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Principles of
Pharmacology and
58
Medicinal Chemistry
S. THOMAS ABRAHAM, MICHAEL L. ADAMS

I. INTRODUCTION.  A complete understanding of the pharmacological actions of drugs requires

an appreciation of their pharmacokinetic and pharmacodynamic properties, as well as the complexity
of the biological responses modulated by these agents. This chapter will focus on the pharmacodynamic
aspect of drugs with an emphasis on the mechanisms and consequences of drug–receptor interactions.
Additionally, the chemical characteristics of pharmacological agents that influence their interactions with
specific receptors will be addressed.

II. RECEPTORS.  Currently, we understand that receptors are unique protein or glycoprotein structures
that are responsible for the reception and transmission of information that ultimately alters the behavior
of cells, organs, or even the entire organism. It is generally understood that endogenous hormones,
neurotransmitters, or growth factors interact with specific receptors to modify cellular behavior.
A. Cell surface receptors and their signal transduction
1. The seven transmembrane G protein–coupled receptors are localized in the plasma membranes
of cells in such a manner as to have seven transmembrane domains, with multiple extracellular
and intracellular domains. This group of receptors is the most heterogeneous of the cell surface
receptors and communicates with intracellular components by activating specific guanine nucle-
otide-binding (G) protein intermediates.
a. Gs-coupled receptors (e.g., b-adrenergic, vasopressin V2, glucagon, dopamine D1). These
receptors are functionally coupled to adenylyl cyclase, which catalyzes the conversion of ad-
enosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), an intracellular sec-
ond messenger (Figure 58-1). cAMP is responsible for the downstream activation of protein

Adenylyl
cyclase
Epi

Gs-protein Figure 58-1.  The cAMP-PKA signaling system

cAMP
ATP is responsible for diverse biological effects such
 receptor as increased heart rate/contractility, vasodilation,
PKA and neurotransmitter release. Epi, epinephrine; GS,
guanine nucleotide-binding protein; ATP, adenosine
triphosphate; cAMP, cyclic adenosine monophosphate;
PKA, protein kinase A.
1135
1136 Chapter 58      II. A

PLC
ACh
Figure 58-2.  The phosphoinositide signaling system
Gq-protein is responsible for physiological responses such as
IP3 + DAG
PIP2 salivary secretion, smooth muscle contraction, and
M1 receptor hormone release. ACh, acetylcholine; Gq, guanine
Calcium PKC nucleotide-binding protein; PLC, phospholipase
release
C; IP3, inositol trisphosphate; DAG, diacylglycerol;
PKC, protein kinase C; PIP2, phosphatidylinositol
bisphosphate.

kinase A (PKA), a multifunctional enzyme that alters the function of multiple substrates to
ultimately produce effects such as increases in heart rate, release of glucose from the liver,
decrease water loss in the kidneys, and increase neurotransmitter release.
b. Gq-coupled receptors (e.g., a1-adrenergic, muscarinic M1, angiotensin AT1). Binding of
­endogenous ligands such as norepinephrine or acetylcholine leads to conformational change
in the relevant receptor and activation of the associated Gq protein, which in turn activates
a membrane-bound phospholipase C. This enzyme catalyzes the hydrolysis of membranous
phosphatidylinositol bisphosphate (PIP2) resulting in the production of inositol trisphos-
phate (IP3) and diacylglycerol (DAG). The hydrophilic IP3 releases stored calcium from the
sarcoplasmic reticulum, whereas DAG activates protein kinase C (Figure 58-2). These pro-
cesses are eventually responsible for biological processes such as smooth muscle contraction,
­aldosterone release, salivary secretion, etc.
c. Gi/o-coupled receptors (e.g., muscarinic M2, a2-adrenergic, opioid). The best characterized
results of activating receptors coupled to Gi/o proteins is the decrease in intracellular cAMP
and opening of K1-channels leading to hyperpolarization. The overall response of these types
of events is inhibitory and leads to responses such as decreasing heart rate and inhibition of
neurotransmitter release.
2. Ion channels found on the membranes of excitable cells (cardiac muscle, nerve cells, etc.) are
important regulators of cellular function and serve as targets for pharmacological intervention.
a. Ligand-gated channels (e.g., nicotinic, GABAA, glutamate). The binding of endogenous
­ligands (acetylcholine, GABA, etc.) on the extracellular domains allows the opening of ion-
selective pores on the protein that allow for the movement of ions such as sodium, chloride,
or calcium. Depending on the ion being conducted, the eventual physiological response may
be skeletal muscle contraction, nerve depolarization, or hyperpolarization.
b. Voltage-gated channels (e.g., calcium, sodium, potassium channels). Depolarizing currents
lead to opening of these channel proteins, allowing the selective movement of specific ions
into (calcium, sodium) or out (potassium) of the cell. These ion fluxes lead to cell depolariza-
tion (calcium, sodium) or repolarization (potassium) in a coordinated fashion to regulated
muscle contraction and nerve action potential.
3. Growth factor receptors (e.g., epidermal growth factor [EGF] receptor, insulin receptor, fibro-
blast growth factor receptor, interleukin-2 receptors). Generally, these receptors are composed
of a single transmembrane domain containing a cytoplasmic tyrosine kinase. Thus, binding of
EGF to its receptor results in receptor dimerization, activation of the tyrosine kinase motif,
followed by cross phosphorylation of their cytoplasmic tail regions. This tyrosine phosphory-
lation on specific sequences serves to produce src-homology binding domains for the dock-
ing of additional proteins that transduce the signal to the interior of the cell. Consequently,
EGF receptor activation leads to recruitment of Grb/Sos to the receptor with subsequent activa-
tion of the extracellular signal-regulated kinase (ERK) pathway to promote cell growth/replica-
tion (Figure 58-3). Similarly, insulin binding and receptor activation promotes insulin receptor
substrate 1/2 (IRS-1/IRS-2) ­recruitment that increases plasma membrane glucose transporter
­expression and enhanced ­glucose uptake.
 Principles of Pharmacology and Medicinal Chemistry 1137

EGF

P
Raf-1
P
MEK
EGF receptor
ERK Figure 58-3.  The ERK-MAPK signaling pathway mediates
the biological processes of growth and differentiation. EGF,
epidermal growth factor; MEK, ERK-kinase; ERK, extracellular
signal-regulated kinase.

4. Membrane transporters, pumps, and miscellaneous receptors (e.g., Na1/K1-ATPase,

­MDR-1 protein, natriuretic factor receptors). The natriuretic peptide family of proteins acti-
vates ­membrane-bound, single-transmembrane domain receptors that contain ­cytoplasmic
guanylyl cyclase activity. Membrane-bound pumps such as the Na/K-ATPase and the
­MDR-1/P-­glycoprotein are also targets for various therapeutic interventions even though they do
not have ­well-characterized endogenous ligands.
B. Intracellular receptors
1. Cytoplasmic receptors may be as diverse as glucocorticoid hormone receptor, soluble guanylyl
cyclase, and other enzymes or proteins that serve as targets for drugs (e.g., HMG-CoA reductase,
tubulin, or calcineurin). The steroid receptors in this group (e.g., glucocorticoid receptor) have
cytoplasmic localization until complexed to corticosteroids at which time they are translocated to
the nucleus to function as transcription factors for gene expression (Figure 58-4).
2. Nuclear receptors include those for thyroid hormone, sex steroids, retinoids, and peroxisome
proliferator activator receptors. The binding of specific hormones to their respective receptors
produces a complex that serves as transcription factors to modulate gene expression. Addition-
ally, DNA and components of the nucleosome may serve as binding sites for specific drugs.
C. Microorganism proteins as drug targets.  Various fungal, bacterial, and viral proteins (e.g., cell wall
transamidase, fungal CYP450, viral thymidine kinase) are targeted for selective pharmacological
­intervention to treat relevant infections. These targets are often critical to the integrity or replication of
the microorganism and their modulation can result in diminished viability of the infecting agent. Drug
selectivity for these targets is achieved because they are structurally the distinction from analogous
mammalian targets, and this often results in complete destruction of the offending microorganism.

III. DRUG–RECEPTOR INTERACTIONS

A. Drug–receptor binding.  At a fundamental level, drug molecules interact with specific receptors
in order to produce the ultimate pharmacological effect. This interaction may be governed by the
formation of hydrogen, ionic, or van der Waals bonds between given drug–receptor pairs. In general,

Cortisol Cytoplasm

Glucocorticoid R

Gene transcription

Figure 58-4.  Signaling by hormones such as cortisol

Nucleus occurs via a cytoplasmic receptor that promotes specific
gene expression after binding the ligand.
1138 Chapter 58      III. A

100 Bmax

(pmol/mg protein) 80
Drug binding

60

Figure 58-5.  The binding of a drug

40 to its receptor follows a rectangular
hyperbolic relationship where the KD
is the concentration at which half the
20 receptors are occupied. The Bmax is
the maximum number of binding sites
KD
(receptors) available to the drug and
0
may be expressed in units such moles/
Drug concentration gram tissue.

these types of bonds are relatively weak and allow for the dissociation of the drug from the recep-
tor, and the eventual pharmacological effect is reversed as the drug concentration at the receptor
­decreases. The tendency of drugs to bind to receptors is determined by its affinity for the receptor site
as well as its concentration at that site, according to the law of mass action. Accordingly, the number
of receptors [R] occupied by a drug depends on its concentration [D] and the drug–receptor associa-
tion (k1) and dissociation (k2) rate constants such that
k1
[D] 1 [R] [D 2 R] Equation 58-1
k2
 This equation suggests that the number of receptors bound by the drug at equilibrium is proportional
to the concentration of the drug and is represented by a rectangular hyperbola (Figure 58-5). The
ratio of k2 to k1 is better known as the dissociation constant (KD) and represents the concentration
of drug required to occupy 50% of the receptor sites in a tissue (Figure 58-5). The inverse of the KD
is equivalent to the affinity of a drug for its receptor and is proportional to the potency of the drug
(below). Some drugs interact with their receptors by the formation of covalent bonds or dissociate
so slowly from the receptor (very small k2) that the drug–receptor binding is irreversible or pseudo-
irreversible at equilibrium. It could be expected that these types of drugs would have longer durations
of action than those that are more rapidly reversible.
B. Drugs as agonists.  Drugs that possess affinity for a specific receptor as well as intrinsic ­activity at that
receptor are termed agonists. Agonists mimic the actions of the endogenous ­ligand (e.g., ­epinephrine
for the b-adrenergic receptor) by modifying the conformation of the ­receptor in a manner that re-
sults in the initiation of intracellular signaling events and a biological response. Thus, dobutamine is
able to mimic the actions of epinephrine at the b-receptor, ­producing increases in rate and contractil-
ity of the myocardium. For an agonist, Equation 58-1 can be ­modified to
k1
[D] 1 [R] [D 2 R] N Response Equation 58-2
k2
 The consequence of drug–receptor complex formation is a biological response that is proportional
to the number of complexes formed. The application of increasing doses of an agonist will produce
increasing biological response until a maximum effect is achieved. This relationship is represented by
a sigmoidal dose–response curve when drug dose is plotted on a logarithmic scale (Figure 58-6).
1. Full agonists are able to produce increasing biological response with increasing dose until a maxi-
mal effect or efficacy (Emax) is achieved, represented by a dose–response relationship (Figure 58-6).
From this relationship, the effective dose that produces 50% of the Emax (ED50) can be determined
as shown in Figure 58-6. The ED50 is a measure of the potency of the agonist such that drug A is
more ­potent than drug C, even though the two have similar Emaxs. Epinephrine is a full agonist at
the b-receptor.
 Principles of Pharmacology and Medicinal Chemistry 1139

Percent maximum response 100

A C

50 Figure 58-6.  For the dose–response curves of

B
three agonists, it can be seen that the A and C can
be classified as full agonists because they are able
to produce the maximal response possible, whereas
B has a lower maximum, indicating a lower efficacy.
0 However, agonist B has a greater potency than drug C
ED50A ED50C because its ED50 is lower than that of C. ED50A: dose
Log drug dose of A producing 50% of its maximal response.

2. Partial agonists possess reduced intrinsic activity or efficacy, which results in reduced Emax rela-
tive to a full agonist (drug B versus drug A or C, Figure 58-6). However, a partial agonist may have
greater affinity for the receptor, resulting in greater potency than a full agonist (compare drug B
and C, Figure 58-6). Oxymetazoline (Afrin®) and buprenorphine (Buprenex®) are partial agonists
at the a-adrenergic and m-opioid receptors, respectively.
C. Drugs as antagonists.  Drugs with affinity for a receptor but lacking intrinsic activity are called
antagonists. These drugs are unable to alter receptor conformation in a way that leads to initia-
tion of intracellular signal transduction processes and have their predominant pharmacological
action by preventing the binding and actions of an endogenous ligand. Thus, atropine binds to the
muscarinic receptor with high affinity but is unable to initiate a biological response; on the other
hand, by occupying the binding site, it prevents the ability of acetylcholine to bind and produce
an effect.
1. Equilibrium-competitive antagonists reversibly interact with the same binding site on the re-
ceptor as the agonist to prevent agonist binding and activation of the receptor. The reversibility
of antagonist binding (Equation 58-1) allows the increasing doses of agonist to displace the an-
tagonist to eventually produce the maximal biological response but with an apparent decrease
in the affinity (increased ED50). On an agonist dose–response curve, the effect of equilibrium-­
competitive antagonists would be to shift the agonist curve to the right without a change in the
maximal response (Figure 58-7A). Atropine is an example of an equilibrium-competitive antago-
nist at the muscarinic receptor.

100 100 Emax

Percent response

Percent response

+ Antagonist Emax
50 50

+ Antagonist

0 0
ED50 ED50 ED50
A Log agonist dose B Log agonist dose

Figure 58-7.  A. The apparent decrease in agonist potency (increase in the ED50 to ED509; dashed line) in
the presence of the antagonist without a decrease in the maximal response is indicative of an equilibrium-
competitive antagonist. B. The decrease in the maximal response of the agonist curve after antagonist
treatment (dashed line) would suggest the actions of a nonequilibrium or irreversible antagonist.
1140 Chapter 58      III. C

2. Nonequilibrium-competitive antagonists interact with their receptors in an irreversible or

­pseudo-irreversible manner, resulting in a very small k2 (Equation 58-1). This irreversibility
(usually due to covalent bonding) would reduce the number of receptors available to produce
a biological response, which results in an agonist dose–response curve with reduced Emax and
variable effect on potency (Figure 58-7B). Phenoxybenzamine (Dibenzyline®) is an example of
nonequilibrium-competitive antagonist at the a-adrenergic receptor.
3. Inverse agonists/antagonists reduce the basal coupling of the receptor to the intracellular signal
transduction processes, producing a negative pharmacological effect even in the absence of recep-
tor agonists. b-Blockers like propranolol (Inderal®) are examples of drugs with both equilibrium-
competitive antagonist and inverse agonist activity.
4. Noncompetitive antagonists interact with a distinct site to that occupied by the agonist to pre-
vent the biological response initiated by the agonist. This distinct site may be on the receptor
itself (tyrosine kinase domain of the EGF receptor) or a downstream signaling molecule from the
receptor (calcineurin in T-cell receptor signaling). The binding of the antagonist for its site cannot
be displaced by increasing doses of agonist because there is no overlap in the two sites—there is
no competition between the two ligands for a common site. Thus, erlotinib (Tarceva®) is a non-
competitive antagonist of EGF at the EGF receptor and would reduce the efficacy of the agonist
(Emax) to stimulate cell growth.
D. Enzymes as drug receptors.  In many instances, cellular enzymes behave similarly to classical recep-
tors in their interaction with drug molecules via ionic, hydrogen, van der Waal’s, or covalent bonding.
However, important differences in the behavior of enzymes warrant separate treatment.
1. Competitive enzyme inhibitors are drugs that bind to the active site of an enzyme in a man-
ner that prevents substrate binding and conversion to a product. Analogous to classical drug–­
receptor interactions, these inhibitors would be considered competitive regardless of whether
drug binding was reversible or irreversible. The inhibition of HMG-CoA reductase by simvastatin
(­Zocor®) would be considered competitive with respect to the substrate HMG-CoA.
a. Transition-state inhibitors mimic the transition state of the enzyme substrate having the
highest free energy of activation and thus a high binding affinity for the substrate/active site
(e.g., captopril [Capoten®] for the angiotensin-converting enzyme).
b. Suicide enzyme inhibitors are drugs that are catalyzed or destroyed in the process of binding
to the active enzyme site; for example, neostigmine (Prostigmin®) is metabolized to a carba-
mate intermediate that covalently binds to the active site of acetylcholinesterase.
2. Allosteric modulators bind to a distinct site from that of the substrate and thereby alter enzyme
activity. Theoretically, this type of modulation can increase or decrease enzyme activity and not
automatically be classified as inhibition. Allosteric modulators that inhibit enzyme activity may be
considered noncompetitive inhibitors; for example, efavirenz (Sustiva®) inhibits the ­polymerase
function of HIV reverse transcriptase.
E. Modulation of receptor sensitivity
1. Desensitization of seven transmembrane-spanning receptors generally occurs with sustained
stimulation of the receptor and occurs due to reduced coupling to G proteins. Uncoupling of
the receptor is due to phosphorylation of the receptor, which prevents its interaction with the
G protein and also reduces the affinity of the agonist for the receptor. Myocardial b-receptors in
patients with heart failure are thought to be desensitized due to sustained sympathetic nervous
system stimulation.
2. Downregulation of the receptor is the result of prolonged receptor stimulation that leads to
­incorporation of the receptor into clathrin-coated pits and removal of the receptor from the
plasma membrane. This process reduces agonist signaling to the intracellular compartment.
­Ultimately, the receptor may be transported to the lysosomal compartment for destruction or
recycled back to the plasma membrane to restore cell signaling. The sustained use of b-agonists
like albuterol (Ventolin®) causes the downregulation of b2-receptors in asthmatic patients.
3. Receptor hypersensitivity/supersensitivity is exhibited by increased response to agonist stimu-
lation and is most likely due to increased receptor number or enhanced coupling of the recep-
tor to intracellular signaling processes. This phenomenon usually occurs with chronic reduction
in receptor stimulation due to diminished endogenous agonists (e.g., after autonomic or motor
nerve destruction). Reversal of prolonged antagonist therapy has also been associated with recep-
tor supersensitivity (e.g., abrupt withdrawal of b-blocker therapy).
 Principles of Pharmacology and Medicinal Chemistry 1141

IV. PHARMACODYNAMICS IN THE CLINICAL POPULATION.  Pharmaco­

logical therapy in the human patient population is fundamentally based on the principles of dose–
response relationships, with higher doses producing greater effects until a maximum is reached. An
inherent assumption of the dose dependency of a drug effect is that it is mediated through a specific
receptor, regardless of whether the drug is an agonist or antagonist. However, the relative potencies of
drugs (as indicated by the ED50s) may not reflect the affinity of the drug for its receptor because this value
can also be influenced by several pharmacokinetic parameters; that is, a high-affinity drug may exhibit
a greater ED50 than a low-affinity drug if the former is poorly absorbed or more quickly inactivated by
hepatic systems.
A. Quantal dose–response relationship may be developed in a patient population based on the dose
required to produce a specific outcome; for example, the dose required to cause sleep or produce a
10% decrease in blood pressure. This would result in some individuals requiring very small doses,
whereas others would need much higher amounts to induce the effect, the overall response following
a Gaussian or normal distribution (Figure 58-8A). The mean of this distribution would be equivalent
to the ED50 and 95% of patients would respond to a dose that is 2 standard deviations above or below
the ED50 (indicated by the range shown in Figure 58-8A). Plotting the same data as the administered
dose versus the cumulative number of patients producing the effect exhibits the recognizable dose–
response curve (Figure 58-8B).
B. Graded dose–response relationship may be seen in a patient population or individuals where
­increasing doses of a drug results in greater pharmacological effect. This is best demonstrated by
drugs that can be titrated to produce a desired outcome; for example, 10, 20, 40, and 80 mg of ator-
vastatin (Lipitor®) can produce 33%, 38%, 45%, and 53% lowering in LDL cholesterol, respectively
(see Figure 10-17).
C. Dose-dependent drug toxicity can also result in the course of pharmacological therapy and follows
a similar normal distribution as demonstrated in Figure 58-8A—only these effects usually occur at
higher doses (e.g., 1% of the population may show toxicity to the same drug at 6 mg/kg). Plotting
graded dose–response curves for the therapeutic and toxic effects of drug may produce relationships
as seen in Figure 58-9. From the graph, it can be seen that the dose-producing toxicity in 50% of the
population (TD50) is larger than the ED50; however, the TD1 is much closer to the ED99 and is an
­indication of the margin of safety of the drug. If the toxic effect being measured is death, then the
lethal dose producing 50% death in the population is called the LD50, and the ratio of the LD50 to the
ED50 is called the therapeutic index. Drugs with a low margin of safety are likely to show toxicity at
doses that are in the therapeutic range (e.g., warfarin [Coumadin®] and digoxin [Lanoxin®]).

15 ED50 100
Cumulative response
Percent responding

ED50
10

50

0 0
ED50
1 2 3 4 5 1 2 3 4 5
A Dose (mg/kg) B Dose (mg/kg)

Figure 58-8.  A. The percentage of patients in a population that respond to a pharmacological intervention
can be represented by a Gaussian distribution where some require only 1 mg and others need as much as
5 mg of the drug to show the desired response. This in effect is the dose–response relationship of the entire
population as demonstrated by the graph (B) where plotting the cumulative number of responders after
each dose gives the classic dose–response curve. In either graph, the dose producing an effect in 50% of the
population (ED50) can be determined as shown.
1142 Chapter 58      V. A

100
Therapeutic Toxic
effect effect
Percent response

50
Figure 58-9.  Drugs can have toxic or undesirable
effects that follow a dose–response relationship;
however, these effects often require higher doses to
ED99 be observe and thus their graph appears shifted to
0 the right of the therapeutic effect (graph on the right).
ED50 TD1 TD50 TD1: dose producing a toxic response in 1% of the
Log dose population.

V. STRUCTURAL DETERMINANTS OF DRUG ACTION

A. Structural specificity is conferred by physical and chemical characteristics, or physicochemical
properties, of drugs that allow for specific binding and modulation of the target receptor. These
physicochemical properties of a drug are influenced by the acid–base character, water solubility, and
stereochemistry, which are dependent on the chemical structure. The physicochemical properties are
also important for absorption, distribution, metabolism, and excretion. This structure-to-function
connection is the basis for structure–activity relationships (SARs) that are defined by changing the
chemical structure and determining its influence on biological activity.
B. Pharmacophore is a term used to describe the critical organic functional groups and their spatial
­relationship within a drug molecule required for a specific pharmacological activity. Drugs with simi-
lar structure and the same pharmacophore typically have similar pharmacological activity but may
have other ADME characteristics or potencies that distinguish them from one another.
C. A functional group is a specific group of atoms that have a distinctive acid–base character, contribu-
tion to water solubility, and chemical reactivity. The combination of multiple functional groups can
influence the properties of adjacent functional groups and together define the physicochemical prop-
erties of the drug molecule. Common functional groups are shown in Tables 58-1, 58-2, and 58-3.
D. A bioisostere is a compound containing an atom or group of atoms that is spatially and electronically sim-
ilar to another molecule that produces a similar biological activity. The goal of bioisosteric replacement is
frequently to increase potency, decrease side effects, separate biological activities, or ­increase the duration
of action by altering metabolism. Additionally, bioisosteric substitutions may result in a compound that is
an antagonist or inhibitor of the parent molecule; for example, ­allopurinol (Zyloprim®) inhibits xanthine
oxidase, which, through a multistep metabolic process, ­converts hypoxanthine to uric acid (Figure 58-10).
E. The stereochemistry of a drug molecule also contributes to the structural specificity of a drug by
defining the three-dimensional spatial arrangement of the functional groups required for receptor
interactions. Stereoisomers have the same atoms and connectivity but different arrangements in
space. Stereoisomers can be divided into three main groups: enantiomers; diastereomers, including
geometric isomers; and conformational isomers.
1. Enantiomers are nonsuperimposable mirror images of each other because they contain at least
one asymmetric, or chiral, center, usually a carbon covalently bound to four different substituents.
A drug containing one chiral carbon can exist in one of two nonsuperimposable isomeric forms,
although a drug with multiple chiral centers (n) has the potential to exist in one of 2n isomeric
forms that are enantiomers or diastereomers (Figure 58-11).
a. Enantiomers have identical physical and chemical properties except for the direction of ­rotation
of plane-polarized light measured in a polarimeter. One isomer will rotate ­plane-polarized
light in a clockwise direction (dextrorotatory; d or 1) and the other in a counterclockwise
direction (levorotatory; l or 2).
b. An equal molar mixture of a pair of enantiomers (1 and 2) is called a racemic mixture or
racemate. A racemate has a net zero rotation of plane-polarized light and is therefore optically
inactive. Currently, some active drugs are marketed both as a racemate (cetirizine [Zyrtec®])
and as an enantiomerically pure product (levocetirizine [Xyzal®]) (Figure 58-11).
 Principles of Pharmacology and Medicinal Chemistry 1143

Table 58-1   NEUTRAL FUNCTIONAL GROUPS

Group Structure Group Structure

CH2 CH3 O
Alkane Ketone
H3C CH2 H3C C CH3

H CH3 H3CH2C CH2CH3

+
C C Amine N
Alkene
(quaternary)
H3C H H3CH2C CH2CH3

Aromatic Ester H3CH2C C OCH2CH3

or
CH3CH2COOCH2CH3

O
Alcohol H3C OH Amide
(primary) H3CH2C C NHCH2CH3

H O
Alcohol H3C C OH
Carbonate
(secondary) H3CH2CO C OCH2CH3
CH3

CH3
O
Alcohol H3C C OH Carbamate
(tertiary) H3CH2CO C NHCH2CH3
CH3

O
O
Ether H3CH2C CH2CH3 Urea
H3CH2CHN C NHCH2CH3

–
O
S +
Thioether H3CH2C CH2CH3 Nitro H3CH2C N
O H3CH2C NO2
or
O
Aldehyde Nitrate H3CH2C O NO2
H3C C H

c. Enantiomers can have large differences in potency, receptor fit, biological activity, transport, and
metabolism. These differences result when the drug molecule has an asymmetric interaction
with a receptor, a transport protein, or a metabolizing enzyme. The enantiomer with the desired
pharmacological effect is called the eutomer, whereas the other isomer is the d ­ istomer. The
distomer may not have pharmacologic activity or may be responsible for ­adverse effects.
d. Enantiomers are distinguishable in a chiral environment, including the human body, or by
determining the rotation of plane-polarized light in a polarimeter. These are properties of the
molecule but they do not reveal information concerning the absolute configuration around the
chiral center. To determine the absolute configuration, the Cahn-Ingold-Prelog (CIP) system for
assigning priority is used (R or S designation). It is important to remember that the CIP absolute
configuration is applied to each chiral center and is independent of the direction of rotation of
plane-polarized light for the molecule as a whole. In a pair of enantiomers, all stereocenters are
opposite in their absolute configuration and therefore also in their CIP ­designation.
2. Diastereomers are stereoisomers that are not enantiomers. More specifically, they are stereoiso-
mers that are not mirror images of each other or superimposable.
a. Like enantiomers, diastereomers can be optically active. But diastereomers have some stereocen-
ters that are identical and some that are opposite in their absolute configuration. ­Diastereomers
 Table 58-2   ACIDIC FUNCTIONAL GROUPS

Group Structure

Carboxylic acid H3CH2C C OH

or CH3CH2COOH
O O
Imide H
H3C C N C CH3
OH
Phenol

Sulfonamide H3CH2C S NHCH2CH3

O
O

Sulfonic acid H3CH2C S OH

O
O O
H
Sulfonimide H3C S N C CH3

O
H
N
N
Tetrazole CH3
N
N
Thiol H3CH2C SH

Table 58-3   BASIC FUNCTIONAL GROUPS

Group Structure

Amine (primary) H3CH2C NH2

H3CH2C

Amine (secondary) NH
H3CH2C
H3CH2C

Amine (tertiary) N CH2CH3

H3CH2C

N
Amine (aromatic)

Imine H3CHC NH
NH
Amidine
H3CH2C C NH2
H3CH2C

Guanidine N

H3CH2C C NH2

1144
 Principles of Pharmacology and Medicinal Chemistry 1145

O CH2CH3 O CH2CH3

N N
N CH2CH3 O CH2CH3
H

H2N H2 N
Procainamide Procaine

OH OH

N
N N
N

N N N N
H H

Allopurinol Hypoxanthine

Figure 58-10.  Bioisosteric pairs procainamide/procaine and allopurinol/hypoxanthine. The isosteric

replacements are boxed.

possess different physicochemical properties and thus differ in properties such as solubility, volatil-
ity, and melting point. For optically active diastereomers, two or more stereocenters are required.
b. Epimers are a special type of diastereomers because epimers are structurally identical in all
respect except for the stereochemistry of one chiral center. The process of epimerization (in
which the stereochemistry of one chiral center is inverted) is important in drug degradation
and inactivation (Figure 58-12).
c. Geometric isomers are diastereomers because they are not mirror images and they have
­different physicochemical properties and pharmacologic activity (Figure 58-13). Geometric
isomers are also called cis–trans isomers and result from restricted rotation around a chemi-
cal bond. This can be an alkene (double bond) or a fused ring system within a molecule that
prevents interconversion between the two isomers.
3. Conformational isomers, also known as rotamers or conformers, are nonsuperimposable orien-
tations of a molecule that results from the free rotation of atoms around a single bond. ­Almost
every drug can exist in more than one conformation, and this ability allows many drugs to bind
to multiple receptors and receptor subtypes. For example, the trans conformation of acetylcholine
binds to the muscarinic receptor, whereas the gauche conformation of acetylcholine binds to the
nicotinic receptor (Figure 58-14). It should be noted that conformational isomers are chemically
indistinguishable (i.e., they have all the same physicochemical properties) from each other be-
cause the only difference between the conformers is the free rotation around a bond.

(+/–)-Cetirizine (Zyrtec)
O O
O O
N OH N OH

N N

H H

(+)-(S)-Cetirizine (–)-(R)-Cetirizine (Xyzal)

Cl Cl

Figure 58-11.  The two enantiomers of cetirizine. The chiral, or asymmetric, carbon is bonded to four different
groups: a piperazine ring, a chlorinated benzene ring, an unsubstituted benzene, and a hydrogen. The structures
shown are mirror images, which cannot be superimposed. A racemic mixture of cetirizine is marketed as Zyrtec,
whereas the enantiomerically pure levocetirizine is marketed as Xyzal.
1146 Chapter 58      VI. A

Figure 58-12.  Epimerization of tetracycline to 4-epitetracycline. The stereochemistry of the 4-dimethylamino

group is inverted; however, the stereochemistry of all other chiral centers remains unchanged.

VI. PHYSIOCHEMICAL DETERMINANTS OF DRUG ACTION.  The polarity and

acid–base property of a drug are two primary physiochemical characteristics of drugs.
A. Polarity of drugs is a measure of their lipid and water solubility and is generally expressed as the
partition coefficient.
1. Partition coefficient (P) of a drug is the ratio of the solubility of the agent in an organic lipophilic
solvent (usually n-octanol) to its solubility in water or aqueous buffer.
[Drug]organic ​ 
P 5 ​ _
[Drug]water
The partition coefficient is often expressed as the logarithmic value, log P.
2. Water solubility or hydrophilicity of a drug is dependent on two major factors: its ionic and
hydrogen-bonding capacity. The presence of oxygen- and nitrogen-containing functional groups
generally enhances water solubility, which is required for
a. drug dissolution in the gastrointestinal (GI) tract,
b. preparation of parenteral drug solutions, and
c. ophthalmic drug solutions.
3. Lipid solubility or lipophilicity is increased by the presence of nonionizable functional groups
(hydrocarbon chains or ring systems) and is important in
a. drug absorption from the GI tract,
b. penetration of drug through biological membranes (e.g., cell membranes, blood–brain barrier),
c. preparation of intramuscular depot injectable formulations,
d. drug absorption via the pulmonary route,
e. increased potency of topically applied formulations, and
f. increased plasma protein binding.

Figure 58-13.  The presence of the double bond in diethylstilbestrol allows for the formation of cis and
trans geometric isomers. The functional groups of these isomers are separated by different distances;
they generally do not fit the same receptor equally well. As a result, the trans isomer has estrogenic
activity and the cis isomer only has 7% the estrogenic activity of the trans isomer.
 Principles of Pharmacology and Medicinal Chemistry 1147

Figure 58-14.  The trans (A)

and gauche (B) conformations of
acetylcholine occur as the result of
rotation around the carbon–carbon
single bond.

B. Acid–base characteristic of drugs influence their ionization in biological fluids. Using the Brønsted–­
Lowry definition, acids donate a proton to become ionized, whereas bases accept a proton to become
ionized.
1. The ionization constant (Ka) indicates the relative strength of the acid or base by indicating the
ratio of the unprotonated species to the protonated species (Figure 58-15). An acid with a Ka of
1 3 1023 is stronger (more ionized [A2] species) than an acid with a Ka of 1 3 1025, whereas a
base with a Ka of 1 3 1027 is weaker (less ionized [BH1] species) than a base with a Ka of 1 3 1029.
2. The ionization constant is more commonly reported as the pKa or the negative log of the ioniza-
tion constant. The pKa also indicates the relative strength of the acid or base. Using the aforemen-
tioned examples, an acid with a Ka of 1 3 1023 has a pKa of 3 and is stronger than an acid with a
Ka of 1 3 1025 (pKa of 5), whereas a base with a Ka of 1 3 1027 (pKa of 7) is weaker than a base
with a Ka of 1 3 1029 (pKa of 9).
3. Acids can be described as strong or weak acids based on their ability to donate a proton.
a. Strong acids are completely ionized when placed in water. Strong acids include hydrochloric
acid (HCl), sulfuric acid (H2SO4), nitric acid (HNO3), hydrobromic acid (HBr), iodic acid
(HIO3), and perchloric acid (HClO4).
b. Weak acids are partially ionized when placed in water. Most organic acids contained in drugs
are weak acids. The following functional groups are weak acids. The approximate pKa range is
shown in parentheses (see Table 58.2).
(1) Carboxylic acid group (MCOOH with a pKa range of 4–6)
(2) Phenolic group (ArMOH with a pKa range of 9–11)
(3) Sulfonic acid group (MSO3H with a pKa range of 0–1)
(4) Sulfonamide group (MSO2NH2 with a pKa range of 9–10)
(5) N-Aryl sulfonamide group (MSO2NHMAr with a pKa range of 6–7)
(6) Imide group (MCOMNHMCOM with a pKa range of 9–10)
(7) Thiol (RMSH with a pKa range of 9–11)
(8) Sulfonimide (MSO2NHMCOM with a pKa range of 5–6)
(9) Tetrazole (five-member ring CHN4 with a pKa range of 4–6)
c. When a weak acid, like acetic acid (pKa 5 4.76), is placed in an acid medium (high [H1], low pH),
the equilibrium shifts to the left and suppresses ionization. This decrease in ionization conforms
to Le Chatelier’s principle, which states that when a stress is placed on an equilibrium reaction, the

B:H B:  H
A-H A  H

[H][A] [H][B:]
Ka  or Ka 
[AH] [BH]
Figure 58-15.  The ionization constant (Ka) and the pKa indicate the
1
pKa  logKa  log equilibrium between the protonated species, the unprotonated species,
Ka
and the strength of the acid or base.
1148 Chapter 58      VI. B

r­ eaction will move in the direction that tends to relieve the stress. When the same weak acid is placed
in an alkaline medium (very low [H1], high pH), the ionization increases producing more H1.
CH3COOH D CH3COO2 1 H1
d. Weakly acidic drugs are less ionized in acid media than in alkaline media. When the pKa of
an acidic drug is greater than the pH of the medium in which it exists, it will be . 50% in its
nonionized form and thus more likely to cross lipid cellular membranes.
4. Bases can be described as strong or weak bases based on their ability to accept a proton.
a. Strong bases are completely ionized when placed in water. Strong bases include sodium
­hydroxide (NaOH), potassium hydroxide (KOH), magnesium hydroxide (Mg(OH)2),
­calcium  hydroxide (Ca(OH)2), barium hydroxide (Ba(OH)2), and quaternary ammonium
­hydroxides.
b. Weak bases are partially ionized when placed in water. Most organic bases contained in drugs
are weak bases. The following functional groups are weak bases. The approximate pKa range is
shown in parentheses (see Table 58.3).
(1) Primary, secondary, and tertiary aliphatic amines (R-NH2, R2MNH, and R3MN,
­respectively, with a pKa range of 9–11)
(2) Aromatic amine (aromatic ring with N included in ring with a pKa range of 5–6)
(3) Arylamine (ArMNH2 with a pKa range of 4–5)
(4) Imine (MCHBNH with a pKa range of 3–4)
(5) Amidine (MNHMCBNM with a pKa range of 10–11)
(6) Guanidine (MNHMCBNH(NH2) with a pKa range of 12–13)
c. When a weak base like ethylamine (pKa 5 10.7) is placed in an acid medium (high [H1], low
pH), the equilibrium shifts to the left and increases the ionization (see Le Chatelier’s principle
in section VI.B.3.c). When the same weak base is placed in an alkaline medium (very low
[H1], high pH), the ionization decreases.
CH3CH2NH31 D CH3CH2NH2 1 H1
d. Weakly basic drugs are less ionized in alkaline media than in acid media. When the pKa of a
basic drug is less than the pH of the medium in which it exists, it will be . 50% in its nonion-
ized form and thus more likely to cross lipid cellular membranes.
5. Percent ionization can be approximated by using the rule of nines. If the |pH 2 pKa| 5 1, then a
90:10 ratio (one nine in the ratio) exists. If the |pH 2 pKa| 5 2, the ratio becomes 99:1 (two nines
in the ratio), and if the |pH 2 pKa| 5 3, the ratio becomes 99.9:0.1 (three nines in the ratio).
The predominant form, ionized or unionized, in these ratios can be easily d ­ etermined.
6. Drug salts are made by the combination of an acid and a base. Because most drugs are organic
molecules, drug salts can be divided into two classes based on the chemical nature of the sub-
stance forming the salt.
a. Inorganic salts are made by combining drug molecules (a weak base or acid) with strong
inorganic acids or bases such as hydrochloric acid, sulfuric acid, potassium hydroxide, or so-
dium hydroxide. The salt form of the drug made from a strong inorganic and a weak organic
generally has increased water solubility in comparison with the parent molecule and increased
aqueous dissolution.
b. Organic salts are made by combining drug molecules with either small hydrophilic organic
compounds (e.g., succinic acid, citric acid) or lipophilic organic compounds (e.g., procaine).
Water-soluble organic salts are used to increase dissolution and bioavailability as well as to aid
in the preparation of parenteral and ophthalmic formulations. Lipid-soluble organic salts are
primarily used to make depot injections.
c. Dissolution of salts can alter the pH of an aqueous medium.
(1) Salts of strong acids (e.g., HCl, H2SO4) and basic drugs dissociate in an aqueous medium
to yield an acidic solution.
(2) Salts of strong bases (e.g., NaOH, KOH) and acidic drugs dissociate in an aqueous
­medium to yield a basic solution.
(3) Salts of weak acids and weak bases dissociate in an aqueous medium to yield an acidic,
basic, or neutral solution, depending on the respective ionization constants involved.
 Principles of Pharmacology and Medicinal Chemistry 1149

(4) Salts of strong acids and strong bases (e.g., NaCl) do not significantly alter the pH of an
aqueous medium.
7. Amphoteric drugs contain both acidic and basic functional groups and are capable of forming
internal salts, or zwitterions, which often have dissolution problems because the ions interact with
each other and not the aqueous environment.
8. A neutralization reaction might occur when an acidic solution of an organic salt (a solution of a
salt of a strong acid and a weak base) is mixed with a basic solution (a solution of a salt of a weak
acid and a strong base). The nonionized organic acid or the nonionized organic base is likely to
precipitate in this case. The reaction is the basis for many drug incompatibilities, particularly
when intravenous solutions are mixed.

VII. NONCLASSICAL ACTIONS OF DRUGS.  Some pharmacological agents appear

to produce their therapeutic effects without interacting with a specific receptor protein, in a manner
described by canonical drug–receptor characteristics. The following list is not exhaustive and may
change as research explains previous “nonspecific” mechanisms; for example, inhalational anesthetics
(e.g., halothane) have been shown to have specific interactions with and modulation of GABAA receptors.
A. Interaction with membranes
1. Polyene antifungal agents (e.g., amphotericin B [Ambisome®]) interact with fungal membrane
sterols to cause pore formation and cell lysis.
2. Alcohols, solvents (e.g., ethanol, isopropyl alcohol, phenol, chlorhexidine) dissolve bacterial
membranes to produce cell lysis.
3. Certain antibiotics (e.g., polymyxin B) interact with phospholipid components of bacterial
membranes to cause cell lysis.
B. Interaction with cytoskeletal components.  Microtubule disruptors (e.g., vincristine [Vincasar®],
­paclitaxel [Taxol®]) interact with tubulin filaments to interfere with their role in mediating cell ­division.
C. Interaction with DNA/RNA
1. Alkylating agents (e.g., nitrosoureas, nitrogen mustards) react with components such as the
­pyrimidine and purine bases causing cross-linking of DNA strands.
2. DNA-intercalating agents (e.g., actinomycin D [Dactinomycin®]) interact with adjacent G-C
bases and the minor groove of the DNA double helix.
3. DNA-cleaving agents (e.g., bleomycin [Blenoxane®]) bind to DNA causing localized oxidative
stress and DNA strand breaks.
D. Neutralizing reactions
1. Acid–base interactions (e.g., aluminum sulfate, calcium carbonate) react with peptic HCl to re-
duce symptoms of dyspepsia. The inactivation of heparin by protamine sulfate is another example
of this type of neutralization.
2. Chelators (e.g., EDTA, dimercaprol) bind metal ions such as Ca21, Pb21, and Hg21 with high
­affinity and enhance their removal from the body.
3. Antibody–antigen complexes (e.g., antivenoms, antidigoxin antibodies [Digibind®]) are admin-
istered to rapidly decrease systemic toxins or drugs via the immune system.

VIII. MAJOR SOURCES OF COMMERCIALLY VIABLE DRUGS

A. Naturally occurring drugs are usually obtained from plant or animal sources.
1. Alkaloids are nitrogen-containing compounds occurring in plants and possessing pharmacologi-
cal activity. Most alkaloids have a basic character (e.g., morphine from opium poppy or atropine
from belladonna), whereas others are neutral amides (e.g., colchicines from autumn crocus). All
alkaloids end in the suffix –ine; however, not all drugs that end with this suffix are alkaloids
(e.g., nifedipine [Procardia®] or meperidine [Demerol®]).
2. Hormones are endogenous chemicals released into the blood by a tissue or organ to act on more
distant tissues or organs. These may be biogenic amines, peptides/proteins, or steroids.
a. Biogenic amines such as epinephrine are released by the adrenal medulla to alter the function
of multiple organ systems during sympathetic activation.
b. Steroids such as testosterone, estradiol, cortisol, etc. are chemical derivatives of cyclopen-
tanoperhydrophenanthrene and often obtained from animal or human sources.
1150 Chapter 58      VIII. A

c. Peptides/proteins such as insulin, glucagon, and somatostatin are obtained from animal
sources or recombinant DNA technology. Generally, peptide and protein drugs have limited
oral activity and have to be administered parenterally.
3. Glycosides are drugs that contain a sugar moiety bound to a nonsugar or aglycone portion via
glycosidic bonds and are most often from plant (e.g., digoxin) or microbial (e.g., streptomycin,
doxorubicin) sources.
4. Polysaccharides are drugs composed of sugar polymers from human or animal sources
(e.g.,  ­heparin, enoxaparin). Structural modification of naturally occurring sugars can yield
­additional drugs (e.g., sucralfate [Carafate®]).
5. Antibiotics are often fungal or other microbial products that have suppressive or lethal effects on
other microorganisms (e.g., penicillin, tetracycline).
6. Vitamins are plant and animal products that function as essential cofactors for various meta-
bolic processes in the body. Water-soluble vitamins include thiamine (B1), riboflavin (B2), ­niacin
(B3), ­pyridoxine (B6), cyanocobalamin (B12), ascorbic acid (C), folic acid, pantothenic acid,
and biotin (H). Fat-soluble vitamins include a-tocopherol (E), ergocalciferol (D), retinol (A),
and ­phytonadione (K).
B. Synthetic products
1. Small organic molecules produced by organic synthesis to mimic the activity of naturally occur-
ring chemicals or found to have unique pharmacological activity not previously i­ dentified.
a. Antimicrobials (e.g., ciprofloxacin [Cipro®] or trimethoprim) are man-made chemicals that
inhibit unique microbial targets such as the DNA gyrase or dihydrofolate reductase to treat
susceptible infections.
b. Receptor ligands compose the largest group of drugs and often mimic endogenous receptor
ligands; for example, propranolol (Inderal®) has structural homology to epinephrine; meperi-
dine (Demerol) mimics the structural features of endorphins at the m-opiate ­receptors.
c. Enzyme inhibitors may be targeted against microbial proteins as in section VIII.B.1.a above or
mammalian enzymes; for example, aliskiren (Tekturna®) against renin, ­pravastatin (­Pravachol®)
against hepatic HMG-CoA reductase, or imatinib (Gleevec®) against c-kit ­tyrosine kinase.
2. Peptides/proteins
a. Peptides. Eptifibatide (Integrilin®) is a synthetic cyclic peptide that mimics components of
­carpet viper venom to prevent platelet aggregation.
b. Proteins. Lepirudin (Refludan®) is a recombinant, synthetic derivate of hirudin, the anticoagu-
lant from leeches.
3. Polysaccharides. The synthetic pentasaccharide fondaparinux (Arixtra®) mimics the portions of
heparins that interact with coagulant proteins.

Study Questions
Directions: Each of the questions, statements, or 2. A 40-year-old teacher was prescribed lovastatin for
incomplete statements in this section can be correctly the treatment of hypercholesterolemia. She wanted
answered or completed by one of the suggested answers or to know the mechanism of the drug before taking it.
phrases. Choose the best answer. Her pharmacist explained to her that lovastatin acts
by blocking the substrate-binding site of the enzyme
1. All of the following are examples of specific receptors
b-hydroxy-b-methylglutaryl-coenzyme A (HMG-CoA)
for drug action except
reductase, which catalyzes the rate-limiting step in
(A) stomach acid. cholesterol biosynthesis. Such drug effect is known as
(B) membrane proteins.
(A) addition.
(C) cytoplasmic proteins.
(B) synergism.
(D) nuclear proteins.
(C) noncompetitive antagonism.
(E) DNA.
(D) potentiation.
(E) competitive antagonism.
 Principles of Pharmacology and Medicinal Chemistry 1151
3. A 70-year-old man had prolonged bleeding
during an elective knee surgery. Subsequently,
the patient admitted to the surgeon that he had
been self-administering 81 mg aspirin daily. The
consultant pharmacist explained to the patient that,
although aspirin has a short plasma half-life, it can
irreversibly inhibit platelet function by acetylating
the nonsubstrate-binding site of the platelet
cyclooxygenase, resulting in prolonged effect on
platelet aggregation. This drug effect is known as
(A) potentiation.
(B) competitive antagonism.
(C) synergism.
(D) addition.
(E) noncompetitive antagonism.
4. A 65-year-old woman with intractable pain secondary
to bony metastasis of breast cancer had been receiving
escalating doses of morphine sulfate intravenously.
At 10 a.m., she was found to be unresponsive, her
respiratory rate was 4 breaths per minute, and
her pupils were pinpointed. Naloxone (Narcan), a
competitive antagonist of the opiate receptor, was
given intravenously and repeated once. She gradually
became conscious and began to complain of pain
unrelieved by morphine given at the previous dose.
This is most likely because
(A) naloxone directly aggravates the pain caused by
the bony metastasis.
(B) naloxone reduces the Emax for morphine.
(C) naloxone reduces the ED50 for morphine.
(D) naloxone increases the Emax for morphine.
(E) naloxone increases the ED50 for morphine.
5. Which of the following statements regarding signal
transduction is incorrect?
(A) Thyroxine-bound receptors act on DNA and
regulate specific transcription of genes.
(B) Cyclic adenosine monophosphate can act as a
second messenger.
(C) The level of drug receptors at the cell surface
increases with chronic stimulation by receptor
agonists.
(D) Binding of ligand to cell surface receptors can
lead to synthesis of proteins.
(E) Antacids act by interacting with small ions
normally found in the gastrointestinal tract.
6. A pharmacist is consulted about selecting a drug that
is relatively safe and effective for treating the patient.
He searches the literature and obtains the following
data that may help guide his decision. The TD0.1 and
ED99.9 for drug A are 20 mg and 0.4 mg, respectively;
whereas the TD0.1 and ED99.9 for drug B are 15 mg
and 0.2 mg, respectively. Which of the following
statements is true?
(A) Drug A has a higher TD0.1 and thus should be the
drug of choice.
(B) Both drugs have the same margin of safety, so
more information is needed.
(C) Drug B has a higher margin of safety and thus is
preferred to drug A.
(D) Drug A is preferred because it has a greater
margin of safety than drug B.
(E) The information obtained is irrelevant.
7. Which of the following statements concerning a drug
receptor is true?
(A) It is only found on the plasma membranes of
cells.
(B) Its expression is induced only by exogenously
added drugs.
(C) It can bind endogenous ligand to produce
physiological activity.
(D) It is mostly composed of sugars (polysaccharides).
(E) Receptor desensitization or downregulation have
no impact on the therapeutic effect of the drug.
8. Which of the following statements concerning
morphine and hydromorphone (Dilaudid) is true?
(A) Hydromorphone is a more effective analgesic
because it has a smaller ED50 than morphine.
(B) Morphine and hydromorphone are equally potent
because they have the same Emax.
(C) Morphine has a greater ED50 and is thus a less
effective analgesic than hydromorphone.
(D) Hydromorphone is a more potent analgesic
because it has a greater Emax than morphine.
(E) Hydromorphone has a smaller ED50 and thus is a
more potent analgesic than morphine.
1152 Chapter 58
9. A 72-year-old man with hypertension has been taking
high-dose propranolol (Inderal) for 20 years. He left
home for a week and forgot to bring his medication
with him. One day, he was found collapsed on the
floor and was brought to the emergency room. His
blood pressure was 300/180, heart rate was 180 beats
per minute, and retinal hemorrhage was observed.
Which of the following best explains this situation?
(A) The b-adrenergic receptors in the cardiac muscles
underwent spontaneous mutation and became
hyperactive.
(B) Reduction in the chronic antagonism of the
b-adrenergic receptor led to downregulation of
the b-adrenergic receptor.
(C) The propranolol that he had previously ingested
remained in his body and acted as a receptor agonist.
(D) Long-term administration of propranolol
results in desensitization of cardiac muscles to
endogenous b-adrenergic stimulation.
(E) Reduction in the chronic level of receptor
blockade results in supersensitivity to stimulation
with endogenous catecholamines.
10. A 42-year-old man with non-small cell lung
carcinoma tells his pharmacist that his doctor had
prescribed erlotinib (Tarceva) for treating his cancer.
The patient asked what erlotinib is and how it works.
His pharmacist explains to him that it is a drug that
(A) prevents the binding of growth factors to their
receptors.
(B) prevents growth factors from activating their
receptors.
(C) boosts the functions of growth factor receptors.
(D) neutralizes a receptor on cancer cells by an
antibody mechanism.
11. A 65-year-old woman experienced anginal pain with
ST-segment elevation on electrocardiogram (ECG).
She was treated with IV heparin, nitroglycerin, and
atenolol (Tenormin) for acute myocardial infarction.
Then 2 hrs later, when her nurse replaced her Foley
bag, she noticed frank blood draining out of the Foley
catheter. The physician checked the patient’s partial
thrombin time, which was . 150 secs. The patient was
then administered protamine, which acts by
(A) promoting thrombosis.
(B) reacting with and neutralizing the effect of
heparin.
(C) directly inhibiting bleeding.
(D) enhancing secretion of procoagulants.
12. Inverse agonist is a relatively new designation for
drug action that a physician asks you about. Your
explanation would include the fact that
(A) these agents may have biological function by
altering the interaction between the receptor and
G protein.
(B) there is no known drug with this type of effect.
(C) these agents can desensitize receptors to agonist
stimulation.
(D) the inverse form of these drugs can stimulate
physiological response.
13. A 55-year-old man with a history of heart disease was
being treated with 20 mg of atorvastatin (Lipitor) but
this was not adequate to bring his LDL cholesterol
down to acceptable levels. So his physician increased
the dose to 40 mg, which resulted in a 30% lowering in
LDL. This would be an example of a
(A) quantal dose–response relationship.
(B) population dose–response relationship.
(C) cumulative dose–response relationship.
(D) graded dose–response relationship.
14. All of the following are examples of non–receptor-
mediated drug effects except
(A) magnesium sulfate for treatment of constipation.
(B) calcium carbonate for relief of heartburn.
(C) halothane for inducing anesthesia.
(D) isopropyl alcohol used for its topical antibacterial
activity.
(E) amphotericin B for fungal infections.
15. Which of the following salts will most likely yield an
aqueous solution with a pH , 7?
(A) Sodium salicylate
(B) Potassium chloride
(C) Magnesium sulfate
(D) Potassium penicillin
(E) Atropine sulfate
16. All of the following functional groups are weak bases
except
(A) aromatic amines.
(B) sulfonamide.
(C) tertiary amines.
(D) imines.
17. The dissociation constant of a drug at its receptor is
most closely related to
(A) the maximal response produced by the drug.
(B) the number of spare receptors available.
(C) the affinity of the drug for the receptor.
(D) the total number of receptors available to the drug.
(E) allosterism.
 Principles of Pharmacology and Medicinal Chemistry 1153

18. All of the following statements about a structurally
specific agonist are true except:
(A) Activity is determined more by its chemical
structure than by its physical properties.
(B) The entire molecule is involved in binding to a
specific endogenous receptor.
(C) The drug cannot act unless it is first bound to a
receptor.
(D) A minor structural change in a pharmacophore
can produce a loss in activity.
(E) The higher the affinity between the drug and its
receptor, the greater the biological response.
22. The solid line on the graph in the following figure
shows the change in mean blood pressure (from
baseline of 90 mm Hg) with increasing bolus doses
of angiotensin II in an experimental animal model.
The dashed line is the response to the same doses of
angiotensin II in the animal 2 hrs after an intravenous
administration of 10 mg/kg of losartan, an antagonist
of the angiotensin receptor. Based on the responses
before and after the angiotensin antagonist, which of the
following statements would most likely be true?
100

(mm Hg from baseline)

19. The dextro (d) form of b-methacholine (structure

Mean blood pressure

shown) is approximately 500 times more active than
the levo (l) enantiomer. The observed difference in
pharmacological activity between the two isomers is 50
most likely the result of differences in + Losartan

0
Log angiotensin II dose
(A) receptor selectivity. (A) Angiotensin II is a partial agonist.
(B) dissolution. (B) Losartan may interact irreversibly with the
(C) distribution. angiotensin receptor.
(D) interatomic distance between pharmacophore (C) Losartan is a partial agonist.
groups. (D) Angiotensin II may be an inverse agonist.
(E) solubility. (E) Angiotensin and losartan are probably working at
20. The compound shown in the figure can be classified different sites in the animal.
as a(n) 23. The structure–activity relationship of a drug can be
altered by all of the following parameters except
(A) stereochemistry.
(B) specific functional groups.
(C) bioisosteric substitution.
(D) cis–trans conformation.
(A) acid. (E) the salt form of the drug.
(B) base. 24. Flurazepam has pKa of 8.2. What percentage of
(C) organic salt. flurazepam will be ionized at a urine pH of 5.2?
(D) organic base.
N(C2H5)2
(E) inorganic salt.
O
21. Which of the following acids has the highest degree of N
ionization in an aqueous solution?
(A) Aspirin; pKa 5 3.5
(B) Indomethacin; pKa 5 4.5 Cl N
(C) Warfarin; pKa 5 5.1 F
Flurazepam
(D) Ibuprofen; pKa 5 5.2 Dalmane
(E) Phenobarbital; pKa 5 7.4

(A) 0.1%
(B) 1%
(C) 50%
(D) 99%
(E) 99.9%
1154 Chapter 58

25. Which of the following isomers can only be distinguished 30. Which of the following statements may be true of
in a chiral environment or by measuring the direction of drugs that are enzyme inhibitors?
rotation of plane-polarized light in a polarimeter? I. They may be destroyed by the enzyme/receptor.
(A) geometric isomers II. They can bind to a site different from that of the
(B) enantiomers substrate.
(C) diastereomers III. They can form covalent bonds with their receptors.
(D) bioisosteres
31. Examples of strong electrolytes (i.e., completely
26. The organic functional groups responsible for a dissociated in an aqueous solution) include
particular pharmacological activity are called a(n) I. acetic acid.
(A) bioisostere. II. pentobarbital sodium.
(B) eutomer. III. diphenhydramine hydrochloride.
(C) epimer.
32. Precipitation may occur when mixing aqueous
(D) pharmacophore.
solutions of meperidine hydrochloride with which of
(E) stereochemistry.
the following solutions?
27. All of the following are basic functional groups except I. Sodium bicarbonate injection
(A) guanidine. II. Atropine sulfate injection
(B) primary amine. III. Sodium chloride injection
(C) amide.
33. Drugs classified as synthetic include which of the
(D) amidine.
following?
(E) tertiary amine.
I. epinephrine
28. The partition coefficient (P) of a drug is best II. morphine
described as III. fondaparinux
(A) the water solubility of a drug at a specific pH.
34. The excretion of a weakly acidic drug is generally
(B) the presence of nonionizable functional groups
more rapid in alkaline urine than in acidic urine.
that make a drug lipid soluble.
This process occurs because
(C) the ratio of drug solubility in a lipophilic solvent
to solubility in an aqueous solvent. I. a weak acid in alkaline media will exist
(D) the presence of ionizable functional groups that primarily in its ionized form, which cannot be
make a drug water soluble. reabsorbed easily.
(E) the characterization of a drug as an acid or a base. II. a weak acid in alkaline media will exist in its
lipophilic form, which cannot be reabsorbed
29. An inorganic salt of imide containing drug can be easily.
made by the addition of which of the following? III. all drugs are excreted more rapidly in an
(A) NaOH alkaline urine.
(B) H2SO4
Questions 35–37: Refer to the drug meperidine
(C) HCl
(Demerol; structure shown).
(D) HNO3
(E) HBr
Directions for questions 30–34: The questions and
incomplete statements in this section can be correctly
answered or completed by one or more of the suggested
answers. Choose the answer, A–E.
A if I only is correct
B if III only is correct
C if I and II are correct
D if II and III are correct
E if I, II, and III are correct 35. Functional groups present in the molecule shown include
I. an ester.
II. a tertiary amine.
III. a carboxylic acid.
 Principles of Pharmacology and Medicinal Chemistry 1155

36. Meperidine is classified as a 38. Which of the following statements regarding digoxin
I. weak acid. (Lanoxin) would be true?
II. salt. I. It is a glycoside.
III. weak base. II. It is a naturally occurring compound.
III. It mimics the actions of an endogenous hormone.
37. Assuming that meperidine is absorbed after oral
administration and that a large percentage of the dose
is excreted unchanged, the effect of alkalinization of
the urine will increase its
I. duration of action.
II. rate of excretion.
III. ionization in the glomerular filtrate.

Directions for questions 39–43: The relationship of each

pair of structures shown in this section is most closely
associated with one of the following terms. The terms may
be used more than once or not at all.
Choose the best answer, A–E.
(A) Geometric isomers
(B) Enantiomers
(C) Diastereomers
(D) Bioisosteres
(E) Conformational isomers
39.

40.

41.

H
N N N

N
H

H3C H3C
1156 Chapter 58
42.
O NH O O
CH3CH2 NH CH3CH2
O O
43.
S S
N Cl
N(CH3)2 (CH3)2N
Answers and Explanations
1. The answer is A [see VII.D.1].
The receptor would be a specific entity of the cell that
drugs interact with to modify cell behavior. Although
stomach acid is neutralized by antacids, it is not con-
sidered a specific receptor.
2. The answer is E [see III.D.1].
Lovastatin reversibly binds to the substrate-binding site
of the enzyme HMG-CoA reductase, which catalyzes
the rate-limiting step in the synthesis of cholesterol,
thus lowering the cholesterol level. Therefore, lovas-
tatin inhibits the enzyme by competitive antagonism.
3. The answer is E [see III.D.2].
Aspirin can covalently modify the platelet cyclooxy-
genase through acetylation of the enzyme other than
the ­substrate-binding site, causing irreversible inhibi-
tion of platelet aggregation. Therefore, aspirin inhibits
platelet function by noncompetitive antagonism of
­cyclooxygenase.
4. The answer is E [see III.C.1].
Naloxone is a competitive antagonist of opiate receptor.
If one compares the log dose–response curve of both
morphine and naloxone to that of morphine alone,
the morphine–naloxone curve is shifted to the right.
As a result, the ED50 for morphine is increased. This
means that a larger than previous dose of morphine is
required for achieving the same analgesic effect.
NH S
NH
N Cl
5. The answer is C [see III.E.2].
The level of drug receptors at the cell surface usually
decreases when the target cells are chronically stimu-
lated by receptor agonists. Downregulation of recep-
tors may be a protective mechanism that can prevent
the target cells from being overstimulated.
6. The answer is C [see IV.C].
The margin of safety of the two drugs can be helpful in
guiding selection of a drug. Margin of safety is the ratio
of TD0.1 to ED99.9. Thus, the margin of safety for drug A
is 20 mg 4 0.4 mg, or 50, whereas the margin of safety
for drug B is 15 mg 4 0.2 mg, or 75. Because drug B has
a greater margin of safety than drug A, drug B is relative-
ly safe at the dosage given to produce the desired effect.
7. The answer is C [see II.A; III.C; III.E.1–2].
A drug receptor, such as muscarinic cholinergic recep-
tor that can bind atropine, normally binds endogenous
acetylcholine to produce the physiological responses
controlled by the parasympathetic autonomic nervous
system. Receptors may be found on plasma mem-
branes, cytoplasm, or nuclei of cells and are primarily
proteinaceous in nature, although they can have sugar
or lipid modifications. Receptor downregulation may
lead to the phenomenon of tachyphylaxis.
 Principles of Pharmacology and Medicinal Chemistry 1157

8. The answer is E [see III.B.1]. 16. The answer is B [see VI.B.3–4; Table 58-2; Table 58-3].
The efficacy of a drug is determined by its Emax, whereas All these groups would accept a proton under physio-
its potency is measured by the ED50. Hydromorphone logical conditions except the sulfonamide, which would
has a smaller ED50 and thus is a more potent analgesic donate a proton instead.
than morphine. Hydromorphone and morphine are
17. The answer is C [see III.A].
both agonists for opiate receptors, and they have the
The dissociation constant of a drug is the concentra-
same analgesic efficacy (i.e., they have the same Emax) if
tion at which half the available receptors are bound
sufficient amounts of both drugs are used.
and the inverse of this value is the affinity of the drug–­
9. The answer is E [see III.E.3]. receptor interaction.
A chronic level of blocking the b-adrenergic ­receptors
18. The answer is B [see V; VI].
by propranolol results in upregulation of the receptor
The binding of a drug to its receptor usually involves
level. When the patient ceased taking the drug, the
only specific functional groups. These groups make
cardiac muscles became supersensitive to stimulation
up what is known as the pharmacophore of the drug
with endogenous catecholamines. This resulted in the
molecule. Although the entire drug molecule is pres-
hypertensive crisis that caused cerebral hemorrhage
ent at the receptor site, only a portion of it, the phar-
and loss of consciousness.
macophore, is required for a biological response. The
10. The answer is B [see III.C.4]. affinity of drug–receptor interaction does not predict
Erlotinib is a small molecule that inhibits the ­tyrosine whether the drug behaves as an agonist (having biolog-
kinase domain of the epidermal growth factor (EGF) ical ­activity) or an antagonist; in fact, antagonists often
receptor on cancer cells. have higher affinities for the receptor than ­agonists.
11. The answer is B [see VII.D.1]. 19. The answer is A [see V.E.1].
Protamine is a chemical antagonist of heparin that acts The term enantiomer and the d and l indicate that the
via an acid–base interaction. b-methacholine has a chiral center and exhibits optical
isomerism. Because the optical isomers have different
12. The answer is A [see III.C].
orientations in space, one orientation will give a bet-
Inverse agonists stabilize the form of the receptor that
ter fit than the other and will most likely have greater
is not bound to G proteins and are not agonists in the
biological activity than the other. Dissolution, distri-
classical sense. This uncoupling of receptor and G pro-
bution, interatomic distances, and solubility are all
tein may reduce basal cellular signaling even in the ab-
related to the physical and chemical properties of the
sence of agonists. b-­Receptor antagonists are thought
two compounds, which are identical because the com-
to have this type of activity apart from preventing the
pounds are enantiomers.
actions of catecholamines.
20. The answer is A [see VI.B.3; Table 58-2].
13. The answer is D [see IV.B].
The aryl sulfonamide donates a proton to behave as
Increasing doses of a drug usually produces greater
an acid due to the electron-withdrawing action of the
responses and this is described as a graded response.
­aromatic ring.
This would be true in an individual or a population of
patients. 21. The answer is A [see VI.B.2].
The pKa (the negative log of the acid ionization con-
14. The answer is C [see VII].
stant) indicates the relative strength of an acidic drug.
All the choices have a nonreceptor mechanism for pro-
The lower the pKa of an acidic drug, the stronger it is as
ducing their effects except for halothane that activates
an acid. A strong acid is defined as one that is complete-
inhibitory receptors on neurons.
ly ionized or dissociated in an aqueous solution; there-
15. The answer is E [see VI.B.6]. fore, the stronger the acid, the greater the ionization.
The solution must contain an acidic substance to have
22. The answer is B [see III.C.2].
a pH , 7. Atropine sulfate is a salt of a weak base
The decrease in the maximal angiotensin II effect
and a strong acid; therefore, its aqueous ­solution is
(Emax) after treatment with losartan would indicate
acidic. Sodium salicylate and potassium penicillin are
that the number of receptors available to produce drug
both salts of strong bases and weak acids; therefore,
effect has been reduced. This occurs when antagonist
their aqueous solutions are alkaline. Magnesium sul-
interacts in an irreversible manner with the receptor
fate and potassium chloride are salts of strong bases
and leaves only a limited number of receptors through
and strong acids; therefore, their aqueous solutions
which the agonist can only produce a less than maxi-
are neutral.
mal response.
1158 Chapter 58
23. The answer is E [see V.A–E].
All of the choices except the salt form of the drug would
influence the interaction of the drug with its receptor.
24. The answer is E [see VI.B.5].
Flurazepam (take note of the suffix, which helps clas-
sify the compound) is a benzodiazepine and thus a
basic compound. Because the pH is less than the pKa,
flurazepam is in an acidic environment and therefore
exists primarily in the ionized form. The percentage
ionized can be easily calculated by using the rule of
nines. The |pH 2 pKa| is 3, so the ratio is 99.9%:0.01%
in favor of the ionized form.
25. The answer is B [see V.E.1.a & d].
Enantiomers are nonsuperimposable mirror images of
each other that have identical physical and chemical
properties except for the rotation of plane-polarized
light. Enantiomers are distinguishable in a chiral en-
vironment. Geometric isomers, diastereomers, and
bioisosteres each have unique physical and chemical
properties.
26. The answer is D [see V.B; V.D; V.E.1.c; V.E.2.b].
The pharmacophore describes the critical organic
functional groups and their spatial relationship ­within
a drug molecule required for a specific pharmacologi-
cal activity. A bioisostere is a compound containing
an atom or group of atoms that is spatially and elec-
tronically similar to another molecule that produces
a similar biological activity. A eutomer is one of a pair
of enantiomers that has the desired pharmacological
activity. The other isomer is the distomer that may
not have pharmacological activity or may cause ad-
verse effects. Epimers are a pair of compounds that
have exactly the same stereochemistry in all positions
except one.
27. The answer is C [see VI.B.4; Table 58-1; Table 58-3].
Primary and tertiary amines are basic because they
have a free pair of electrons that can accept a pro-
ton. The quaternary amines are neutral because there
are no free electrons available to accept a proton.
Guanidines and amidines also have free electrons to
­accept a proton and therefore they are basic function-
al groups. Amides are neutral compounds although
they appear to have a free pair of electrons like the
amines, but the difference is that the electrons on
the amide nitrogen are in resonance with the double
bond on the carbonyl, making them unavailable to
accept a proton.
28. The answer is C [see VI.A.1].
The partition coefficient is defined as the ratio of the
solubility of an agent in an organic lipophilic solvent
(i.e., n-octanol) to its solubility in an aqueous buffer.
The functional groups present, either ionizable or non-
ionizable, influence the partition coefficient.
29. The answer is A [see Table 58-2; VI.B.3.a, 4.a, & 6.a].
The imide is a weak acid, so adding a strong base like
sodium hydroxide (NaOH) or potassium hydroxide
(KOH) will produce an inorganic salt. All the other
choices (i.e., sulfuric acid, hydrochloric acid, nitric
acid, and hydrobromic acid) are strong acids and
would not produce a salt upon addition to the weak
acid imide.
30. The answer is E (I, II, and III) [see III.D].
Suicide inhibitors are drugs that are metabolized or
­destroyed in the process of inhibiting enzymatic activity,
whereas allosteric inhibitors target a site distinct from
that for the substrate. Some drugs interact irreversibly
with their enzyme target due to covalent bonding.
31. The answer is D (II, III) [see VI.B.6].
Almost all salts (with very few exceptions) are strong
electrolytes, and the terminology pentobarbital sodium
and diphenhydramine hydrochloride indicates that each
compound is salt. Acetic acid is a weak acid; therefore,
it is a weak electrolyte.
32. The answer is A (I) [see VI.B].
When meperidine hydrochloride solution is mixed
with the alkaline solution of sodium bicarbonate, a
neutralization reaction occurs with the possible pre-
cipitation of the water-insoluble free base meperidine.
A neutralization reaction occurs when acidic solutions
are mixed with basic solutions, or conversely. No reac-
tion, in terms of acid–base, occurs when solutions are
mixed with other acidic or neutral solutions or when
basic solutions are mixed with other basic or neutral
solutions. There should be no reaction, then, when the
meperidine hydrochloride solution, which is acidic, is
mixed with the acidic solution of atropine sulfate or the
neutral solution of sodium chloride.
33. The answer is B (III) [see VIII.B.3].
Both epinephrine and morphine are naturally occur-
ring, whereas fondaparinux is a synthetic derivative of
heparin.
34. The answer is A (I) [see VI.B].
A weakly acidic drug will be more ionized in an al-
kaline urine; therefore, it will be more polar and thus
more soluble in the aqueous urine. It would also be less
liposoluble, less likely to undergo tubular reabsorption,
and thus more likely to be excreted.
35. The answer is C (I, II) [see VI.B; Table 58-1].
The molecule contains a basic nitrogen, which is bond-
ed to three carbon atoms (i.e., a tertiary amine), and an
ethyl carboxylate, which is an ester group. An ester is
the product of the reaction of an alcohol with a carbox-
ylic acid that forms an alkyl carboxylate. There is no
free carboxylic acid present. However, if this molecule
is subjected to hydrolysis, it forms a carboxylic acid
and ethyl alcohol.
 Principles of Pharmacology and Medicinal Chemistry 1159
36. The answer is B (III) [see VI.B; Table 58-3].
Because meperidine contains a tertiary amine, it is clas-
sified as a base; because it is an organic base, it is consid-
ered weak. The nitrogen is not protonated. It is not ionic
and therefore is not a salt.
37. The answer is A (I) [see VI.B].
Alkalinization of the urine decreases the ionization of
meperidine, making it more liposoluble and thus more
likely to undergo reabsorption in the kidney tubule.
This results in a decreased rate of excretion and an in-
creased duration of action. The six-member, nonaro-
matic ring is a piperidine ring that is substituted at the
4-position (nitrogen is position 1) with a phenyl ring.
The compound does not contain a piperazine ring or a
propyl group.
38. The answer is C (I, II) [see VIII.A].
The cardiac glycoside digoxin occurs naturally in fox-
glove and strophanthus plants but it does not substitute
or mimic the actions of endogenous hormones.
39. The answer is C [see V.E.2].
These molecules are isomers that have two asymmet-
ric carbon atoms. They are not superimposable and
are not mirror images; therefore, they are known as
diastereomers.
40. The answer is B [see V.E.1].
These molecules are isomers that have one asymmet-
ric carbon atom. They are nonsuperimposable mirror
­images; therefore, they are enantiomers.
41. The answer is A [see V.E.2.c].
These molecules have different spatial arrangements;
however, these molecules do not have an asymmetric
center. The presence of the double bond, which re-
stricts the rotation of the groups on each carbon atom
involved in the double bond, characterizes this type of
isomerism as geometric.
42. The answer is D [see V.D].
These molecules are neither isomers nor the same
compound because one contains three oxygens, where-
as the other contains two oxygens and a sulfur. Because
oxygen and sulfur are in the same periodic family, they
are isosteric and are known as bioisosteres.
43. The answer is E [see V.E.3].
These structures are actually two views of the same
compound. Rotation around the side chain single bonds
connecting the ring nitrogen to the tertiary nitrogen
produces these two different conformations. Thus, these
are conformational isomers.