, 664t, 679t, 686t gosere in, 664t, 687t pharmaco ogy, 119t, 140t
dexamethasone, 664t, 686t histre in, 664t, 687t Guanadre , 277t, 287t
prednisone, 664t, 679t, 686t eupro ide, 664t, 679t, 680, 687t Guan acine
carbohydrate and protein metabo ism, na are in, 664t, 687t antihypertensive, 277t, 286t
467, 468 triptore in, 664t, 687t pharmaco ogy, 119t, 140t
dependence, 505–506, 507 pharmaco ogy and actions Gynecomastia treatment
dermato ogic, 707t, 722, 723, 724t androgen secretion, 425 gonadotropin, 427, 428
adverse e ects, 723, 724t GnRH, 422t, 429t, 680 testosterone, 456, 457
potency, 723t gosere in, 422t, 429t
triamcino one acetonide, 707t, histre in, 423t, 429t H
723t, 724t eupro ide, 423t, 425–426, 429t H 1 receptor antagonists
triamcino one hexacetonide, 707t, na are in, 422t, 427, 428, 429t adverse e ects, 4–6, 347, 350
723t, 724t triptore in, 422t, 429t gastric acid disease, 490t, 491 , 496t
dexamethasone, 664t, 686t Gonadotropin-re easing hormone (GnRH) cimetidine, 491, 492 , 494, 495
dose tapering, 465 antagonists, 423t, 429t amotidine, 490t, 492 , 496t
drug interactions and dosing, 464 anticancer, 665t, 687t mechanisms o action, 490t, 491
drugs against (See Antig ucocorticoids) abare ix, 665t, 687t nizatidine, 490t, 492 , 496t
genera princip es, 464b cetrore ix, 665t, 687t ranitidine, 490t, 492 , 496t
gout, 369t, 370 degare ix, 665t, 687t to erance, 491, 494, 495
immunotherapeutic, 375t, 384t ganire ix, 665t, 687t uses, 6
ophtha mic, 691t, 705t pharmaco ogy and actions H 1 receptor antagonists, rst generation,
dexamethasone, 691t, 705t cetrore ix, 423t, 429t 19–22, 346t, 352–354t
di uprednate, 691t, 705t ganire ix, 423t, 429t adverse e ects, 89–90, 347
uocino one, 691t, 705t Gonadotropins brompheniramine ma eate, 346t, 354t
uorometo one, 691t, 705t or gynecomastia, 427, 428 carbinoxamine, 346t, 353t
otepredno , 691t, 705t neuroendocrine contro , 447 ch orpheniramine, 346t, 354t
predniso one, 691t, 705t secretion, 447 c emastine umarate, 346t, 353t
rimexo one, 691t, 705t Gosere in cyc izine, 346t, 350, 352, 354t, 502t
triamcino one, 691t, 705t anticancer, 664t, 687t cyproheptadine, 346t, 354t
osteoarthritis and diabetes type II, pharmaco ogy and actions, 422t, 429t dermato ogic, 718t
467, 468 Gout, 369t, 370 dimenhydrinate, 346t, 353t
prednisone, 664t, 679t, 686t Gout drugs, 368b, 369–370, 369t, 374 diphenhydramine, 3–6, 346t, 347–350
rheumatoid arthritis, 463–465 g ucocorticoids, 369t, 370 doxepin, 346t, 353t
topica , 465 microtubu e disruptors, 369t drowsiness, 19–20
toxicities, 464b co chicine, 369t, 370, 373t e der y, 69
G ucose-6-phosphate (G6PD), 586 NSAIDs, 369t hydroxyzine, 346t, 354t
G ucose-6-phosphate (G6PD) de ciency urate oxidase, recombinant, 369t ionization and ipid membrane
dapsone with, 584, 585–586 rasburicase, 369t, 374t di usion, 19–20, 20
primaquine with, 527, 528 uricosuric agents, 369t, 370 mechanisms o action, 346t, 347
G ucuronidation, neonata , 70b probenecid, 369t, 370, 374t mec izine, 346t, 350, 352, 354t
G ucuronosy trans erase, in ants, 68 xanthine oxidase inhibitors, 369t motion sickness, 350, 352
G yburide, 470t, 472 , 479t a opurino , 369t, 370–372, 373t phenindamine, 346t, 354t
G ycerin diuretic, 268t, 283t ebuxostat, 369t, 370, 374t pregnancy and actation, 348
G ycopeptides GPIIb/IIIa antip ate et agents, 323t, promethazine, 346t, 350–352, 354t
teicop anin, 569t, 570 , 577t 324–325, 332t pyri amine, 346t, 353t
vancomycin, 569t, 570 , abciximab, 323t, 324–325, vs. second generation, 347b–348b
572–575, 577t 331–332, 332t tripe ennamine, 346t, 353t
G ycopyrro ate epti batide, 323t, 324–325, 332t H 1 receptor antagonists, second
bowe antispasmodic, 498t, 508t mechanisms o action, 323t generation, 347t, 355t
pharmaco ogy, 96t, 113t tiro ban, 323t, 324–325, 332t acrivastine, 347t, 355t
GM, 405t, 407t, 408 , 409–410, 418t G protein–coup ed receptors (GPCRs), 3t, 4 advantages, 348
GnRH. See Gonadotropin-re easing Granisetron, 130t, 147t aze astine, 347t, 355t
hormone (GnRH) Graves disease, 432t, 434t, 435–439 cetirizine, 347t, 348, 348b, 351–352, 355t
Goiter, 437, 438 Gray baby syndrome, 68 dermato ogic, 718t
Go imumab Griseo u vin, 588t, 593–596, 598t, 721, 722 des oratadine, 347t, 355t
immunotherapy, 376t, 386t Growth actor signa ing, 670 . See also speci c ebastine, 347t, 355t
rheumatoid arthritis, 368t growth actors and agents exo enadine, 347t, 355t
Gonadotropin-re easing hormone (GnRH), Growth hormone (GH), 423, 424 vs. rst generation, 347b–348b
422t, 429t, 680 antagonist drug, pegvisomant, 422t, 424, ketoti en umarate, 347t, 355t
anticancer, 664t, 680, 687t 425 , 428t evocabastine, 347t, 355t
Gonadotropin-re easing hormone (GnRH) receptor antagonism, 423, 425 evocetirizine, 347t
agonists, 680 recombinant, 422t, 427, 428, 428t oratadine, 347t, 348, 348b,
anticancer, 664t, 679–680, 687t secretion and actions, 423, 424 351–352, 355t
busere in, 664t, 687t Guai enesin, 390t, 404t mechanisms o action, 347t
751
mizo astine, 347t, 355t β adrenergic receptor agonists, 311t Hematopoietic agents, 405–420,
nonionization and brain concentrations, dobutamine, 302t, 307–308, 405t–406t, 419t
20, 38 308t, 311t copper supp ement, 406t, 419t
o opatadine, 347t, 355t dopamine, 302t, 307–308, 308t, 311t cupric su ate, 406t, 419t
pregnancy and actation, 348, 348b, mechanisms o action, 302t cytokine–ce interactions, 408
351–352 mechanisms o action, heart, erythropoiesis-stimu ating agents,
H 1 receptors, 4 307–308 405t, 418t
H 2 receptor antagonists β adrenergic receptor antagonists, 286t, darbepoetin a a, 405t, 406–409, 418t
dermato ogic, 718t 304, 310t (See also β adrenergic epoetin a a, 405t, 406–409, 418t
e der y, 73b receptor antagonists) indications, 406–409
mechanisms o action, 347t, 491, 491 bisopro o , 301t, 309, 310, 310t iron de ciency rom, 409
structure, 491, 492 carvedi o , 301t, 309, 310, 310t mechanisms o action, 405t
to erance, 491, 494, 495 mechanisms o action, 301t toxicities and hazards, 409
H 2 receptors, 4 metopro o , 301t, 303–304, 306, 310t hematopoietic growth actors, 407t
H 3 receptor antagonists, 347t Brater’s a gorithm, 270t, 273t, 276 , 285t erythropoietin, 407t, 408
H 3 receptors, 4 diuretics, 284t–285t, 301t, 304, 311t (See FL -3 igand, 407t, 408
H 4 receptor antagonists, 347t also Diuretics) inter eukins, 407t, 408
H 4 receptors, 4 ep erenone, 269t, 280–281, 285t mechanisms o action, 407t, 408
Haemophilus in uenzae meningitis prophy- mechanisms o action, 301t–302t sites o action, 408
axis, ri amycins, 578t, 579 –580 , Na+-K+-A Pase inhibitors, 303 , 311t stem ce actor, 407t, 408
581–586, 586t. See also Ri amycins digoxin, 301t, 306, 307, 311t iron supp ements, ora , 406t, 419t
Ha cinonide, 460t. See also Corticosteroids mechanisms o action, 301t errous aspartate, 406t, 413–414, 419t
Ha - i e (t 1/2), 34b, 37 , 39b natriuretic peptide receptor agonists errous umarate, 406t, 413–414, 419t
e der y, 77 mechanisms o action, 302t errous g uconate, 406t, 413–414, 419t
Ha -maxima e ective concentration (EC50), nesiritide, 302t, 311t errous sa ts, 406t, 413–414, 419t
6 , 7b, 9 nesiritide, 269t, 280, 284t errous succinate, 406t, 413–414, 419t
Ha -time, context-sensitive, anesthetic, phosphodiesterase 3 inhibitors, 307, 309, errous su ate, 406t, 413–414, 419t
214, 214 310, 311t in ants and chi dren, 413
Ha operido , 151t, 159, 163 , 171t, 175t inamrinone, 302t, 308, 308t, 311t mechanisms o action, 405t
Ha othane, 210t, 215t, 222t mechanisms o action, 302t, 308 optimizing e ects, 413–414
Ha progin, 598t mi rinone, 302t, 308, 308t, 311t po ysaccharide errihydrite comp ex,
HDAC inhibitors, 645t, 660t pharmaco ogy, 308t 406t, 413–414, 419t
romidepsin, 645t, 660t rationa e, 303b, 305 pregnancy, 413–414
vorinostat, 645t, 646t, 660t sites o action, 302 , 303 iron supp ements, parentera ,
HDL-C eve s, 337t to vaptan, 279t, 281, 288t 406t, 419t
HDL-C metabo ism, 335 vasodi ators, 304t, 311t erumoxyto , 406t, 419t
Heart ai ure arteria , 278t, 287t (See also Vasodi a- iron dextran, 406t, 419t
A rican-American, 306, 306b, 309, 310 tors, arteria ) iron sucrose, 406t, 419t
BiDi , 306, 306b mechanisms o action, 301t mechanisms o action, 406t
Brater’s a gorithm, 270t, 273t, Heavy meta che ators, 66t sodium erric g uconate, 406t, 419t
276 , 285t Heavy meta s, 41t, 43t, 65t–66t mye oid growth actors, 405t, 407t, 418t
characteristics and causes, 302b, 302 Helicobacter pylori trip e therapy, 492, G-CSF, 405t, 407t, 408 , 409–410, 416,
comorbidities, 302b 494t, 495 417, 418t
hypertension and diabetes risk, 304–305 He ium gas, therapeutic, 211t, 224t G-CSF, pegy ated recombinant, 405t,
ibupro en risk, 304 He minth in ection drugs, 536–541 407t, 408 , 409–410, 418t
pu monary congestion and periphera benzimidazo es, 540t GM-CSF, 405t, 407t, 408 ,
edema, 305–306 a bendazo e, 536, 540t 409–410, 418t
stages, 303, 303b, 305 mebendazo e, 536, 540t indications and choice, 409–410
symptoms, 302b diethy carbamazine, 538–540, 540t mechanisms o action, 405t, 407t
verapami on, 306 doxycyc ine, 540t sites o action, 408
Heart ai ure drugs. See also speci c drugs and ivermectin, 537–540, 540t thrombopoietic growth actors, 405t, 406t,
drug classes metri onate, trich or on, 541t 407t, 419t
a dosterone receptor antagonists, 311t nic osamide, 539, 540, 541t e trombopag, 406t, 419t
ep erenone, 302t, 311t oxamniquine, 541t IL-11 (opre vekin), 406t,
mechanisms o action, 302t piperazine, 541t 410–411, 419t
spirono actone, 302t, 307, 311t pork tapeworm, 539, 540 mechanisms o action, 405t,
or angina, 294t praziquante , 537, 539, 540, 540t 407t, 408
angiotensin-converting enzyme inhibitors, pyrante pamoate, 536, 539, romip ostim, 406t, 417, 418, 419t
272 , 276 , 279, 285t, 303–304, 310t 540, 541t vitamins, B12, 406t, 420t
(See also Angiotensin converting He minth in ections absorption and distribution, 412
enzyme (ACE) inhibitors) Brugia malayi, 538 cyanocoba amin, 406t, 420t
mechanisms o action, 270t, 273t, sh tapeworm, 537, 538–539 de ciency, 411b, 412 , 413b, 414–415,
274–276, 275 , 301t incidence, 537 417–418
angiotensin receptor b ockers, 273t, 274, onchocerciasis, 537–540 o ate interactions, 410b, 412
279, 280, 285t, 301t, 310t (See also pinworm, 536, 539, 540 genera princip es, 411b–412b
Angiotensin (A 1) receptor schistosomiasis, 537, 539, 540, 540t hydroxycoba amin, 406t, 420t
b ockers (ARBs)) Wuchereria bancrof i, 538 mechanisms o action, 406t, 420t
752
Hematopoietic agents (Cont.) treatment, 260–262 Homatropine hydrobromide, 96t, 114t
vitamins, o ic acid and derivatives, 406t, withdrawa , 260, 261t Hormesis, 6b
412 , 415b, 420t Herpes simp ex virus (HSV) in ection Hormone rep acement therapy, 441t–442t,
absorption and distribution, 412 agents (See Antiherpes agents) 445t–448t, 446–448,
de ciency, 412 , 413b, 414–415 eye, 701 455–457, 458t
o ic acid, 406t, 412 , 414–417, 414b, Hexamethy endiamine, 627t, 651t brand names and ormu ations,
415b, 420t mechanisms o action, 627t, 445t–446t
o inic acid, 406t, 416, 417–418, 420t 628b–629b, 630 estrogen/progestin, 446t, 455,
genera princip es, 414b mechanisms o resistance, 627t, 457, 458t
mechanisms o action, 406t 632–633, 632b ethiny estradio /progesterone ormu a-
vitamin B12 interactions, 410b, 412 toxicities, 632b–633b, 651t tions, 441t, 446t, 447, 457t
vitamins, pyridoxine, 406t, 419t High-dose methotrexate with eucovorin res- indications and e ects, 456, 457
mechanisms o action, 406t cue (HDM-L), 635t, 638–640, 653t mechanisms o action, 441t–442t
pyridoxine, 406t, 419t mechanisms and sites o action, 620 , risks, 447–448
ribo avin, 406t, 419t 635t, 637 , 638 Horner’s syndrome, 698t
Hematopoietic growth actors, 407t. See also mechanisms o resistance, 638b, 640 Human chorionic gonadotropin (hCG), 423t,
Hematopoietic agents; pharmacogenetics, 635t, 637 , 638–640, 639 427, 428, 430t
speci c types toxicities, 653t choriogonadotropin a a, 423t, 427,
erythropoietin, 407t, 408 uses, 637t 428, 430t
FL -3 igand, 407t, 408 High (narrow) speci city, 5b, 9 Human immunode ciency virus (HIV),
inter eukins, 407t, 408 Histamine 614–619. See also Antivira agents;
mechanisms o action, 407t, 408 actions, 3 speci c drugs and drug classes
sites o action, 408 in a ergic reactions, 349–350 atazanavir-ritonavir, 617–619
stem ce actor, 407t, 408 CNS neurotransmitter, 4–5 combination therapy, 518, 519, 617, 618
Heme biosynthesis, 58 structure, vs. H 2 receptor drug resistance, 614
Hemog obin A1c, 473 antagonists, 492 en uvirtide, 617–618
or monitoring diabetes me itus, 473, trip e response o Lewis, 347b, 348 opinavir, 618, 619
474t, 475–476 Histamine receptor antagonists and mast ce rep icative cyc e, 608
Henderson-Hasse ba ch equation, 19b stabi izers, 3. See also H 1 receptor treatment princip es, 614
Heparin, 323t, 325, 327 , 333t antagonists; speci c types treatment recommendations, 614
Heparin-induced thrombocytopenia (HI ), actions and adverse e ects, 4–6 zidovudine- amivudine-abacavir, 604 ,
325, 330, 331 active ingredient, 3 608 , 614–615
Heparinoid anticoagu ants, parentera , 323t, a ergy, 351–352 Human so ute carrier (SLC) super ami y
325, 333t drug c ass, 3 transporters, 23b–24b, 25t–26t
ardeparin, 323t, 325, 333t ophtha mic, 691t, 705t Huntington’s disease, 248–249, 248
da teparin, 323t, 325, 333t aze astine, 691t, 705t tetrabenazine or, 239t, 249, 253t
enoxaparin, 323t, 325, 333t bepotastine, 691t, 705t Hya uronate, ophtha mic, 692t, 706t
ondaparinux, 323t, 325, 333t cromo yn sodium, 691t, 705t Hydantoins, antiseizure, 225t, 236t
heparin, 323t, 325, 327 , 333t emedastine di umarate, 691t, 705t osphenytoin, 225t, 236t
ovenox, 325–326, 326 epinastine, 691t, 705t phenytoin, 225t, 231, 234, 235, 236t
ow-mo ecu ar-weight heparins, 323t, ketoti en umarate, 691t, 705t Hydra azine, 278t, 287t
324–325, 325 , 333t odoxamide tromethamine, 691t, 705t Hydroch orothiazide, 269t, 271, 273–274,
mechanisms o action, 323t nedocromi , 691t, 705t 282, 283, 284t
nadroparin, 323t, 325, 333t o opatadine, 691t, 705t Hydrocodone, 195t, 200t, 208t
tinzaparin, 323t, 325, 333t pemiro ast, 691t, 705t structure and activity o , 464
Hepatic metabo ism and c earance. See also Histamine receptors, 3t, 4 to erance, 264, 265
speci c drugs and drug classes Histre in Hydrocortisone, 460t, 464, 464 . See also
e der y, 75b, 76 , 76t–77t, 77 anticancer, 664t, 687t Corticosteroids
Hepatic microsoma enzymes. See also GnRH agonist pharmaco ogy, 423t, 429t adrena insu ciency, 461 , 465
speci c types HMG-CoA reductase, 337 drug interactions and dosing, 464
antiseizure drug interactions, 227t HMG-CoA reductase inhibitors (statins), genera princip es, 464b
Hepatitis 334t, 343t mechanisms o action, 460t
agents (See Antihepatitis agents) adverse e ects, 338 physio ogic unctions and pharmaco ogic
u minant, 231 atorvastatin, 334t, 343t e ects, 462t–463t
hepatitis B, 61 choice, 342, 343 pu monary, 390t, 403t
hepatitis C, chronic, 613–614 uvastatin sodium, 334t, 343t toxicities, 464b
Her2/neu, 672–673 ovastatin, 334t, 341, 342, 343t trade names and preparations, 460t
Heroin. See also Opioid pharmaco ogy mechanisms o action, 334t, 337 Hydro umethiazide, 269t, 284t
entany with, 260 other drugs with, 339 Hydro ysis reactions, drug metabo ism, 32t
vs. methadone responses, 260, 260 pitavastatin ca cium, 334t, 343t Hydromorphone, 194t, 195t, 200t, 208t
overdose, 203–204 pravastatin ca cium, 334t, 343t Hydroquinone, or hyperpigmentation,
to erance, 260 pregnancy risks, 340 710t, 727t
toxidrome, 53t rosuvastatin ca cium, 334t, 338, 343t Hydroxych oroquine
Heroin addiction, 259–262, 260 , 261t simvastatin, 334t, 343t dermato ogic, 708t, 725t
addictabi ity, 259–261 Hodgkin’s ymphoma, ABVD regimen, 630 , ma aria chemotherapy, 521t, 522t,
overdose, 260 643t, 645–647 523–524, 526, 529t
to erance, 260 Homatropine, ophtha mic, 690t, 695t, 704t rheumatoid arthritis, 368t
753
Hydroxych oroquine su ate, 522t eszopic one, 177t, 192t human chorionic gonadotropin, 423t, 427,
1α-Hydroxycho eca ci ero , 481t, 488t za ep on, 177t, 192t 428, 430t
Hydroxycoba amin, 406t, 414–415, zo pidem, 177t, 178–179, 192t choriogonadotropin a a, 423t, 427,
417–418, 420t benzodiazepine receptor antagonists, 428, 430t
Hydroxyethy ce u ose, ophtha mic, umazeni , 41t, 42t, 65t, 177t, insu in- ike growth actor-1, mecasermin,
692t, 706t 179–180, 192t 422t, 428t
Hydroxyprogesterone caproate, 679t benzodiazepines, 176t, 178b, 180, uteinizing hormone, utropin a a,
Hydroxyprophy methy ce u ose, 189–190, 191t–192t (See also 423t, 430t
ophtha mic, 692t, 706t Benzodiazepines) organs, hormones, and targets, 426
Hydroxypropy ce u ose, ophtha mic, carisoprodo , 177t, 193t posterior pituitary hormones, 423t, 429t
692t, 706t ch ora hydrate, 177t, 193t arginine vasopressin, 423t, 424 , 429t
Hydroxypropy methy ce u ose, ophtha mic, c omethiazo e, 177t, 193t (See also Vasopressin)
692t, 706t etomidate, 177t, 193t oxytocin, 423t, 424 , 430t
11β-Hydroxysteroid dehydrogenase, 464 , GABAA receptor, 178 , 179 pro actin-secreting pituitary
467, 468 insomnia categories, 178b, 179 adenoma, 426
Hydroxyurea (HU), 630 , 645t, ong-term use, 179 somatostatin ana ogs, 422t, 428t
646t, 659t me atonin congeners, rame teon, 177t, anreotide, 422t, 428t
Hydroxyzine, 346t, 354t 189, 190, 192t octreotide, 422t, 428t
Hyoscyamine, 498t, 508t meprobamate, 177t, 193t Hypothyroidism, 431t, 432–434, 432t,
Hyperca cemia, 483–484 para dehyde, 177t, 193t 433 , 434t
bisphosphonates, 483 propo o , 177t, 193t diagnosis, 432, 432t, 433
pamidronate, 481t, 488t toxidrome, 53t iodine-induced, 432, 434t, 435t, 438, 439
zo edronate, 481t, 485, 488t Hypoca cemia, cinaca cet, 481t, 488t evothyroxine or, 431t, 432–434, 433 ,
ca citonin, 480t, 481t, 483–484, Hypoch orhydria, age-re ated, 73b 434t, 437–439, 439t
483 , 488t Hypog ycemia subc inica , 437–439
ung cancer, 483–484, 486, 487 drugs promoting, 477t
vitamin D and ana ogs or, recurring, 476 I
481t, 488t Hypog ycemia agents, 471t, 479t I, 431t, 435, 437–439, 440t
131
Hypercortiso ism, 465–466 diazoxide, 471t, 472 , 476, 479t Ibandronate, 481t, 485, 488t
Hyperg ycemia. See also Antidiabetic agents; g ucagon, 471t or osteoporosis, 481t, 485, 488t (See also
Diabetes me itus mechanisms o action, 471t Bisphosphonates)
drugs promoting, 477t Hypogonadism, 456, 457 Ibupro en
Hyperparathyroidism agents, Hypotha amic-pituitary axis, 422–430, 461 . on antihypertensive drugs, 282, 283
481t, 488t See also speci c hormones and heart ai ure risk, 304
Hyperphosphatemia agents regulators menstrua cramping, 364
anthanum, 481t, 488t organs, hormones, and targets, 426 pain target and site o action, 205t
seve amer, 481t, 488t Hypotha amic-pituitary axis agents, Ibuti ide
Hyperpigmentation agents, 710t, 727t 422–430 antiarrhythmic, 312t, 317t, 322t
aze aic, 710t, 727t dopamine agonists, 422t, 428t e ectrophysio ogic actions, 317t
hydroquinone, 710t, 727t bromocriptine, 422t, 426, 428t Icatibant, 347t, 355t
mequino , 710t, 727t cabergo ine, 422t, 426, 428t Idarubicin, 643t, 658t
monobenzone, 710t, 727t pro actin-secreting pituitary mechanisms o action, 630 , 643t,
Hypersensitivity reactions. See also adenoma, 426 645–647
speci c drugs quinago ide, 422t, 426, 428t mechanisms o resistance, 645b
immediate, 349–350 o ic e-stimu ating hormone, Idiosyncratic reactions, 46t
penici ins, 550 , 552, 554, 555 423t, 429t IDL-C metabo ism, 335
Hypertension o itropin α, 423t, 430t Idoxuridine, 600t, 602t, 605–606, 619t
criteria, 270t o itropin β, 423t, 430t I os amide, 627t, 632t, 651t
diabetes with, 273–274 menotropin, 423t, 429t activation, in vivo, 631, 631
drugs (See Antihypertensive drugs) uro o itropin, 423t, 429t mechanisms o action, 626, 627t, 628,
icorice, 467, 468 gonadotropin-re easing hormone agonists 628b, 630
pregnancy, 277–278, 278 on androgen secretion, 425 mechanisms o resistance, 627t,
progression, 269–270, 270t GnRH, 422t, 429t, 680 632–633, 632b
Hyperthyroidism, 432t, 434t, gosere in, 422t, 429t toxicities, 631–632, 632b–633b,
435–439 histre in, 423t, 429t 632t, 651t
Hypertrophic cardiomyopathy, angina eupro ide, 423t, 425–426, 429t uses, 629t
drugs, 294t na are in, 422t, 427, 428, 429t IgE antibodies, in anaphy axis, 56
Hyperuricemia, 370 triptore in, 422t, 429t IL-1, 407t, 408
Hypnotics and sedative-hypnotics, gonadotropin-re easing hormone antago- IL-1 inhibitors, 376t, 386t. See also under
176–193, 191t–193t. See also nists, 423t, 429t Bio ogica immunosuppressants
speci c types cetrore ix, 423t, 429t anakinra, 376t, 386t
adverse e ects, 179 ganire ix, 423t, 429t canakinumab, 376t, 386t
barbiturates, 177t, 180–182, 181t, 192t growth hormone antagonist, pegvisomant, ri onacept, 376t, 386t
(See also Barbiturates) 422t, 424, 425 , 428t IL-2, 407t, 408
benzodiazepine receptor agonists, nove , growth hormone, recombinant, IL-3, 407t, 408
177t, 192t 422t, 427, 428, 428t IL-4, 407t, 408
754
IL-5, 407t Immunity monoc ona antibody, anti-CD52,
IL-6, 407t, 408 adaptive, 376b a emtuzumab, 376t, 378, 386t
IL-7, 407t innate, 376b po yc ona antibodies, immune
IL-8, 407t Immunization, passive, 377t–378t, 381t g obu in preparations, 376t, 377 ,
IL-9, 407t Immunomodu ators, 381t–382t. See also 377t–378t, 378, 385t
IL-10, 407t speci c drugs and drug classes risks, 379
IL-11 Immunostimu ants, 381t ca cineurin inhibitors, 375t, 385t
mechanisms o action, 407t, 408 anthracenedione derivative, cyc osporine, 368t, 375t, 377 , 380,
therapeutic, 406t, 410–411, 419t mitoxantrone, 382t 382–383, 385t
IL-12, 407t Baci us Ca mette-Guerin, 381t mechanisms o action, 375t, 377
I operidone, 151t, 170t, 175t monoc ona antibody, nata izumab, 382t tacro imus, 375t, 377 , 383, 385t
I oprost, 391t, 404t passive immunization, 377t–378t, 381t Crohn’s disease, 381
Imatinib (mesy ate), 661t, 666–669 recombinant cytokines, 381t g ucocorticoids, 375t, 384t
adverse e ects, 669 a des eukin, 381t immuno ogica to erance and costimu atory
anticancer, targeted, 661t, 666–669, 681, inter eron-α-2b, 381t b ockade, 380b, 380
682, 683t inter eron-β-1a, 381t, 382 immunosuppressants and
cancers, 669 inter eron-β-1b, 381t, 382 anti-in ammatories,
chronic mye ogenous eukemia, Ph +, 661t, inter eron-γ-1b, 381t dermato ogic, 709t, 724t, 726t (See
666–668 tha idomide and ana ogs also Immunosuppressants and
mechanisms o resistance, 666–668, ena idomide, 381t anti-in ammatories,
681, 682 tha idomide, 381t dermato ogic)
pharmacodynamics, 14–15 universa APLs, g atiramer acetate, 382t mechanisms o action, 375t–376t
Imidazo es and triazo es, 588t, 589 , Immunosuppressants and anti-in ammatories, organ transp ant, 378–379
590, 597t dermato ogic, 709t, rheumatoid arthritis, severe,
CYP interactions, 590, 590t 724t, 726t 380–381
drug interactions, 590t–592t b eomycin, 709t, 724t, 726t Impetigo, 714
uconazo e, 588t, 590, 595, 596, dapsone, 709t, 724t, 726t Imp antab e cardioverter-de bri ator (ICD)
597t, 719 doxorubicin, 709t, 726t ventricu ar bri ation, 316
itraconazo e, 597t imiquimod, 709t, 724t, 726t ventricu ar tachycardia, 318
posaconazo e, 597t mycopheno ate mo eti , 709t, 724t, 726t Inactive con ormation, 4, 5
voriconazo e, 588t, 589 , 590t–592t, tha idomide, 709t, 724t, 726t Inamrinone, 302t, 308, 308t, 311t
592–593, 595, 596, 597t vinb astine, 709t, 724t, 726t Indacatero , 390t, 402t
Imidazo es and triazo es, topica , 588t, Immunosuppressants, ocu ar, 691t, 705t Indapamide, 269t, 284t
597t–598t 5- uorouraci (FU), 691t, 705t Indinavir, 601t, 603t, 608 , 609 , 621t
butoconazo e, 597t cyc osporine A, 691t, 705t Indomethacin, 357t, 361t, 373t
c otrimazo e, 597t mitomycin, 691t, 705t Indoramin, 120t, 141t
econazo e, 597t Immunotherapeutic agents, 375–388 Inducing agents, anesthesia, 212 , 213–214,
ketoconazo e, 598t antipro i erative/antimetabo ic, 213 , 213t. See also Anesthetic
miconazo e, 594, 597t 375t, 385t agents, parentera
oxiconazo e, 598t azathioprine, 368t, 375t, 380, 385t Induction speed, anesthesia, 215–216,
sertaconazo e, 598t evero imus, 375t, 385t 215t, 216
su conazo e, 598t MPA, 375t, 385t In ants. See Chi dren
terconazo e, 597t mycopheno ate mo eti , 375t, 383, In estation agents, dermato ogic,
tioconazo e, 597t 384, 385t 708t, 725t
Iminosti benes, antiseizure, 225t, 236t siro imus, 375t, 377 , 383, 384, 385t benzy a coho , 708t, 725t
carbamazepine, 225t, 226 , bio ogica immunosuppressants crotamiton, 708t, 725t
232–235, 236t adverse e ects, 378b ivermectin, 708t, 725t
oxcarbazepine, 225t, 236t anti- NF reagents, 376t, 386t indane, 708t, 725t
Imipenem, 558t ada imumab, 368t, 376t, 381, ma athion, 708t, 725t
Imipenem-ci astatin, 554–555 383, 384, 386t permethrin, 708t, 725t
Imipramine, 150t, 173t certo izumab pego , 376t, 381, 386t In ammatory bowe disease agents,
Imiquimod etanercept, 376t, 380, 386t 498t–499t, 509t
antivira , 601t, 602t, 621t go imumab, 376t, 386t ada imumab, 499t, 509t
dermato ogic, 709t, 724t, 726t in iximab, 368t, 376t, 380, 381, 386t azathioprine, 498t, 502–503,
Immediate hypersensitivity reactions, IL-1 inhibitors, 376t, 386t 503 , 509t
349–350 anakinra, 376t, 386t ba sa azide, 498t, 503 , 509t
Immune g obu in preparations, 376t, 377 , canakinumab, 376t, 386t budesonide, 498t, 509t
377t–378t, 378, 385t ri onacept, 376t, 386t certo izumab pego , 499t, 509t
agents, synonyms, and origins, 377t–378t LFA-1 & LFA-3 inhibitors cyc osporine, 499t, 509t
mechanisms o action, 376t a e acept, 376t, 386t in iximab, 499t, 509t
toxicities, 385t e a izumab, 376t, 386t mechanisms o action, 498t–499t
uses, 377b, 385t monoc ona antibody, anti-CD3, mesa amine, 498t, 503 , 509t
Immune response, 376b. See also Hypersensi- muromonab-CD3, 376t, 378, 385t methotrexate, 499t, 509t
tivity reactions; speci c types monoc ona antibody, anti-CD25, 376t, nata izumab, 499t, 509t
Immune (idiopathic) thrombocytopenic 379, 386t o sa azine, 498t, 503 , 506, 507, 509t
purpura (I P), 406t, 417, basi iximab, 376t, 386t su asa azine, 381, 498t, 502, 503 , 505,
418, 419t dac izumab, 376t, 386t 507, 509t
755
In ammatory response, 357b g yburide, 470t, 472 , 479t Iontophoresis, 203
In iximab mechanisms o action, 470t, 477, 478 Ion trapping, 20b
Crohn’s disease, 381, 503 Integrase inhibitor Ipratropium (bromide)
dermato ogic, 709t, 714t, 726t mechanisms o action and resistance, 603t COPD, 390t, 402, 403t
immunotherapy, 368t, 376t, 380, 381, 386t ra tegravir, 601t, 603t, 611 , 623t pharmaco ogy, 96t
in ammatory bowe disease, 499t, 509t Interactions. See Drug interactions; pu monary, 390t, 402, 403t
rheumatoid arthritis, 368t, 376t, 380, 386t speci c drugs Irbesartan, 273t, 285t
In uenza agents. See Anti-in uenza agents Interceptor mo ecu es, 62 Irinotecan (CP -111), 643t, 649–651, 657t
Inha ed administration. See also speci c drugs Inter erons (IFNs), antihepatitis, 600t–602t, mechanisms o action, 630 , 643t,
and drug classes 606 , 620t 649–651
e der y, 74t adverse e ects, 614 mechanisms o resistance, 630 , 643t,
Inha ers, combination, 395, 397, 398, hepatitis C, chronic, 613–614 644b–645b, 649–651
401–402 IFN di erences, 613–614 Iron
Inhibitory concentration (IC), mechanisms o action and resistance, recommended dietary a owances,
513–514, 514 602t, 606 , 613 nonvegetarians, 411t
Inhibitory postsynaptic potentia (IPSP), 86, Inter eron-α-2b, 381t requirement, dai y, 411t
86 , 106 Inter eron-β-1a, 381t, 382 Iron de ciency
Inhibitory sigmoid Emax curve, 513, 513 , Inter eron-β-1b, 381t, 382 unctiona , 409
514, 514 Inter eron-γ-1b, 381t rom proton pump inhibitors, 495
Innate immunity, 376b Inter eukin-2 (IL-2) receptor agonists, Iron dextran, 406t, 419t
Inotropic agents. See also Digoxin; anticancer, 663t, 685t Iron poisoning, 54–55
Dobutamine; Dopamine (DA); a des eukin, 663t, 682, 683, 685t de erasirox, 41t, 65t
Phosphodiesterase 5 (PDE5) deni eukin di itox, 663t, 671t, 685t de eroxamine, 42t, 55, 65t
inhibitors mechanisms o resistance, 663t Iron sucrose, 406t, 419t
mechanisms o action, 307–308 Inter eukins. See also IL entries Iron supp ements, ora , 406t, 419t
pharmaco ogy, 30–34, 308t hematopoietic growth actors, 407t, 408 errous aspartate, 406t, 413–414, 419t
INR, 328, 330b mechanisms o action, growth actor, 407t errous umarate, 406t, 413–414, 419t
Insecticides. See also speci c types Intestina bypass surgery, 486, 487 errous g uconate, 406t, 413–414, 419t
a dicarb, 100t, 115t Intrace u ar enzymes, 3t errous sa ts, 406t, 413–414, 419t
anticho inesterase, 102, 102b, 103 , Intramuscu ar administration, 21t errous succinate, 406t, 413–414, 419t
103t, 104 e der y, 74t errous su ate, 406t, 413–414, 419t
antidotes, 40t, 41t, 42t, 65t, 100t, 102 neonates, in ants, and chi dren, 67b in ants and chi dren, 413
carbamate, 100t, 102, 115t Intranasa administration, e der y, 74t mechanisms o action, 405t
treatment, 42t, 65t Intravenous administration, 21t optimizing e ects, 413–414
carbary , 100t, 115t Intrinsic ce u ar responses, 2b po ysaccharide errihydrite comp ex, 406t,
diazinon, 100t, 103t, 115t Intrinsic sympathomimetic activity (ISA), 413–414, 419t
ma athion, 100t, 102t, 115t 15, 16 pregnancy, 413–414
organophosphate, 100t, 102, 102b, 103 , Inverse agonists, 4, 4b, 4 , 9, 16, 17 Iron supp ements, parentera , 406t, 419t
103t, 104 , 115t In vitro binding studies, 8 erumoxyto , 406t, 419t
propoxur, 100t, 115t Iodide, 431t, 440t iron dextran, 406t, 419t
Insomnia Iodine iron sucrose, 406t, 419t
categories, 178b, 179 drugs with, 434t mechanisms o action, 406t
zo pidem, 177t, 178–179, 192t high eve s, 437, 438 sodium erric g uconate, 406t, 419t
Insu in hypothyroidism rom, 435t, 438, 439 ISDN, 289t, 300t
g argine, 476 radioactive, 438–439 ISMN, 289t, 298, 299, 300t
vs. ispro, 478 radioactive (131I), 431t, 435, Isocarboxazid, 130t, 147t, 150t, 173t
hospita ized, 477, 478 437–439, 440t Isoetharine, 125t, 143t
mechanisms o action, 470t, 471 , supp ementation, post-thyroidectomy, Iso urophate, 103t, 104
472 , 473 437, 438 Iso urane, 210t, 215t, 222t
secretion regu ation, 470t, 472 Iodine de ciency (goiter), 437, 438 Isoniazid
sensitivity, 477, 478 Ion channe s, 3, 3t, 86, 86 –88 , 89t. See also adverse e ects, 582, 585, 586
signa ing pathways, 471 speci c types and drug classes drug interactions, 582, 583t
Insu in- ike growth actor-1 (IGF-1), Ca , 86, 87 , 89t
2+
mechanisms o action, 578t, 580
422t, 428t C −, 86 tubercu osis, 578t, 580 , 582, 583t, 587t
Insu in- ike growth actor-1 (IGF-1) receptor K+, 86, 87 vitamin B6 with, 582
signa ing pathway, 666 igand-gated receptor structure, 88 Isoniazid-resistant tubercu osis, 583
Insu in secretagogues Na+, 86, 87 Isoprostanes, 358
nonsu ony urea, 470t, 472 , 479t vo tage-dependent, 86, 87 Isoprotereno , 125t, 142t
nateg inide, 470t, 472 , 479t Ionic thyroid inhibitors, 431t, 440t Isosorbide, 268t, 283t
repag inide, 470t, 472 , 479t iodide, 431t, 440t Isosorbide-5-mononitrate (ISMN), 289t, 298,
su ony urea, 470t, 472 , 479t sodium iodide, 431t, 440t 299, 300t
adverse e ects, 475 Ionization Isosorbide dinitrate (ISDN), 289t, 300t
g ic azide, 470t, 472 , 479t kidney tubu es, 21–22 Isotretinoin, 707t, 721, 722, 724t
g imepiride, 470t, 472 , 477, p asma–gastric juice partitioning, Isradipine
478, 479t 19b–20b, 20 , 21–22 antihypertensive, 277t, 287t
g ipizide, 470t, 472 , 479t Ionized mo ecu es, di usion, 19b, 19 myocardia ischemia, 290t, 300t
756
131
I-tositumomab, 662t, 671t, 684t Lapatinib, 661t, 673, 683t Levetiracetam, 225t, 234–235, 237t
Itraconazo e, 588t, 589 , 590, 597t l -asparaginase (L-ASP), 630 , 643t, 644t, Levobetaxo o , 126t, 145t
Ivermectin, 708t, 725t 648–650, 659t Levobuno o , 125t, 144t
Ixabepi one, 643t, 644b, 650, 657t Latanoprost, ophtha mic, 691t, 705t ophtha mic, 691t, 695t, 704t
Laxatives, 497t, 498t, 507t, 507t–508t Levocabastine, 347t, 355t
J bisacody , 498t, 508t Levocetirizine, 347t
Jaw osteonecrosis, bisphosphonate, 481t, bowe e ects, 500t Levodopa, 238t, 242, 243–245, 243 ,
485, 488t c assi cation, 500t 244 , 252t
Jimson weed, 101–102, 101t, 694 , docusate sodium, 498t, 508t Levo oxacin, 544, 544 , 545, 548t
698, 698t actu ose, 497t, 505, 506–507, 507t Levonorgestre , 443t, 444t, 446t
magnesium citrate, 497t, 507t Levorphano , 194t, 195t, 200t, 209t
K magnesium hydroxide, 497t, 507t Levothyroxine, 431t, 432–434, 434t,
KA, 6b, 8 magnesium su ate, 497t, 507t 436–439, 439t
Ka ikrein inhibitors, 347t mechanisms o action, 497t–498t, 498b, adverse e ects, 434
Kanamycin, 559–566, 559b, 567t 498t, 499 actors in, 434t
K+ channe s, 86, 87 po yethy ene g yco , 497t, 507t hypothyroidism
KD, 6b, 8 sa ine, 497t, 507t pregnancy dosing, 437–439
Keratitis, 700 sodium phosphate, 497t, 507t subc inica , 437, 438–439
unga , 701 LDL-C eve s therapeutic goa s, 432
vira , 701 c assi cation, 337t mechanisms o action, 431t
Kernicterus, 68 treatment, 336t thyroid cancer, 436
Ketamine, LDL-C metabo ism, 335 Lico e one, 358
ana gesics, 217 Lead, 41t, 43t, 57–58, 57b, 58 , 63, 64, 65t Licorice, 467, 468
anesthetic, 210t, 213t, 214 , 217, 222t Lead poisoning, 43t, 63, 64, 65t Lidocaine, 224t
Ketanserin, 120t, 133t, 141t, 147t dimercapro , 41t, 42t, 66t antiarrhythmic, 312t, 316, 317t,
Ketoconazo e, 459t, 469t, 588t, 598t dimercaptosuccinic acid, 41t, 42t, 66t 319, 320, 321t
anticancer, 665t, 687t ED A CaNa2, 41t, 42t, 63, 64, 66t e ectrophysio ogic actions, 317t
mechanisms o action, 668 hea th e ects, 57b ventricu ar bri ation, 316
Ketoro ac, 357t, 361t, 373t heme biosynthesis, 58 ventricu ar tachycardia, 319, 320
ophtha mic, 691t, 705t mechanisms, 41t Ligand-gated receptors, 88
Ketoti en umarate, 347t, 355t Le unomide, 368t Lincosamides, 568t, 574, 575, 576t
ophtha mic, 691t, 705t Le ventricu ar dys unction, angina drugs, 293t Lindane, 708t, 725t
Kidney Leishmaniasis, viscera , 534 Linezo id, 569t, 576t
passive di usion, excretion, Lena idomide, 381t Liotrix, 431t, 439t
and pH, 20b anticancer, 663t, 666 , 685t Lipid membrane di usion, 19–20, 20
tubu e ionization, 21–22 immunostimu ant, 381t Lipopeptides, 569t, 570 , 573, 575, 577t
Kinin receptor antagonists, 347t, 355t Lennox-Gastaut syndrome, 232 Lipoxins, 358
K+-sparing diuretics, 269t, 271t, 272 , 285t Leprosy drugs Lipoxygenase pathways, 358 , 359
minera ocorticoid antagonists c o azimine, 579t, 583, 587t Lirag utide, 471t, 472 , 479t
ep erenone, 269t, 280–281, 285t combination therapy, 583–584 Lisdexam etamine, 120t, 141t
spirono actone, 269t, 285t, 307 dapsone, 579t, 581 , 583–586, 587t Lisinopri
Na+-channe inhibitors, 269t, 271t, 272 , 284t therapeutic princip es, 584b heart ai ure, 306, 309, 310
ami oride, 269t, 284t MC-207, 579t, 587t pharmaco ogy and actions, 273t,
triamterene, 269t, 282, 283, 284t Letha dose, 44 281, 282, 285t
vs. e ective dose, 44 Lispro. See also Diabetes me itus; Insu in
L median (LD50), 44 , 45 vs. g argine, 478
LABAs. See β2 adrenergic receptor Letrozo e Lithium, 151t, 164–166, 175t
agonists, ong-acting anticancer, 664t, 677t, 679t, 686t adverse e ects, 164t
Labeta o , 126t, 128t, 146t pharmaco ogy, 442t, 458t e der y, 165–166
Lacosamide, 226t, 237t Leucovorin. See High-dose methotrexate ibupro en, 165, 168, 169
Lacrima system, 698 with eucovorin rescue (HDM-L) ithium carbonate, 151t, 175t
Lactation, FDA ru es, 72b Leukotriene antagonists, pu monary, 390t, ithium citrate, 151t, 175t
Lactu ose, 497t, 505, 506–507, 507t 403t–404t overdose, 166–167
Lambert-Eaton syndrome, 104 5-LOX inhibitors, zi euton, 390t, 403t Lithium carbonate, 151t, 175t
Lamivudine, 601t, 602t, 607 , 621t asthma, severe, 396 , 397 Lithium citrate, 151t, 175t
adverse e ects, 615 eukotriene antagonists, 390t, 404t Liver metabo ism and c earance.
antihepatitis, 600t, 602t, 607 , 620t monte ukast, 390t, 404t See also speci c drugs and
mechanisms o action and resistance, za r ukast, 390t, 404t drug classes
602t, 604 , 607 , 608 , 614–615 mechanisms o action, 390t, 396 e der y, 75b, 76 , 76t–77t, 77
structure, 607 Leukotrienes, 358 L-methy o ate. See Fo ic acid and
Lamotrigine, 225t, 232, 237t Leucovorin ca cium, 406t, 416, 417–418, 420t derivatives
anticonvu sants, 151t, 165, 175t Leupro ide LMWH. See Low-mo ecu ar-weight
va proic acid with, 235 anticancer, targeted, 664t, 679t, 680, 687t heparins (LMWHs)
Lanreotide, 422t, 428t prostate cancer, 423t, 425–426, 429t Loading dose, 39b
Lansoprazo e, 490t, 493 , 496t Leva butero creatine c earance, 34
Lanthanum, 481t, 488t pharmaco ogy, 125t, 143t Loca anesthetics. See Anesthetic agents,
Lanthanum carbonate, 481t, 484, 488t pu monary, 389t, 402t oca ; speci c agents
757
Lodoxamide tromethamine, ophtha mic, Lymphocyte immune (ALG), 376t, 377 , 378, Ma athion, 89
691t, 705t 378t, 385t dermato ogic, 708t, 725t
Lometrexo , 635t, 653t pharmaco ogy, 100t, 102t, 115t
mechanisms o action, 635t M Mannito , 268t, 283t
mechanisms o resistance, 638b Macro ides and keto ides, 568t, 570 , 576t MAO inhibitors
Lomustine (CCNU), 627t, 630 , 652t azithromycin, 568t, 570 , 576t 5-H concentration a tering, 130t, 147t
mechanisms o action, 627t, c arithromycin, 568t, 570 , 571, 576t ood contraindications, 135, 137
628b, 630 drug interactions, macro ide, 572 with SSRIs, 133
mechanisms o resistance, 627t, erythromycin, 568t, 570 , 576t Maproti ine, 150t, 173t
632–633, 632b te ithromycin, 568t, 570 , 576t Maraviroc, 601t, 603t, 608 , 611 , 623t
toxicities, 652t toxicities, 571 Marijuana, 263
uses, 629t Macrophage co ony stimu ating actor medicina e ects, 265, 266
Long Q syndrome, 313–315, 315b (M-CSF), 407t, 408 withdrawa syndrome, 263, 263t
Loop diuretics, 269t, 271t, 272 , 284t Macu ar degeneration agents, 692t, 706t Mast ce stabi izers. See Histamine
bumetanide, 269t, 282, 283, 284t bevacizumab, 692t, 706t receptor antagonists and mast ce
ethacrynic acid, 269t, 284t pegaptanib, 692t, 706t stabi izers
urosemide, 269t, 280, 284t, 306 ranibizumab, 692t, 706t MDR1 transporter, 23t, 24t, 25t, 38
torsemide, 269t, 284t vertepor n, 692t, 703, 706t MDR3 (ABCB4) transporter, 25t
Loperamide Magnesium citrate, 497t, 507t Mecamy amine, 106t, 117t
antidiarrhea , 209t, 498t, Magnesium hydroxide, 497t, 507t Mecasermin, 422t, 428t
500–501, 508t Magnesium su ate Mech orethamine, dermato ogic, 708t,
mechanisms o action, 498t antiarrhythmic, 317t, 322t 724t, 726t
Lopinavir, 601t, 603t, 615, 622t e ectrophysio ogic actions, 317t Mech orethamine HC , 627t, 651t
adverse e ects, 615 axative, 497t, 507t mechanisms o action, 626, 627t, 628,
CYP3A4 metabo ism, 618, 619 Ma aria chemoprophy axis, 521–522, 522t 628b, 630
drug interactions, 615 atovaquone-proguani , 521–522, 522t, 526 mechanisms o resistance, 627t,
HIV, 618, 619 ch oroquine phosphate, 522t 632–633, 632b
mechanisms o action and resistance, doxycyc ine, 522t toxicities, 632b–633b, 651t
603t, 615 genera advice, 526–527 uses, 629t
Loracarbe , 557t hydroxych oroquine su ate, 522t Mec izine, 346t, 350, 352, 354t
Loratadine, 89–90 me oquine, 522t, 524 Median e ective dose (ED50), 44 , 45
H 1 receptor antagonist, 347t, 348, 348b, primaquine, 522t, 525–526 Median etha dose (LD50), 44 , 45
351–352, 355t Ma aria chemotherapy, 520–529, Medication errors, 56–57, 57t
pregnancy and actation, 348, 348b, 520t–521t, 529t Medroxyprogesterone, targeted anticancer
351–352 artemisinin, 520t, 529t therapy, 664t, 679t, 686t
Lorazepam, 176t, 189, 190, 191t, 192t artemether, 520t, 529t Medroxyprogesterone acetate (MPA) conju-
Losartan, 273t, 285t artemether- ume antrine, 520t, 521, gated estrogen +, 441t
Lotepredno , ophtha mic, 691t, 705t 527, 529t hormone rep acement therapy, 442t, 458t
Lou Gehrig’s disease. See Amyotrophic artesunate, 520t, 529t MedWatch, 47
atera sc erosis (ALS) dihydroartemisinin, 520t, 529t Me oquine, ma aria
Lovastatin, 334t, 341, 342, 343t atovaquone, meprone, 520t, 529t chemoprophy axis, 522t, 524
Lovenox, 325–326, 326 atovaquone-proguani , 520t, 527, 529t chemotherapy, 521t, 522t, 524, 527, 529t
Low-mo ecu ar-weight heparins (LMWHs), chemoprophy axis, 521–522, 522t, 526 Mega ob astic anemia, 417–418. See also
323t, 324–325, 325 , 333t. See also ch oroquine/hydroxych oroquine, 521t, Vitamin B12 de ciency
speci c agents 522t, 523–524, 526, 529t sh tapeworm, 537–540
indications, 325t ch oroquine-resistant P. alciparum, Megestro , anticancer, 665t, 687t
ovenox, 325–326, 326 523 , 524 Megestro acetate, 442t, 458t
mechanisms o action, 325 cinchonism, 524 anticancer, 664t, 679t, 686t
monitoring, 325, 330b dermato ogic agents, 708t, 725t Me arsopro , 530t, 534, 535t
Low (broad) speci city, 5b, 9 ch oroquine, 708t, 725t Me atonin congeners, 177t, 189, 190, 192t
Loxapine, 151t, 175t hydroxych oroquine, 708t, 725t Me pha an, 627t, 632t, 651t
5-LOX inhibitors, 390t, 403t quinacrine, 708t, 725t mechanisms o action, 626, 627t, 628,
Lubiprostone, 497t, 507t endemic countries, 523, 523 628b, 630
Lumiracoxib, 363t mechanisms o action, 520t–521t mechanisms o resistance, 627t,
Lumbar puncture me oquine, 521t, 522t, 524, 527, 529t 632–633, 632b
seque ae, 219 pregnancy, 527 toxicities, 632b–633b, 632t, 651t
spina anesthesia, 217–219 primaquine, 521t, 522t, 525–526, 526t, uses, 629t
Lung cancer, hyperca cemia in, 483–484, 527, 529t Memantine, 239t, 246–247, 251, 252, 253t
486, 487 proguani , 520t, 529t Menotropin, 423t, 429t
ca citonin or, 480t, 483–484, 488t pyrimethamine-su adoxine, 521t, 529t Menstrua cramping, 364–365
Luteinizing hormone (LH) therapy, 423t, 429t quinine/quinidine, 521t, 524, 527, 529t Meperidine, 195t, 200t, 204, 208t
Lutropin a a, 423t, 430t su adoxine, 521t, 529t, 543t, 548t MAO inhibitors contraindication, 204
Lymphocyte unction-associated antigen treatments o choice, 526–527 toxicity, 204, 206, 208
(LFA-1 & LFA-3) inhibitors Ma aria parasite Mephentermine, 119t, 139t
a e acept, 376t, 386t deve opmenta stages, 525, 526t Mephobarbita , 177t, 181t, 192t
e a izumab, 376t, 386t i e cyc e, 525–526, 525 Mepivacaine, 224t
758
Meprobamate, 177t, 193t skin, treatment, 714–715 Methy xanthines, pu monary, 390t, 403t
Meprone, 520t, 529t tetracyc ines, 571 COPD, 395
Mequino , 710t, 727t Methimazo e, 431t, 435–436, 438, mechanisms o action, 390t
6-Mercaptopurine (6-MP), 636t, 439, 440t theophy ine, 390t, 392 , 397, 403t
641–642, 655t Methohexita , 177t, 192t Methysergide, 130t, 147t
mechanisms o action, 630 , 636t, anesthetic, 210t, 213t, 222t Metiprano o , 125t, 144t
641–642 mechanisms and sites o action, 635t ophtha mic, 691t, 695t, 704t
mechanisms o resistance, 636t, Methotrexate, 635t, 653t Metoc opramide
639b, 642 + 5-FU, 648, 649 antiemetic, 502t, 504, 506
toxicities, 642, 655t anticancer bowe disorders, 497t, 504, 506, 507t
uses, 637t, 655t mechanisms and sites o action, 630 , Meto azone, 269t, 284t
Mercury, 41t, 43t, 59–60, 59 , 65t 635t, 637 , 638–639 Metopro o
Meropenem, 558t mechanisms o resistance, 635t, heart ai ure, 301t, 303–304, 306, 309,
Mesa amine, 357t, 373t 638b, 640 310, 310t
Mesa amine (5-ASA), 498t, 503 , 509t dermato ogic, 708t, 715, 721–722, myocardia ischemia, 300t
Metabo ic syndrome, 339–340. See also 724t, 725t pharmaco ogy, 126t, 127–129, 128t, 145t
Dys ipidemia drugs psoriasis, 715–716, 721–722 Metronidazo e, 530t, 532–534, 535t
Metabo ism, drug, 20b, 28b. See also speci c o inic acid with, 416, 417–418 a coho reaction, 533, 534
drugs and drug classes in ammatory bowe disease, amebic co itis, 530t, 532–533, 535t
acetaminophen, 28–29, 50–54, 50 , 52t, 499t, 509t duodena u cer, 492, 494t
207, 208 mechanisms and sites o action, 635t giardiasis, 530t, 532–533, 535t
chi dren, 70b mechanisms o resistance, 638b, 640 Metyrapone, 459t, 466, 469t
CYP super ami y, 30, 30b–31b, 32t, 33 pharmacogenetics, 637 , 639 Mexi etine
drug–drug interactions on, 48, 48b, 48t rheumatoid arthritis, 368b, 368t, 380 antiarrhythmic, 312t, 317t, 321t
e der y, 73t–74t, 75b toxicities, 653t e ectrophysio ogic actions, 316
nuc ear receptors inducing, 33t, 34 uses, 637t Mez oci in, 552t, 556t
phase 1, 28b, 33 , 35, 38 Methoxsa en photochemotherapy, 707t, Mianserin, 150t, 174t
neonata , 70b 716t, 725t Mica ungin, 588t, 589 , 598t
phase 2, 28–29, 28b, 33 , 35, 39 6-Methoxy-arabinosy -guanine. Michae is-Menten equation, 35b
poisoning, 52 See Ne arabine Miconazo e, 588t, 594, 597t
reactions, 32t Methscopo amine, 498t, 508t Microtubu e-damaging agents. See also
Meta s, heavy (toxic), 41t, 43t, 65t–66t. Methscopo amine bromide, 96t, 114t Co chicine; axanes;
See also speci c types Methsuximide, 225t, 236t Vinca a ka oids
che ators, 66t Methy amino evu inate photodynamic ther- estramustine, 630 , 643t, 650, 657t
Metaprotereno apy, 708t, 725t ixabepi one, 643t, 644b, 650, 657t
pharmaco ogy, 125t, 143t Methy -CCNU. See Semustine Microtubu e disruptors, 369t
pu monary, 389t, 402t (methy -CCNU) co chicine, 369t, 370, 373t
Metaramino , 119t, 139t Methy ce u ose, ophtha mic, 692t, 706t Midazo am, 176t, 191t, 192t, 214
Met ormin, 470t, 479t Methyc othiazide, 269t, 284t Midodrine, 119t, 139t
diabetes me itus type 2 a er, Methy dopa Mi epristone, 442t, 458t, 459t, 469t
hemog obin A1c, 475–476 antihypertensive, 277t, 286t Mig ito , 471t, 479t
+ g imepiride, 477, 478 pharmaco ogy, 119t, 140t Migraine
Methacho ine, 99t, 112t Methy enedioxymethamphetamine (MDMA) 5-H in, 133–134, 133t
mechanisms o action, 95t 5-H 2 receptor ora contraceptives with, 455, 456–457
pharmaco ogy, 99t, 112t a nity, 265, 266 Mi nacipran, 150t, 174t
Methadone, 194t, 195t, 200t, 201–203, L-Methy o ate. See Fo ic acid and derivatives Mi rinone, 302t, 308, 308t, 311t
202t, 208t Methy hydrazines, 629t, 652t Mi te osine, 530t, 534, 535t
cancer pain, 201–203, 202t mechanisms o action, 628b, 628t, 630 Mi nacipran, 130t, 147t
routes o administration, 202–203 mechanisms o resistance, 628t, Minera ion homeostasis disorder drugs,
conversion guide ines, ora morphine to 632–633, 632b 480–489
methadone, 202t procarbazine, 629t, 652t ca cimimetics, cinaca cet, 481t, 486,
vs. heroin responses, 260, 260 toxicities, 632b–633b, 652t 487, 488t
or opioid addiction, 260–261 uses, 629t hormones
Methamphetamine, 120t, 141t Methy me amines, 627t, 651t. See also Ethy - ca citonin, 480t, 483–484, 483
Methano , 42t, 49–50, 49 eneimines and methy me amines teriparatide, 480t
metabo ism and poisoning, 49–50, Methy na trexone hyperca cemia, 483–484
49 , 178 bowe disorders, 498t, 499, 505, 506, 507t vitamin D and ana ogs, 481t, 488t
Methano antidote constipation, opioid, 199, 498t, 499, 505, 1α-hydroxycho eca ci ero , 481t, 488t
ethano , 42t, 50, 65t 506, 507t 22-oxaca citro parica cito , 481t, 488t
omepizo e, 41t, 42t, 65t, 178 mechanisms o action, 498t ca cipotrio , 481t, 488t
Methenamine, 548t opioid receptor antagonism, 195t, 199, 209t ca citrio , 481t, 482 , 488t
Methici in, 551, 552t, 554, 555, 555t Methy paraben, 220, 221 dihydrotachystero , 481b
Methici in-resistant Staphylococcus aureus Methy phenidate, 120t, 141t doxerca ci ero , 481b
(MRSA), 551, 571 Methy predniso one, 460t. See also ergoca ci ero , 481t, 488t
doxycyc ine, 571 Corticosteroids parica cito , 481t, 488t
minocyc ine, 571 pu monary, 390t, 403t therapeutic uses, 481b
759
Minera ocorticoid receptor antagonists o atumumab, 662t, 684t Mu tip e sc erosis (MS)
(K+-sparing), 269t, 271t, rituximab, 662t, 671t, 681, 682, 684t IFN-β-1a and IFN-β-1b, 381t
272 , 285t CD33, anticancer, 662t, 684t pathophysio ogy, 382
ep erenone, 269t, 280–281, 285t gemtuzumab ozogamicin, 662t, 667t, Mupirocin, 569t, 573, 577t
spirono actone, 269t, 285t, 307 672t, 684t Muromonab-CD3, 376t, 378, 385t
Minimum a veo ar concentration (MAC), mechanisms o resistance, 662t Muscarine
215, 215t CD52, anticancer, 662t, 667t, 671t, 684t mushrooms, 97
Minimum e ective concentration a emtuzumab, 662t, 667t, 671t, 684t pharmaco ogy, 99t
(MEC), 36 mechanisms o resistance, 662t Muscarinic acety cho ine receptors
Minimum inhibitory concentration denosumab, 481t, 488t (mAChRs), 98t–99t
(MIC), 513 growth actor antibodies (VEGF), Muscarinic receptor agonists, 99t, 112t.
Minocyc ine anticancer, 662t, 673–675, 684t See also speci c types
MRSA, 571 bevacizumab, 662t, 671t, 674–675, 684t bethanecho , 95t, 99t, 112t
rheumatoid arthritis, 368t dose, 671t mechanisms o action, 95t
Minoxidi ranibizumab, 662t, 684t Muscarinic receptor antagonists, 99t, 100,
androgenic a opecia, 710t, 726t toxicities, 671t, 674–675, 684t 101b, 101t, 112t–114t. See also
hypertension and edema, 278t, 287t growth actor receptor, anticancer, speci c types
Miosis, 698, 698t 662t, 683t mechanisms o action, 96t
Mirtazapine, 150t, 174t cetuximab, 662t, 669–672, 683t overactive b adder, 100, 101t
Misoprosto , 490t, 493, 494, 495, 496t dose and toxicities, 671t Muscarinic receptors, 82 , 97
gastric acid disease, 490t, 493, 494, EGFR targeting, 669–672 atropine, 80–82
495, 496t HER2/neu, 667t, 682t muscarine, 97, 99t
GERD in pregnancy, 494, 495 panitumumab, 662t, 669–672, 683t Mushrooms, catecho aminergic, 97, 100
with NSAID-induced duodena trastuzumab, 662t, 671t, 672–673, 681, Musse s, saxitoxin, 221, 222
u cer, 493 682, 683t MXR transporter, 24t
Mitomycin, ophtha mic, 691t, 705t nata izumab, 382t Myasthenia gravis, 104–105, 105
Mitomycin (mitomycin-C), 630 , 643t, Monocyte/macrophage co ony stimu ating Mycobacterium avium comp ex drugs
646b, 658t actor (M-CSF, CSF-1), 407t, 408 cyc oserine, 579t, 587t
Mitotane, 679t Monte ukast, 390t, 404t ethambuto , 578t, 583, 587t
anticancer, 644t, 659t Morphine, 194t, 195t, 200t, 206–208, 208t therapeutic princip es, 584b
pharmaco ogy, 459t, 469t constipation rom, 92 MC-207, 579t, 587t
Mitoxantrone conversion guide ines, ora morphine to Mycobacterium intracellulare, 579t, 583, 584,
anticancer, 630 , 643t, 645b, 658t methadone, 202t 584b, 587t
immunostimu ant, 382t in ant dosing, 72, 74 Mycobacterium kansaii
Mivacurium, 106t, 107t, 117t metabo ism ethambuto , 578t, 583, 587t
Mizo astine, 347t, 355t chi dren, 68 MC-207, 579t, 587t
Moda ni , 120t, 142t rst-pass, 206, 207 Mycobacterium spp., MC-207, 579t, 587t
Moexipri , 273t, 285t morphine-6-g ucuronide, 206, 207–208 Mycobacterium tuberculosis drugs.
Mo indone, 151t, 175t Morphine-6-g ucuronide, 206, 207–208 See ubercu osis drugs
Mometasone, 390t, 403t Mosquito bite, 347b, 348 Mycopheno ate mo eti (MMF)
Monoamine oxidase inhibitors (MAOIs), Motion sickness, 350, 352 dermato ogic, 709t, 724t, 726t
150t, 157, 173t. See also Moxi oxacin, 544, 544 , 545, 548t immunotherapy, 375t, 383, 384, 385t
speci c agents MPA. See Medroxyprogesterone acetate mechanisms o action, 375t, 383, 384
isocarboxazid, 150t, 173t (MPA) Mydriasis, 694 , 698, 698t
meperidine contraindication, 204 MPA immunotherapy, 375t, 385t Mydriasis agents, 694 , 698, 698t
phene zine, 150t, 173t MRP1 (ABCC1) transporter, 23t Mye oid growth actors, 405t, 407t, 418t
se egi ine, 150t, 173t MRP2 (ABCC2) transporter, 23t G-CSF, 405t, 407t, 408 , 409–410, 416,
SSRI a er, 157 MRP3 (ABCC3) transporter, 24t 417, 418t
structures, dosing, and adverse MRP4 (ABCC4) transporter, 24t G-CSF, pegy ated recombinant, 405t, 407t,
e ects, 156t MRP5 (ABCC5) transporter, 24t 408 , 409–410, 418t
trany cypromine, 150t, 173t MRP6 (ABCC6) transporter, 24t GM-CSF, 405t, 407t, 408 , 409–410, 418t
Monobenzone, 710t, 727t MRSA. See Methici in-resistant indications and choice, 409–410
Monoc ona antibodies (mAbs) Staphylococcus aureus (MRSA) mechanisms o action, 405t, 407t
anti-CD3, muromonab-CD3, 376t, M A. See Pemetrexed (M A) sites o action, 408
378, 385t m OR, 384 Myocardia in arction
anti-CD25 (anti-IL-2 R), 376t, m OR inhibitors, 663t, 685t aspirin prophy axis, dai y, 365
379, 386t evero imus, 663t, 685t drugs, 324–325, 324 (See also
basi iximab, 376t, 386t mechanisms o action, 663t, 675 T romboembo ic disorder drugs)
dac izumab, 376t, 386t mechanisms o resistance, 663t, 676 p ate et adhesion and aggregation, 324,
anti-CD52, a emtuzumab, 376t, rapamycin, 663t, 675–676, 685t 324 (See also Antip ate et agents)
378, 386t temsiro imus, 663t, 675–676, 685t Myocardia ischemia
CD20, anticancer, 662t, 667t, 684t Muco ytics, 390t, 404t c assi cation, 290t
99
Y-ibritumomab, 662t, 671t, 684t DNase (dornase a a), 390t, 404t percutaneous coronary
131
I-tositumomab, 662t, 671t, 684t N-acety cysteine, 390t, 404t interventions, 297
dose and toxicities, 671t, 684t Mu tip e mye oma, bortezomib, 663t, 681, stents, drug-e uting coronary, 297, 297b
mechanisms o resistance, 662t 682–683, 685t symptoms, 289b–290b
760
Myocardia ischemia drugs, 289–300. See also Na+-K+ exchange, sarco emma , 303 microtubu e-damaging agents: taxanes,
speci c drugs and drug classes Na buphine, 195t, 200t, 209t 642t, 648–650, 656t
β adrenergic receptor antagonists, 289t, Na me ene, 177t, 193t docetaxe , 630 , 642t, 644b,
291 , 292–294, 300t Na oxone, 16, 17, 41t, 42t, 65t, 195t, 648–650, 656t
Ca2+ channe antagonists, 290t, 294–295, 203–204, 205, 207, 209t mechanisms o action, 630 , 642t,
295t–296t, 297–299, 300t opioid overdose, 203–204, 205, 207 648–650
c audication, 295b precautions, 203 mechanisms o resistance,
mechanisms o action, 289t–290t route o administration, 205, 207 642t, 644b
Na+ channe b ocker, rano azine, 290t, toxicity use, 41t, 42t, 65t nab-pac itaxe , 630 , 642t, 644b,
298, 299, 300t Na trexone 648–650, 656t
nitrate vasodi ators, organic, 22, 289t, a coho ism, 177t, 186–187, 186t, 203, 257 pac itaxe , 630 , 642t, 644b,
291–292, 291b, 291 , 294, or opioid addiction, 262 648–650, 656t
297–299, 300t opioid receptor antagonism, 193t, 195t, 209t toxicities, 656t
periphera vascu ar disease, 295b Naphazo ine, 120t, 142t uses, 644t, 656t
phosphodiesterase 5 inhibitors, 291b, ophtha mic, 690t, 695t, 705t microtubu e-damaging agents: vinca
292, 300t NAPQI (N-acety -p-benzoquinone imine), a ka oids, 642t, 656t
unstab e angina, 296–297 29, 48, 53 mechanisms o action, 630 , 642t
variant angina, 297 Naratriptan, 130t, 147t mechanisms o resistance, 642t, 644b
vasospastic angina with sinus bradycardia, Nata izumab, 382t toxicities, 656t
297, 298 Nateg inide, 470t, 472 , 479t uses, 644t, 656t
Natriuresis, 270b vinb astine su ate, 630 , 642t, 644b,
N Natriuretic agents 644t, 656t
Na+-2C - symporter inhibitors. See T iazide/ atria natriuretic peptide, 269t, vincristine su ate, 630 , 642t, 644b,
thiazide- ike diuretics 280, 284t 644t, 656t
Na+ ba ance disorder agents, 279t, 280–281, diuretics (See Diuretics) vinore bine, 630 , 642t, 644b,
281 . See also Diuretics Natriuretic peptide receptor agonists, heart 644t, 656t
Nabi one, 498t, 502, 508t ai ure topoisomerase inhibitors: camptothecin
Nab-pac itaxe , 642t, 648–650, 656t mechanisms o action, 302t ana ogs, 643t, 657t
mechanisms o action, 630 , 642t, nesiritide, 302t, 311t irinotecan, 630 , 643t, 644b–645b,
648–650 Natura products, cytotoxic, 642t–644t, 649–651, 657t
mechanisms o resistance, 642t, 644b 645–647 mechanisms o action, 630 , 643t,
toxicities, 656t antibiotics, anticancer, 630 , 643t, 658t 649–651
uses, 644t, 656t b eomycin, 630 , 643t, 645b, 658t mechanisms o resistance, 643t,
N-acety cysteine (NAC), 40t, 42t, 54, 65t mechanisms o action, 643t 644b–645b
muco ytic, 390t, 404t mechanisms o resistance, 643t, topotecan, 630 , 643t, 644b–645b,
Na+ channe b ockers 645b–646b 649–651, 657t
antiarrhythmic, 312t, 320t–321t mitomycin (mitomycin-C), 630 , 643t, toxicities, 657t
disopyramide, 312t, 317t, 321t 646b, 658t uses, 644t, 657t
ecainide, 312t, 317t, 321t uses, 644t, 658t topoisomerase inhibitors:
idocaine, 312t, 316, 317t, 319, antibiotics, anticancer: actinomycins, epipodophy otoxins, 643t, 657t
320, 321t dactinomycin, 630 , 643t, 658t etoposide, 630 , 643t, 645b, 657t
mexi etine, 312t, 317t, 321t antibiotics, anticancer: anthracyc ines and mechanisms o action, 630 , 643t
procainamide, 312t, 316, 317t, 320t anthracenediones, mechanisms o resistance, 643t, 645b
propa enone, 312t, 317t, 321t 643t, 658t teniposide, 630 , 643t, 645b, 657t
quinidine, 312t, 317t, 320t daunorubicin, 630 , 643t, 645b, 658t toxicities, 657t
myocardia ischemia, rano azine, 290t, doxorubicin, 630 , 643t, 645–647, uses, 644t, 657t
298, 299, 300t 645b, 658t trabectedin, 643t, 659t
Na channe s, 86, 87
+
epirubicin, 630 , 643t, 645b, 658t uses, 644t
antiseizure drug-enhanced inactivation, idarubicin, 630 , 643t, 645b, 658t Nausea drugs. See Antinauseants and
225t, 225t–226t, 226 , 232 mechanisms o action, 630 , 643t antiemetics
vo tage-gated mechanisms o resistance, 643t, 645b Nebivo o , 126t, 128t, 146t
oca anesthetics on, 217 mitoxantrone, 630 , 643t, 645b, 658t Nedocromi , ophtha mic, 691t, 705t
structure and unction, 218 uses, 644t, 658t Ne azodone, 150t, 174t
Nado o , 125t, 128t, 144t va rubicin, 630 , 643t, 645b, 658t Negative rein orcement, 265, 266
Nadroparin, 323t, 325, 333t enzymes Ne arabine, 636t, 655t
Na are in, 422t, 427, 428, 429t, 664t, 686t l -asparaginase (l -ASP), 630 , 643t, mechanisms o action, 630 , 636t,
Na ci in, 551, 552t, 554, 555, 555t 644t, 648–650, 659t 641–642
Na i ne, 589 , 599t pegaspargase (PEG-l -asparaginase), uses, 637t
Na+-K+-2C - symporter inhibitors. 643t, 659t Ne navir, 601t, 603t, 608 , 609 , 622t
See Loop diuretics uses, 644t Neomycin, 559–566, 559b, 567t
Na+-K+-A Pase inhibitors mechanisms o action, 630 , 642t–643t Neosporin, 573
antiarrhythmic, 312t, 322t mechanisms o resistance, 644b–646b Neostigmine, 104
digoxin, 312t, 317t, 319, 320, 322t microtubu e-damaging agents Neostigmine bromide, 100t, 114t
heart ai ure, 303 , 311t epothi ones: ixabepi one, 643t, 644b, Neostigmine methy su ate, 100t, 114t
digoxin, 301t, 306, 307, 311t 650, 657t Nepa enac, 357t, 361t, 373t
mechanisms o action, 301t estramustine, 630 , 643t, 650, 657t ophtha mic, 691t, 705t
761
Nephrons, 270b Neurotransmitters, 85, 86b, 86 mechanisms o resistance, 627t,
Nerve gases actions and termination, 89, 90 632–633, 632b
organophosphate, 100t, 103t, 116t CNS, 86b, 91–92, 91t mech orethamine HC , 627t, 651t
sarin, 100t, 103t, 115t PNS, 83t–84t, 86b, 92 me pha an, 627t, 632t, 651t
soman, 100t, 103t, 116t receptors, 89b toxicities, 632b–633b, 632t, 651t
tabun, 100t, 103t, 116t Nevirapine, 601t, 603t, 615, 622t uses, 629t
Nerve impu se transmission, 85–86, 85b, 86 HIV, 615 Nitrog ycerin
Nerve injury pain, 197b, 197 mechanisms o action and resistance, administration, timing, 291–292
Nesiritide (BNP), 269t, 280, 284t, 302t, 311t 603t, 608 , 610 , 615 adverse e ects, 292
Neti micin, 559–566, 559b, 567t structure, 610 angina prevention, 291
Neurodegenerative disease drugs, 238–253. New drug testing, 44 , 45, 45t rst-pass e ect, 22, 291, 299
See also speci c diseases phases, 45t myocardia ischemia, 22, 289t, 291–292,
and drugs Niacin, 335t, 340, 341, 342, 343t 291b, 291 , 300t
A zheimer’s disease, 239t, adverse e ects, 341, 342 PDE5 inhibitor interactions, 291b, 292,
245–248, 253t Nicardipine, 277t, 287t 298, 299
amyotrophic atera sc erosis, 239t, Nicotine pharmaco ogy, 22, 289t
249, 253t addiction, 258–259 Nitroprusside, 278t, 287t
Huntington’s disease, 239t, 248–249, negative rein orcement, 265, 266 Nitrosoureas, 652t
248 , 253t poisoning, acute, 106t, 108, 108b carmustine, 632t, 652t
Parkinson’s disease, 238t–239t, 239–245, withdrawa syndrome, 258–259, 259t omustine, 652t
239b, 242t, 250–251, 252t–253t Nicotine gum or ozenge, 106t, 108, 108b, mechanisms o action, 627t, 628b, 630
Neuroe ector junction, 97 117t, 259 mechanisms o resistance, 627t,
Neuro eptic ma ignant syndrome, 172t Nicotine nasa spray or vapor inha er, 106t, 632–633, 632b
Neuromuscu ar b ocking agents 108, 108b, 117t, 259 semustine, 652t
anesthetic adjuncts, 211t, 223t Nicotine transderma patch, 106t, 108, 108b, streptozocin, 652t
c assi cation, 107t 117t, 259 toxicities, 632b–633b, 652t
competitive, 97 , 105 , 106 , 106t, 107t, Nicotinic ACh receptor agonists, 106, 117t uses, 629t
116t–117t Nicotinic acid, 335t, 343t Nitrous oxide, 210t, 215t, 223t
depo arizing, 97 , 105 , 107t, 108, 116t mechanisms o action, 335t Nizatidine
mechanisms o actions, 106t niacin, 335t, 340, 341, 342, 343t gastric acid disease, 490t, 496t
Neuromuscu ar junction Nicotinic receptors, 82 , 93, 94 structure, 492
acety cho ine, 105 Ni edipine Nocardia, 579t, 587t
drugs at, mechanisms o action, 106t antihypertensive, 277t, 287t Nociception. See also Opioid
sites o action, 105 myocardia ischemia, 290t, 300t pharmaco ogy; Pain
somatic, neurotransmitters, 82 , 93, 94 Ni urtimox, 531t, 535t acute, 197b, 197
(See also speci c types) Ni otinib Noncompetitive antagonists, 4b, 5
Neuropeptides, 91t mechanisms o resistance, 668 Nonionized mo ecu es
Neuropeptide Y (NPY), 122 pharmacodynamics, 15 b ood-brain barrier, 19–20, 19b–20b, 19 ,
Neurotransmission, 80–94 Ni utamide, 442t, 458t, 665t, 679t, 687t 20 , 35, 37–38
a prazo am, 92 Nimodipine, 290t, 300t di usion, 19–20, 19b–20b, 19 , 20 , 35,
atropine, 80–82 Niso dipine 37–38
autonomic nervous system, 80, 81 , antihypertensive, 277t, 287t Non-nuc eoside reverse transcriptase inhibi-
82 , 85b myocardia ischemia, 290t, 300t tors (NNR Is), 601t, 603t, 608 ,
b ood-brain barrier, 94 Nitazoxanide, 530t, 532, 535t 610 , 623t
brain signa transduction, 85, 86b, 86 Nitrates de avirdine, 601t, 603t, 608 , 610
cho inergic antagonist, 81 , 82 , 83t–84t, rst-pass e ect, 22, 291, 299 e avirenz, 601t, 603t, 608 , 610 , 623t
93, 94, 95t PDE5 inhibitor interactions, 291b, 292, etravirine, 601t, 603t, 608 , 610 , 623t
cho inesterase inhibitor, 89 298, 299 mechanisms o action and resistance,
CNS drugs, 91–92 Nitrate vasodi ators, myocardia ischemia, 603t, 608 , 610
diphenhydramine vs. oratadine, 89–90 289t, 291 , 300t nevirapine, 601t, 603t, 608 , 610 ,
drug-induced sedation/depression, with Ca2+ channe b ockers, 297 615, 622t
hyperexcitabi ity a er, isosorbide-5-mononitrate, 289t, 298, structures, 610
89–90, 94 299, 300t Nonsteroida anti-in ammatory drugs
enteric nervous system, 82–83 isosorbide dinitrate, 289t, 300t (NSAIDs), 356–373
excitatory and inhibitory, 86, 86 nitrog ycerin, 22, 289t, 291–292, 291b, acetic acid derivatives
ion channe s, 86, 86 –88 , 89t 291 , 300t brom enac, 357t, 373t
morphine, constipation, 92 PDE5 inhibitor interactions, 291b, 292, dic o enac, 357t, 362t, 371, 372, 373t
muscarinic receptors, 82 298, 299 etodo ac, 357t, 361t, 373t
nerve impu se, 85–86, 85b, 86 Nitric oxide gas, therapeutic, 211t, 223t indomethacin, 357t, 361t, 373t
neuropeptides, 91t Nitro urantoin, 545, 546, 547, 548t ketoro ac, 357t, 361t, 373t
neurotransmitters, 85, 86b, 86 , 89, 90 , Nitrogen mustards, 627t, 651t nepa enac, 357t, 361t, 373t
91–92 activation, in vivo, 631, 631 su indac, 357t, 361t, 373t
nicotinic receptors, 82 , 93, 94 bendamustine, 627t, 651t to metin, 357t, 361t, 373t
receptors, 89b cyc ophosphamide, 627t, 631 , 632t, 651t adverse e ects, 364t, 365b, 367–368
somatic nerves, 82 , 85, 92 i os amide, 627t, 632t, 651t arthritis, 366–368
sympathetic vs. parasympathetic mechanisms o action, 626, 627t, 628, ba sa azide, 357t
nervous systems, 82 , 85, 92 628b, 630 choice and dosing, 366–367
762
Nonsteroida anti-in ammatory drugs (Cont.) emedastine di umarate, 691t, 705t strabismus and b epharospasm agents,
c assi cation, 360 , 361t–363t epinastine, 691t, 705t 692t, 706t
di unisa , 357t, 360t, 373t ketoti en umarate, 691t, 705t abobotu inumtoxin A, 692t, 706t
mesa amine, 357t, 373t odoxamide tromethamine, 691t, 705t onabotu inumtoxin A, 692t, 706t
o sa azine, 357t, 373t nedocromi , 691t, 705t surgery agents, ophtha mic,
ophtha mic, 691t, 705t o opatadine, 691t, 705t 691t–692t, 706t
brom enac, 691t, 705t pemiro ast, 691t, 705t chondroitin su ate, 692t, 706t
dic o enac, 691t, 705t antivira s, 693t, 701 cyanoacry ate, 692t, 706t
urbipro en, 691t, 705t autonomic agents, 690t–691t, 695t, 700, brogen ge , 692t, 706t
ketoro ac, 691t, 705t 704t–705t hya uronate, 692t, 706t
nepa enac, 691t, 705t acety cho ine, 690t, 695t, 704t hydroxypropy methy ce u ose,
rheumatoid arthritis, 380 aprac onidine, 690t, 695t, 702, 692t, 706t
sa icy ate, 357t, 373t 703, 704t po ydimethy si oxanes, 692t, 706t
sa sa ate, 357t, 373t atropine, 690t, 695t, 704t povidone iodine, 691t, 706t
su asa azine, 357t, 368t, 373t, 381 betaxo o , 691t, 695t, 704t vitreous substitutes, 692t, 706t
u cers rom, 492 brimonidine, 690t, 695t, 704t systemic drugs with ocu ar adverse
Non-S –segment-e evation myocardia carbacho , 690t, 695t, 704t e ects, 696t
in arction, 290t, 291 . See also carteo o , 691t, 695t, 704t wetting agents/tear substitutes,
Myocardia ischemia cyc opento ate, 690t, 695t, 705t 692t, 706t
drugs, 296–297 dipive rin, 690t, 695t, 704t carboxymethy ce u ose, 692t, 706t
percutaneous coronary interventions, 297 echothiophate, 690t, 695t, 704t hydroxyethy ce u ose, 692t, 706t
Norepinephrine (NE), 85, 93, 118t, homatropine, 690t, 695t, 704t hydroxypropy ce u ose,
135, 137, 139t evobuno o , 691t, 695t, 704t 692t, 706t
on bronchia air ow, 135, 137 metiprano o , 691t, 695t, 704t hydroxypropy methy ce u ose,
metabo ism, 121 naphazo ine, 690t, 695t, 705t 692t, 706t
synthesis, storage, and re ease, 122 pheny ephrine, 690t, 695t, 705t methy ce u ose, 692t, 706t
Norepinephrine (NE) receptors, 122 pi ocarpine, 690t, 695t, 704t ty oxapo , 692t, 706t
Nor oxacin, 544, 544 , 545, 548t scopo amine, 690t, 695t, 704t Ocu ar route o administration, 697t
Nortripty ine, 150t, 173t tetrahydrozo ine, 690t, 695t, 705t O atumumab, 662t, 684t
Nuc ear actor o activated ymphocytes timo o , 691t, 695t, 696–697, 697 , 704t O ce o Pediatric T erapeutics (OP ) ,
(NFA ), 383 tropicamide, 690t, 695t, 705t FDA, 72b
Nuc ear receptors, 3t. See also carbonic anhydrase inhibitors, 691t, 705t O -target interactions, 5b
speci c types brinzo amide, 691t, 705t O oxacin, 544, 544 , 545, 548t
drug metabo ism, 33t, 34 dorzo amide, 691t, 705t O anzapine, 130t, 147t, 151t, 165, 168, 170t,
Nuc eoside reverse transcriptase inhibitors g ucocorticoids, 691t, 705t 171–172, 175t
(NR Is), 601t, 603t, 607 , dexamethasone, 691t, 705t O mesartan medoxomi , 273t, 285t
608 , 621t di uprednate, 691t, 705t O opatadine, 347t, 355t
abacavir, 601t, 603t, 607 , 608 , 621t uocino one, 691t, 705t ophtha mic, 691t, 705t
adverse e ects, 615 uorometo one, 691t, 705t O sa azine, 357t, 373t
didanosine, 601t, 603t, 607 , 608 , 621t otepredno , 691t, 705t in ammatory bowe disease, 498t, 503 ,
emtricitabine, 601t, 603t, 607 , 608 , 621t predniso one, 691t, 705t 506, 507, 509t
HIV, 614–615 rimexo one, 691t, 705t NSAID properties, 357t, 373t
amivudine, 601t, 602t, 607 , 621t triamcino one, 691t, 705t Oma izumab, 390t, 397, 404t
mechanisms o action and resistance, immunosuppressives and antimitotics, Omeprazo e, 490t, 493 , 496t
602t–603t, 604 , 608 , 614–615 691t, 705t Onabotu inum toxin A, 106t, 117t
stavudine, 601t, 603t, 607 , 608 , 621t 5- uorouraci (FU), 691t, 705t Onabotu inumtoxin A, 692t, 706t
structures, 607 cyc osporine A, 691t, 705t Onabotu inumtoxin, A ophtha mic, 692t, 706t
teno ovir disoproxi , 601t–603t, 607 , mitomycin, 691t, 705t Onchocerciasis (Onchocerca volvulus),
608 , 621t Jimson weed, 694 , 698, 698t 537–540
za citabine, 601t, 621t macu ar degeneration agents, 692t, 706t Ondansetron
zidovudine, 601t, 602t, 607 , 608 , 621t bevacizumab, 692t, 706t antidiarrhea , 498t, 501, 502t, 505,
Nystatin, 599t pegaptanib, 692t, 706t 506, 508t
ranibizumab, 692t, 706t chemotherapy prophy axis, 505, 506
O vertepor n, 692t, 703, 706t mechanisms o action, 498t
Octreotide, 422t, 428t mydriasis, 694 , 698, 698t pharmaco ogy, 130t, 133t, 147t
antidiarrhea , 498t, 508t NSAIDs, 691t, 705t 1α-Hydroxycho eca ci ero , 481t, 488t
Ocu ar administration, e der y, 74t brom enac, 691t, 705t 1α-Hydroxy ase, 482 , 486, 487
Ocu ar pharmaco ogy, 690–706 dic o enac, 691t, 705t Onychomycosis, 595–596, 721, 722
absorption pathways, 697 urbipro en, 691t, 705t Ophtha mic, brinzo amide, 691t, 705t
antibacteria s, topica , 692t–693t ketoro ac, 691t, 705t Ophtha mic pharmaco ogy. See Ocu ar
anti unga s, 694t, 701 nepa enac, 691t, 705t pharmaco ogy
antihistamines and mast ce stabi izers, prostag andin ana ogs, 691t, 705t Ophtha mic surgery agents, 691t–692t, 706t
691t, 705t bimatoprost, 691t, 705t chondroitin su ate, 692t, 706t
aze astine, 691t, 705t atanoprost, 691t, 705t cyanoacry ate, 692t, 706t
bepotastine, 691t, 705t travoprost, 691t, 705t brogen ge , 692t, 706t
cromo yn sodium, 691t, 705t route o administration, 697t hya uronate, 692t, 706t
763
hydroxypropy methy ce u ose, Opioid receptor agonists, 194t–195t, mannito , 268t, 283t
692t, 706t 201–208, 202t, 208t–209t urea, 268t, 283t
po ydimethy si oxanes, 692t, 706t actions and receptor se ectivities, Osteoc ast ormation, RANKL, 482
povidone iodine, 691t, 706t 194t–195t Osteodystrophy, rena , 482 , 484
vitreous substitutes, 692t, 706t adjuvant ana gesic use, 205, 207 vitamin D, 481t, 482 , 484, 488t
Opiates. See also Opioid pharmaco ogy; a entani , 195t, 208t Osteoma acia, 484
speci c types codeine, 195t, 200t, 206, 208, 208t Osteonecrosis o jaw, bisphosphonate, 481t,
adverse e ects dosing, 200t 485, 488t
constipation, 198–199 entany , 194t, 195t, 203, 205–207, 208t Osteoporosis. See also Bisphosphonates
mood, reward, and addiction, hydrocodone, 195t, 200t, 208t denosumab, 488t
197–198, 198 hydromorphone, 194t, 195t, 200t, 208t ibandronate, 481t, 485, 488t
respiratory depression, 196b, 199 evorphano , 194t, 195t, 200t, 209t teriparatide, 481t, 488t
e der y, 71, 77b mechanisms o action, 195t types and pathophysio ogy, 482 ,
Opioid addiction, 259–262, 260 , 261t meperidine, 195t, 200t, 204, 208t 484–485
overdose, 260 methadone, 194t, 195t, 200t, 201–203, zo edronate, 481t, 485, 488t
to erance, 260 202t, 208t 22-Oxaca citro , 481t, 488t
withdrawa , 260, 261t morphine, 194t, 195t, 200t, Oxaci in, 551, 552t, 554, 555, 555t
Opioid addiction treatment, 260–262 206–208, 208t Oxa ip atin, 628t, 653t
buprenorphine and buprenorphine/ oxycodone, 195t, 200t, 208t mechanisms o action, 628b–629b, 628t,
na oxone, 261–262 oxymorphone, 195t, 200t, 208t 630 , 633
c onidine, 261 propoxyphene, 195t, 200t, 208t mechanisms o resistance, 628t, 632b,
detoxi cation, 260–261 remi entani , 195t, 208t 634–635
methadone, 260–261 su entani , 194t, 195t, 205, 207, 208t toxicities, 632b–633b, 633–634
na trexone, 262 tapentado , 195t, 209t uses, 629t, 653t
Opioid antagonists, bowe disorders tramado , 195t, 200t, 209t Oxazepam, 176t, 189, 190, 191t, 192t
a vimopan, 498t, 507t Opioid receptor antagonists, 203–205, 209t a coho withdrawa , 256
mechanisms o action, 498t actions and receptor se ectivities, 195t Oxazo idinones, 569t, 576t
methy na trexone, 498t, 499, 505, mechanisms o action, 195t Oxcarbazepine, 225t, 236t
506, 507t methy na trexone, 195t, 199, 209t Oxiconazo e, 588t, 598t
Opioid pharmaco ogy. See also speci c drugs na oxone, 195t, 203–204, 205, Oxidative reactions, metabo ic, 32t
and drug classes 207, 209t Oxybutynin, 96t, 99t, 100, 101b, 101t, 113t
actions and receptor se ectivities, na trexone, 193t, 195t, 209t Oxycodone, 195t, 200t, 208t
194t–195t therapeutic uses, 203–204 concerns, 254
adverse e ects Opre vekin, 406t, 410–411, 419t dependence, physica , 264, 266
constipation, 198–199 Ora administration, 21t. See also speci c agents dose doub ing, 255, 255t
respiratory depression, 196b, 199, 201 bioavai abi ity, in ant, 72, 74 dose-response curves, idea ized,
antidiarrhea s, 195t, 209t e der y, 73t 255, 256
antitussives, 196t, 209t, 210t Ora contraceptives, 441t–444t, 448–450, ong-acting, 256
dosing data, 200t 458t. See also Contraceptives, ora ; to erance, 255, 256t
drug-re ated deaths, 51t Estrogen antagonists; Estrogens; toxidrome, 53t
mechanisms o action, 195t–196t speci c agents Oxycodone-acetaminophen toxicity, 28–29,
ana gesia, 196–197, 196 , 197 Organic anion-transporting po ypeptide 50–54, 50 , 52t, 207, 208
mood, reward, and addiction, (OA P), 24b, 38 Oxygen gas, therapeutic, 211t, 223t
197–198, 198 Organophosphates, 53t, 63, 64, 102, 102b, Oxymetazo ine, 120t, 136, 137, 142t
metabo ism, rst-pass, 206, 207 103 , 103t, 104 Oxymorphone, 195t, 200t, 208t
pain diphenhydramine, 40t, 42t, 65t Oxytocin, 424
guide ines, 201t insecticides, 100t, 102, 102b, 103t, 104 , 115t
target and site o action, 205t mechanisms, 100t P
pain, cancer nerve gases, 100t, 103t, 116t PA-824, 579t, 587t
methadone, 201–203, 202t poisoning, 63, 64 Pac itaxe , 642t, 648–650, 656t
routes o administration, 202–203 symptoms, 102, 102b mechanisms o action, 630 , 642t,
pain states, 197b, 197 toxidrome, 53t 648–650
to erance, 206, 207 Organ transp ant therapy mechanisms o resistance, 642t, 644b
toxidrome, 53t genera princip es, 378b toxicities, 656t
withdrawa , 260, 261t immunosuppressant risks/adverse e ects, uses, 644t, 656t
Opioid receptor agonist/antagonists and 378–379, 378b, 379 Paget disease
partia agonists, 194t–195t, 209t immunotherapeutic agents bisphosphonates, 481t, 488t (See also
actions and receptor se ectivities, (See Immunotherapeutic agents; Bisphosphonates)
194t–195t speci c agents) ca citonin, 481t, 488t
buprenorphine, 194t, 195t, 200t, pre-transp antation, 378 Pain
203, 209t rejection prophy axis, 378–379 breakthrough, 202, 206, 207
butorphano , 194t, 195t, 200t, Orthostatic hypertension, 306, 306b incident, 202
203, 209t Orthosteric site, 3b mechanisms, 196–197, 196 , 197
dosing, 200t Ose tamivir, 601t, 602t, 604 , 620t targets and sites o action, 205t
mechanisms o action, 195t Osmotic diuretics, 268t, 271t, 283t Pain, cancer
na buphine, 195t, 200t, 209t g ycerin, 268t, 283t methadone, 201–203, 202t
pentazocine, 195t, 209t isosorbide, 268t, 283t routes o administration, 202–203
764
Pain management. See also speci c agents Paroxysma ventricu ar tachycardia (PSV ), mechanisms o action, 630 , 636t, 641–642
anticonvu sants, 205t 314t, 318 uses, 637t
COX-2 inhibitors, 205t Partia agonist, 4b, 4 , 7b, 9 Pentoxi y ine, 295b
drug targets and sites o action, 205t Passive di usion, 19b, 19 Peptic u cer disease, 571
morphine and opiates, 192 , 196b, kidney, 20b Percutaneous absorption, 710b, 711–715,
197, 199, 205t (See also Opioid Passive immunization, 377t–378t, 381t 711t, 713
pharmaco ogy) Passive transport, 19b, 19 e der y, 74t
NSAIDs, 205t Patho ogica toxicity, 46t important considerations, 711–712, 711t
opioid (See Opioid pharmaco ogy) Patient-contro ed ana gesia (PCA), 202 rate- imiting step, 721, 722
tricyc ic antidepressants, 205t Peak e ect, 36 or topica in ections, 714–715
Pain states, 197b, 197 . See also Opioid Peak p asma concentration, 514, 515, vehic es, 712–714, 712t
pharmaco ogy 515 , 519 Pergo ide, 130t, 148t
Pa iperidone, 151t, 170t, 175t Pediatric Research Equity Act o 2003 Perindopri , 273t, 285t
Pa onosetron, 130t, 147t (PREA), 71b Periora tremor, 172t
2-PAM, 41t, 42t, 65t Pediatrics. See Chi dren Periphera nervous system (PNS)
Pamidronate, 481t, 488t Pegaspargase (PEG-l -asparaginase), neurotransmitters, 83t–84t, 86b, 92
Panaeolus, 97 643t, 659t Periphera vascu ar disease, 295b
Pancreatic β ce , 471 , 472 , 473 Peg grastim, 405t, 407t, 408 , 409–410, 418t Permethrin, 708t, 725t
Pancuronium, 97 , 105 , 106 , 106t, Peginter eron a pha, 613–614 Pernicious anemia, 417–418. See also
107t, 116t Peginter erons, 601t Vitamin B12 de ciency
Panitumumab, 662t, 669–672, 683t Pegvisomant, 422t, 424, 425 , 428t Peroxisome pro i erator-activated
Pantoprazo e, 490t, 493 , 496t Pegy ated recombinant GCSF receptors (PPARs), 341, 342
Papi ary thyroid cancer, 436 (peg grastim), 405t, 407t, 408 , Perphenazine, 150t, 174t
Para-aminopheno derivative. See 409–410, 418t Pesticide poisoning, 89
Acetaminophen Pemetrexed (M A), 635t, 638b, 640, 653t PGE1 ana og, 356t
Parace u ar transport, 19b, 19 mechanisms and sites o action, 630 , pH
Para dehyde, 177t, 193t 635t, 639 di usion, 19–20, 19b–20b, 19 , 20 , 35,
Parasympathetic nervous system, 82 , mechanisms o resistance, 635t, 37–38
85, 92, 107t 638b, 640 tissue uptake, 21b
Parathion, 101t uses, 637t urine, excretion, 20b, 21–22
Parathyroid hormone (P H), 483 Pemiro ast, ophtha mic, 691t, 705t Pharmacodynamics, 2–17. See also speci c
Parecoxib, 363t Pemo ine, 120t, 141t drugs and drug classes
Parica cito , 481t, 488t Penbuto o , 128t active ingredient, 3
Parkinsonism, 172t Pencic ovir, 600t, 602t, 604 , 605, 605 , adverse e ects, 4–6, 5b, 9–12
Parkinson’s disease, 239–245, 250–251 608, 619t a nity (KA), 6b, 8
basa gang ia, 240–241, 241 Penetration, drug. See Barrier penetration a ergy drug case study, 3–6
cardina eatures, 239b Penici amine, 42t, 66t antihistamine, 3
dopamine neurotransmission, Penici in G, 552, 555t competitive antagonists, 4b, 5b, 5 , 7b,
240–241, 241 Penici ins, 549t, 555t–556t 16, 17
dopamine synthesis, neurona , 239, 240 a ergy, 550 , 552, 554, 555 concentration–response curve, 6b, 6 ,
pathophysio ogy, 239 aminog ycoside inactivation, 565, 566 11 , 12
prognosis, 241 amoxici in, 552t, 555t de nition, 2b
Parkinson’s disease drugs, 239–245, 250–251, ampici in, 552t, 555t dose–response curves, 4 –7 , 8–9
252t–253t az oci in, 552t drug deve opment, 6–9
amantadine, 239t, 242t, 245, 253t carbenici in, 552t, 556t drug–receptor interactions, 3b–5b, 4
apomorphine, 239t, 242t, 253t c assi cation, 552t e cacy, 4b, 4 , 7b, 7 , 9
bromocriptine, 242t mechanisms o action, 549t, equi ibrium association constant (KA),
carbidopa, 238t, 244 550–551, 550 6b, 8
carbidopa/ evodopa, 238t, 242, 250, mez oci in, 552t, 556t equi ibrium dissociation constant (KD),
251, 252t penici inase-resistant, 554, 555 6b, 8, 16, 17
dosing, 242t c oxaci in, 551, 552t, 555t ractiona occupancy ( ), 7b, 8
ear y treatment options, 242–243, 242t, dic oxaci in, 551, 552t, 555t genetic po ymorphisms, 10t, 12–14, 13
252t–253t methici in, 551, 552t ha -maxima e ective concentration
entacapone, 238t, 242t, 244 , 251, 252t na ci in, 551, 552t, 554, 555, 555t (EC50), 6 , 7b, 9
evodopa, 238t, 242–245, 243 , 244 , 252t oxaci in, 551, 552t, 555t imatinib, 14–15
mechanisms o action, 238t–239t penici in G and V, 552, 555t interindividua variabi ity, 12
pramipexo e, 238t, 242t, 245, piperaci in, 552t, 556t inverse agonists, 4, 4b, 4 , 9, 16, 17
250–252, 252t resistance, 549t, 550b, 551 ionization, kidney tubu es, 21–22
rasagi ine, 239t, 242t, 244 , 245, 253t structures, 550 postmarketing survei ance, 9–11, 46–48
ropiniro e, 238t, 242t, 245, 250, 251, 252t ticarci in, 552t, 556t resistance, 15
se egi ine, 238t, 242t, 244 , 245, 250, toxicity/a ergy, 55–56 speci city, 5b, 9
251, 253t Penici in V, 552, 555t therapeutic index, 11, 11 , 39b, 62, 64
to capone, 238t, 242t, 244 , 252t Pentamidine, 531t, 535t therapeutic window, 11, 12, 12 , 16, 17,
trihexyphenidy HC , 242t Pentazocine, 195t, 209t 35b, 36
Paromomycin, 531t, 532–533, 535t Pentobarbita , 177t, 181t, 192t war arin sensitivity, 10t, 12–14, 13 ,
Paroxetine, 130t, 146t, 150t, 157, 174t Pentostatin, 636t, 656t 329b–330b
765
Pharmacogenetics. See also CYP (cytochrome Pharmacokinetics, chi dren si dena , 391t, 398–402, 399 , 404t
P-450 super ami y); speci c drugs absorption, 67b tada a , 391t, 398–402, 399 , 404t
o ic acid ana ogs, 637 , 639 distribution, 68b Photochemotherapy, 707t, 716t, 725t
high-dose methotrexate with eucovo- excretion, 69b methoxsa en, 707t, 716t, 725t
rin rescue (HDM-L), 635t, 637 , metabo ism, 70b photopheresis, 716t
638–640, 639 p asma protein binding, 68b PUVA, 716–717, 716t, 725t
methotrexate, 637 , 639 Pharmacokinetics, e der y trioxsa en, 716t
war arin dosing, 10t, 12–14, 13 absorption and bioavai abi ity, 73b, 73 , Photodynamic therapy, 708t, 716t, 725t
Pharmacokinetics, 18–39. See also speci c 73t–74t amino evu inic acid, 708t, 725t
drugs and drug classes c earance, 75b, 76 , 76t–77t, 77 methy amino evu inate, 708t, 725t
absorption, 20b, 20 distribution and vo ume o distribution, Photopheresis, 716t
acetaminophen, 28–29, 50–54, 50 , 52t, 74b, 75t Physio ogica receptors, 2b, 3t
207, 208 excretion, 76b, 78t Physostigmine (sa icy ate), 41t, 100t, 102, 114t
administration (See also Administration) rst-pass c earance, 73t–74t antidote, 42t, 65t, 102
repeated, 38b, 38 ha - i e, 77 mechanisms o action, 100t
route o , 20b, 21t metabo ism, 73t–74t, 75b Pi ocarpine, 95t, 99t, 112t
bioavai abi ity, 20b, 33b p asma concentration–time curves, 73 , 73t mechanisms o action, 95t
biotrans orming enzymes, 29b, 29t p asma protein binding, 74b, 75t ophtha mic, 690t, 695t, 704t
b ood-brain barrier, 19–20, 19b–20b, 19 , tissue binding, 75t pharmaco ogy, 99t
20 , 28 , 35, 37–38 Phase 1 unctiona ization, 28b, 33 , 35, 38 uses and toxicities, 112t
c earance, 33b, 35, 35b–36b, 36 , neonata , 70b Pi ocarpine hydroch oride, 95t, 99t, 112t
37 , 39 Phase 1 metabo ism, 28b, 33 , 35, 38 Pimecro imus, 708t, 724t, 726t
c inica , 33b–34b neonata , 70b Pindo o , 126t, 128t, 145t
c opidogre dosing, 22, 28, 331–332 Phase 2 conjugation, 28–29, 28b, 33 , Piog itazone, 470t, 475–476, 479t
de nition, 2b 35, 39 Pipecuronium, 97 , 105 , 106 , 106t, 107t, 116t
digoxin, 30–34, 308t neonata , 70b Piperaci in, 552t, 556t
diphenhydramine, 19–20, 40t, 65t (See Phenazopyridine, 548t Piperazines, 352
also Diphenhydramine) Phene zine, 130t, 147t, 150t, 173t Pirbutero
distribution, 20 , 21b Phenindamine, 346t, 354t pharmaco ogy, 125t, 143t
CNS, 24b Phenobarbita , 177t, 181t, 189, 190, 192t pu monary, 389t, 402t
dosing, 30–31 Phenoxybenzamine, 120t, 136, 137, 141t Pitavastatin (ca cium), 334t, 343t
drug interactions, 28 Phento amine, 120t, 141t Pituitary adenoma, pro actin-secreting, 426
e imination t1/2, 34b, 37 , 39b Pheny ephrine, 119t, 139t Pituitary g and
excretion, 20 ophtha mic, 690t, 695t, 705t anterior, 424
weak acids, 36, 39 Phenytoin posterior, 424
rst-pass e ect, 20b, 22, 35, 36–37 antiseizure, 225t, 231, 234, 235, 236t Pituitary hormones, posterior, 423t, 429t
genetic po ymorphisms, 10t, e ectrophysio ogic actions, 316 arginine vasopressin, 423t, 424 , 429t (See
12–14, 13 Pheochromocytoma, 136, 137 also Vasopressin)
interindividua variabi ity, 12 Phi ade phia chromosome-positive (Ph +) oxytocin, 423t, 424 , 430t
drug response and toxicity, 22, 24b, chronic mye ogenous eukemia, pKa, 19–20, 19b–20b, 20 , 35, 37–38
28, 34b 664–669 P asma concentration–time curves,
ionization, p asma–gastric juice rst- ine treatment, 665–666 36b, 37
partitioning, 19b–20b, mo ecu ar mechanism, 665–666 e der y, 73 , 73t
20 , 21–22 Phosphate binders, 481t, 484, 488t P asma–gastric juice partitioning,
ionization state, 19–20, 19b–20b, 20 anthanum carbonate, 481t, 484, 488t 19b–20b, 20 , 21–22
ong-term therapy, rationa , 35, 39 mechanisms o action, 481t, 488t P asma protein binding, 22b
metabo ism, 20b, 28–29, 28b, 32t rena osteodystrophy, 482 , 484 chi dren, 68b
phase 1, 28b, 33 , 35, 38 seve amer hydroch oride, 481t, 484, 488t e der y, 74b, 75t
movement and avai abi ity Phosphodiesterase 3 (PDE3) inhibitors, heart Plasmodium alciparum treatment, 579t, 581 ,
characteristics, 18b ai ure, 307, 309, 310, 311t 583–586, 587t
nitrog ycerin, rst-pass e ect, 22, inamrinone, 302t, 308, 308t, 311t P ate et-activating actor (PAF), 359
291, 299 mechanisms o action, 302t, 308 P ate et adhesion and aggregation,
passive vs. active transport, 19b, 19 mi rinone, 302t, 308, 308t, 311t 324, 324
pH and di usion, 19–22, 19b–20b, 19 , pharmaco ogy, 308t P ate et drugs. See Antip ate et agents
20 , 35, 37–38 Phosphodiesterase 5 (PDE5) inhibitors P atinum coordination comp exes, 628t,
pKa, 19b–20b, 20 myocardia ischemia, 300t 633–635, 653t
p asma protein binding, 22b nitrate interactions, 291b, 292 carbop atin, 628t, 629t, 653t
rate o distribution and equi ibration, 20 , si dena , 300t ce cyc e speci city, 630
36b–37b, 37 tada a , 300t cisp atin, 628t, 629t, 632t, 653t
steady state, 19 , 30–31, 34, 38b vardena , 300t mechanisms o action, 628t, 630 , 633
St. John’s wort, 29–30, 33 , 34 ocu ar e ects, 703 mechanisms o resistance, 628t, 632b,
tissue binding, 22b–23b pu monary, 391t, 404t 634–635
transporters adverse e ects, 398, 399 , 400 oxa ip atin, 628t, 629t, 653t
ABC, 23t, 23t–25t mechanisms o action, 391t toxicities, 632b–633b, 632t,
membrane, 23b–24b, 23t–25t pu monary artery hypertension, 633–634, 653t
SLC super ami y, 23b–24b, 25t–26t 398–400, 399 uses, 629t, 653t
766
P icamycin, 481t, 488t Pravastatin (ca cium), 334t, 343t hydroxyprogesterone caproate, 679t
Podophy in, 727t Prazosin medroxyprogesterone, 664t,
Poisoning. See also oxicity, c inica antihypertensive, 277t, 286t 679t, 686t
and environmenta ; pharmaco ogy, 119t, 121–124, 123 , 140t megestro acetate, 664t, 679t, 686t
speci c poisons Precocious puberty, 422t, 427, 428, 429t hormone rep acement therapy,
ABDE treatment, 52t Predniso one 442t, 458t
initia treatment, 63, 64 ophtha mic, 691t, 705t mechanisms o action, 442t, 458t
argest number ata ities, 52t pu monary, 390t, 403t medroxyprogesterone acetate (MPA),
management, 50–52 Prednisone. See also Corticosteroids 442t, 458t
initia , 63, 64 adverse e ects, 467, 468 megestro acetate, 442t, 458t
princip es, 50–52 cancer progesterone micronized, 442t,
most common substances, 51t chemotherapy, 664t, 679t, 686t 445t, 458t
most requent substances, 51, 51t target, 664t, 679t, 686t progesterone s ow-re ease intrauterine
pharmacokinetics, 52 cessation, adverse e ects, 465 device, 442t, 458t
prevention, chi dren, 62–64 Crohn’s disease, 465, 467, 468 progesterone vagina ge , 442t, 458t
Po yc ona antibodies, 376t, 377 , 377t–378t, dose tapering, 465 progesterone vagina insert,
378, 385t pu monary, 390t, 403t 442t, 458t
Po ycystic ovary syndrome, 452 rheumatoid arthritis, 463–465 structura eatures, 451
Po ydimethy si oxanes, ophtha mic, Pregaba in, 225t, 237t Proguani , 520t, 529t
692t, 706t Pregnancy, 365 Prokinetics, bowe disorders, 497t, 507t
Po yethy ene g yco , 497t, 507t FDA ru es, 72b cisapride, 497t, 504, 506, 507t
Po ymixins, 573 iron supp ements, 406t, 413–414, 419t domperidone, 497t, 507t
po ymyxin B, 569t, 576t Prehypertension, 269–270, 270t erythromycin, 497t, 507t
po ymyxin E, 569t, 576t Premature ventricu ar beats, 314t ubiprostone, 497t, 507t
Po ymorphisms, genetic post-MI, 314t, 319, 320 mechanisms o action, 497
CYP, 27t, 28, 31b (See also CYP Pre-surgery prophy axis, 515b, 516 metoc opramide, 497t, 504, 506, 507t
(cytochrome P-450 super ami y)) Pri ocaine, 224t pruca opride, 497t, 507t
drug response, 10t, 12–14, 13 , 27t Primaquine Pro actin
Po ymyxin-bacitracin-neosporin, 569t, 573, G6PD de ciency, 527, 528 GH receptor antagonism, 423, 425
576t, 577t ma aria secretion and actions, 424 , 425
Po ysaccharide errihydrite comp ex, chemoprophy axis, 522t, 525–526 Pro actin-secreting pituitary adenoma, 426
406t, 419t chemotherapy, 521t, 522t, 525–526, Promethazine, 350–352, 354t
Po ythiazide, 269t, 284t 526t, 527, 529t antiemetic, 351, 352, 502t
Pork tapeworm, 539, 540 mechanisms o action, 521t co d medication, 346t, 350
Posaconazo e, 588t, 589 , 590, 597t parasite deve opment stage, 526t mechanisms o action, 346t
Postantibiotic e ect (PAE), 515 regimens, 522t motion sickness, 352
cepha osporins, 564, 565 Primary agonists, 3b, 8 Propa enone
Posterior pituitary hormones, 423t, 429t Primary site, 3b, 8 antiarrhythmic, 312t, 317t, 321t
arginine vasopressin, 423t, 424 , 429t (See Prinzmeta angina, 290t, 291 , 297. See also e ectrophysio ogic actions, 317t
also Vasopressin) Myocardia ischemia Proparacaine, 224t
oxytocin, 423t, 424 , 430t Probenecid, 369t, 370, 374t Propionic acid derivatives, 362t–363t, 373t
Postmarketing survei ance, 9–11, Procainamide, 312t, 317t enopro en, 362t, 373t
46–48 antiarrhythmic, 312t, 316, 317t, 320t urbipro en, 357t, 363t, 373t
Postsynaptic potentia s, autonomic, 106 e ectrophysio ogic actions, 317t ibupro en, 357t, 362t, 364–365, 373t
Potency, 7b, 7 ventricu ar bri ation, 316 ketopro en, 357t, 363t, 373t
Potency, re ative, 7 Procaine, 224t naproxen, 357t, 362t, 373t
Potentiation Procarbazine, 628t, 652t oxaprozin, 357t, 363t, 373t
drug–drug interaction, 48b mechanisms o action, 628b–629b, Propo o
mechanisms, 4b, 5 628t, 630 anesthetic, 210t, 213t, 214 , 220,
Povidone iodine, ophtha mic, 691t, 706t mechanisms o resistance, 628t, 221, 222t
Pra atrexate, 635t, 639, 653t 632–633, 632b context-sensitive ha -time, 214
Pra idoxime ch oride (2-PAM), 41t, 42t, 65t, toxicities, 632b–633b, 652t sedative-hypnotic, 177t, 193t
100t, 102, 116t uses, 629t, 652t use, common, 220, 221
mechanisms o action, 100t, 104 Procatero , 125t, 143t Propoxur, 100t, 115t
uses and toxicities, 41t, 42t, 65t, 100t, Prodrugs, 28b Propoxyphene, 195t, 200t, 208t
102, 116t Progesterone micronized, 442t, 445t, 458t Proprano o
Pramipexo e Progesterone receptor antagonists, antiarrhythmic, 312t, 317t, 321t
Parkinson’s disease, 238t, 242t, 245, 250, 442t, 458t e ectrophysio ogic actions, 317t
251, 252, 252t Progesterone receptor modu ator, se ective, myocardia ischemia, 300t
pharmaco ogy, 130t, 148t u iprista , 442t, 444t, 452, 458t pharmaco ogy, 125t, 128t, 136,
Pram intide, 471t, 479t Progesterone s ow-re ease intrauterine 138, 144t
Pramoxine, 224t device, 442t, 458t Propy hexedrine, 120t, 142t
Prasugre , 323t, 324, 325, 325t, 332t Progesterone vagina ge , 442t, 458t Propy thiouraci , 431t, 439t
bioactivation, 325t Progesterone vagina insert, 442t, 458t Prostacyc in (PGI2) and ana ogs, 391t, 404t
mechanisms o action, 323t, Progestins adverse e ects, 400
330, 331 anticancer, 664t, 679t, 686t epoprosteno , 391t, 398–400, 399 , 404t
767
i oprost, 391t, 404t neosporin, 573 Pseudoephedrine, 120t, 142t
mechanisms o action, 391t Oxazo idinones, inezo id, 569t, 576t Psilocybe, 97
treprostini , 391t, 404t streptogramins, quinupristin/da opristin, Psi ocybin, 97
Prostag andins and ana ogs 568t, 572, 575, 576b Psoriasis, 715–716
mechanisms o action, 356t–357t tetracyc ines, 568t, 569 , 576t ada imumab, 709t, 714t, 722, 723
ophtha mic, 691t, 705t doxycyc ine, 568t, 569 , 571, 576t bio ogic agent mechanisms o
bimatoprost, 691t, 705t ood contraindications, 574, 575 action, 710
atanoprost, 691t, 705t MRSA in ections, 571 immunopathogenesis, 711
travoprost, 691t, 705t photosensitivity, 574, 575 methotrexate, 715–716, 721–722
PGE1, 356t, 372t tetracyc ine, 568t, 569 , 576t Psychopharmaco ogy, 149–175. See also
a prostadi , 356t, 372t tigecyc ine, 568t, 569 , 576t speci c drugs and drug classes
PGE1 ana og, 356t, 372t Protein tyrosine kinase inhibitors, anticonvu sants, ma aria, 151t, 175t
misoprosto , 356t, 372t 661t, 683t carbamazepine, 151t, 164–165, 175t
PGE2, 356t, 372t dasatinib, 661t, 668, 683t amotrigine, 151t, 165, 175t
dinoprostone, 356t, 372t er otinib, 661t, 670–672, 683t va proic acid, 151t, 164–165, 169,
PGE2α ana og, 356t, 372t ge tinib, 661t, 670–672, 683t 173, 175t
bimatoprost, 356t, 372t imatinib mesy ate, 661t, 666–669, 681, antidepressants
carboprost, 356t, 372t 682, 683t actions and e ects, 152–154, 152
atanoprost, 356t, 372t apatinib, 661t, 673, 683t adverse e ects, 154
travoprost, 356t, 372t mechanisms o resistance, 661t disposition, 158t
tromethamine, 356t, 372t ni otinib, 661t, 668, 683t phases o treatment, 153–154
PGI2, 357t, 372t sora enib, 661t, 674, 683t sites o actions, 152
prostacyc in, 357t sunitinib, 661t, 674, 683t structures, dosing, and adverse e ects,
PGI2 ana og, 357t, 372t Prothrombin time (P ) assay, 328, 330b 155t–156t
i oprost, 357t, 372t Proton pump inhibitors, 490t, 491 , 492, antidepressants, atypica , 150t, 156t, 174t
treprostini , 357t, 372t 493 , 496t atomoxetine, 150t, 174t
Prostate cancer dex ansoprazo e, 490t, 496t bupropion, 150t, 174t
utamide, 442t, 454, 456, 457, 679t e der y, 73b mianserin, 150t, 174t
eupro ide, 423t, 425–426, 429t esomeprazo e, 490t, 495, 496t mirtazapine, 150t, 174t
metastatic, 678–680 gastroesophagea re ux disease, ne azodone, 150t, 174t
Protease inhibitors, 601t, 603t, 621t–622t 492, 493 reboxetine, 150t, 174t
amprenavir, 601t, 603t, 608 , 609 , 622t iron de ciency rom, 495 structures, dosings, and adverse
atazanavir, 601t, 603t, 608 , 609 , 622t ansoprazo e, 490t, 493 , 496t e ects, 156t
darunavir, 601t, 603t, 608 , 609 , 622t mechanisms o action, 490t, 491 , 495 trazodone, 150t, 174t
indinavir, 601t, 603t, 608 , 609 , 621t omeprazo e, 490t, 493 , 496t antipsychotics
opinavir, 601t, 603t, 615, 622t pantoprazo e, 490t, 493 , 496t adverse e ects, 172t
mechanisms o action and resistance, rabeprazo e, 490t, 493 , 496t e der y, 77b, 168, 169, 171
603t, 608 , 609 structures, 492, 492 , 493 nonpsychotic disorders, 163b
ne navir, 601t, 603t, 608 , 609 , 622t or u cers, 492, 493, 494t, 495 antipsychotics, atypica , 175t
ritonavir, 601t, 603t, 608 , 609 , vitamin B12 absorption, 492 aripiprazo e, 151t, 170t, 175t
615–619, 622t Protozoa drugs, 530–535 chemica structures, dosages, and main-
saquinavir, 601t, 603t, 608 , 609 , 621t amebic co itis, 532–533 tenance, 160t–161t
tipranavir, 601t, 603t, 608 , 609 , 622t amphotericin (B), 530t, 534, 535t metabo ism, 170t
Proteasome inhibitors, 663t, 681, benznidazo e, 530t–531t, 535t o anzapine, 151t, 165, 168, 170t,
682–683, 685t cryptosporidia diarrhea, 532 171–172, 175t
Protein binding, drug–drug e ornithine, 530t, 535t potencies, 162t
interactions on, 48t umagi in, 530t, 535t quetiapine, 151t, 171t, 175t
Protein drug receptors, 2b giardiasis, 531–532 risperidone, 151t, 168, 169,
Protein synthesis inhibitors, 568–577 eishmaniasis, viscera , 534 171t, 175t
aminocyc ito s, spectinomycin, 569t, 576t mechanisms o action, 530t–531t antipsychotics, typica , 151t, 175t
bacitracin, 569t, 577t me arsopro , 530t, 534, 535t asenapine, 151t, 170t, 175t
ch oramphenico , 568t, 569 , 571, 576t metronidazo e, 530t, 532–534, 535t chemica structures, dosages,
incosamides, c indamycin, 568t, 574, mi te osine, 530t, 534, 535t and maintenance, 160t
575, 576t ni urtimox, 531t, 535t c ozapine, 151t, 167–169, 170t,
macro ides and keto ides, 568t, nitazoxanide, 530t, 532, 535t 172, 175t
570 , 576t paromomycin, 531t, 532–533, 535t i operidone, 151t, 170t, 175t
azithromycin, 568t, 570 , 576t pentamidine, 531t, 535t metabo ism, 170t
c arithromycin, 568t, 570 , sodium stibog uconate, 531t, pa iperidone, 151t, 170t, 175t
571, 576t 534, 535t potencies, 162t
drug interactions, 572 toxop asmosis, 532b sertindo e, 151t, 175t
erythromycin, 568t, 570 , 576t Trichomonas vaginalis, 533, 534 ziprasidone, 151t, 171t, 175t
te ithromycin, 568t, 570 , 576t Trypanosoma brucei rhodesiense, 534 antipsychotics, typica , other, 151t, 175t
toxicities, 571 trypanosomiasis, 533, 534 droperido , 151t, 175t
mechanisms o action, 568t–569t, Protripty ine, 150t, 173t ha operido , 151t, 159, 163 , 171t, 175t
569 , 570 Pruca opride, 497t, 507t oxapine, 151t, 175t
MRSA, 571 Pruritus, 720, 720t mo indone, 151t, 175t
768
Psychopharmaco ogy (Cont.) structures, dosing, and adverse mechanisms o action, 390t, 392 , 393
receptor occupancy and c inica e ects, 155t methy predniso one, 390t, 403t
response, 163 trimipramine, 150t, 173t predniso one, 390t, 403t
antipsychotics, typica , phenothiazines, Psychosis drugs. See Antipsychotics prednisone, 390t, 403t
150t, 174t Pteroy g utamic acid (PteG u). See Fo ic acid endothe in-1 receptor antagonists,
ch orpromazine, 150t, 171t, 174t and derivatives 391t, 404t
uphenazine, 150t, 174t P H-re ated protein (P HrP), 483 adverse e ects, 400
perphenazine, 150t, 174t Pu monary artery hypertension (PAH), ambrisentan, 391t, 398–400, 399 , 404t
tri uoperazine, 150t, 174t 398–400, 399 bosentan, 391t, 398–400, 399 , 404t
anxio ytics, benzodiazepine, 174t Pu monary drugs, 389–404 mechanisms o action, 391t
anxio ytics, non-benzodiazepine, anti-IgE monoc ona antibodies, oma i- pu monary artery hypertension,
150t, 174t zumab, 390t, 397, 404t 398–400, 399
buspirone, 150t, 174t anti eukotrienes, 390t, 403t–404t expectorants, guai enesin, 390t, 404t
bipo ar disorder, 164–166 5-LOX inhibitors, zi euton, 390t, 403t gastroesophagea re ux
e der y, 77b asthma, severe, 396 , 397 disease (GERD), 400
ithium, 151t, 164–166, 175t eukotriene antagonists, 390t, 404t methy xanthines, 390t, 403t
adverse e ects, 164t monte ukast, 390t, 404t COPD, 395
e der y, 165–166 za r ukast, 390t, 404t mechanisms o action, 390t
ibupro en, 165, 168, 169 mechanisms o action, 390t, 396 theophy ine, 390t, 392 , 397, 403t
ithium carbonate, 151t, 175t antitussives, 209t, 391t, 404t muco ytics, 390t, 404t
ithium citrate, 151t, 175t benzonatate, 391t, 404t DNase (dornase a a), 390t, 404t
overdose, 166–167 codeine, 209t, 391t, 404t N-acety cysteine, 390t, 404t
monoamine oxidase inhibitors (MAOIs), dextromethorphan, 391t, 404t muscarinic cho inergic antagonists, 390t,
150t, 157, 173t mechanisms o action, 391t 401–402, 403t
isocarboxazid, 150t, 173t asthma, 393–397, 396 adverse e ects, 395
phene zine, 150t, 173t β2 adrenergic receptor agonists, asthma, severe, 397
se egi ine, 150t, 173t ong-acting, 390t, 402t COPD, 394–395
SSRI a er, 157 adverse e ects, 392b, 398 ipratropium bromide, 390t, 402, 403t
structures, dosing, and adverse ar ormotero , 390t, 402t mechanisms o action, 390t
e ects, 156t asthma, 393–394, 396–397, 402 tiotropium bromide, 390t,
trany cypromine, 150t, 173t COPD, 395 401–402, 403t
psychosis, acute, 160t–161t ormotero , 390t, 402t phosphodiesterase 5 inhibitors,
schizophrenia indacatero , 390t, 402t 391t, 404t
chemica structures, dosages, and main- mechanisms o action, 390t, 391b, adverse e ects, 398, 399 , 400
tenance, 160t–161t 391 , 394 mechanisms o action, 391t
with drug abuse history, 159, 162–163 sa metero , 390t, 402t pu monary artery hypertension, 398–
se ective serotonin reuptake inhibitors β2 adrenergic receptor agonists, 400, 399
(SSRIs) (See Se ective serotonin short-acting, 389t, 401, 402t si dena , 391t, 398–402, 399 ,
reuptake inhibitors (SSRIs)) adverse e ects, 392b 404t, 703
serotonin/norepinephrine reuptake inhib- a butero , 389t, 402t tada a , 391t, 398–402, 399 , 404t
itors (SNRIs), 150t, 154, 157, 174t asthma, 393–394 prostacyc in (PGI2) and ana ogs,
de ay o onset, 157 eva butero , 389t, 402t 391t, 404t
desven a axine, 150t, 174t mechanisms o actions, 389t, 391b, adverse e ects, 400
disposition, 158t 391 , 394 epoprosteno , 391t, 398–400,
du oxetine, 150t, 174t metaprotereno , 389t, 402t 399 , 404t
mi nacipran, 150t, 174t pirbutero , 389t, 402t i oprost, 391t, 404t
ven a axine, 150t, 154, 157, 174t terbuta ine, 389t, 402t mechanisms o action, 391t
serotonin/norepinephrine reuptake inhib- combination inha ers, 395, 397, 398, treprostini , 391t, 404t
itors (SNRIs), secondary amine 401–402 pu monary artery hypertension,
tricyc ics, 150t, 173t COPD, 394–395 398–400, 399
amoxapine, 150t, 173t corticosteroids, inha ed, 390t, 403t venti atory stimu ants, doxapram,
desipramine, 150t, 173t adverse e ects, 393b, 397–398 391t, 404t
maproti ine, 150t, 173t asthma, 393–394, 395–397 Pu monary edema, 303. See also Edema
nortripty ine, 150t, 173t bec omethasone dipropionate, 390t, 403t drugs; Heart ai ure
protripty ine, 150t, 173t bioavai abi ity, 467, 468 Pupi e ects, 698, 698t
structures, dosing, and adverse budesonide, 390t, 402, 403t, 460t Purine ana ogs, 636t, 641–642, 655t–656t
e ects, 155t candidiasis, ora , 467, 468 PUVA photochemotherapy, 716–717,
serotonin/norepinephrine reuptake cic esonide, 390t, 403t 716t, 725t
inhibitors (SNRIs), tertiary amine COPD, 395 Pyoderma, 714
tricyc ics, 150t, 173t uniso ide, 390t, 403t Pyrazinamide, 578t, 580b, 586t
amitripty ine, 150t, 152–154, 152 , 168, uticasone, 390t, 403t Pyridostigmine bromide, 100t, 114t
169, 173t mechanisms o action, 390t, 392 , 393 Pyridoxine, 406t, 419t
c omipramine, 150t, 173t mometasone, 390t, 403t mechanisms o action, 406t
disposition, 158t triamcino one, 390t, 403t pyridoxine, 406t, 419t
doxepin, 150t, 173t corticosteroids, systemic, 390t, 403t ribo avin, 406t, 419t
imipramine, 150t, 173t hydrocortisone, 390t, 403t Pyri amine, 346t, 353t
769
Pyrimethamine-su adoxine, 521t, 529t Rasagi ine, 239t, 242t, 244 , 245, 250, angiotensin (A 1) receptor b ockers
Pyrimidine ana ogs, 635t–636t, 251, 253t (ARBs), diabetics, 274
640–641, 654t Rasburicase, 369t, 374t c assi cation, 270t
5- uorouraci (5-FU), 630 , 635t, Rate o distribution, 20 , 36b–37b, 37 direct renin inhibitors, 270t,
638b–639b, 638 , 640–641, 654t Reboxetine, 150t, 174t 273t, 286t
azacytidine, 636t, 654t Receptor, drug. See also speci c drugs a iskiren, 273t, 282, 283, 286t
capecitabine, 630 , 635t, 638 , 654t and receptors mechanisms o action, 273t
cytarabine (Ara-C), 630 , 635t, 639b, 648, con ormation-se ective drugs, 4, 4 structure, 275
649, 654t de nition, 2b e ects, 273t, 274
decitabine, 636t, 654t drug–drug interactions, on binding, 48t mechanisms o action, 270t, 273t, 278t
F oxuridine (FUdR), 630 , 635t, unctions, 2b physio ogic actors, 272 , 275b
638b–639b, 638 , 654t nervous system, 89b structures, 275
gemcitabine, 630 , 636t, 639b, 654t nuc ear, 3t, 33t, 34 vasodi ators, 270t, 278t
mechanisms and sites o action, 630 , physio ogica , 2b Renin inhibitors, direct, 270t, 273t, 286t
635t–636t, 638 , 640 primary (orthosteric) site, 3b, 8 a iskiren, 273t, 282, 283, 286t
mechanisms o resistance, 638b–639b, Receptor antagonism, 48b mechanisms o action, 273t
640–641 Receptor or activating NF-κB igand structure, 275
toxicities, 637t, 654t (RANKL), 482 Renin inhibitors/vasodi ators, direct. See
uses, 637t, 654t Receptor occupancy theory, 6b Direct renin inhibitors
Recta administration, e der y, 73t Renin re ease pathways, 272
Q Rein orcement, negative, 265, 266 Repag inide, 470t, 472 , 479t
Q interva , ong, 313–315, 315b Re ative e cacy, 7b, 7 , 9 Repeated administration, 38b, 38
Quanta dose-response phenomenon, Re ative potency, 7 Reserpine, 277t, 286t
44 , 45 Remi entani , 195t, 208t Resistance, 15, 515b, 517
Quazepam, 176t, 191t, 192t Rena epithe ia Na+-channe inhibitors, 269t, antimicrobia , 515b
Quetiapine, 130t, 147t, 151t, 171t, 175t 271t, 272 , 284t β- actam antibiotics, 516–517
Quinacrine, 708t, 725t ami oride, 269t, 284t β- actamase, 517, 519
Quinago ide, 422t, 426, 428t triamterene, 269t, 282, 283, 284t dosing schedu e, 515
Quinapri , 273t, 285t Rena unction ef ux pumps, 515b, 517
Quinethazone, 269t, 284t e der y, 76b, 78t mutations, 517
Quinidine, antiarrhythmic, 312t, 317t, 320t in ants and chi dren, 69b suppression, dosing schedu e, 515
Quinine/quinidine, ma aria, 521t, 524, Rena osteodystrophy, 482 , 484 Respiratory depression, opiate, 196b,
527, 529t vitamin D, 481t, 484, 488t 199, 201
Quino ones, 544, 544 , 545, 548t Renin-angiotensin system (RAS) Retapamu in, 708t, 725t
cipro oxacin, 544, 544 , 545, 548t inhibitors, 270t Retep ase, 323t, 333t
evo oxacin, 548t ACE inhibitors, 270t, 273t, 285t Retinoic acid receptors (RARs), 717
mechanisms o action, 544 , 545 acute MI, 279 Retinoids, 707t, 717–718, 717b, 724t
moxi oxacin, 548t adverse e ects, 276 acitretin, 707t, 724t
nor oxacin, 548t angioedema, 279 adapa ene, 707t, 724t
o oxacin, 548t benzapri , 273t, 285t a itretinoin, 707t, 724t
resistance, 544 captopri , 273t, 279, 285t bexarotene, 707t, 724t
Quinupristin/da opristin, 568t, 572, cautions, 274–276 cytotoxic actions and pharmaco ogy, 645t,
575, 576b diabetics, 274 646t, 659t
ena apri , 273t, 274–276, 275 , 285t isotretinoin, 707t, 721, 722, 724t
R ena apri at, 273t, 285t pregnancy warning, 721, 722, 724t
Rabbit syndrome, 172t osinopri , 273t, 285t tazarotene, 707t, 724t
Rabeprazo e, 490t, 493 , 496t isinopri , 273t, 281, 282, 285t, tretinoin, 707t, 724t
Radioactive iodine (131I), 431t, 435, 306, 309, 310 Rheumatoid arthritis, 380
437–439, 440t mechanisms o action, 270t, 273t, Rheumatoid arthritis drugs, 357,
Ra oxi ene 274–276, 275 368b, 368t
anticancer, 664t, 686t moexipri , 273t, 285t disease-modi ying anti-rheumatic drugs,
SERM, 442t, 458t perindopri , 273t, 285t 368b, 368t, 379–380
Ra tegravir, 601t, 603t, 611 , 623t quinapri , 273t, 285t (See also Disease-modi ying anti-
Ra titrexed, 635t, 653t ramipri , 273t, 285t rheumatic drugs (DMARDs))
Rame teon, 177t, 189, 190, 192t structure, 275 immunotherapeutic agents, 380–381
Ramipri , 273t, 285t trando apri , 273t, 285t NSAIDs, 366–368, 380 (See also
Ranibizumab, 662t, 684t angiotensin II e ects, 274 Nonsteroida anti-in ammatory
Ranitidine angiotensin receptor b ockers (ARBs), drugs (NSAIDs))
gastric acid disease, 490t, 496t 270t, 273t, 285t prednisone, 463–465
structure, 492 candesartan ci exeti , 273t, 285t Ribavirin, 601t, 602t, 620t
Rano azine, 290t, 298, 299, 300t irbesartan, 273t, 285t adverse e ects, 614
Rapamycins osartan, 273t, 285t hepatitis C, chronic, 613–614
anticancer, 663t, 675–676, 685t o mesartan medoxomi , 273t, 285t Ribo avin, 406t, 419t
congeners, temsiro imus, 663t, 675–676 structure, 275 Ri abutin, 578t, 579 , 580 , 586t
mechanisms o action, 662t, 675 te misartan, 273t, 285t Ri ampin, 581–586, 586t
toxicities, 675–676 va sartan, 273t, 280, 282, 283, 285t adverse e ects, 582
770
Ri ampin (Cont.) S Se ective estrogen receptor modu ators
H. in uenzae meningitis prophy axis, Sa ety (SERMS), 442t, 458t
578t, 579 , 581–582, 586t FDA Sa ety and Innovation ra oxi ene, 442t, 458t
mechanisms o action, 578t, 579 Act o 2012, 72b tamoxi en, 442t, 451, 456, 457,
mechanisms o resistance, 578t, 580 medication, chi dren, 71b–72b 458t, 667
tubercu osis, 578t, 579 , 581–586, 586t Sa butamo toremi ene, 442t, 458t
Ri amycins, 578t, 581–586, 586t pharmaco ogy, 125t, 127, 135, Se ective estrogen receptor modu ators
H. in uenzae meningitis prophy axis, 137, 143t (SERMs), targeted anticancer,
578t, 581–586, 586t pu monary, 389t, 402t 664t, 686t
tubercu osis, 578t, 586t Sa icy ate, 357t, 373t mechanisms o resistance, 664t
mechanisms o action, 578t, 579 Sa icy ate toxidrome, 53t ra oxi ene, 664t, 686t
mechanisms o resistance, 578t, 580 Sa ine axative, 497t, 507t tamoxi en, 664t, 667 , 676–678, 677t,
ri abutin, 578t, 586t Sa metero 679t, 686t
ri ampin, 578t, 579 , 581–586, 586t pharmaco ogy, 125t, 143t toremi ene, 664t, 677t, 679t, 686t
ri apentine, 578t, 586t pu monary, 390t, 402t uses, 677t, 686t
Ri apentine, 578t, 579 , 580 , 586t Sa sa ate, 357t, 373t Se ective progesterone receptor modu ator
Rigidity agents, cho inergic, 106t, 117t Saquinavir, 601t, 603t, 608 , 609 , 621t (u iprista ), 442t, 444t, 452, 458t
Ri onacept, 376t, 386t Sargramostim, 405t, 407t, 408 , Se ective serotonin reuptake inhibitors
Ri uzo e, 239t, 249, 251, 252, 253t 409–410, 418t (SSRIs), 130t, 131–133, 131 , 136,
Rimabotu inum toxin B, 106t, 117t Sarin, 100t, 103t, 115t 138, 146t
Rimantadine, 601t, 602t, 604 , 620t Saxag iptin, 471t, 472 , 479t case question, 136, 138
Rimexo one Saxitoxin, musse s, 221, 222 cita opram, 150t, 174t
ophtha mic, 691t, 705t Schizophrenia de ay o onset, 157
Rimonanbant, 98t drug abuse history, 159, 162–163 disposition, 158t
Risedronate, 481t, 488t drug structures, dosages, and mainte- drug interactions, 157
Risperidone, 130t, 147t, 151t, 168, 169, nance, 160t–161t uoxetine, 150t, 157, 174t
171t, 175t Scopo amine uvoxamine, 150t, 174t
Ritodrine, 125t, 144t antiemetic, 502t MAO inhibitors with, 133
Ritonavir, 601t, 603t, 608 , 609 , motion sickness, 346t, 350, 352 a er MAOIs, 157
615–619, 622t ophtha mic, 690t, 695t, 704t mechanisms o action, 136, 138
adverse e ects, 615 pharmaco ogy, 96t, 112t paroxetine, 150t, 157, 174t
on CP3A4, 617–619 Sea ood a ergies, 349–350 sertra ine, 150t, 174t
drug interactions, 616 Secobarbita , 177t, 180, 192t sites o actions, 152
mechanisms o action and resistance, Sedation, drug-induced. See also structures, dosing, and adverse e ects,
603t, 608 , 609 , 615 speci c drugs 155t–156t
Rituximab hyperexcitabi ity a er, 89–90, 94 Se ective -ce costimu ation
anticancer, 662t, 671t, 681, Sedative-hypnotics, 176–193, 177t, b ockers, 387t
682, 684t 191t–193t. See also Hypnotics and Se egi ine
rheumatoid arthritis, 368t sedative-hypnotics; speci c drugs Parkinson’s disease, 238t, 242t, 244 , 245,
toxicities, 684t and drug classes 250, 251, 253t
uses, 684t adverse e ects, 179 psychopharmaco ogy, 150t, 173t
Rivaroxaban, 323t, 328, 333t barbiturates, 177t, 180–182, 181t, 192t Semustine (methy -CCNU), 627t, 652t
Rivastigmine, 100t, 115t benzodiazepine receptor agonists, nove , mechanisms o action, 627t,
A zheimer’s disease, 239t, 246, 177t, 192t 628b, 630
247t, 253t benzodiazepine receptor antagonists, mechanisms o resistance, 627t,
Rizatriptan, 130t, 147t umazeni , 41t, 42t, 65t, 177t, 632–633, 632b
RNA virus rep icative cyc es, 604 179–180, 192t toxicities, 652t
Rocuronium, 97 , 105 , 106 , 106t, benzodiazepines, 176t, 178b, 180, uses, 629t
107t, 117t 189–190, 191t–192t (See also Serotonergic (5-H ) 5-H receptor
Romidepsin (depsipeptide), 645t, 660t Benzodiazepines) agonists, 130t, 133–134, 133t,
Romip ostim, 406t, 417, 418, 419t GABAA receptor, 178 , 179 134 , 147t
Ropiniro e insomnia categories, 178b, 179 Serotonergic (5-H ) 5-H receptor antago-
Parkinson’s disease, 238t, 242t, 245, 250, ong-term use, 179 nists, 130t, 131–133, 133t, 147t
251, 252t me atonin congeners, rame teon, 177t, Serotonergic (5-H ) pharmaco ogy
pharmaco ogy, 130t, 148t 189, 190, 192t actions and c inica indications,
Ropivacaine, 224t toxidrome, 53t 131–133, 133t
Rosig itazone, 470t, 475–476, 479t Seizure disorders adverse e ects, 133
Rosuvastatin (ca cium), 334t, 338, 343t agents and princip es, 227b, 228 a motriptan, 130t, 147t
Rotigotine, 130t, 148t c assi cation, 228, 229t a osetron, 130t, 147t
Route o administration. See Administration, drug choice, 227b buspirone, 130t, 133t, 136, 138, 147t
routes ear y diagnosis and treatment, 228 cita opram, 130t, 146t
Rubidomycin, 643t, 658t genera princip es, 227b c ozapine, 130t, 147t, 170t
mechanisms o action, 630 , 643t, treatment (See Antiseizure drugs) desven a axine, 130t, 147t
645–647 Se ective estrogen-receptor downregu ators do asetron, 130t, 147t
mechanisms o resistance, 645b (SERDs), 664t drug interactions, 133
Ru namide, 226t, 237t u vestrant, 664t, 677t, 686t du oxetine, 130t, 147t
771
e etriptan, 130t, 147t structures, dosing, and adverse bupropion or, 259
ergot a ka oids and derivatives, 120t, e ects, 155t negative rein orcement, 265, 266
141t, 147t trimipramine, 150t, 173t withdrawa syndrome, 258–259, 259t
escita opram, 130t, 146t ven a axine, 150t, 154, 157, 174t Sodium 2,3-dimercaptopropane su onate
uoxetine, 130t, 131–133, 131 , 133t, Serotonin (5-H ) receptor agonists, 130t, (DMPS), 41t, 66t
146t, 157 133–134, 133t, 134 , 147t Sodium channe b ockers. See Na+ channe
uvoxamine, 130t, 146t Serotonin (5-H ) receptor antagonists, 130t, b ockers
rovatriptan, 130t, 147t 131–133, 133t, 147t Sodium channe s. See Na+ channe s
granisetron, 130t, 147t Serotonin (5-H ) receptors Sodium erric g uconate, 406t, 419t
isocarboxazid, 130t, 147t autoreceptor c asses, 134, 134 Sodium iodide, 431t, 440t
ketanserin, 133t, 147t subtypes, 132 Sodium iodine (131I), 431t, 435, 437–439, 440t
MAO inhibitors Serotonin (5-H 2) receptors, MDMA and Sodium phosphate, 497t, 507t
a tering 5-H concentrations, DOM a nity, 265, 266 Sodium stibog uconate, 531t, 534, 535t
130t, 147t Sertaconazo e, 588t, 598t Sodium thiopenta , 210t, 213t, 214 , 222t
oods prohibited, 135, 137 Sertindo e, 151t, 175t So i enacin, 96t, 101t, 113t
mechanisms o action, 130t Sertra ine, 130t, 133t, 136, 138, 146t, Soman, 100t, 103t, 116t
methysergide, 130t, 147t 150t, 174t Somatic motor nerves, 82
mi nacipran, 130t, 147t Seve amer, 481t, 488t neurotransmitters, 82 , 93, 94 (See also
naratriptan, 130t, 147t Seve amer hydroch oride, 481t, 484, 488t speci c types)
o anzapine, 130t, 147t Sevo urane, 210t, 215t, 223t Somatic nervous system, 82 , 85, 92
ondansetron, 130t, 133t, 147t Short-acting inha ed β2 agonists (SABAs). See Somatostatin (SS ), 424 , 433
pa onosetron, 130t, 147t β2-adrenergic receptor agonists, Somatostatin (SS ) ana ogs, 422t, 428t
paroxetine, 130t, 146t, 157 short-acting anreotide, 422t, 428t
phene zine, 130t, 147t Sibutramine, 130t, 147t octreotide, 422t, 428t
quetiapine, 130t, 147t Si dena Sora enib, 661t, 674, 683t
receptor subtypes, 132t myocardia ischemia, 300t Sota o
risperidone, 130t, 147t ocu ar e ects, 703 antiarrhythmic, 312t, 317t, 321t
rizatriptan, 130t, 147t pu monary, 391t, 398–402, 399 , 404t e ectrophysio ogic actions, 317t
sertra ine, 130t, 133t, 136, pu monary artery hypertension, 398–402 Spasticity agents, cho inergic, 106t, 117t
138, 146t Si odosin, 119t, 140t Specia popu ations, 67–78. See also
sibutramine, 130t, 147t Simvastatin, 334t, 343t Chi dren; E der y
sumatriptan, 130t, 133–134, 133t, Sinus bradycardia, vasospastic angina with, Speci city. See also speci c agents
134 , 147t 297, 298 adverse e ects, 9
trany cypromine, 130t, 135, Siro imus (rapamycin) de nition, 5b
137, 147t immunotherapy, 375t, 377 , 383, 384, 385t high (narrow), 5b, 9
ven a axine, 130t, 147t mechanisms o action, 375t, 383, 384 ow (broad), 5b, 9
zo mitriptan, 130t, 147t Sitag iptin, 471t, 472 , 479t Spectinomycin, 569t, 576t
Serotonin (5-H ) 6-Mercaptopurine (6-MP), 636t, Spina anesthesia, 217–219
in migraine, 133–134, 133t 641–642, 655t Spirono actone, 269t, 285t
synthesis and inactivation, 131 mechanisms o action, 630 , 636t, adverse e ects, 307
Serotonin, norepinephrine, and dopamine 641–642 heart ai ure, 302t, 307, 311t
reuptake inhibitors, 130t, 147t mechanisms o resistance, 636t, Stab e angina, 290t, 291 . See also
Serotonin/norepinephrine reuptake inhibi- 639b, 642 Myocardia ischemia
tors (SNRIs), 130t, 147t, 150t, 154, toxicities, 642, 655t Staphylococcus aureus treatment,
157, 174t uses, 637t, 655t cyc oserine, 579t, 587t
de ay o onset, 157 6-T ioguanine (6- G), 630 , 636t, 655t Statins. See HMG-CoA reductase
desven a axine, 150t, 174t mechanisms o action, 630 , 636t, inhibitors (statins)
disposition, 158t 641–642 Stavudine, 601t, 603t, 621t
du oxetine, 150t, 174t mechanisms o resistance, 636t mechanisms o action and resistance,
mi nacipran, 150t, 174t Skin absorption, 710b, 711–715, 711t, 713 603t, 607 , 608
secondary amine tricyc ics, 150t, 173t important considerations, 711–712, 711t structure, 607
amoxapine, 150t, 173t neonates, in ants, and chi dren, 67b Steady state
desipramine, 150t, 173t rate- imiting step, 721, 722 dosing, 19 , 30–31, 34, 38b
maproti ine, 150t, 173t or topica in ections, 714–715 repeated administration, 38b, 38
nortripty ine, 150t, 173t vehic es, 712–714, 712t Stem ce actor (SCF), 407t, 408
protripty ine, 150t, 173t Skin disorders. See Dermato ogic disorders Stents, drug-e uting coronary, 297, 297b
structures, dosing, and adverse Skin structure, 713 Steroidogenesis inhibitors, 665t, 687t
e ects, 155t SLC super ami y transporters, 23b–24b, abiraterone, 665t, 668 , 680, 687t
sites o actions, 152 25t–26t ketoconazo e, 665t, 687t
tertiary amine tricyc ics, 150t, 173t S eep apnea, opiates and respiratory depres- Steroid synthesis pathways, 668
amitripty ine, 150t, 152–154, 152 , 168, sion, 196b, 199, 201 St. John’s wort
169, 173t S eeping sickness, 534 on CYP3A4, 619
c omipramine, 150t, 173t Sma mo ecu es, rheumatoid arthritis, 368t pharmacokinetics, 29–30, 33 , 34
disposition, 158t Smoking, 258–259 Strabismus agents, 692t, 706t
doxepin, 150t, 173t addiction, 258–259 abobotu inumtoxin A, 692t, 706t
imipramine, 150t, 173t benzo[a]pyrene, 41t, 63–65 onabotu inumtoxin A, 692t, 706t
772
Streptogramins, quinupristin/da opristin, adrenergic neuron b ocking agents, antiandrogens, nonsteroida , 665t,
568t, 572, 575, 576b 277t, 286t 679t, 687t
Streptomycin, 559–566, 559b, 567t guanadre , 277t, 287t bica utamide, 665t, 687t
Streptozocin (streptozotocin), 627t, 652t reserpine, 277t, 286t utamide, 665t, 679t, 687t
mechanisms o action, 627t, 628b, 630 α1 adrenergic receptor antagonists, 277t ni utamide, 665t, 687t
mechanisms o resistance, 627t, doxazosin, 277t, 286t antiandrogens, steroida , 665t, 687t
632–633, 632b prazosin, 277t, 286t cyproterone, 665t, 687t
uses, 629t terazosin, 277t, 286t megestro , 665t, 687t
Stroke, tPA or, 323t, 329–330, 329 , 333t β adrenergic receptor antagonists, antiestrogens, aromatase inhibitors, 664t,
Subcutaneous administration, 21t doxazosin, 277t 679t, 686t
e der y, 74t centra y acting adrenergics anastrozo e, 664t, 677t, 679t, 686t
Suberoy ani ide hydroxamic acid (SAHA), α2 adrenergic receptor antagonists, exemestane, 664t, 677t, 679t, 686t
645t, 646t, 660t 277t, 286t etrozo e, 664t, 677t, 679t, 686t
Sub ingua administration, 22 c onidine, 277t, 286t antiestrogens, se ective estrogen receptor
e der y, 73t guanabenz, 277t, 286t downregu ators (SERDs), 664t
Succimer, 41t, 42t, 66t guan acine, 277t, 286t u vestrant, 664t, 677t, 686t
Succinimides, antiseizure, 225t, 236t methy dopa, 277t, 286t antiestrogens, se ective estrogen receptor
ethosuximide, 225t, 230–231, 234, mechanisms o action, 277t modu ators (SERMs),
235, 236t Sympathomimetics, 120t, 123 , 141t–142t. 664t, 686t
methsuximide, 225t, 236t See also α-Adrenergic receptor mechanisms o resistance, 664t
Succiny cho ine, 97 , 105 , 107t, 108, 116t agonists ra oxi ene, 664t, 686t
Sucra ate, 490t, 496t Sympathomimetic toxidrome, 53t tamoxi en, 664t, 667 , 676–678, 677t,
Su entani , 194t, 195t, 205, 207, 208t Synergistic drug–drug interaction, 48b 679t, 686t
Su bactam, 549t, 553, 558t Synthetic conjugated estrogens, 441t toremi ene, 664t, 677t, 679t, 686t
Su conazo e, 588t, 598t Syntopic interaction, 4b, 5 , 8 uses, 677t, 686t
Su adiazine, 543 , 543t, 547t co ony-stimu ating actors, 663t, 685t
Su adoxine, 521t, 529t, 543t, 548t T dose and toxicities, 671t
Su amethoxazo e, 56–57 abun, 100t, 103t, 116t EGFR (ErbB1), 667t
a ergy, 56–57 achyarrhythmia estrogens, 664t, 665t, 679t, 686t, 687t
urinary tract in ections, 543 , 543t, 547t drugs (See Antiarrhythmic drugs) (See also Estrogens)
Su apyridine, 502, 503 , 505–506, 507 mechanisms, 313b g ucocorticoids, 664t, 686t
Su asa azine, 357t, 368t, 373t, 381 acrine dexamethasone, 664t, 686t
adverse e ects, 368t A zheimer’s disease, 239t, 247t, 253t prednisone, 664t, 679t, 686t
Crohn’s disease and u cerative co itis, 381, pharmaco ogy, 100t, 115t gonadotropin-re easing hormone
498t, 502, 503 , 505, 507, 509t acro imus, 375t, 377 , 383, 385t agonists, 664t, 679–680, 687t
in ammatory bowe disease, 381, 498t, dermato ogic, 708t, 724t, 726t busere in, 664t, 687t
502, 503 , 505, 507, 509t mechanisms o action, 375t, 383, 384 des ore in, 664t
rheumatoid arthritis, 368t ada a GnRH, 664t, 680, 687t
structure, 503 myocardia ischemia, 300t gosere in, 664t, 687t
su apyridine in, 502, 503 , 505, 507 ocu ar e ects, 703 histre in, 664t, 687t
Su ation, neonata , 70b pu monary, 391t, 398–402, 399 , 404t eupro ide, 664t, 679t, 680, 687t
Su soxazo e, in ants, 68 pu monary artery hypertension, 398–402 na are in, 664t, 686t
Su te, oca anesthetics, 220, 221 Taenia solium, 539, 540 triptore in, 664t, 686t
Su onamides amoxi en, 442t, 451, 456, 457, 458t, 676–678 gonadotropin-re easing hormone
absorption and excretion kinetics, 543t anticancer, 664t, 667 , 676–678, 677t, antagonists, 665t, 686t
bacteria vs. mamma ian sensitivity, 679t, 686t abare ix, 665t, 687t
546, 547 bene cia e ects, 677–678 cetrore ix, 665t, 687t
ma enide, 546, 547, 548t mechanisms o action, 442t, 664t, 676 degare ix, 665t, 687t
pregnancy, 546, 547 mechanisms o resistance, 664t, 677 ganire ix, 665t, 687t
si ver su adiazine, 543t, 547t structure and metabo ites, 667 inter eukin-2 receptor agonists,
structures, 543 toxicities, 677–678, 686t 663t, 685t
su acetamide, 543 , 543t, 547t uses, 676, 677t, 686t a des eukin, 663t, 682, 683, 685t
su adiazine, 543 , 543t, 547t amsu osin, 119t, 140t deni eukin di itox, 663t, 671t, 685t
su adoxine, 543t, 548t apentado , 195t, 209t mechanisms o resistance, 663t
su amethoxazo e, 543 , 543t, 547t ape test, 536 monoc ona antibodies: CD20, 662t,
su asa azine, 543t, 547t apeworm 667t, 684t
su soxazo e, 543 , 543t, 547t sh, 537–540 99
Y-ibritumomab, 662t, 671t, 684t
Su indac, 357t, 361t, 373t pork, 539, 540 131
I-tositumomab, 662t, 671t, 684t
Sumatriptan, 130t, 133–134, 133t, ardive dyskinesia, 172t dose and toxicities, 671t, 684t
134 , 147t arget mechanisms o resistance, 662t
Sunitinib, 661t, 674, 683t drug, 2b (See also Receptor, drug) o atumumab, 662t, 684t
Sunscreens, 710t, 719b, 726t drugabi ity, 7 rituximab, 662t, 671t, 681, 682, 684t
Sympathetic nervous system, 82 , 85, va idity, 7 monoc ona antibodies: CD33, 662t, 684t
92, 107t argeted anticancer therapies, 661–687 gemtuzumab ozogamicin, 662t, 667t,
Sympatho ytics, antihypertensive, androgens, 664t, 679t, 686t (See also 672t, 684t
270t, 277t Androgens; speci c types) mechanisms o resistance, 662t
773
monoc ona antibodies: CD52, 662t, 667t, -ce costimu ation b ockers, se ective, 387t etraethy ead, 57
671t, 684t ear substitutes. See Wetting agents/tear etrahydrozo ine, ophtha mic, 690t,
a emtuzumab, 662t, 667t, 671t, 684t substitutes 695t, 705t
mechanisms o resistance, 662t eicop anin, 569t, 570 , 577t T a idomide, 381t
monoc ona antibodies: growth e bivudine, 601t, 602t, 607 , 608 , 620t anticancer, 663t, 666 , 685t
actor antibodies (VEGF), 662t, e ithromycin, 568t, 570 , 576t dermato ogic, 709t, 724t, 726t
673–675, 684t e misartan, 273t, 285t immunostimu ant, 381t
bevacizumab, 662t, 671t, 674–675, 684t emazepam, 176t, 191t, 192t T eophy ine
dose, 671t emozo omide, 652t asthma, 397
ranibizumab, 662t, 684t mechanisms o action, 628b, 628t, 630 pu monary, 390t, 392 , 397, 403t
toxicities, 671t, 674–675, 684t mechanisms o resistance, 628t, T erapeutic drug, 44 , 46, 46t
monoc ona antibodies: growth actor 632–633, 632b monitoring, 39b
receptors, 662t, 683t toxicities, 632b–633b, 652t toxicity, 44 , 46, 46t
cetuximab, 662t, 669–672, 683t uses, 629t T erapeutic gases. See Gases, therapeutic;
dose and toxicities, 671t emsiro imus, 663t, 675–676, 685t speci c agents
EGFR targeting, 669–672 enectep ase, 323t, 333t T erapeutic index, 11, 11 , 62, 64
HER2/neu, 667t, 682t eniposide (VM-26), 643t, 657t determining, 44 , 45
panitumumab, 662t, 669–672, 683t mechanisms o action, 630 , 643t digoxin, 31
trastuzumab, 662t, 671t, 672–673, 681, mechanisms o resistance, 643t, 645b narrow, 22b, 31, 39b
682, 683t toxicities, 657t T erapeutic window, 11, 12, 12 , 16, 17
m OR inhibitors, 663t, 685t uses, 644t, 657t c earance, 35b
evero imus, 663t, 685t eno ovir disoproxi , 601t–603t, 621t in vitro binding studies, 8
mechanisms o action, 663t, 675 mechanisms o action and resistance, tempora characteristics, 36
mechanisms o resistance, 663t, 676 602t, 603t, 607 , 608 T iazide/thiazide- ike diuretics, 269t, 271,
rapamycin, 663t, 675–676, 685t structure, 607 271t, 272 , 284t
temsiro imus, 663t, 675–676, 685t erazosin bendro umethiazide, 269t, 284t
progestins, 664t, 679t, 686t antihypertensive, 277t, 286t ch orothiazide, 269t, 284t
hydroxyprogesterone caproate, 679t pharmaco ogy, 119t, 140t ch ortha idone, 269t, 284t
medroxyprogesterone, 664t, erbina ne, 588t, 589 , 596, 598t hydroch orothiazide, 269t, 271, 273–274,
679t, 686t erbuta ine 282, 283, 284t
megestro acetate, 664t, 679t, 686t pharmaco ogy, 125t, 143t hydro umethiazide, 269t, 284t
proteasome inhibitors, bortezomib, 663t, pu monary, 389t, 402t indapamide, 269t, 284t
681, 682–683, 685t erconazo e, 588t, 597t methyc othiazide, 269t, 284t
protein tyrosine kinase inhibitors, eriparatide, 480t meto azone, 269t, 284t
661t, 683t osteoporosis, 481t, 488t po ythiazide, 269t, 284t
dasatinib, 661t, 668, 683t er ipressin, 279t, 288t quinethazone, 269t, 284t
er otinib, 661t, 670–672, 683t ertiary amine tricyc ics. See Serotonin/nor- trich ormethiazide, 269t, 284t
ge tinib, 661t, 670–672, 683t epinephrine reuptake inhibitors T iazide/thiazide- ike diuretics (Na+-2C -
imatinib mesy ate, 661t, 666–669, 681, (SNRIs), tertiary amine tricyc ics symporter inhibitors), 269t, 271,
682, 683t estosterone, 442t, 458t 271t, 272 , 284t
apatinib, 661t, 673, 683t adverse e ects, 454 T iazo idinediones, 470t, 475–476, 479t
mechanisms o resistance, 661t e ects, direct and mediated, 449 adverse e ects, 476
ni otinib, 661t, 668, 683t gynecomastia, 456, 457 mechanisms o action, 470t
sora enib, 661t, 674, 683t hypogonadism, 456, 457 piog itazone, 470t, 475–476, 479t
sunitinib, 661t, 674, 683t metabo ism, 449 rosig itazone, 470t, 475–476, 479t
steroidogenesis inhibitors, 665t, 687t secretion, hCG, 422t, 427, 428, 429t T ienopyridines, 325t. See also C opidogre ;
abiraterone, 665t, 668 , 680, 687t synthesis, 449 Prasugre ; ic opidine
ketoconazo e, 665t, 687t estosterone bucca tab et, 442t, 458t bioactivation, 325t
tha idomide and derivatives, estosterone cypionate, 442t, 458t mechanisms o action, 323t, 330, 331
663t, 685t estosterone enanthate, 442t, 458t 6-T ioguanine (6- G), 636t, 655t
ena idomide, 663t, 666 , 685t estosterone ge , 442t, 458t mechanisms o action, 630 , 636t,
mechanisms o action, 666 estosterone patch, 442t, 458t 641–642
tha idomide, 663t, 666 , 685t estosterone rep acement, 442t, 452–454, 453 mechanisms o resistance, 636t
axanes, 642t, 648–650, 656t estosterone supp ement T iopenta , 177t, 181t, 192t
docetaxe , 630 , 642t, 644b, adverse e ects, 454 context-sensitive ha -time, 214
648–650, 656t detection, 454 T iopurine methy trans erase ( PM ),
mechanisms o action, 630 , 642t, estosterone undecanoate, 442t, 458t 502–503, 503 , 506, 507
648–650 etrabenazine, 239t, 249, 253t T iotepa, 627t, 632t, 651t
mechanisms o resistance, 642t, 644b etracaine, 224t mechanisms o action, 627t,
nab-pac itaxe , 630 , 642t, 644b, etracyc ine, 568t, 569 , 574, 575, 576t 628b–629b, 630
648–650, 656t etracyc ines, 568t, 569 , 576t mechanisms o resistance, 627t,
pac itaxe , 630 , 642t, 644b, doxycyc ine, 568t, 569 , 571, 576t 632–633, 632b
648–650, 656t ood contraindications, 574, 575 toxicities, 632b–633b, 632t, 651t
toxicities, 656t MRSA in ections, 571 T rombin inhibitors, direct,
uses, 644t, 656t photosensitivity, 574, 575 323t, 333t
azarotene, 707t, 724t tetracyc ine, 568t, 569 , 576t argatroban, 323t, 330, 331, 333t
azobactam, 549t, 553, 558t tigecyc ine, 568t, 569 , 576t biva irudin, 323t, 333t
774
T rombin inhibitors (Cont.) T yrotoxicosis, 435 irinotecan, 630 , 643t, 644b–645b,
dabigatran etexi ate, 323t, 328, 333t T yrotropin-re easing hormone ( RH), 425 , 649–651, 657t
desirudin, 333t 426, 432, 433 mechanisms o action, 630 , 643t,
mechanisms o action, 323t T yroxine ( 4) 649–651
T romboembo ic disorder drugs, 323–333 unction test, 431t mechanisms o resistance, 643t,
anticoagu ants (See Anticoagu ants) hypothyroidism, 432 644b–645b
antip ate ets (See Antip ate et agents) iagabine, 226t, 237t topotecan, 630 , 643t, 644b–645b,
brino ytics, 323t, 329–330, 329 , 333t icarci in, 552t, 556t 649–651, 657t
(See also Fibrino ytics, tPA) ic opidine toxicities, 657t
T rombopoietic growth actors, 405t, 406t, antip ate et, 323t, 332t uses, 644t, 657t
407t, 419t bioactivation, 325t epipodophy otoxins, 643t, 657t
e trombopag, 406t, 419t mechanisms o action, 323t, 330, 331 etoposide, 630 , 643t, 645b, 657t
IL-11 (opre vekin), 406t, 410–411, 419t igecyc ine, 568t, 569 , 574, 575, 576t mechanisms o action, 630 , 643t
mechanisms o action, 405t, 407t, 408 i udronate, 481t, 488t mechanisms o resistance, 643t, 645b
romip ostim, 406t, 417, 418, 419t imo o teniposide, 630 , 643t, 645b, 657t
T rombopoietin ( PO, Mp igand), 407t, 408 myocardia ischemia, 300t toxicities, 657t
T romboxane A2, 324, 324t, 324 , 325 ophtha mic, 691t, 695t, 696–697, uses, 644t, 657t
T yroid and antithyroid drugs, 431–440 697 , 704t opotecan, 643t, 649–651, 657t
antithyroid compounds, 435t pharmaco ogy, 126t, 128t, 145t mechanisms o action, 630 , 643t,
antithyroid drugs, 431t, 439t–440t inea corporis, 719 649–651
carbimazo e, 431t, 439t inzaparin, 323t, 325, 333t mechanisms o resistance, 643t,
methimazo e, 431t, 435–436, 438, ioconazo e, 588t, 597t 644b–645b
439, 440t iotropium, 96t, 113t oremi ene, 442t, 458t
propy thiouraci , 431t, 439t iotropium bromide, 390t, 401–402, 403t anticancer, 664t, 677t, 679t, 686t
hyperthyroidism, 432t, 434t, 435–439 ipranavir, 601t, 603t, 608 , 609 , 622t toxicities, 686t
hypothyroidism, 431t, 432–434, 432t, iro ban, 323t, 324–325, 332t uses, 686t
433 , 434t issue binding, 22b–23b orsade de pointes, 313–315, 315b
ionic thyroid inhibitors, 431t, 440t e der y, 75t antiarrhythmics or, 314t
iodide, 431t, 440t issue distribution, 21b orsemide, 269t, 284t
sodium iodide, 431t, 440t issue injury, pain, 197b, 197 oxicity, c inica and environmenta , 40–66.
mechanisms o action, 431t issue per usion, e der y, 74b See also speci c substances
papi ary thyroid cancer, 436 izanidine ABCDE emergency care, 51, 52t
radioactive iodine (131I), 431t, 440t amyotrophic atera sc erosis, ABCDE treatment, 52t
thyroid hormones, 431t, 439t 239t, 249, 253t acetaminophen, 28–29, 50–54, 50 , 52t,
desiccated thyroid, 431t, 439t pharmaco ogy, 119t, 140t 207, 208
evothyroxine, 431t, 432–434, 434t, MC-207 acety cysteine, 40t, 42t, 54, 65t
436–439, 439t eprosy, 579t, 587t adverse drug events, 56–57
iotrix, 431t, 439t Mycobacterium avium comp ex, a atoxin B1, 41t, 60–62, 61
triiodothyroxine, 431t, 439t 579t, 587t anaphy axis, 56
T yroid cancer, papi ary, 436 obacco. See Smoking antidotes, 42t, 65t
T yroid, desiccated, 431t, 439t obramycin, 559–566, 559b, 566t arsenic, 41t, 43t, 63, 64, 66t
T yroid disease o capone, 238t, 242t, 244 , 252t atropine, 40t, 65t
hyperthyroidism, 432t, 434t, o erance benzo[a]pyrene, 41t, 63–65
435–439 barbiturates, 181–182 cadmium, 41t, 43t, 65t
hypothyroidism, 431t, 432–434, 432t, heroin, 260 carcinogens, 43t, 60–62, 60 , 61
433 , 434t, 439t opioid, 206, 207 che ators, heavy meta , 66t
symptoms, 432t oxycodone, 255, 256t chromium, 41t, 43t, 66t
T yroidectomy, 437, 438 o erogens, 381t deaths, drug-re ated, 51, 51t
T yroid unctions tests, 431t o metin, 357t, 361t, 373t de erasirox, 41t, 65t
T yroid hormone, 431t, 439t o na ate, 598t de eroxamine, 40t, 42t, 55, 65t
anti-thyroid hormone compounds, 435t o terodine, 96t, 101t, 113t dimercapro , 41t, 42t, 66t
biosynthesis and re ease o vaptan, 279t, 281, 288t dimercaptosuccinic acid, 41t, 66t
pathways, 433 opica administration, 710b, 711–715, diphenhydramine, 40t, 42t, 65t (See also
desiccated thyroid, 431t, 439t 711t, 713 Diphenhydramine)
evothyroxine, 431t, 432–434, 434t, important considerations, dose-response re ationships, 44 , 45
436–439, 439t 711–712, 711t drug–drug interactions, 48, 48b, 48t
iotrix, 431t, 439t rate- imiting step, 721, 722 drug interactions, 47
mechanisms o action, 431t systemic spread, 702, 703 drug overdose, initia management,
secretion regu ation, 433 or topica in ections, 714–715 63, 64
triiodothyroxine, 431t, 439t vehic es, 712–714, 712t drug-re ated deaths, agents, 51t
T yroid inhibitors, ionic, 431t, 440t opiramate ED A CaNa2, 41t, 42t, 63, 64, 66t
iodide, 431t, 440t antiseizure, 226t, 235, 236, 237t, e ective vs. etha dose, 44
sodium iodide, 431t, 440t 702, 703 ethano , 41t, 49 , 65t
T yroid-stimu ating hormone ( SH) g aucoma rom, 702, 703 ethano antidote, 42t, 50, 65t
unction test, 431t, 432, 437, 438 opoisomerase inhibitors, 643t, 657t FDA drug approva process, 44 , 45t,
pathway and actions, 432, 433 camptothecin ana ogs, 643t, 657t 46–48, 46t
775
umazeni , 41t, 42t, 65t, 177t, ravoprost, ophtha mic, 691t, 705t ubercu in skin test reaction, 582, 585, 586
179–180, 192t razodone, 150t, 174t ubercu osis drugs, 578–587, 578t–579t,
omepizo e, 41t, 42t, 65t, 178 reprostini , 391t, 404t 586t–587t
iron poisoning, 54–55 retinoin capreomycin, 579t, 587t
argest number ata ities, 52t cytotoxic, 645t, 646t, 659t combination therapy, 581
ead, 41t, 43t, 57–58, 57b, 58 , 63, dermato ogic, 707t, 724t cyc oserine, 579t, 587t
64, 65t riamcino one, 390t, 403t de nitive therapy, 581b
management, 50–52 ophtha mic, 691t, 705t ethambuto , 578t, 583, 587t
management, initia , 63, 64 riamcino one acetonide, 707t, 722, 723, ethionamide, 579t, 587t
medication errors, 56–57, 57t 723t, 724t isoniazid, 578t, 580 , 582, 583t, 587t
mercury, 41t, 43t, 59–60, 59 , 65t riamcino one hexacetonide, 707t, 722, 723, isoniazid-resistance, 583
meta s, heavy, 41t, 43t, 65t–66t 723t, 724t mechanisms o action, 578t–579t, 579
methano , 42t, 49–50, 49 riamterene, 269t, 282, 283, 284t mechanisms o resistance,
most common substances, 51t riazenes, 628t, 652t 578t–579t, 580
most requent substances, 51, 51t dacarbazine, 628t, 629t, 630 , PA-824, 579t, 587t
na oxone, 41t, 42t, 65t (See also Na oxone) 645–647, 652t penetration, 585, 586
new drug testing, 44 , 45, 45t mechanisms o action, 628b, 628t, 630 prophy axis criteria, 580b
organophosphates, 53t, 63, 64, 100t mechanisms o resistance, 628t, pyrazinamide, 578t, 580b, 586t
penici amine, 42t, 66t 632–633, 632b resistant and mu tidrug-resistant B,
penici in, 55–56 temozo omide, 652t 584, 584b
pharmacokinetics, 52 toxicities, 632b–633b, 652t ri amycins, 578t, 581–586, 586t
physostigmine, 41t, 42t, 65t, 102 uses, 629t mechanisms o action, 578t, 579
postmarketing survei ance, 9–11, 46–48 riazo am, 176t, 191t, 192t mechanisms o resistance, 578t, 580
pra idoxime ch oride, 41t, 42t, 65t, riazo es, 588t, 589 , 590, 597t. See also Imid- ri abutin, 578t, 586t
100t, 102 azo es and triazo es ri ampin, 578t, 579 , 581–586, 586t
prevention, chi dren, 62–63, 64 rich ormethiazide, 269t, 284t ri apentine, 578t, 586t
sodium 2,3-dimercaptopropane, 41t, 66t Trichomonas vaginalis, 533, 534 tubercu in skin test reaction, 582,
spectrum o e ects, pharmaceutica , 44 ricyc ic antidepressants ( CAs). See also 585, 586
succimer, 41t, 42t, 66t Antidepressants 22-oxaca citro parica cito , 481t, 488t
su amethoxazo e, 56–57 adverse e ects, 154 2-PAM. See Pra idoxime ch oride (2-PAM)
therapeutic drug, 44 , 46, 46t e der y, 71, 72, 75 y oxapo , ophtha mic, 692t, 706t
therapeutic index, 62, 64 pain target and site o action, 205t ypica angina, 290t, 291 . See also Myocar-
toxidromes, 51, 53t sites o actions, 152 dia ischemia
types, therapeutic drugs, 46, 46t ri uoperazine, 150t, 174t yrosine kinase ( K) growth actor receptor
urine testing, 51–52 ri uridine, 601t, 602t, 606, 619t signa ing pathway, 666
oxidromes, 51, 53t. See also speci c agents rig yceride eve s, 337t
and types rihexyphenidy hydroch oride U
oxop asmosis, 532b Parkinson’s disease, 242t U cerative co itis
tPA, 323t, 333t. See also Fibrino ytics, tPA pharmaco ogy, 96t, 114t azathioprine, 502–503, 503 , 506, 507
a tep ase, 323t, 329–330, 329 , 333t riiodothyronine ( 3) su asa azine, 381, 502, 543t, 547
mechanisms o action, 323t unction test, 431t thiopurine methy trans erase, 502–503,
retep ase, 323t, 333t hypothyroidism, 432 503 , 506, 507
tenectep ase, 323t, 333t riiodothyroxine, 431t, 439t U cers
PM , 502–503, 503 , 506, 507 rimethaphan, 106t, 117t NSAID-induced, 492
rabectedin, 643t, 659t rimethoprim-su amethoxazo e, proton pump inhibitors, 492, 493, 494t,
ramado , 195t, 200t, 209t 542–543, 548t 495 (See also Proton pump
rando apri , 273t, 285t a ergy, 56, 543 inhibitors)
ransendothe ia ux, 28b, 28 bacteria vs. mamma ian sensitivity, U iprista , 442t, 444t, 452, 458t
ransepithe ia ux, 28b, 28 546, 547 Undecy enic acid, 599t
ransmembrane enzymes, 3t o ate de ciency, 543, 543 Unstab e angina, 290t, 291 , 296–297. See also
ransport resistance, 543 Myocardia ischemia
active, 19b, 19 , 20b structure, 543 drugs, 296–297
parace u ar, 19b, 19 urinary tract in ections, 56, 542–543, percutaneous coronary
passive vs. active, 19b, 19 543 , 546, 547, 548t interventions, 297
ransporters. See also speci c types rimetrexate, 635t, 640, 653t Uptake transporters, 24b
ABC, 23t, 23t–25t rimipramine, 150t, 173t Urapidi , 120t, 141t
catecho amine p asma membrane, 124t rioxsa en photochemotherapy, 716t Urate oxidase, recombinant, 369t, 374t
ef ux, 24b ripe ennamine, 346t, 353t Urea, diuretics or, 268t, 283t
e der y, 75t rip e response o Lewis, 347b, 348 Urea substitutes, 630 , 645t, 646t, 659t
p asma membrane, catecho amine, 124t riptore in, 422t, 429t Uric acid, 370
SLC super ami y, 23b–24b, 25t–26t anticancer, 664t, 686t Uricosuric agents, 369t, 370, 374t
uptake, 24b ropicamide, 96t, 114t Uridine diphosphate-g ucuronosy trans erase
rany cypromine, 130t, 135, 137, 147t, ophtha mic, 690t, 695t, 705t (UG ), antiseizure drugs
150t, 173t rospium ch oride, 96t, 101t, 113t and, 227t
rastuzumab, 662t, 671t, 672–673, 681, Trypanosoma brucei rhodesiense, 534 Urinary tract in ection agents, 542–548
682, 683t rypanosomiasis, 533, 534 ana gesics, phenazopyridine, 548t
776
Urinary tract in ection agents (Cont.) arteria and venous, 278t, 287t Vira in ections
antiseptics nitroprusside, 278t, 287t cytomega ovirus retinitis, 609–612,
methenamine, 548t heart ai ure, 301t, 304t, 311t 617, 618
nitro urantoin, 545, 546, 547, 548t Vasopressin, 279t, 288t drugs (See antivira agents)
quino ones, 544, 548t Vasopressin receptor agonists, 288t eye, 701
cipro oxacin, 544, 544 , 545, 548t mechanisms o action, 279t, 280 hepatitis C, chronic, 613–614
evo oxacin, 548t V1 receptor, 279t, 288t herpes simp ex virus, 605–608
mechanisms o action, 544 , 545 ter ipressin, 279t, 288t HIV, 614–619 (See also Human
moxi oxacin, 548t vasopressin, 279t, 288t immunode ciency virus (HIV))
nor oxacin, 548t V2 receptor, 279t, 288t HSV, eye, 701
o oxacin, 548t desmopressin, 279t, 288t in uenza A, immunocompromised,
resistance, 544 Vasopressin receptor antagonists 612–613
structures, 543 mechanisms o action, 279t, 280 rep icative cyc es, 604
su adiazine, 543 , 543t, 547t V1aR/V2R, nonse ective, conivaptan, 279t, varice a zoster virus (shing es), 608
su amethoxazo e, 543 , 543t, 547t 281, 288t virus rep ication stages and targets, 612t
trimethoprim-su amethoxazo e, 56, V2 receptor, se ective, to vaptan, 279t, Vitamin A de ciency, 703, 704
542–543, 543 , 546, 547, 548t 281, 288t Vitamin B12, 406t, 420t
uncomp icated U I, 542–543 Vasospastic angina, sinus bradycardia with, absorption, 412
Urinary tract in ections, 548t 297, 298 proton pump inhibitors on, 492
Urine Vecuronium, 97 , 105 , 106 , 106t, 107t, cyanocoba amin, 406t, 420t
acidi cation and a ka ization, 39 108, 116t distribution, 412
pH, 20b, 21–22 Ven a axine, 130t, 147t, 150t, 154, o ate interactions, 410b, 412
testing, 51–52 157, 174t genera princip es, 411b–412b
Uro o itropin (uFSH), 423t, 429t Venti atory stimu ants, 391t, 404t hydroxycoba amin, 406t, 420t
Ventricu ar bri ation, 314t, 316 mechanisms o action, 406t, 420t
V antiarrhythmics, 314t, 316 (See also Vitamin B12 de ciency, 412 , 413b,
Va acyc ovir, 601t, 605, 608 Antiarrhythmic drugs) 414–415, 417–418
Va gancic ovir, 601t. See also Acyc ovir imp antab e cardioverter-de bri ator, 316 causes, 411b, 412
Va proic acid Ventricu ar tachycardia sh tapeworm, 537–540
anticonvu sants, 151t, 164–165, 169, antiarrhythmics, 314t Vitamin D 1α-hydroxy ase, 482 , 486, 487
173, 175t imp antab e cardioverter-de bri ator, 318 Vitamin D and ana ogs, 481t, 482 , 484, 488t
antiseizure, 225t, 231–232, 234, nonsustained, 318 1α-hydroxycho eca ci ero , 481t, 488t
235, 236t Verapami 22-oxaca citro parica cito , 481t, 488t
with amotrigine, 235 antiarrhythmic, 312t, 317t, 322t ca cipotrio , 481t, 488t
Va rubicin, 643t, 658t antihypertensive, 277t, 287t ca citrio , 481t, 482 , 488t
mechanisms o action, 630 , 643t, e ectrophysio ogic actions, 317t dihydrotachystero , 481b
645–647 heart ai ure, 306 doxerca ci ero , 481b
mechanisms o resistance, 645b myocardia ischemia, 290t, 300t ergoca ci ero , 481t, 488t
uses, 644t, 658t toxidrome, 53t hyperca cemia, 481t, 488t
Va sartan, 273t, 280, 282, 283, 285t Vi dag iptan, 471t, 472 , 479t intestina bypass surgery, 486, 487
Va vu ar heart disease, angina drugs, 294t Vigabatrin parica cito , 481t, 488t
Vancomycin, 569t, 570 , 572–575, 577t antiseizure, 226t, 235, 236, 237t, rena osteodystrophy, 481t, 482 ,
empirica treatment, 572 702, 703 484, 488t
IV, hazards, 573, 574, 575 ocu ar e ects, 702, 703 therapeutic uses, 481b
mechanisms o action, 569t, 572 Vinb astine (su ate), 642t, 656t Vitamin K1, war arin antidote, 14, 42t
resistance, 569t, 573 dermato ogic, 709t, 724t, 726t Vitamin K antagonist, 333t
Vardena mechanisms o action, 630 , 642t, 647 mechanisms o action, 323t
myocardia ischemia, 300t mechanisms o resistance, 642t, 644b war arin (See War arin)
ocu ar e ects, 703 toxicities, 656t Vitamin K cyc e, 327–328, 327
Varenic ine, 106t, 117t uses, 644t, 656t Vitreous substitutes
nicotine addiction, 259 Vinb astine su ate, 630 , 642t, 644b, ophtha mic, 692t, 706t
Variant angina, 290t, 291 , 297. See also 644t, 656t VKORC1, 13–14, 13
Myocardia ischemia Vinca a ka oids, 642t, 656t. See also VLDL-C metabo ism, 335
Vascu ar endothe ia growth speci c types VM-26. See eniposide (VM-26)
actor (VEGF) mechanisms o resistance, 642t, 644b Vog ibose, 471t, 479t
cancer angiogenesis, 673–674 toxicities, 656t Vo tage-dependent ion channe s, 86, 87
monoc ona antibodies targeting, 662t, uses, 644t, 656t Vo tage-gated Na+ channe s
671t, 673–675 Vincristine su ate, 630 , 642t, 644b, oca anesthetics on, 217
Vasodi ators, 270t, 278t, 301t 644t, 656t structure and unction, 218
arteria , 278t, 287t mechanisms o action, 630 , 642t Vo ume o distribution (V), 30, 33b, 34b
diazoxide, 278t, 287t mechanisms o resistance, 642t, 644b de nition and equation, 34b
eno dopam, 278t, 287t uses, 644t, 656t digoxin, 30
hydra azine, 278t, 287t Vinore bine, 630 , 642t, 644b, 644t, 656t e der y, 74b, 75t
hypertension and edema, mechanisms o action, 630 , 642t variations, 34b
278t, 287t mechanisms o resistance, 642t, 644b Vomiting drugs. See Antinauseants
minoxidi , 278t, 287t uses, 644t, 656t and antiemetics
777
Voriconazo e, 588t, 590, 592–593, Weak e ectro ytes, transmembrane Y
595–596, 597t distribution, 19–20, 19b–20b, Y-ibritumomab, 662t, 671t, 684t
99
adverse e ects, 593, 595, 596 19 , 20 , 35, 37–38 Yohimbine, 120t, 141t
drug interactions, 590t–592t, 593 Wetting agents/tear substitutes, 692t, 706t
mechanisms o action, 588t, 589 , 592 carboxymethy ce u ose, 692t, 706t Z
Vorinostat (SAHA), 645t, 646t, 660t hydroxyethy ce u ose, 692t, 706t Za r ukast, 390t, 404t
VP-16-213. See Etoposide (VP-16-213) hydroxypropy ce u ose, 692t, 706t Za citabine, 601t, 621t
Vytorin, 344t, 350 hydroxypropy methy ce u ose, mechanisms o action and resistance, 601t
692t, 706t structure, 607
W methy ce u ose, 692t, 706t Za ep on, 177t, 192t
War arin, 323t, 325–328, 333t ty oxapo , 692t, 706t Zanamivir, 601t, 602t, 604 , 620t
a tered activity, 329b Whit e d’s ointment, 599t Zidovudine, 601t, 602t, 621t
a tered anticoagu ant activity, 329b–330b Wo -Parkinson-White syndrome adverse e ects, 615
atria bri ation, 327 arrhythmias, 314t mechanisms o action and resistance, 517,
counse ing, 328 Wound in ection prophy axis, 514b, 516 602t, 604 , 607 , 608 , 614–615
ood–drug interactions, 328 structure, 607
indications, 325t X Zi euton, 390t, 403t
mechanisms o action, 327–328, 327 Xanthine oxidase inhibitors, gout, 369t Ziprasidone, 151t, 171t, 175t
monitoring, 325, 325t, 328, 330b a opurino , 369t, 370–372, 373t Zo edronate, 481t, 485, 488t
post-stenting, 325 ebuxostat, 369t, 370, 374t Zo mitriptan, 130t, 147t
risks and toxicities, 328 Xenobiotic metabo izing enzymes, Zo pidem, 177t, 178–179, 192t
therapeutic index, 329b 29b, 29t Zona g omeru osa, 461 , 467, 468
War arin sensitivity, 10t, 12–14, 13 Xenon, 211t, 215t, 223t Zonisamide, 226t, 237t
vitamin K (K1), 14, 42t Xy ometazo ine, 120t, 142t
778