USMLE Step 1 Pharma Flashcards PDF

ty of Miami School of Medicine 129.171.150.66] at [02/16/16]. Copyright © McGraw-Hill Global Education Holdings, LLC.
Not to be redistributed or modified in an

l of Medicine 129.171.150.66] at [02/16/16]. Copyright © McGraw-Hill Global Education Holdings, LLC. Not to be redistribute
ADDITIONAL RESOURCES
To access the additional content included only with purchase of USMLE Step 1 Pharmacology Flashcards,
please follow the directions below:
• Use your web browser to go to: www.langetextbooks.com/crisp.
• You will now have access to the USMLE Step 1 Pharmacology Flashcards Lecture Series by Terriann Crisp.
Crisp_FM_i-xiv.indd i 18/07/14 10:18 AM

This page intentionally left blank
USMLE Step 1
Pharmacology Flashcards
Terriann Crisp, PhD
Crisp Enterprises: Pharmacology
Instruction and Consultation, LLC
Ankeny, Iowa
New York / Chicago / San Francisco / Athens / London / Madrid

Mexico City / Milan / New Delhi / Singapore / Sydney / Toronto
Crisp_FM_i-xiv.indd iii 18/07/14 10:18 AM

Notice
Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge,
changes in treatment and drug therapy are required. The authors and the publisher of this work have
checked with sources believed to be reliable in their efforts to provide information that is complete
and generally in accord with the standards accepted at the time of publication. However, in view of the
possibility of human error or changes in medical sciences, neither the authors nor the publisher nor
any other party who has been involved in the preparation or publication of this work warrants that the
information contained herein is in every respect accurate or complete, and they disclaim all responsi-
bility for any errors or omissions or for the results obtained from use of the information contained in
this work. Readers are encouraged to confirm the information contained herein with other sources. For
example and in particular, readers are advised to check the product information sheet included in the
package of each drug they plan to administer to be certain that the information contained in this work
is accurate and that changes have not been made in the recommended dose or in the contraindications
for administration. This recommendation is of particular importance in connection with new or infre-
quently used drugs.
Crisp_FM_i-xiv.indd iv 18/07/14 10:18 AM

ty of Miami School of Medicine 129.171.150.66] at [02/16/16]. Copyright © McGraw-Hill Global Education Holdings, LLC. Not to be redistributed or modified in an
Copyright © 2015 by McGraw-Hill Education. All rights reserved. Except as permitted under the United
States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form
or by any means, or stored in a database or retrieval system, without the prior written permission of
the publisher, with the exception that the program listings may be entered, stored, and executed in a
computer system, but they may not be reproduced for publication.
ISBN: 978-0-07-180437-0
MHID: 0-07-180437-4
The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-179963-8,
MHID: 0-07-179963-X.
eBook conversion by codeMantra

Version 1.0
All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every
occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the
trademark owner, with no intention of infringement of the trademark. Where such designations appear in
this book, they have been printed with initial caps.
McGraw-Hill Education eBooks are available at special quantity discounts to use as premiums and sales
promotions or for use in corporate training programs. To contact a representative, please visit the Contact
Us page at www.mhprofessional.com.
TERMS OF USE
This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in and to the
work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and
the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer,
reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or
sublicense the work or any part of it without McGraw-Hill Education’s prior consent. You may use the
work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your
right to use the work may be terminated if you fail to comply with these terms.
THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS
MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR
COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUD-
ING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK
OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED,
INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR
FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill Education and its licensors do not warrant
or guarantee that the functions contained in the work will meet your requirements or that its operation
will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors shall be liable to
you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any
damages resulting therefrom. McGraw-Hill Education has no responsibility for the content of any information
accessed through the work. Under no circumstances shall McGraw-Hill Education and/or its licensors be
liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the
use of or inability to use the work, even if any of them has been advised of the possibility of such damages.
This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises
in contract, tort or otherwise.
Contents
Preface ix
Acknowledgments xi
About the Author xiii
Section 1 Autonomic Pharmacology 1–19

Section 2 Cardiovascular Pharmacology 20–66
Section 3 Neuropharmacology 67–95
Section 4 Antibiotics 96–110
Section 5 Pharmacokinetic and Pharmacodynamic Principles 111–128
Figures and Tables 129–158
vii
Crisp_FM_i-xiv.indd vii 18/07/14 10:18 AM

Preface
The USMLE Step 1 Pharmacology Flashcard Series and the companion PowerPoint presentations are intended
to clearly and succinctly review high-yield USMLE Step 1 pertinent information on 5 major areas of Medical
Pharmacology. Emphasis is placed on drug mechanism(s) of action, clinical indications, and major adverse
drug reactions/toxicities.
Section I reviews USMLE-relevant information on Autonomic Pharmacology. In both the flash card
series and PowerPoint presentations, beautifully-drawn artwork is provided in figures and tables to help empha-
size and explain critical points. This will be especially helpful for those students who tend to be visual learners.
Section II covers important areas of Cardiovascular Pharmacology. Multiple figures are provided
to explain the mechanisms of action and clinical indications of these critically important agents. For medical
students preparing for the USMLE Step 1, all 5 sections of this flash card series were designed to provide the
most high-yield pharmacological information available, and cardiovascular pharmacology is certainly one of
the most important areas of the examination.
Section III reviews the highest yield information available in Neuropharmacology, which is another of
the most essential modules on the USMLE Step 1. Dr. Crisp has scoured through the most respected phar-
macology textbooks available to bring neuropharmacology to life for those students who might have had
difficulty putting this information together by themselves. Her intent is to help students make sense of vast
amounts of neuropharmacological information by compressing it into more tenable parts.
In Section IV, the Antibiotics are discussed along with mnemonics to help students remember the names
of the numerous drugs comprising this section (e.g., the ‘flox’ drugs are fluoroquinolones etc.). Dr. Crisp has
succinctly incorporated the high-yield mechanisms of action, clinical indications, and adverse drug reactions
ix
Crisp_FM_i-xiv.indd ix 18/07/14 10:18 AM

for each of the major classes of antibiotics. Medical students taking the USMLE Step 1 will need to be especially
skilled at identifying microbiological infections and bacterial cultures. Understanding the appropriate antimi-
crobial treatment regimens and drug mechanisms will be paramount on the examination.
In the final Section V, important Pharmacokinetic and Pharmacodynamic Principles will be
described along with USMLE Step 1 relevant examples. Students will be expected to understand the principles
underlying cytochrome P-450 (CYP) inducers and inhibitors, zero- versus first-order kinetics, and the use
of the Henderson-Hasselbalch equation to explain behavior of weak acids and weak bases in different pH
environments in the body. It is our hope that this information will help students competently succeed on the
Step 1 examination and move on toward a successful and rewarding career in medicine.
Crisp_FM_i-xiv.indd x 18/07/14 10:18 AM

Acknowledgments
“If I have seen further than others, it is by standing on the shoulders of giants.”
…Sir Isaac Newton
As scientists, no one person is solely responsible for important discoveries or scientific advances and I am
certainly no exception. Mentors, colleagues, and role models have helped to inspire and guide me through my
training and profession. Throughout a 30-year career in medical education, I have worked with some outstand-
ing mentors and friends, including Dr. Michael E. Trulson, Dr. David J. Smith, Dr. Laurie Brown-Croyts, Drs.
Robert and Betty Bush, Dr. Gary Rankin, Dr. Edward P. Finnerty, Dr. Daniel Deavers, Dr. Wayne Terry, Dr. Traci
Ann Bush, Phyllis and John Griffith, and many others. I publicly offer my deepest respect and gratitude to
these individuals for their forbearance, patience, and tutelage. I also want to thank my amazing family for their
continued support and faith.
xi
Crisp_FM_i-xiv.indd xi 18/07/14 10:18 AM

About the Author
Dr. Terriann Crisp has served as an academic pharmacologist for almost 30 years. She earned her Ph.D. from
Marshall University School of Medicine in 1985 prior to completing a postdoctoral research fellowship at
Robert C. Byrd Health Sciences Center. Dr. Crisp worked through the academic ranks as a professor of medical
pharmacology at Northeast Ohio Medical University College of Medicine and later at Des Moines University.
xiii
Crisp_FM_i-xiv.indd xiii 18/07/14 10:18 AM

SECTION 1
Autonomic Pharmacology
Location of Drugs Drugs Important Clinical Clinical Clinical Adverse Drug Effects of α-1
Muscarinic, Affecting the Affecting the Muscarinic Indications Indications Indications for Reactions of the and α-2
Nicotinic
Cholinergic Adrenergic Receptor of of Muscarinic Antimuscarinics Adrenoceptor
and
Adrenergic Nerve Nerve Agonist Muscarinic AChEIs Blocking Drugs Activation
(α and β) Terminal Terminal Actions Agonists (Figure 4) (Antimuscarinics)
Receptors (Figure 2) (Figure 3) (Figure 4)
(Continued)
Crisp_Sec01_001-019.indd 1 17/07/14 3:02 PM

Autonomic Pharmacology (Cont'd.)
Effects of β-1 Signal Clinical Clinical Clinical Indirect-Acting Clinical Clinical Clinical Uses
and β-2 Transduction Uses of α-1 Uses of α-2 Uses of β-1 Sympathomimetics Uses of α-1 Uses of of β-1
Adrenoceptor Mechanisms Adrenergic Adrenergic and β-2 and α-2 Nonselective “Cardioselective”
Activation for α- and β- Agonists Agonists Adrenergic Receptor β-1 and β-2 β-Blockers
Adrenoceptors Agonists Antagonists Adrenoceptor
Antagonists
Crisp_Sec01_001-019.indd 2 17/07/14 3:02 PM

SECTION 1
Location of Muscarinic, Nicotinic and Adrenergic (α and β) Receptors

Muscarinic receptors (M2 and M3 sites) are located on target tissues on smooth muscle, the eye,
the cardiac muscle, and the exocrine glands (Figure 1).
Nicotinic cholinoceptors are located on postganglionic parasympathetic and sympathetic fibers,
the adrenal medulla (NN), and skeletal muscle cells (NM).
Crisp_Sec01_001-019.indd 2 17/07/14 3:02 PM

α-adrenoceptors can be found on postsynaptic effector cells in the ciliary epithelium of the eye,
vasculature smooth muscle, and the glands (Figure 1).
β1-adrenoceptors are located on cardiac cells and the juxtaglomerular tissue of the kidney.
β2-adrenoceptors can be found on the bronchial and the vasculature smooth muscle, the uterus,
and the pancreatic islet cells.
Crisp_Sec01_001-019.indd 3 17/07/14 3:02 PM

SECTION 1
Drugs Affecting the Cholinergic Nerve Terminal (Figure 2)

Acetylcholine (ACh) is an endogenous agonist at muscarinic and nicotinic cholinoceptors.
Hemicholinium blocks the reuptake of choline by inhibiting the Na+-dependent choline
transporter (blocks ACh synthesis).
Vesamicol blocks the vesicle-associated transporter (VAT), inhibiting the vesicular transport
of ACh (blocks ACh storage).
Botulinum toxin (Botox) blocks exocytotic release of ACh by proteolytic degradation of
soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) proteins
(i.e., synaptobrevin) in the vesicles and the plasma membrane that are important for vesicular
fusion and exocytosis.
Crisp_Sec01_001-019.indd 3 17/07/14 3:02 PM

Acetylcholinesterase (AChE) is the endogenous enzyme that terminates the action of ACh.
Edrophonium, Neostigmine, Parathion, and Soman are AChE inhibitors (AChEIs) that block
the enzymatic activity of AChE.
Crisp_Sec01_001-019.indd 4 17/07/14 3:02 PM

SECTION 1
Drugs Affecting the Adrenergic Nerve Terminal (Figure 3)

Reserpine inhibits the vesicular monoamine transporter (VMAT), blocking the vesicular
transport of dopamine (DA), norepinephrine (NE), and other biogenic amines (5-HT). Reserpine
acts in the central nervous system (CNS) and peripheral nervous system (PNS).
The monoamine oxidase inhibitors (MAOIs), phenelzine and tranylcypromine, block the
enzymatic activity of intracellular monoamine oxidase (MAO), increasing the levels of NE, DA,
and 5-HT inside the nerve terminal.
Crisp_Sec01_001-019.indd 4 17/07/14 3:02 PM

Guanethidine inhibits Ca2+-dependent exocytosis of NE from the presynaptic terminal.
Guanethidine does not cross the blood-brain barrier, but acts as a sympathoplegic agent and
inhibits the release of NE from sympathetic nerve endings.
Cocaine blocks the reuptake of DA (in CNS) and NE (mostly PNS) into the presynaptic terminal.
Amphetamine enters the terminal through the reuptake transporter and indirectly increases
synaptic concentrations of DA or NE in the CNS and PNS by reversing the transport mechanism.
Crisp_Sec01_001-019.indd 5 17/07/14 3:02 PM

SECTION 1
Important Muscarinic Receptor Agonist Actions

Eye—miosis and accommodation (contraction for near vision)
Lung—bronchoconstriction and bronchial gland secretion
Gastrointestinal (GI) tract—increased motility and acid secretion
Heart—SA node—decreased rate (negative chronotropic effect), decreased AV conduction
(negative dromotropic effect), and minimal decrease in ventricular contractility (negative
inotropic effect)
Crisp_Sec01_001-019.indd 5 17/07/14 3:02 PM

Vasculature—vasodilation (sympathetic action)
Urinary bladder—contraction of detrusor muscle (urination) and relaxation of trigone
and sphincter
Glands—SLUDE (mnemonic): salivation/sweating, lacrimation (tears), urination, defecation,
and emesis (nausea and vomiting)
Crisp_Sec01_001-019.indd 6 17/07/14 3:02 PM

SECTION 1
Clinical Indications of Muscarinic Agonists (Figure 4)

Carbachol—decreases intraocular pressure in patients with glaucoma by increasing the diameter
of the canal of Schlemm and increasing the drainage of aqueous humor.
Pilocarpine—used clinically to treat glaucoma (increases the diameter of the canal of Schlemm);
increases the drainage of aqueous humor.
Bethanechol—treats urinary retention (the “U” in SLUDE stands for urination)
Crisp_Sec01_001-019.indd 6 17/07/14 3:02 PM

Methacholine—used in diagnostic tests to detect familial dysautonomia (doses of methacholine
having no effect in normal individuals produce significant miosis in patients with dysautonomia).
Methacholine is also used as a diagnostic test for asthma (bronchial hyper-reactivity) and in the
chloride sweat test for diagnosing cystic fibrosis.
ACh N
Smooth muscle,
ACh cardiac muscle and
M endocrine glands
Medulla
Muscarinic cholinoceptors in the periphery are upregulated after damage to the parasympathetic nerve, inducing
supersensitivity and miosis.
Crisp_Sec01_001-019.indd 7 17/07/14 3:02 PM

SECTION 1
Clinical Indications of Acetylcholinesterase Inhibitors (Figure 4)

Neostigmine—myasthenia gravis, reversal of tubocurarine-induced neuromuscular blockade
Pyridostigmine and Ambenonium—myasthenia gravis
Demecarium, Physostigmine, and Echothiophate—glaucoma
Donepezil, Rivastigmine and Galantamine—CNS AChEIs used to treat memory loss in patients
with Alzheimers
Crisp_Sec01_001-019.indd 7 17/07/14 3:02 PM

Edrophonium—differentiation between “cholinergic crisis” and “myasthenic crisis”
Physostigmine—reverses antimuscarinic toxicity in the CNS and peripheral nervous system
(from atropine-like drugs, tricyclic antidepressants, phenothiazines, and other drugs with
antimuscarinic actions)
Crisp_Sec01_001-019.indd 8 17/07/14 3:02 PM

SECTION 1
Clinical Indications for Muscarinic Blocking Drugs (Antimuscarinics)

Atropine—antispasmodic, decrease secretions, management of overdose of AChEIs, antidiarrheal,
ophthalmology
Tropicamide—ophthalmology (topical)
Ipratropium and Tiotropium—asthma and chronic obstructive pulmonary disease (COPD)
(inhalational), no CNS entry
Crisp_Sec01_001-019.indd 8 17/07/14 3:02 PM

Scopolamine—used in motion sickness, causes sedation, and short-term memory block
Benztropine and Trihexyphenidyl—lipid-soluble (CNS entry); used in Parkinsonism and to
treat acute extrapyramidal symptoms induced by antipsychotics
Crisp_Sec01_001-019.indd 9 17/07/14 3:02 PM

SECTION 1
Adverse Drug Reactions of the Antimuscarinics

Dry mouth
Visual disturbances—cycloplegia (paralysis of accommodation), photophobia, and blurred vision
Constipation
Difficulty in urination
Elevated body temperature
Dry hot skin
Crisp_Sec01_001-019.indd 9 17/07/14 3:02 PM

Note of Importance
Many classes of drugs block muscarinic cholinoceptors and may induce antimuscarinic side effects,
including the tricyclic antidepressants (TCA), phenothiazine antipsychotics (chlorpromazine),
antiarrhythmic agents (quinidine), amantadine (an antiviral agent and DA-releaser used in
Parkinson disease), and meperidine (an opiate).
Crisp_Sec01_001-019.indd 10 17/07/14 3:02 PM

SECTION 1
Effects of α-1 and α-2 Adrenoceptor Activation

α-1 Mediated Effects
Contraction of radial muscle in eye (dilation of pupil—mydriasis)
Contraction of arterial and venous smooth muscle (vasoconstriction)
Ejaculation
10
Crisp_Sec01_001-019.indd 10 17/07/14 3:02 PM

α-2 Mediated Effects
Inhibition of sympathetic outflow from CNS
Contraction of arterial and venous smooth muscle (vasoconstriction)
Inhibition of lipolysis
Inhibition of insulin secretion from the pancreas
10
Crisp_Sec01_001-019.indd 11 17/07/14 3:02 PM

SECTION 1
Effects of β-1 and β-2 Adrenoceptor Activation

β-1 Mediated Effects (mostly in heart and kidney)
Increase automaticity—HR (positive chronotropic effect)
Increase conduction velocity (positive dromotropic effect)
Increase contractility (positive inotropic effect)
Increase renin secretion
11
Crisp_Sec01_001-019.indd 11 17/07/14 3:02 PM

β-2 Mediated Effects
Relaxation of bronchial smooth muscle (bronchodilation)
Relaxation of vascular smooth muscle (vasodilation)
Increase glycogenolysis, gluconeogenesis
Relaxation of uterine smooth muscle
Increase insulin secretion from the pancreas
11
Crisp_Sec01_001-019.indd 12 17/07/14 3:02 PM

SECTION 1
Signal Transduction Mechanisms for α- and β-Adrenoceptors

α-1 Adrenoceptors
Phospholipase C activation (Gq-coupled), ↑ release of inositol triphosphate (IP3) and
diacylglycerol (DAG)
IP3-↑ intracellular Ca2+
DAG-activates Protein Kinase C
12
Crisp_Sec01_001-019.indd 12 17/07/14 3:02 PM

α-2 Adrenoceptors
Gi-coupled; inhibition of adenylate cyclase, ↓ cAMP
β-1, β-2, and D-1 Adrenoceptors
GS-coupled; activation of adenylate cyclase, ↑ cAMP
12
Crisp_Sec01_001-019.indd 13 17/07/14 3:02 PM

SECTION 1
Clinical Uses of α-1 Adrenergic Agonists

α-1 Adrenergic Agonists
Phenylephrine—vasoconstriction-induced decongestant action treats nasal congestion
Methoxamine—used to treat nasal congestion and postural hypotension
DA, NE, and EPI (catecholamines)—all have affinity for the α-1 adrenoceptor
EPI – α-1, α-2, β-1, and β-2 agonist
• prolongs the duration of action of local anesthetics
• treats anaphylactic shock
• counteracts complete heart block and cardiac arrest
NE – α-1, α-2, and β-1 agonist
• vasoconstriction, used to treat hypotension
13
Crisp_Sec01_001-019.indd 13 17/07/14 3:02 PM

DA – α-1, α-2, β-1, and D-1 agonist properties
• treats patients with cardiogenic circulatory failure
• maintains glomerular filtration rate (GFR) and is used to sustain renal blood flow in
CHF patients with impaired renal function (via interacting with D1 receptors in the
kidney vasculature).
• intermediate doses of DA will increase cardiac contractility
13
Crisp_Sec01_001-019.indd 14 17/07/14 3:02 PM

SECTION 1
Clinical Uses of α-2 Adrenergic Agonists

α-2 Adrenergic Agonists
Clonidine—stimulates α-2 adrenoceptors in the brainstem—↓ blood pressure by inhibiting the
release of sympathetic transmitters (NE) in periphery, ↓ PVR, and ↓ blood pressure.
Clonidine—diminishes the effects of an overactive sympathetic nervous system in patients
withdrawing from narcotics, alcohol, and tobacco.
α-Methyldopa—converted to α-methyl NE in the CNS; centrally active mechanism same as
clonidine; preferable agent for treating hypertension in pregnancy.
14
Crisp_Sec01_001-019.indd 14 17/07/14 3:02 PM

Note of Importance
Antihypertensive medications are used to treat hypertension in women who are not pregnant
(e.g., ACEIs and ARBs). However, these agents can potentially cause adverse drug reaction to the
fetus. α-Methyldopa is indicated in pregnancy.
14
Crisp_Sec01_001-019.indd 15 17/07/14 3:02 PM

SECTION 1
Clinical Uses of β-1 and β-2 Adrenergic Agonists

Non-selective β-1 and β-2 Adrenergic Agonists
Isoproterenol—bronchodilation, once used to treat asthma.
β-1 Selective Adrenergic Agonists
Dobutamine—↑ contractility of the heart; used for acute treatment of congestive heart
failure (CHF) and short-term treatment of cardiac decompensation post-myocardial
infarction (MI)
15
Crisp_Sec01_001-019.indd 15 17/07/14 3:02 PM

β-2 Selective Adrenergic Agonists
Albuterol—bronchodilator used for the treatment of asthma and COPD
Terbutaline—bronchodilator used for the treatment of asthma and COPD
Metaproterenol—bronchodilator used for the treatment of asthma and COPD
Salmeterol—long-acting bronchodilator used for the treatment of asthma and COPD
Ritodrine—inhibits uterine contraction to prevent premature labor (tocolytic agent)
15
Crisp_Sec01_001-019.indd 16 17/07/14 3:02 PM

SECTION 1
Indirect-Acting Sympathomimetics
Specific Drugs
The pharmacological actions of these drugs are generally due to their ability to ↑ the release
of NE. Sympathetic-like effects include vasoconstriction (↑ BP) and ↑ HR.
Amphetamine—CNS stimulant that releases NE in the periphery; induces vasoconstriction
(↑ BP) and ↑ HR. (In CNS, amphetamine ↑ release of both DA and NE.)
Tyramine—an amino acid contained in certain foods (processed meat, aged cheese, and soy
sauce, vegetables such as beets, broccoli, eggplant, fava beans, lima beans, and navy beans)
and drinks (unpasteurized beer, some red, and sparkling wines)
16
Crisp_Sec01_001-019.indd 16 17/07/14 3:02 PM

Tyramine—produces its pharmacological effects by releasing NE in the periphery, causing
vasoconstriction (↑ BP) and ↑ HR.
Ephedrine—(mixed-acting sympathomimetic)—has agonist actions α- and β-adrenoceptors.
Also increases the release of NE from sympathetic neurons.
16
Crisp_Sec01_001-019.indd 17 17/07/14 3:02 PM

SECTION 1
Clinical Uses of α-1 and α-2 Receptor Antagonists

Non-selective α-1 and α-2 Antagonists
Phentolamine—treats pheochromocytoma (adrenal medullary tumor that secretes large
quantities of catecholamines into the circulation) and hypertension
Phenoxybenzamine—pheochromocytoma
Selective α-1 Receptor Antagonists
Prazosin—hypertension; facilitates urine flow in patients with BPH (first-dose hypotension)
Doxazosin—hypertension; facilitates urine flow in patients with benign prostatic
hyperplasia (BPH)
17
Crisp_Sec01_001-019.indd 17 17/07/14 3:02 PM

Terazosin—hypertension; facilitates urine flow in patients with BPH
Tamsulosin—treats BPH by relaxing the smooth muscle in the prostate, which facilitates
micturition. Minimal affinity for vascular α-1 receptor.
Selective α-2 Receptor Antagonists
No specific FDA-approved clinical use
17
Crisp_Sec01_001-019.indd 18 17/07/14 3:02 PM

SECTION 1
Clinical Uses of Nonselective β-1 and β-2 Adrenoceptor Antagonists

Nonselective β-1 and β-2 Antagonists (note the ‘olol’ in spelling)
Propranolol—used in acute MI to prevent recurrence; relieves angina, palpitations, and
syncope in patients with hypertrophic obstructive cardiomyopathy; treats supraventricular
arrhythmias, hyperthyroidism and is used in migraine prophylaxis
Nadolol—useful in hypertension angina pectoris, cardiac arrhythmias, and migraine
prophylaxis (unlabeled use)
Timolol—post-MI to prevent recurrence; useful for treating glaucoma (by preventing the
synthesis of aqueous humor)
18
Crisp_Sec01_001-019.indd 18 17/07/14 3:02 PM

Pindolol—(partial agonist; ISA properties) treats hypertension in patients with diabetes,
peripheral vascular disease (Raynaud disease), and bronchoconstrictive disorders (asthma
and COPD)
Labetalol—(competitive antagonist at both α-1 and β-1 and β-2 adrenoceptors)—treats chronic
hypertension and angina. Used to reverse cocaine overdose
18
Crisp_Sec01_001-019.indd 19 17/07/14 3:02 PM

SECTION 1
Clinical Uses of β-1 “Cardioselective” β-Blockers

Cardioselective β-1-blockers
Acebutolol—has ISA properties
• partial agonist with greater agonist than antagonist effects at β-2 sites
• treats hypertension in patients with diabetes, peripheral vascular disease (Raynaud’s),
and bronchoconstrictive disorders (asthma and COPD)
Atenolol—useful for treating hypertension, arrhythmias, and angina pectoris; also reduces the
risk of heart complications following myocardial infarction
Esmolol—administered IV (rapid onset and short duration); used during surgery to prevent or
treat tachycardia; useful in severe postoperative hypertension; suitable for use when cardiac
output, heart rate, and blood pressure are increased
19
Crisp_Sec01_001-019.indd 19 17/07/14 3:02 PM

Metoprolol—↓ mortality in patients with stable CHF, ↓ remodeling
Carvedilol—also blocks α-1 adrenoceptors; ↓ mortality in patients with CHF (inhibits O2 free
radical–initiated lipid peroxidation and vascular smooth muscle mitogenesis; ↓ remodeling)
Bisoprolol—↓ mortality in patients with stable CHF, ↓ remodeling
19
Crisp_Sec01_001-019.indd 20 17/07/14 3:02 PM

SECTION 2
Cardiovascular Pharmacology
List of Antihyper- Antihypertensive Antihyper- Antihyper- Antihyper- Antihyper- Antihypertensive Angiotensin

Antihypertensive tensive Centrally Active tensive tensive tensive tensive Angiotensin Receptor
Agents Drugs α-2 Agonists α-1 β-Blockers Ca2+ Channel Direct-Acting Converting Blockers and
(Figures 5) Interfering (Figures 5 and 6) Antagonists Blockers Vasodilators Enzyme Inhibitors Renin
with Storage (Figures 7 (Figure 9) Antagonist
Vesicles and 8) (Figure 9)
(Continued)
20
Crisp_Sec02_020-066.indd 20 18/07/14 10:39 AM

Cardiovascular Pharmacology (Cont'd.)
Diuretics — Other Anti- Classification of Antiarrhythmic Treatment Antianginal ‘Pharm-Man’ Diuretics Diuretic- Drugs to
Anti- Antihyper- hypertensive Antiarrhythmic Agents of Pharma- Says… (Figure 10, Induced Treat
hypertensive tensive Drugs in Agents Congestive cology Antianginal Table 1) Changes in Lipid
Agents Agents Comorbid (Figures 11–14) Heart Pharmacology Body pH Disorders
(Figure 10; Conditions Failure
Table 1)
20
Crisp_Sec02_020-066.indd 21 18/07/14 10:39 AM

SECTION 2
List of Antihypertensive Agents (Figure 5)

Drugs Interfering with Storage Vesicles
Reserpine
Guanadrel
Drugs Altering Sympathetic Nervous System Activity
α-2 agonists—Clonidine, α-Methyldopa (Figure 6)
α-antagonist—Prazosin, Doxazosin, Terazosin, Tamsulosin
β-blockers—Metoprolol, Acebutolol, Atenolol
Calcium Channel Blockers
Nifedipine, Amlodipine, Felodipine, Verapamil, Diltiazem
Direct-acting Vasodilators (Figure 7)
Hydralazine, Diazoxide, Minoxidil, Nitroprusside
21
Crisp_Sec02_020-066.indd 21 18/07/14 10:39 AM

Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor
Blockers (ARBs)
Captopril, Enalapril, Lisinopril (ACEIs)
Losartan, Valsartan (ARBs)
Diuretics
Thiazides—Hydrochlorothiazide, Chlorthalidone, Metolazone, Indapamide
Loop diuretics—Furosemide, Ethacrynic Acid, Bumetanide
Bosentan
Treats pulmonary artery hypertension
Antihypertensive Drugs in Comorbid Conditions
21
Crisp_Sec02_020-066.indd 22 18/07/14 10:39 AM

SECTION 2
Antihypertensive Drugs Interfering with Storage Vesicles

Drugs Interfering with Central and Peripheral Adrenergic Storage Vesicles
Reserpine—referred to as a “sympathoplegic” agent because it paralyzes the sympathetic
nervous system. Reserpine easily crosses the blood-brain barrier (BBB).
Mechanism of Action
Reserpine binds to storage vesicles in central and peripheral neurons and destroys the vesicular
membrane-associated transporter (VMAT2). Storage vesicles can no longer concentrate and
store NE, DA, and 5-HT.
NE, DA, and 5-HT leak into the cytoplasm and are metabolized by MAO (Figures 3 and 5).
Recovery of function requires synthesis of new storage vesicles, which takes days to weeks after
discontinuation of the drug.
Reserpine lowers BP by a combination of ↓ CO and ↓ TPR (↓ NE in periphery).
22
Crisp_Sec02_020-066.indd 22 18/07/14 10:39 AM

Adverse Drug Reactions
• Sedation and inability to concentrate or perform complex tasks.
• Suicidal ideation and depression (reserpine must be discontinued at the first sign
of depression).
(Continued)
22
Crisp_Sec02_020-066.indd 23 18/07/14 10:39 AM

SECTION 2
Antihypertensive Drugs Interfering with Storage Vesicles

Drugs Interfering with Adrenergic Storage Vesicles
Guanethidine—produces profound sympathoplegia (rarely used clinically but mechanisms are
important to recognize for the USMLE)
Mechanism of Action
Guanethidine does not cross the BBB, so it does not produce suicidal ideation like reserpine.
Guanethidine accumulates into sympathetic nerve endings by the NET reuptake pump,
concentrates in transmitter vesicles, and causes a gradual depletion of NE from sympathetic
nerve endings (Figures 3 and 5).
Guanethidine ↓ BP by ↓ CO and ↓ TPR
• Uptake through the NET is essential for the antihypertensive actions of guanethidine.
If tricyclic antidepressants are administered to patients taking guanethidine, the
antihypertensive effects of guanethidine are blocked and severe hypertension may occur.
23
Crisp_Sec02_020-066.indd 23 18/07/14 10:39 AM

• postural hypotension
• delayed or retrograde ejaculation
23
Crisp_Sec02_020-066.indd 24 18/07/14 10:39 AM

SECTION 2
Antihypertensive Centrally Active Alpha-2 Agonists (Figures 5 and 6)

Centrally Active Alpha-2 Agonists
Clonidine—centrally acting α-2 agonist
α–Methyldopa—converted to α-methyl NE in the CNS
Mechanism of Action (Figure 6)
These drugs act on α-2 adrenoceptors in the vasomotor center of the brainstem—decrease
sympathetic nervous system activity (and ↓ NE release from periphery)—↓ CO, ↓ TPR
24
Crisp_Sec02_020-066.indd 24 18/07/14 10:39 AM

Clinical Uses
Mild-to-moderate hypertension (α-Methyldopa is used for hypertension management in
pregnancy)
Opiate withdrawal (clonidine patch)
Positive Coombs test (α-Methyldopa), CNS depression, edema
Rebound hypertension following abrupt withdrawal of clonidine—treat with phentolamine
(α-antagonist) and propranolol (β-blocker)
24
Crisp_Sec02_020-066.indd 25 18/07/14 10:39 AM

SECTION 2
Antihypertensive α-1 Antagonists

α-1 Antagonists
Prazosin
Doxazosin
Terazosin
Tamsulosin—greater potency (and affinity) in inhibiting contraction in prostate smooth
muscle versus vascular smooth muscle
Mechanism of Action
Block α-1 adrenoceptors in the periphery—↓ arteriolar and venous resistance, ↓ BP
Clinical Uses
Hypertension
BPH (tamsulosin—relaxes smooth muscle in the prostate)
25
Crisp_Sec02_020-066.indd 25 18/07/14 10:39 AM

• “First-dose syncope”—severe orthostatic hypotension occurs within 30 to 90 minutes
(or longer) of the initial dose of the drug (tolerance develops after the first few doses)
• Reflex tachycardia
• Advantage—favorable effect on lipid profile (↓ LDL, ↑ HDL)
25
Crisp_Sec02_020-066.indd 26 18/07/14 10:39 AM

SECTION 2
Antihypertensive β-Blockers
β-Blockers
Propranolol
Metoprolol
Atenolol
Labetalol—a competitive α-1 and β-antagonist
Pindolol—intrinsic sympathomimetic activity (ISA) agent (partial agonist with greater agonist
than antagonist actions at β-2 sites)
Acebutolol—ISA agent
Mechanism of Action
↓ CO and ↓ renin release
26
Crisp_Sec02_020-066.indd 26 18/07/14 10:39 AM

Unfavorable lipid profile (β-blockers ↑ LDL and ↓ HDL).
Use nonselective β-blockers with caution in patients with diabetes, peripheral vasculature
disease (Raynaud’s disease), or asthma/COPD.
Use ISA drugs (Pindolol or Acebutolol) or cardioselective agents (Acebutolol, Atenolol, or
Metoprolol) in patients with diabetes, peripheral vasculature disease (Raynaud’s disease)
or asthma/COPD.
26
Crisp_Sec02_020-066.indd 27 18/07/14 10:39 AM

SECTION 2
Antihypertensive Ca2+ Channel Blockers

Calcium Channel Blockers (Figure 5)
Nifedipine—dihydropyridine
Amlodipine—dihydropyridine
Felodipine—dihydropyridine
Verapamil
Diltiazem
27
Crisp_Sec02_020-066.indd 27 18/07/14 10:39 AM

Mechanism of Action/Uses
• The Ca2+ channel blockers block activated and inactivated L-type calcium channels.
• The Ca2+ channel blockers are equally efficacious at lowering blood pressure.
• Nifedipine and the other dihydropyridine agents are more selective as vasodilators (little or
no direct cardio-depressant effects).
• Dihydropyridines (nifedipine)—reflex ↑ HR or CO
27
Crisp_Sec02_020-066.indd 28 18/07/14 10:39 AM

SECTION 2
Antihypertensive Direct-Acting Vasodilators (Figure 7 and Figure 8)

Direct-Acting Vasodilators
Hydralazine—↓ BP by ↑ nitric oxide (NO) release; ↓ TPR via arteriolar dilation
Minoxidil—↓ BP by opening K+ channels and hyperpolarizes vascular smooth muscle
Nitroprusside (parenterally available)—used in hypertensive emergencies; ↓ TPR by releasing
NO, which activates the guanylyl cyclase–cyclic GMP–PKG pathway, leading to vasodilation
of both arterioles and venules (Figures 7 and 8)
• rarely use direct-acting vasodilators as sole therapy of hypertension (Figure 7).
These drugs may induce compensatory reflex tachycardia and fluid retention.
Hydralazine—SLE-like syndrome in slow acetylators
Reflex tachycardia and fluid retention (treat with β-blockers and diuretics)
Minoxidil—Hypertrichosis (excessive hair growth); reflex tachycardia and fluid retention
28
Crisp_Sec02_020-066.indd 28 18/07/14 10:39 AM

Nitroprusside—cyanide toxicity—treat with sodium thiosulfate or sodium nitrite; reflex
tachycardia and fluid retention
Note of Interest:
Keep in mind: One man’s side effect can be another man’s therapy. Topical minoxidil is indicated
for use in male-pattern baldness.
28
Crisp_Sec02_020-066.indd 29 18/07/14 10:39 AM

SECTION 2
Antihypertensive Angiotensin Converting Enzyme Inhibitors (Figure 9)

Angiotensin Converting Enzyme Inhibitors (the “prils”)
Captopril
Enalapril
Lisinopril
The angiotensin converting enzymes (ACEs) prevent:
• vasoconstriction by blocking the formation of angiotensin II
• fluid retention by blocking aldosterone release from the adrenal cortex, and
• the degradation of bradykinin, facilitating vasodilation.
29
Crisp_Sec02_020-066.indd 29 18/07/14 10:39 AM

• The ACEIs are useful in treating patients with chronic kidney disease because they diminish
proteinuria and stabilize renal function (particularly valuable in diabetes).
• ACEIs and angiotensin receptor blockers (ARBs)—DOC for treating patients with CHF;
ACEIs and ARBs ↓ preload and ↓ afterload, slowing ventricular dilation (↓ remodeling).
29
Crisp_Sec02_020-066.indd 30 18/07/14 10:39 AM

SECTION 2
Angiotensin Receptor Blockers and Renin Antagonist (Figure 9)

Angiotensin Receptor Blockers (“sartans”)
Losartan
Valsartan
Eprosartan
• The ARBs decrease PVR by competitively blocking Angiotensin II at A1 receptors.
Provide similar clinical benefits as the ACEIs in patients with heart failure and chronic
kidney disease.
• The ARBs do not interfere with bradykinin metabolism (do not induce a dry cough).
• The angiotensin II receptor (AT1) is a Gq G-protein coupled receptor. When angiotensin II
interacts with the AT1 receptor, it activates phospholipase C to produce diacylglycerol and
inositol-1,4,5-triphosphate (IP3). Blocked by ARBs.
30
Crisp_Sec02_020-066.indd 30 18/07/14 10:39 AM

Renin Antagonist – Aliskiren (Figure 9)
• Aliskiren is a direct renin inhibitor, ↓ conversion of angiotensinogen to angiotensin I.
• Used to treat hypertension (alone or in combination with other antihypertensive drugs).
30
Crisp_Sec02_020-066.indd 31 18/07/14 10:39 AM

SECTION 2
Diuretics—Antihypertensive Agents (Figure 10, Table 1)

Thiazides
↓ blood volume, ↓ BP. The thiazides inhibit the reabsorption of NaCl in the distal convoluted
tubule, producing diuresis. The thiazides also ↑ Ca2+ reabsorption and are used to treat kidney
stones (nephrolithiasis).
Hydrochlorothiazide
Chlorthalidone
Metolazone
Indapamide
Loop Diuretics
↓ blood volume, ↓ BP. Block the luminal Na+/K+/2Cl– transporter in the ascending limb of the
loop of Henle (Figure 10, Table 1). The loops also ↑ Mg2+ and Ca2+ excretion and are used to treat
hypercalcemia.
Furosemide
Ethacrynic Acid—no sulfa group
Bumetanide
31
Crisp_Sec02_020-066.indd 31 18/07/14 10:39 AM

Adverse Drug Effects
• Hypokalemia
• Hyperuricemia; loops and thiazides may precipitate gouty arthritis attacks
• Loops and thiazides—↑ Na+ delivery to the collecting duct where it is reabsorbed into the
blood, ↑ secretion and excretion of K+ and H+, inducing hypokalemia and metabolic alkalosis
(“Diuretic-Induced Changes in Body pH” in the Diuretic section below).
• Loop diuretics may cause a dose-related and reversible hearing loss (more common in
patients receiving other ototoxic agents such as aminoglycoside antibiotics).
31
Crisp_Sec02_020-066.indd 32 18/07/14 10:39 AM

SECTION 2
Other Antihypertensive Agents

Bosentan
An endothelin antagonist used to treat pulmonary arterial hypertension.
• Stimulation of endothelin receptors causes vasoconstriction.
• Bosentan blocks both ETA and ETB endothelin receptors on vascular endothelium and
smooth muscle, inducing vasodilation (↑ affinity for the ETA endothelin receptor subtype).
• Used to treat pulmonary artery hypertension
32
Crisp_Sec02_020-066.indd 32 18/07/14 10:39 AM

SECTION 2
Antihypertensive Drugs in Comorbid Conditions
Indication Drugs to be Used

Hypertension and angina β-Blockers, CCBs
Hypertension and diabetes ACEIs, ARBs
Hypertension and BPH α-Blockers (tamsulosin)
Hypertension and post-MI β-Blockers
Hypertension and CHF ACEIs, ARBs
Hypertension and hyperlipidemias α-Blockers, CCBs, ACEIs/ARBs
ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BPH, benign prostatic
hyperplasia; CCB, calcium channel blockers; CHF, congestive heart failure; MI, myocardial infarction.
33
Crisp_Sec02_020-066.indd 33 18/07/14 10:39 AM

SECTION 2
Classification of Antiarrhythmic Agents (Figures 11–14)

Antiarrhythmic agents reduce ectopic pacemaker activity and modify conduction in re-entry
circuits to disable circus movement (Figure 11). The pharmacologic mechanisms currently
available for accomplishing these goals are:
Na+ channel blockade (Class I)
β-blockade (Class II)
K+ blockade (Class III)
Ca2+ channel blockade (Class IV)
Class I (Na+ Channel Blockers)
Ia—Quinidine, Procainamide, Disopyramide
Ib—Lidocaine, Phenytoin
Ic—Flecainide Propafenone—Proarrhythmic (Table 2—Specific Antiarrhythmic Drug
Contraindications)
34
Crisp_Sec02_020-066.indd 34 18/07/14 10:39 AM

Class II (β-Blockers)
Propranolol
Acebutolol
Carvedilol
Labetalol
Bisoprolol
(Continued)
34
Crisp_Sec02_020-066.indd 35 18/07/14 10:39 AM

SECTION 2
Classification of Antiarrhythmic Agents (Figures 11–14)

Class III (K+ Channel Blockers)
Amiodarone
Sotalol
Ibutilide
Class IV (Ca2+ Channel Blockers)
Verapamil
Diltiazem
35
Crisp_Sec02_020-066.indd 35 18/07/14 10:39 AM

Class V Antiarrhythmics
Adenosine
Magnesium sulfate—treats torsades de pointes
Digoxin
Atropine
35
Crisp_Sec02_020-066.indd 36 18/07/14 10:39 AM

SECTION 2
Antiarrhythmic Agents
Class Ia Na+ Channel Blockers
Quinidine
• Na+ and K+-channel blocker, ↑ action potential duration (APD) and ↑ the effective
refractory period (ERP)
Antimuscarinic effects (↑ HR, dry mouth, blurred vision, GI upset). When treating atrial
fibrillation, addition of low-dose digoxin ↓s HR and ↓s AV nodal conduction.
Quinidine has α-blocking properties (vasodilation)
• Clinical use in atrial and ventricular arrhythmias (Figure 11)
36
Crisp_Sec02_020-066.indd 36 18/07/14 10:39 AM

• Cinchonism (headache, dizziness, and tinnitus)
• Prolongation of the QT-interval—torsades de pointes
Drug Interactions
• Quinidine displaces digoxin from tissue-binding sites, enhancing digoxin toxicity.
(Continued)
36
Crisp_Sec02_020-066.indd 37 18/07/14 10:39 AM

SECTION 2
Class Ia Na+ Channel Blockers (Continued)
Procainamide
Disopyramide
• Similar to Quinidine (Na+ channel blockers in cardiac myocytes)
Clinical use in atrial and ventricular arrhythmias (Figures 11–13)
37
Crisp_Sec02_020-066.indd 37 18/07/14 10:39 AM

• Procainamide is metabolized via N-acetyltransferase to N-acetyl procainamide (NAPA).
Slow acetylators develop a systemic lupus erythematosus (SLE)-like syndrome with chronic
use, consisting of arthralgia and arthritis, pleuritis, pericarditis, or parenchymal pulmonary
disease (characterized by a dry, unproductive cough and dyspnea on exertion).
• Excessive accumulation of NAPA has been implicated in torsades de pointes.
• Class 1a Na+ channel blockers have antimuscarinic properties (↑ HR). A drug that slows
AV conduction (digoxin) may be administered with disopyramide when treating atrial
flutter or fibrillation.
• Disopyramide has a strong negative inotropic action and may aggravate heart failure.
(Continued)
37
Crisp_Sec02_020-066.indd 38 18/07/14 10:39 AM

SECTION 2
Class Ib Antiarrhythmic Agents
Lidocaine
Phenytoin
Mexiletine—orally-available congener of lidocaine
• Block sodium channel in the inactivated state (Figure 14).
• Class Ib drugs suppress spontaneous depolarizations and re-entry mechanisms in
ventricular tissue
38
Crisp_Sec02_020-066.indd 38 18/07/14 10:39 AM

• Preferential action on ischemic (partially depolarized) tissue – useful for treating digoxin-
induced arrhythmias, ventricular arrhythmias post-MI and post-open heart surgery.
• Shortens the ERP and APD within the His-Purkinje system.
• Phenytoin causes gingival hyperplasia.
(Continued)
38
Crisp_Sec02_020-066.indd 39 18/07/14 10:39 AM

SECTION 2
Class Ic Antiarrhythmic Agents (Table 2)
Flecainide
Encainide
http://www.ncbi.nlm.nih.gov/pubmed/1900101
The Class 1c agents are potent blockers of Na+ and K+.
Useful in atrial fibrillation in patients without CAD.
39
Crisp_Sec02_020-066.indd 39 18/07/14 10:39 AM

• Proarrhythmic
Acceleration of ventricular rate in patients with atrial flutter
Increased frequency of re-entrant ventricular tachycardia
Increased mortality in patients post-MI
(Continued)
39
Crisp_Sec02_020-066.indd 40 18/07/14 10:39 AM

SECTION 2
Class II (β-blockers) (Figure 12) 0
Phase 0
Propranolol −20
Phase 3
Acebutolol −40
Carvedilol −60 Phase 4
Labetalol ake
r
−80 cem t
Pa urren
Bisoprolol c
Na+, Ca2+ / K+
−100
Slow Ca2+ current
Delayed rectifier K+ current
Mechanism of Action/Uses Cardiac action potentials in slow-response fibers
• β-adrenoceptor blockers ↓ the slope of phase 4, ↓ SA

and ↓ AV nodal conduction (useful in terminating
re-entrant arrhythmias involving the AV node)
• In acutely ischemic tissue, β-blockers increase the energy required to induce cardiac
arrhythmias and are efficacious at controlling ventricular response in atrial fibrillation
or flutter.
• β-blockers prevent recurrent infarction and sudden death in patients recovering from acute
myocardial infarction (drug of choice post-MI)
40
Crisp_Sec02_020-066.indd 40 18/07/14 10:39 AM

• Non-cardioselective and non-ISA β-blockers can induce bronchospasm, aggravation of CHF,
worsen symptoms of peripheral vascular disease and mask symptoms of hypoglycemia in
diabetic patients
(Continued)
40
Crisp_Sec02_020-066.indd 41 18/07/14 10:39 AM

SECTION 2
Class III (K+ channel blockers)
Amiodarone
Sotalol
Ibutilide
• K+ channel blockers can prolong repolarization in cardiac myocytes, ↑ the refractory period.
• Amiodarone has a biologic t½ of approximately 100 days and possesses pharmacodynamic
properties of class I, II, III, and IV antiarrhythmic agents. Sotalol is also a β-blocker.
• These drugs are K+ channel blockers that ↑ action potential duration and ↓ automaticity.
These agents treat both atrial and ventricular arrhythmias.
• Ibutilide used for acute termination of atrial flutter and fibrillation (available IV), and
converts atrial fibrillation to sinus rhythm in patients after cardiac surgery and in those with
the Wolff–Parkinson–White syndrome.
41
Crisp_Sec02_020-066.indd 41 18/07/14 10:39 AM

• Amiodarone adverse effects include pulmonary fibrosis, blue pigmentation of the skin
(“smurf skin”), corneal microdeposits, phototoxicity, hypo- and hyperthyroidism, hepatic
necrosis, and ↑ risk of the risk of torsades de pointes.
• Dronedarone is a non-iodinated derivative of amiodarone with adrenergic blocking properties
and a shorter t½ (<30 hours) approved for the treatment of atrial fibrillation.
• Dronedarone is contraindicated in severe or deteriorating heart failure.
41
Crisp_Sec02_020-066.indd 42 18/07/14 10:39 AM

SECTION 2
Class IV (Ca2+ Channel Blockers)
Verapamil
Diltiazem
Mechanism of Action
• Verapamil and diltiazem block L-type calcium channel to ↓ SA rate and ↓ AV nodal
conduction.
• Supraventricular tachycardia is the major indication for verapamil and diltiazem. Verapamil
reduces ventricular rate in atrial fibrillation and flutter.
42
Crisp_Sec02_020-066.indd 42 18/07/14 10:39 AM

• Additive AV block with β-blockers and digoxin.
• Contraindicated in sinus or AV node dysfunction (Table 2).
• Verapamil (like quinidine) displaces digoxin from tissue-binding sites.
(Continued)
42
Crisp_Sec02_020-066.indd 43 18/07/14 10:39 AM

SECTION 2
Class V Antiarrhythmic Agents
Adenosine—activates K+ current in the atrium and sinus and AV nodes, resulting in
hyperpolarization and slowing of normal automaticity.
Adenosine is administered as a rapid intravenous bolus for the termination of acute re-entrant
supraventricular arrhythmias.
Magnesium sulfate (MgSO4; commonly called Epsom salt)—indicated for the treatment of
torsades de pointes associated with acquired long QT syndrome (LQTS) in adults and
children (mechanism of action unknown).
43
Crisp_Sec02_020-066.indd 43 18/07/14 10:39 AM

Digoxin—low (parasympathetic-like) doses of digoxin ↓ AV nodal conduction; useful for
terminating re-entrant arrhythmias involving the AV node and in controlling ventricular
response in patients with atrial fibrillation.
Digoxin may be helpful in patients with comorbidities (CHF). Heart failure can be
exacerbated by the negative inotropic actions of Ca2+ channel blockers and β-blockers,
which also ↓ AV nodal conduction.
Atropine—useful in the treatment of symptomatic bradycardia due to increased
parasympathetic tone. Atropine blocks muscarinic M2 receptors in the heart.
43
Crisp_Sec02_020-066.indd 44 18/07/14 10:39 AM

SECTION 2
Treatment of Congestive Heart Failure

Pharmacotherapy of Congestive Heart Failure is Aimed at:
↑ Contractility of the heart (↑ CO)
↓ Preload
↓ Afterload
↓ Fluid retention
↓ Remodeling of cardiac muscle
Drugs Proven Effective for Treating Patients with Congestive Heart Failure (Figure 10,
Figures 15, 16, 17, and 18)
Cardiac Glycosides (Digoxin and Digitoxin)
ACEIs and ARBs (“prils” and “sartans”)
Aldosterone Antagonists (Spironolactone, Eplerenone)
44
Crisp_Sec02_020-066.indd 44 18/07/14 10:39 AM

Phosphodiesterase Inhibitors (Inamrinone, Milrinone)
β-1 adrenoceptor Agonists (Dobutamine)
β-Blockers (Carvedilol, Metoprolol)
Diuretics (Loops and Thiazides)
Vasodilators (Hydralazine, Prazosin, Nitrovasodilators)
Nesiritide
(Continued)
44
Crisp_Sec02_020-066.indd 45 18/07/14 10:39 AM

SECTION 2

Cardiac Glycosides
Aglycone O
Digoxin (genin) 21 23 C O
Digitoxin HO 20 22 Lactone
18
CH3
Mechanism of Action (Figure 16) 12 17
H
• The therapeutically useful 19
11 13 16
HH
cardiac glycosides (digoxin and H3 C 14 15
1 9
digitoxin) inhibit Na+/K+-ATPase, 2 10 8 OH
B
a membrane-bound transporter 3 5 7
known as the “sodium–potassium Sugar O 4 6
Digoxin
pump.” H
Steroid
• By inhibiting Na+/K+-ATPase,
digoxin ↑ cytosolic Na+ and Digoxin
(Reproduced, with permission, from Katzung BG et al [editors]:
prevents Na+ extrusion, decreasing Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)
the Na+ gradient necessary to drive
Na+–Ca2+ exchange.
45
Crisp_Sec02_020-066.indd 45 18/07/14 10:39 AM

• As a consequence, less Ca2+ is removed from the cell and more Ca2+ is accumulated in the
sarcoplasmic reticulum (SR) by sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). The ↑
of releasable Ca2+ from the SR is the mechanism by which cardiac glycosides ↑ myocardial
contractility (Figure 16).
• The cardiac glycosides ↑ contraction of the cardiac sarcomere by increasing the free Ca2+
concentration in the vicinity of the contractile proteins during systole.
(Continued)
45
Crisp_Sec02_020-066.indd 46 18/07/14 10:39 AM

SECTION 2

Cardiac Glycosides (Continued)
In a nutshell, digoxin/digitoxin:
• Inhibit Na+/K+-ATPase → ↑ intracellular Na+
• ↓ Na+/Ca2+ exchange → ↑ intracellular Ca2+
• ↑ Ca2+ released from sarcoplasmic reticulum → ↑ actin–myosin interaction
• ↑ contractile force (Figures 16 and 17)
46
Crisp_Sec02_020-066.indd 46 18/07/14 10:39 AM

• At low therapeutic doses, digoxin induces vagal stimulation (↓ AV nodal conduction).
• Cardiac glycosides are contraindicated in sinus or AV node dysfunction (Table 2).
• At higher toxic doses, digoxin produces sympathetic-like effects in the heart (cardiac
arrhythmias and digitalis-induced bigeminy).
• The GI tract is a common site of digitalis toxicity (anorexia, nausea, vomiting, and diarrhea),
caused in part by direct effects of digoxin on the GI tract and partly by stimulation of
chemoreceptor trigger zone.
(Continued)
46
Crisp_Sec02_020-066.indd 47 18/07/14 10:39 AM

SECTION 2

Angiotensin Converting Enzyme Inhibitors (Figure 9)
Captopril
Enalapril
Lisinopril
• ACE inhibitors (with diuretics) are considered as first-line therapy for CHF.
Angiotensin Receptor Blockers (Figure 9)
Losartan
Valsartan
Candesartan
• The ARBs and ACEIs produce beneficial hemodynamic effects.
• Clinical trials suggest that ARBs are best reserved for patients who cannot tolerate ACEIs
(usually because of cough).
47
Crisp_Sec02_020-066.indd 47 18/07/14 10:39 AM

Mechanism of Action
• The ACEIs/ARBs ↓ PVR and ↓ afterload.
• These agents also ↓ aldosterone secretion, ↓ salt and water retention and ↓ preload.
• ACEIs/ARBs ↓ angiotensin II-induced vasoconstriction
• The ACEIs and ARBs ↓ remodeling of the heart and vessels, ↓ mortality and morbidity
• Hyperkalemia, angioedema
• Renal blood flow (RBF) and glomerular filtration rate (GFR) significantly reduced in patients
with bilateral renal artery stenosis.
• Contraindicated in pregnancy—teratogenic effects on fetal renal function
• Oligohydramnios and Potter syndrome
(Continued)
47
Crisp_Sec02_020-066.indd 48 18/07/14 10:39 AM

SECTION 2

Aldosterone Antagonists (Figure 9)
Spironolactone
Eplerenone
Mechanism of Action
• Spironolactone and eplerenone ↓ morbidity and mortality in patients with CHF by
decreasing the remodeling process.
• Eplerenone acts similarly to spironolactone but lacks the anti-androgenic action.
48
Crisp_Sec02_020-066.indd 48 18/07/14 10:39 AM

Adverse Drug Reaction/Contraindications
• Spironolactone is an inhibitor of testosterone synthesis and has anti-androgenic effects
(gynecomastia).
(Continued)
48
Crisp_Sec02_020-066.indd 49 18/07/14 10:39 AM

SECTION 2

Phosphodiesterase Inhibitors
Inamrinone—PDE 3 inhibitor
Milrinone—PDE 3 inhibitor
Sildenafil—PDE 5 inhibitor
• Inamrinone and Milrinone are approved for short-term circulatory support in acute and
exacerbation of advanced CHF.
• These phosphodiesterase inhibitors ↑ cAMP, which induces vasodilation (↓ afterload)
and (+) inotropic effects.
↑ cAMP in vascular smooth muscle—↓ TPR(↓ afterload)
↑ cAMP in heart muscle—(+) inotropic action
• Sildenafil is used to treat patients with right ventricular systolic failure (pulmonary artery
hypertension). Also used for treating male erectile dysfunction.
49
Crisp_Sec02_020-066.indd 49 18/07/14 10:39 AM

Adverse Drug Reaction
• The PDE 3 inhibitors can cause headache, hypotension, and ventricular arrhythmias.
• Sildenafil can cause headaches, flushing, and dyspepsia.
(Continued)
49
Crisp_Sec02_020-066.indd 50 18/07/14 10:39 AM

SECTION 2

Positive Inotropic Agent (Figures 16 and 17)
Dobutamine
• Dobutamine is a β1 agonist indicated for the short-term in hospital treatment of CHF.
• Dobutamine produces a (+) inotropic action, ↑ cardiac contractility (Figure 17).
• Dobutamine ↑ cardiac output (CO) and stroke volume (SV) without producing a marked ↑
in HR.
50
Crisp_Sec02_020-066.indd 50 18/07/14 10:39 AM

• ↑ myocardial O2 consumption.
• In patients with CAD, there is some potential for dobutamine-induced angina or arrhythmias.
(Continued)
50
Crisp_Sec02_020-066.indd 51 18/07/14 10:39 AM

SECTION 2

β-Blockers and Congestive Heart Failure
Carvedilol
Metoprolol
• Carvedilol is a nonselective β-blocker with α1-selective antagonist actions approved for the
management of mild-to-severe CHF.
• Metoprolol is a cardioselective β1-blocker.
• Proposed mechanisms include:
↓ in the adverse effects of catecholamines (e.g., apoptosis)
↓ HR and ↓ remodeling through inhibition of catecholamine-induced mitogenesis.
51
Crisp_Sec02_020-066.indd 51 18/07/14 10:39 AM

• Low-dose carvedilol or metoprolol ↓ mortality in patients with LV ejection fractions <35%
and are particularly useful in patients with both hypertension and CHF.
• It is generally recommended that low-dose carvedilol be combined with an ACE inhibitor or
AT1 receptor antagonist and diuretics for the treatment of CHF.
(Continued)
51
Crisp_Sec02_020-066.indd 52 18/07/14 10:39 AM

SECTION 2

Diuretics and Congestive Heart Failure (Table 1)
Loop Diuretics
Furosemide
Ethacrynic acid
Bumetanide
Thiazides
Hydrochlorothiazide
Chlorthalidone
Indapamide
Potassium-sparing Diuretics (Figure 10)
Spironolactone
Amiloride
Triamterene
52
Crisp_Sec02_020-066.indd 52 18/07/14 10:39 AM

Mechanism of Action/Uses (Table 1)
• Diuretics are the mainstay of therapy for symptomatic heart failure with edema.
• Diuretics ↓ extracellular fluid volume and ventricular filling pressure (↓ preload).
These drugs control volume overload and subsequent worsening in LV function.
(Continued)
52
Crisp_Sec02_020-066.indd 53 18/07/14 10:39 AM

SECTION 2

Diuretic Mechanisms of Action/Uses (Table 1)
• The loop diuretics (Furosemide, Ethacrynic Acid, and Bumetanide) inhibit the active Na+/
K+/2Cl– co-transport system in the thick ascending limb of the loop of Henle (Figure 10),
and prevent the reabsorption of Na+, K+ and Cl–.
• Loop diuretics are usually reserved for patients with impaired renal function with
pulmonary edema, CHF or hypertension.
• The thiazides inhibit Na+ reabsorption in the distal convoluted tubule by inhibition of the
Na+/Cl– co-transporter on the luminal membrane. This action increases NaCl excretion.
53
Crisp_Sec02_020-066.indd 53 18/07/14 10:39 AM

• Potassium loss (combine K+-sparing diuretic)
• Thiazides—K+ loss, hypercalcemia, hyperuricemia, hyperglycemia
• Loops—K+ loss, ototoxicity, hypocalcemia
(Continued)
53
Crisp_Sec02_020-066.indd 54 18/07/14 10:39 AM

SECTION 2

Vasodilators (Figure 18)
Hydralazine
Nitrovasodilators (Isosorbide Dinitrate)
Sodium Nitroprusside
• The nitrovasodilators (nitroglycerin, isosorbide dinitrate) are pro-drugs of nitric oxide,
↓ preload, ↓ cardiac work, and ↓ cardiac O2 requirements.
• In patients with high filling pressures (principal symptom is dyspnea), venodilators such
as the nitrovasodilators (isosorbide dinitrate, nitroglycerin) will ↓ filling pressures and
↓ symptoms of pulmonary congestion.
• Arteriolar dilators (hydralazine) are used to ↑ CO in patients with fatigue as a primary
symptom. Hydralazine ↑ the synthesis of endothelial NO, which decreases afterload and ↑ CO.
54
Crisp_Sec02_020-066.indd 54 18/07/14 10:39 AM

• Dilation of both arterioles and veins is required (with hydralazine and isosorbide dinitrate) in
patients with severe chronic CHF with ↑ filling pressures and ↓ cardiac output.
• Nesiritide is a recombinant form of human B-type natriuretic peptide (rh BNP) that binds to
guanylate cyclase in vascular smooth muscle and endothelial cells, ↑ cGMP → vasodilation
(Figure 18).
• Nesiritide ↓ pulmonary capillary wedge pressure (PCWP) and systemic arterial pressure.
Used in acutely decompensated CHF.
54
Crisp_Sec02_020-066.indd 55 18/07/14 10:39 AM

SECTION 2
Antianginal Pharmacology
Nitrovasodilators (Figure 18)
Nitroglycerin
Isosorbide
Amyl Nitrite
Amlodipine
Nifedipine
Verapamil
Diltiazem
Bepridil
55
Crisp_Sec02_020-066.indd 55 18/07/14 10:39 AM

18/07/14 10:39 AM
(Continued)
55
β-adrenoceptor Antagonists
Crisp_Sec02_020-066.indd 56
Propranolol
Metoprolol
Atenolol
Nadolol
SECTION 2
Nitrovasodilators
Nitroglycerin
These drugs ↑ exercise tolerance and ↓ the frequency of anginal
Isosorbide Dinitrate
attacks by ↓ preload and ↓ afterload.
Amyl Nitrite
Mechanism of Action/Uses (Figure 18)
• The nitrovasodilators treat classic and vasospastic angina by ↑ the release of nitric oxide
(NO), ↑ guanylyl cyclase, and ↑ cGMP, → venodilation.
• By inducing venodilation, the nitrates cause venous pooling and a decrease in preload
(Figure 18). There is also some ↓ in afterload, which ↓ cardiac work.
• A ↓ preload will ↓ ventricular volume and wall tension, ↓ cardiac work, and O2 demand.
• This ↓ preload also causes ↓ cardiac output and ↓ BP.
56
Crisp_Sec02_020-066.indd 56 18/07/14 10:39 AM

• Postural hypotension, tachycardia, headache, and flushing
• Drug interactions → synergistic hypotension with phosphodiesterase type 5
inhibitors (sildenafil)
• Methemoglobinemia—treat with methylene blue
(Continued)
56
Crisp_Sec02_020-066.indd 57 18/07/14 10:39 AM

SECTION 2
Amlodipine
Nifedipine The Ca2+ channel blockers treat ischemic tissue in the heart by restoring
Verapamil the balance between myocardial oxygen supply and demand (by ↑ O2
Diltiazem supply and/or ↓ O2 demand).
Bepridil
• These drugs block L-type Ca2+ channels and ↓ entry of Ca2+ into the plasma membrane of
vascular smooth muscle and cardiac cells.
• The dihydropyridines (“-dipines”) amlodipine and nifedipine cause vasodilation—↑ O2
supply.
• Verapamil and diltiazem—↓ HR, ↓ AV nodal conduction, and ↓ contractility—↓ O2
demand
57
Crisp_Sec02_020-066.indd 57 18/07/14 10:39 AM

• Gingival hyperplasia (nifedipine and other dihydropyridines)
• Headache
• Hypotension
(Continued)
57
Crisp_Sec02_020-066.indd 58 18/07/14 10:39 AM

SECTION 2
β-Blockers
Atenolol
Metoprolol The β-blockers are used in the management of classic (exercise-induced)
Nadolol angina and acute MI, but are not to be used in vasospastic angina.
Propranolol
• These drugs block exercise-induced angina (by preventing ↑’s in myocardial O2 demand
and tachycardia).
• The β-blockers prevent reflex tachycardia induced by the nitrovasodilators (nitroglycerine)
and the dihydropyridine Ca2+ channel blockers (nifedipine).
• β-blockers ↓ the risk of recurrence of myocardial infarction (drugs of choice post-MI)
and improve survival.
58
Crisp_Sec02_020-066.indd 58 18/07/14 10:39 AM

• Negative inotropic actions (dangerous in CHF)
• Unfavorable lipid profile (↑ LDL, ↓ HDL)
• Combination of verapamil or diltiazem with a β-blocker will significantly ↓ CO
and should be avoided.
58
Crisp_Sec02_020-066.indd 59 18/07/14 10:39 AM

SECTION 2
”Pharm-Man” Says…Antianginal Pharmacology
‘Pharm-Man’ says…..
It is important to remember
that β-blockers are not indicated
for vasospastic angina.
59
Crisp_Sec02_020-066.indd 59 18/07/14 10:39 AM

SECTION 2
Diuretics (Figure 10, Table 1)

Class of Diuretic Agents Used in Clinical Practice
Osmotic Diuretics
Mannitol
Urea
Glycerol
Isosorbide
Carbonic Anhydrase Inhibitors
Acetazolamide
Dorzolamide
Loop Diuretics
Furosemide
Ethacrynic acid
Bumetanide
60
Crisp_Sec02_020-066.indd 60 18/07/14 10:39 AM

Thiazide Diuretics
Hydrochlorothiazide
Chlorthalidone
Indapamide
Trichlormethiazide
Potassium-Sparing Diuretics
• co-administered with thiazides and loops diuretics
Spironolactone and Eplerenone—aldosterone receptor antagonist
Amiloride
Triamterene
(Continued)
60
Crisp_Sec02_020-066.indd 61 18/07/14 10:39 AM

SECTION 2
Diuretics (Figure 10, Table 1)

Class of Diuretic Agents Used in Clinical Practice (continued)
Osmotic Diuretics
Mannitol
Urea
Glycerol
Isosorbide
• parenterally available agents used clinically to ↑ H2O excretion and treat patients with
cerebral edema, acute renal failure due to shock, and glaucoma by pulling H2O from the
tissues to the blood.
61
Crisp_Sec02_020-066.indd 61 18/07/14 10:39 AM

Carbonic Anhydrase Inhibitors (Figure 10)
Acetazolamide
Dorzolamide
• The CA inhibitors (acetazolamide, dorzolamide) block the reabsorption of Na+HCO3– ions
from the proximal convoluted tubules. This action ↑ urinary pH. These drugs are useful for ↑
the renal excretion of weak acids (e.g., aspirin).
• Chronic reduction of Na+HCO3– stores in the body results in metabolic acidosis → can
be used to counteract respiratory alkalosis in high-altitude sickness (see diuretic-induced
changes in pH at the end of this section).
• CA inhibitors ↓ the rate of aqueous humor formation and ↓ intraocular pressure in patients
with glaucoma.
(Continued)
61
Crisp_Sec02_020-066.indd 62 18/07/14 10:39 AM

SECTION 2
Diuretics
Loop Diuretics (Figure 10)
Furosemide
Ethacrynic acid
Bumetanide
• The “loops” are usually reserved for treating patients with impaired renal function with
pulmonary edema, CHF, or mid/moderate hypertension.
• These drugs deliver large amounts of Na+ to distal segments of the nephron, leading to a
potent loss of Na+, Cl–, K+, Mg2+, Ca2+, HCO3–, and H2O.
62
Crisp_Sec02_020-066.indd 62 18/07/14 10:39 AM

• The loops prevent the reabsorption of Ca2+ and Mg2+ (↑ their excretion) → used to treat
hypercalcemia.
• Hearing and vestibular function can be adversely affected (ototoxicity tinnitus, ear pain,
vertigo, and reversible hearing loss).
• The loops can compete with uric acid for the renal organic acid secretory system exacerbating
gout attacks.
(Continued)
62
Crisp_Sec02_020-066.indd 63 18/07/14 10:39 AM

SECTION 2
Diuretics
Thiazides (Figure 10, Table 1)
Hydrochlorothiazide
Chlorthalidone
Indapamide
Trichlormethiazide
• The thiazides are the mainstay of antihypertensive therapy and are used to treat the
symptoms of CHF (↓ edema), hypercalciuria (by promoting Ca2+ reabsorption), and
diabetes insipidus (mechanism unclear).
• The thiazides ↓ urinary Ca2+ content by promoting its reabsorption (treat nephrolithiasis).
63
Crisp_Sec02_020-066.indd 63 18/07/14 10:39 AM

• Organic acid transport competitors such as uric acid, probenecid, penicillin, and salicylates
can block the diuretic action of the thiazides.
• Patients with diabetes mellitus can become hyperglycemic when taking thiazides (impaired
pancreatic release of insulin).
• Unfavorable lipid profile (↓ HDL, ↑ LDL).
(Continued)
63
Crisp_Sec02_020-066.indd 64 18/07/14 10:39 AM

SECTION 2
Diuretics
Lumen- Collecting Interstitium-
Class of Diuretic Agents Used in Clinical urine blood
tubule
Practice (continued) Cl–
K+-Sparing Diuretics (Figure 10, Table1)
Principal cell
Amiloride ENaC + R Aldosterone
Triamterene
Spironolactone and Eplerenone Na+
• The potassium-sparing diuretics block +
Na+
Na+ reabsorption (promoting Na+ K +
ATP
excretion) and ↓ K+ and H+ secretion
K+
(promoting K+ and H+ retention) in the
late distal tubule and collecting duct.
• The K+-sparing diuretics are used as Intercalated cell
adjuncts to loop and thiazide diuretics to HCO3–
prevent K+ depletion. ATP
Cl–
H+

Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)
64
Crisp_Sec02_020-066.indd 64 18/07/14 10:39 AM

• Aldosterone ↑ the number of Na+ and K+ channels and ↑ the activity of Na+/K+ ATPase to
promote salt and water retention.
• Spironolactone and eplerenone are aldosterone antagonists that compete with aldosterone for
intracellular cytoplasmic receptor sites, ↓ Na+ and fluid retention.
64
Crisp_Sec02_020-066.indd 65 18/07/14 10:39 AM

SECTION 2
Diuretic-Induced Changes in Body pH
Diuretic Class Body pH

Carbonic anhydrase inhibitors ↓ pH (metabolic acidosis)
Loop diuretics ↑ pH (metabolic alkalosis)
Thiazide diuretics ↑ pH (metabolic alkalosis)
K+-sparing diuretics ↓ pH (metabolic acidosis)
65
Crisp_Sec02_020-066.indd 65 18/07/14 10:39 AM

SECTION 2
Drugs to Treat Lipid Disorders

Bile Acid-Binding Resins—↓ LDL, ↑ HDL
Cholestyramine
Colestipol
HMG-CoA Reductase Inhibitors—↓ LDL, ↓ VLDL, ↑ HDL
Atorvastatin
Lovastatin
Pravastatin
Simvastatin
66
Crisp_Sec02_020-066.indd 66 18/07/14 10:39 AM

Lipoprotein Lipase Stimulators (Fibrates)—↓ VLDL, ↑ HDL
Gemfibrozil
Fenofibrate
Niacin—↓ LDL, ↓ VLDL, ↑ HDL
Inhibitors of Cholesterol Absorption—↓ LDL
Ezetimibe
66
Crisp_Sec02_020-066.indd 67 18/07/14 10:39 AM

SECTION 3
Neuropharmacology
Review of Presynaptic Presynaptic Sedative- List of First- Second- Antidepressants Tricyclic

Pharmacology of Pharma- hypnotic Anti- generation generation Antidepressants
Dopamine and cology of and psychotics ‘Typical’ ‘Atypical’ (TCAs)
Norepinephrine Serotonin Anxiolytic Drugs Anti- Antipsychotic
in the Central (5-HT) in Drugs psychotics Agents
Nervous System the CNS
(Continued)
67
Crisp_Sec03_067-095.indd 67 18/07/14 10:39 AM

Neuropharmacology (Cont'd.)
Serotonin Monoamine Atypical Drug Therapy Dopaminergic Opiate Opiate Drugs of

Selective Oxidase Antidepressant for Parkinson and Cholinergic Analgesics Receptor Abuse
Reuptake Inhibitors Agents Disease Influence in Antagonists
Inhibitors (MAOIs) Parkinson
(SSRIs) Disease
67
Crisp_Sec03_067-095.indd 68 18/07/14 10:39 AM

SECTION 3
Review of Presynaptic Pharmacology of Dopamine and Norepinephrine

in the Central Nervous System
Na+
α-Methyltyrosine—inhibits tyrosine Nerve
Axon
Tyrosine
A
terminal
hydroxylase and inhibits catecholamine Tyrosine
− Metyrosine
synthesis. Presynaptic
TH
Dopa
receptors Hetero- MAO
Reserpine—interferes with the presynaptic receptors
Dopamine +
VMAT and blocks the ability of presynaptic Auto-
receptor
H −
Reserpine
vesicles to take up and store DA, NE and 5-HT. VMAT Calcium

NE channel
Bretylium—inhibits NE release. ATP, P Ca2+
+
Amphetamine and Tyramine—promote release
VAMPs
of DA and NE from the presynaptic neuron. NE
ATP, P Bretylium,
NET −
guanethidine
Cocaine and Imipramine—block DA reuptake. −
SNAPs
Bupropion—blocks DA reupdate. Cocaine,
tricyclic
NE
Diffusion
anti-
Imipramine/Amitriptyline—block 5-HT/NE depressants
reuptake
Postsynaptic Adrenoceptors Other
Clorgyline—inhibits MAOA; blocks breakdown cell receptors
of NE. (Reproduced with permission from Barrett et al [editors]:

th
Ganong’s Review of Medical Physiology, 24 ed, 2012.)
68
Crisp_Sec03_067-095.indd 68 18/07/14 10:39 AM

Selegiline—inhibits MAOB; blocks DA metabolism.
Pargyline and Tranylcypromine—nonspecific inhibitors of MAOA and MAOB
Tolcapone—COMT inhibitor in CNS
Entacapone—COMT inhibitor in PNS
68
Crisp_Sec03_067-095.indd 69 18/07/14 10:39 AM

SECTION 3
Presynaptic Pharmacology of Serotonin (5-HT) in the Central Nervous System

Aromatic L-amino
p-Chlorophenylalanine (pCPA)—↓ the acid transporter
Na+
synthesis of 5-HT by inhibiting tryptophan
Tryptophan Tryptophan
hydroxylase. Serotonergic
neuron Tryptophan hydroxylase
Reserpine—interferes with the presynaptic (rate limiting)
VMAT and blocks the ability of presynaptic 5-Hydroxy-

tryptophan
vesicles to take up and store DA, NE, and 5-HT.
Aromatic L-amino
Action acid decarboxylase
5-HT is preferentially metabolized by MAOA. potential
CO2
Clorgyline—specific inhibitor of MAOA. 5HT
5HT
Serotonin
transporter H+
Pargyline and Tranylcypromine—MAOA and Na+
MAOB inhibitors. 5HT

5HT 5HT
VMAT
Na+
5HT
Methylenedioxymethamphetamine (MDMA; 5HT Ca2+
Ecstasy)—↑ release of 5-HT from the MAO
5HT1D/iB receptor
presynaptic neuron. 5-hydroxyindole
acetaldehyde
5HT (autoreceptor)
5HT
5HT
(Reproduced with permission from Barrett et al [editors]:

Ganong’s Review of Medical Physiology, 24th ed, 2012.)
69
Crisp_Sec03_067-095.indd 69 18/07/14 10:39 AM

Fluoxetine, Paroxetine, Sertraline, Escitalopram—5-HT re-uptake blockers.
Sumatriptan (“triptans”) and dihydroergotamine (DHE)—interact as agonists at presynaptic
5-HT1D/1B receptors and inhibit the release of vasodilatory mediators thought to be responsible for
migraine headaches (prostaglandins, CGRP, substance P).
69
Crisp_Sec03_067-095.indd 70 18/07/14 10:39 AM

SECTION 3
Sedative-hypnotic and Anxiolytic Drugs

Benzodiazepines (“pams” and “lams”) GABA site
Alprazolam Benzodiazepine site Barbiturate site
Chlordiazepoxide
Diazepam
Lorazepam
Steroid site
Midazolam anesthetics
Oxazepam or anxiogenics
Temazepam
Barbiturates
Amobarbital
Pentobarbital Picrotoxin site
Phenobarbital Cl– convulsants
Thiopental
Sedative-hypnotics zzzz
Zolpidem
Zaleplon
Eszopiclone
70
Crisp_Sec03_067-095.indd 70 18/07/14 10:39 AM

Antihistamines
Diphenhydramine
Hydroxyzine
Non-sedating Anxiolytic Drugs
Buspirone
Propranolol
(Continued)
70
Crisp_Sec03_067-095.indd 71 18/07/14 10:39 AM

SECTION 3
Sedative-hypnotic and Anxiolytic Drugs (Figure 19, Table 3)

Benzodiazepines (Short-, Medium-, and Long-acting)
Alprazolam—M
Chlordiazepoxide—L
Diazepam—L
Lorazepam—M
Midazolam—S
Oxazepam—M
Mechanism of Action/Uses (Figure 19, Table 3)
• BZDs are used to treat anxiety, seizures, insomnia, muscle spasms, and spasticity by
potentiating GABA-induced inhibition at all levels of the spinal cord and brain (Table 3).
• BZDs bind to the BZD1 site on the chloride ionophore → ↑ the affinity of GABA for the
GABA1 receptor → induce a conformational change and ↑ the frequency of Cl– channel
openings in CNS neurons → hyperpolarization.
• The barbiturates, on the other hand, bind to the barbiturate site on the chloride ionophore
and ↑ the duration of Cl– ion channel openings. (Mnemonic: There is a “u” in the word
“barbiturate” and a “u” in the word “duration.”)
71
Crisp_Sec03_067-095.indd 71 18/07/14 10:39 AM

• To review… BZDs ↑ the frequency of Cl– ion channel openings, while barbiturates ↑ the
duration of Cl– ion channel openings.
• Flumazenil is a competitive antagonist at the GABAA receptor and reverses the actions of the
BZDs. The barbiturates have no competitive antagonist.
• BZDs have fewer adverse effects and are safer in overdose than the barbiturates.
• Motor incoordination, impaired cognitive processing, dizziness, and drowsiness.
(Continued)
71
Crisp_Sec03_067-095.indd 72 18/07/14 10:39 AM

SECTION 3

Barbiturates (duration of action/hours)
Amobarbital (5–10 hours)
Pentobarbital (10–15 hours)
Phenobarbital (>15 hours)
Thiopental (<1 hour)
• As a group, the barbiturates have similar mechanisms and differ mainly on pharmacokinetic
parameters (duration of action).
• The barbiturates bind to the barbiturate site on the chloride ionophore, facilitate GABA
binding and ↑ the duration of Cl– ion channel openings (Figure 19).
• At higher concentrations, the barbiturates can directly activate chloride channels (direct
GABA-mimetic actions).
72
Crisp_Sec03_067-095.indd 72 18/07/14 10:39 AM

• Thiopental—useful in treatment of status epilepticus (Lorazepam is the first-line drug).
• The therapeutic use of barbiturates has declined due to the use of the BZDs, which are less
toxic and safer (have a competitive receptor antagonist; flumazenil).
• The barbiturates continue to be used for the treatment of seizure disorders and for the
induction of anesthesia.
(Continued)
72
Crisp_Sec03_067-095.indd 73 18/07/14 10:39 AM

SECTION 3

Barbiturates (continued)
• Combination of barbiturates with other CNS depressants causes severe CNS depression.
• Respiratory depressants; ↓ response to hypercapnia (↑ CO2) and hypoxia (↓ O2)
• Impairment of mood and judgment; diminished fine motor skills
• Dose-dependent ↓ in BP and ↓ responsiveness of the baroreceptor reflex
73
Crisp_Sec03_067-095.indd 73 18/07/14 10:39 AM

Contraindications and Drug Interactions
• The barbiturates ↑ porphyrin synthesis and are contraindicated in patients with porphyria.
• Barbiturates are inducers of cytochrome P450 enzymes in the liver and accelerate their
own metabolism as well as the metabolism of other drugs that undergo phase I enzymatic
biotransformation.
• Barbiturates accelerate vitamin D metabolism and may alter bone mineralization and lower
Ca2+ absorption.
• These CNS depressants augment the metabolism of vitamin K and can induce coagulation
defects.
• Barbiturate-induced hepatic enzyme induction ↑ the metabolism of endogenous steroid
hormones and oral contraceptives, which may result in unwanted pregnancies.
(Continued)
73
Crisp_Sec03_067-095.indd 74 18/07/14 10:39 AM

SECTION 3

Hypnotics—(the “ZZZZ-snoring” compounds)
Zolpidem
Zaleplon
Eszopiclone
Mechanism of Action
• Zolpidem, zaleplon, and eszopiclone bind selectively to a subgroup of GABA1 receptors and
induce membrane hyperpolarization and rapid hypnosis.
• The BZD antagonist flumazenil also binds at a site on the chloride ionophore and can
reverse the hypnotic effects of zolpidem.
• These “Z” compounds are less effective as anticonvulsants or muscle relaxants than the
BZDs.
74
Crisp_Sec03_067-095.indd 74 18/07/14 10:39 AM

• Aggressive behavior
• Complex sleep-related behavior and hallucinations
• Amnesia
(Continued)
74
Crisp_Sec03_067-095.indd 75 18/07/14 10:39 AM

SECTION 3

Non-sedating Anxiolytic Drugs
Buspirone
Propranolol
• Buspirone relieves chronic generalized anxiety without causing marked sedative, hypnotic or
euphoric effects.
• Buspirone acts as a partial agonist at brain serotonin 5-HT1A receptors and as an antagonist
of the dopamine-D2 receptor.
• The anxiolytic effects of buspirone take more than a week to become established.
75
Crisp_Sec03_067-095.indd 75 18/07/14 10:39 AM

• Buspirone is not a BZD and has no anticonvulsant or muscle relaxant properties and less
abuse liability than BZDs or barbiturates.
• Propranolol is used to treat performance anxiety and social anxiety. β-blockers are
administered prior to stressful events (e.g., public speaking or acting).
75
Crisp_Sec03_067-095.indd 76 18/07/14 10:39 AM

SECTION 3
List of Antipsychotic Drugs

First-generation “Typical” Antipsychotic Drugs—D2 Receptor Antagonists
Phenothiazines (prolongation of QT interval; torsades de pointes)
Chlorpromazine
Fluphenazine
Thioridazine—Torsades de Pointes
Trifluoperazine
Thioxanthenes
Thiothixene
Butyrophenones—( potency at D2 receptor confers EPS; Figure 20)
Haloperidol
76
Crisp_Sec03_067-095.indd 76 18/07/14 10:39 AM

Second-generation “Atypical” Antipsychotic Agents—D2C/5-HT2 Antagonists
Quetiapine
Aripiprazole
Clozapine
Loxapine
Risperidone
Olanzapine
76
Crisp_Sec03_067-095.indd 77 18/07/14 10:39 AM

SECTION 3
First-generation “Typical” Antipsychotics

First-generation “Typical” Antipsychotics—D2 Receptor Antagonists
Phenothiazines—Antipsychotic potency is correlated with affinity for D2 receptors (Figure 20).
As a class, the phenothiazines have the potential to cause torsades.
Chlorpromazine—lower potency, ↑ anticholinergic and antihistaminergic side effects
Fluphenazine
Thioridazine—torsades de pointes, cardiac conduction block, and sudden death
Trifluoperazine
Thioxanthenes
Thiothixene
77
Crisp_Sec03_067-095.indd 77 18/07/14 10:39 AM

Butyrophenones—↑ potency confers ↑↑ extrapyramidal side effects (EPS; Figure 20)
Haloperidol—the most widely used typical antipsychotic drug, in spite of the fact that it induces
the highest level of EPS compared to other antipsychotic drugs.
Mechanism of Action
• These first-generation “typical” antipsychotics induce their effects by blocking D2 sites in the
striatum.
(Continued)
77
Crisp_Sec03_067-095.indd 78 18/07/14 10:39 AM

SECTION 3
First-generation “Typical” Antipsychotics (Continued)

Extrapyramidal Side Effects (EPS; haloperidol > phenothiazines)
• Akathisia (motor restlessness)
• Acute dystonias (involuntary muscle movements)—spasms, protruding tongue, torticollis
• Parkinson-like syndrome (pseudoparkinsonism)—rigidity, bradykinesia, and tremor
• Tardive dyskinesia (supersensitivity of D2 receptors)—late-developing grimacing, tongue
protrusion, lip smacking, repetitive, involuntary, and purposeless movements
• Neuroleptic malignant syndrome—life-threatening, neurological disorder; symptoms
include high fever, muscular rigidity and autonomic dysfunction (unstable blood pressure)
• Treat with dantrolene, ice baths and monitor vital signs
78
Crisp_Sec03_067-095.indd 78 18/07/14 10:39 AM

Anticholinergic Side Effects
• Include dry mouth, blurred vision (cycloplegia), and GI upset
78
Crisp_Sec03_067-095.indd 79 18/07/14 10:39 AM

SECTION 3
Second-generation “Atypical” Antipsychotic Agents

”Atypical” Antipsychotic Agents—D2C/5-HT2 Antagonists
Quetiapine
Aripiprazole
Clozapine
Loxapine
Risperidone
Olanzapine
Mechanism of Action
• The newer “atypical” antipsychotics act as antagonists at D2C/5-HT2 receptors in the
mesolimbic and mesocortical systems, respectively.
• The atypical antipsychotics show better compliance, fewer EPS and anticholinergic side
effects.
79
Crisp_Sec03_067-095.indd 79 18/07/14 10:39 AM

• ↓ tendency to induce extrapyramidal side effects (EPS)
• Agranulocytosis and leukopenia (Clozapine)
• Gynecomastia and galactorrhea (Risperidone)
79
Crisp_Sec03_067-095.indd 80 18/07/14 10:39 AM

SECTION 3
Antidepressants
Tricyclic Antidepressants (TCAs)
Amitriptyline
Clomipramine
Desipramine
Imipramine
Nortriptyline
Selective Serotonin Reuptake Inhibitors (SSRIs)
Fluoxetine
Paroxetine
Sertraline
Citalopram
Escitalopram
Monoamine Oxidase Inhibitors (MAOIs)
Phenelzine
Tranylcypromine
Selegiline
80
Crisp_Sec03_067-095.indd 80 18/07/14 10:39 AM

Atypical Antidepressants (Miscellaneous)
Bupropion
Hypericum
Mirtazapine
Trazodone
Venlafaxine
Duloxetine
Milnacipran
80
Crisp_Sec03_067-095.indd 81 18/07/14 10:39 AM

SECTION 3

Amitriptyline (nortriptyline is an active metabolite)
Clomipramine—treats OCD
Desipramine
Imipramine (desipramine is an active metabolite)
Nortriptyline
Mechanism of Action/Indications (Figure 21)
The TCAs inhibit the reuptake of 5-HT and NE.
• Amitriptyline and Imipramine—5-HT > NE uptake inhibitor
• Nortriptyline and Desipramine—NE > 5-HT uptake inhibitor
• Amitriptyline is also used to treat neuropathic pain
• Imipramine is used to treat enuresis
81
Crisp_Sec03_067-095.indd 81 18/07/14 10:39 AM

• Cardiotoxic effects of the TCAs—life threatening quinidine-like effects on cardiac conduction
(Na+-channel blocking properties ↑ QRS complex, torsades de pointes; syncope). No more
than a 1-week supply should be provided to new patients.
• TCAs ↓ seizure threshold.
• Sexual dysfunction
81
Crisp_Sec03_067-095.indd 82 18/07/14 10:39 AM

SECTION 3
Serotonin Selective Reuptake Inhibitors (SSRIs)

Selective Serotonin Reuptake Inhibitors (SSRIs)
Fluoxetine
Paroxetine
Sertraline
Citalopram
Escitalopram
The SSRIs potentiate and prolong the action of neuronally released 5-HT.
Long-term treatment with SSRIs desensitizes presynaptic receptors and alters the postsynaptic
transduction systems.
82
Crisp_Sec03_067-095.indd 82 18/07/14 10:39 AM

Adverse Side Effects/Drug Interactions
• Serotonin syndrome (especially when co-administered with MAOIs, methadone, meperidine,
linezolid, triptans, ergot alkaloids and others)
• Fluoxetine, fluvoxamine, and other TCAs and SSRIs inhibit cytochrome P450 isozymes and
can significantly elevate levels of drugs metabolized by these hepatic enzymes.
• Meperidine (an opiate with 5-HT uptake blocking properties) combined with MAOIs can
cause life-threatening serotonin syndrome.
• Sexual dysfunction
82
Crisp_Sec03_067-095.indd 83 18/07/14 10:39 AM

SECTION 3

Phenelzine
Tranylcypromine
Selegiline
Phenelzine—irreversible inhibitor of MAO-A and MAO-B
Tranylcypromine—irreversible inhibitor of MAO-A and MAO-B
Selegiline—MAOB inhibitor, ↑ DA in synapse (DA is metabolized by MAOB)
83
Crisp_Sec03_067-095.indd 83 18/07/14 10:39 AM

• Serotonin syndrome (especially when co-administered with MAOIs, methadone, meperidine,
linezolid, triptans, ergot alkaloids and others)
• Tyramine cheese effect (MAOIs can induce hypertensive crisis if the patient ingests large
quantities of products high in tyramine, including aged cheese, processed meats, avocados,
dried fruits, and red wines).
• CNS excitation, suppression of REM sleep
• Sexual dysfunction, weight gain
83
Crisp_Sec03_067-095.indd 84 18/07/14 10:39 AM

SECTION 3
Atypical Antidepressant Agents

Atypical Antidepressant Drugs
Bupropion—DA uptake blocker
Mirtazapine—5-HT2 and α2 (autoreceptor) antagonist
Trazodone—5-HT uptake inhibitor
Venlafaxine NSRI—NE and 5-HT uptake
Duloxetine blockade; may be used to treat
Milnacipran neuropathic pain
Mechanism of Action
These agents ↑ synaptic levels of 5-HT, NE, and/or DA by different mechanisms.
84
Crisp_Sec03_067-095.indd 84 18/07/14 10:39 AM

Bupropion—↓ seizure threshold
Serotonin syndrome
Trazodone—sedation and priapism
Sexual dysfunction
84
Crisp_Sec03_067-095.indd 85 18/07/14 10:39 AM

SECTION 3
Drug Therapy for Parkinson Disease
Anti-Parkinson Drugs Mechanism of Action

Levodopa (L-DOPA) and Carbidopa Carbidopa facilitates L-DOPA transport across BBB before being
converted to DA.
Dopamine agonists Interact directly with DA receptors in basal ganglia
Bromocriptine
Ropinirole
Pramipexole
Antimuscarinics Inhibit excessive cholinergic influence accompanying DA deficiency.
Benztropine
Trihexyphenidyl
Amantadine Antiviral agent that ↑ synaptic DA levels in the brain. It may stimulate
DA release or block the DA reuptake site (DAT).
MAO inhibitors (MAOIs) Inhibits MAOB in the basal ganglia; used as an adjunct to L-DOPA/
Selegiline carbidopa to ↑central DA activity (Figure 22)
COMT inhibitors (COMTIs) Tolcapone and entacapone block COMT and prevent the breakdown
Tolcapone (CNS and PNS)* of catecholamines (e.g., L-DOPA, DA, NE, EPI). Used as adjuncts to
Entacapone (PNS)* L-DOPA/carbidopa to ↑ central DA.
*Tolcapone has both central and peripheral effects, whereas entacapone acts primarily in the periphery. See dopamine metabolic
pathways in Figure 22.
85
Crisp_Sec03_067-095.indd 85 18/07/14 10:39 AM

SECTION 3
Dopaminergic and Cholinergic Influence in Parkinson Disease
ACh Benztropine
trihexphenidyl
L-DOPA DA
carbidopa
86
Crisp_Sec03_067-095.indd 86 18/07/14 10:39 AM

• Parkinsonism—Characterized by a ↓ in striatal dopamine levels.
• The lack of striatal DA ↑ activity of striatal cholinergic (ACh) pathways.
• Drug therapy for patients with Parkinson disease focuses on restoring the DA (L-DOPA/
Carbidopa) and ACh imbalance (trihexyphenidyl or benztropine) in order to improve motor
function.
86
Crisp_Sec03_067-095.indd 87 18/07/14 10:39 AM

SECTION 3
Opiate Analgesics
Strong Mu (μ) Opiate Receptor Agonists
Morphine—prototype μ agonist
Fentanyl—strong lipophilic μ agonist
Meperidine—has an active metabolite (normeperidine) that is proconvulsant.
Methadone—long duration; used to treat patients with opiate addiction
Oxycodone—used for breakthrough pain (postsurgical pain)
Sufentanil—strong lipophilic μ agonist
Heroin—diacetylmorphine (Highly abused but not approved for medical use in the
United States.)
87
Crisp_Sec03_067-095.indd 87 18/07/14 10:39 AM

Moderate Opiate Agonists
Codeine—catalyzed by P450 enzymes to morphine (P-450 inhibitors ↓ codeine’s efficacy)
Hydrocodone—combined with either acetaminophen or ibuprofen
(Continued)
87
Crisp_Sec03_067-095.indd 88 18/07/14 10:39 AM

SECTION 3
Opiate Analgesics (Continued)

Mechanism of Action/Indications
Opiates:
• are used as the mainstay of therapy for acute and chronic moderate to severe pain.
• bind to μ opioid receptors in the spinal cord and inhibit the release of the nociceptive
neurotransmitters substance P and glutamate.
• interact with opioid receptors in the periaqueductal gray (PAG) and stimulate the
descending pain inhibitory system (activating spinal 5-HT and NE).
• induce euphoria by interacting with opioid receptors in the ventral tegmental area and
nucleus accumbens in the brain.
88
Crisp_Sec03_067-095.indd 88 18/07/14 10:39 AM

• High doses of opiates ↓ the responsiveness of the respiratory center to increases in CO2
tension, inducing respiratory depression.
• Meperidine, methadone and fentanyl can induced a serotonin syndrome if administered with
SSRIs, MAOIs or TCAs
• Sedation, drowsiness, mental clouding, and coma (at toxic doses)
• Miosis (pinpoint pupils)
88
Crisp_Sec03_067-095.indd 89 18/07/14 10:39 AM

SECTION 3
Opiate Receptor Antagonists

Mu (μ) Opiate Blockers
Naloxone—parenteral opiate antagonist
Naltrexone—orally available
Nalmefene—orally available
Mechanism of Action
• Opiate antagonists competitively block μ opioid receptors.
89
Crisp_Sec03_067-095.indd 89 18/07/14 10:39 AM

Clinical Indications
Opiate antagonists are used clinically to manage:
• cravings of ETOH-dependent people trying to quit drinking ETOH (naltrexone).
• respiratory depression caused by the overdose of opiates (heroin or oxycodone).
• the compulsive use of opiates. Naltrexone blocks opiate cravings and ↓ recidivism by
competitively blocking opioid receptors in the ventral tegmental area (VTA) and the nucleus
accumbens (NA), areas mediating euphoria.
89
Crisp_Sec03_067-095.indd 90 18/07/14 10:39 AM

SECTION 3
Drugs of Abuse
Ethanol (ETOH)
Alcohol Acetaldehyde
Ethanol Acetaldehyde Acetic acid
dehydrogenase dehydrogenase
(cytoplasm) (mitochondria)
90
Crisp_Sec03_067-095.indd 90 18/07/14 10:39 AM

Mechanism of Action
• ETOH interacts with the GABA ionophore to potentiate GABA-induced increases in chloride
ion flux → hyperpolarization and neuronal inhibition.
• ETOH also inhibits glutamate-induced NMDA receptor-mediated ion currents.
• Long-term ETOH ingestion causes a persistent ↓ in glutamate function, which induces an
up-regulation of NMDA receptors (EAA may mediate some ETOH withdrawal symptoms).
(Continued)
90
Crisp_Sec03_067-095.indd 91 18/07/14 10:39 AM

SECTION 3
Drugs of Abuse
ETOH (Continued)
• Wernicke–Korsakoff syndrome
• Fetal Alcohol Syndrome (FAS)—mid-facial hypoplasia, microcephaly, and marked CNS
dysfunction, including mental impairment.
• Cirrhosis of the liver
Signs of Withdrawal: delirium tremens, seizures, ↑ heart rate, and ↑ blood pressure
Treat ETOH withdrawal with oxazepam and lorazepam, benzodiazepines that are not
as dependent on hepatic metabolism (remember lorazepam and oxazepam undergo
Phase 2 conjugation).
(Continued)
91
Crisp_Sec03_067-095.indd 91 18/07/14 10:39 AM

SECTION 3
Drugs of Abuse
Methanol and Ethylene Glycol
Ethylene Glycol—metabolized to oxalic acid, which causes renal failure.
Methanol—metabolized to formic acid, which can induce permanent blindness by destruction
of the optic nerve.
Ethylene Alcohol Aldehyde Glycolic Oxalic

Glycoaldehyde
glycol dehydrogenase dehydrogenase acid acid
1. CNS depression
2. Severe metabolic acidosis
3. Nephrotoxicity
Alcohol Aldehyde
Methanol Formaldehyde Formic acid
1. Respiratory failure
2. Severe anion gap metabolic acidosis
3. Ocular damage
92
Crisp_Sec03_067-095.indd 92 18/07/14 10:39 AM

• Alcohol dehydrogenase can be blocked by fomepizole.
• Aldehyde dehydrogenase can be blocked by disulfiram.
(Continued)
92
Crisp_Sec03_067-095.indd 93 18/07/14 10:39 AM

SECTION 3
Drugs of Abuse
Amphetamine/Methamphetamine
• Enter through the DAT, ↑ release of DA and NE from mobile pool through DAT acting in
reverse, blocks NE and DA reuptake, and act as MAO inhibitors.
• ↑ DA release in various brain areas and the nucleus accumbens.
• Release of NE from peripheral nerves in sympathetic nervous system (can induce
myocardial infarction, cerebrovascular hemorrhage, seizures, and death).
93
Crisp_Sec03_067-095.indd 93 18/07/14 10:39 AM

Amphetamine abuse causes euphoria, insomnia, psychomotor stimulation, anxiety, loss of
appetite, improved concentration and ↓ fatigue.
Long-term use produces a toxic psychosis that is indistinguishable from paranoid schizophrenia
(treat with antipsychotic agents; haloperidol, or chlorpromazine).
(Continued)
93
Crisp_Sec03_067-095.indd 94 18/07/14 10:39 AM

SECTION 3
Drugs of Abuse
3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy)
Mechanism of Action
• MDMA has a strong affinity for the serotonin transporter (SERT) and acts by ↑ 5-HT
release from central serotonergic neurons.
• MDMA degenerates serotonergic neuronal terminals, causing 5-HT depletion.
94
Crisp_Sec03_067-095.indd 94 18/07/14 10:39 AM

• MDMA induces stimulant and psychedelic effects; withdrawal involves long-term depression
and aggressiveness.
• Reported to cause a long-term cognitive impairment in heavy users.
• Initial excess 5HT release may induce serotonin syndrome (fatal hyperthermia and
dehydration).
(Continued)
94
Crisp_Sec03_067-095.indd 95 18/07/14 10:39 AM

SECTION 3
Drugs of Abuse
Cocaine
• Powerful psychostimulant with strong reinforcing properties
• Potent local anesthetic (Na+-channel blocker)
• Strong vasoconstrictor (α-adrenergic agonist)
• Inhibits reuptake of NE and DA in the CNS producing profound euphoria.
• Inhibits reuptake of NE in the PNS—↑ HR, ↑contractility, and ↑ blood pressure.
• Continual use induces psychotic episodes, paranoia, hallucinations and dyskinesias.
95
Crisp_Sec03_067-095.indd 95 18/07/14 10:39 AM

• The liver combines cocaine and ETOH to manufacture a substance known as cocaethylene
(the euphoric effects of cocaethylene are intensified).
Cocaine (and cocaethylene) produce aggression, hypertension and arrhythmias.
95
Crisp_Sec03_067-095.indd 96 18/07/14 10:39 AM

14/07/14 10:54 AM
SECTION 4
Pharmacology
Antibiotics
Antibiotic
Review of
96
SECTION 4
Review of Antibiotic Pharmacology

Cell Wall Synthesis Inhibitors (Figure 24) β-lactam ring
Penicillins (β-lactam structure; bactericidal) H H H S H

Penicillin G—Narrow-spectrum penicillins C N C C C
(Treponema pallidum) H
Penicillin V—Group A Streptococcus infection O C N C
O C CH2
Dicloxacillin
Nafcillin and Oxacillin—methicillin-sensitive COOH
Site of cleavage by bacterial
Staphylococcus aureus β-lactamases or by acid
97
Crisp_Sec04_096-110.indd 97 14/07/14 10:54 AM

Extended-spectrum amino penicillins (administer with β-lactamase inhibitors, clavulanate)
• Amoxicillin—otitis media, community-acquired pneumonia, and sinusitis
• Ampicillin—suspected Listeria meningitis
• Piperacillin and Ticarcillin—used to treat methicillin-sensitive Staphylococcus aureus
and some gram (−) infections such as Pseudomonas and Klebsiella
Mechanism of Action
The beta-lactam antibiotics (penicillins and cephalosporins) bind covalently to penicillin-
binding proteins (PBPs) and inhibit the transpeptidation reaction. This halts peptidoglycan
synthesis and causes death of the bacterium.
(Continued)
97
Crisp_Sec04_096-110.indd 98 14/07/14 10:54 AM

SECTION 4

Penicillins (continued)
• Penicillin G can induce a Jarisch-Herxheimer reaction in patients treated for syphilis.
• The Jarisch–Herxheimer reaction is caused by the release of endotoxins from spirochetes,
(cytokines, TNF, IL-6, and IL-8) as bacteria die.
98
Crisp_Sec04_096-110.indd 98 14/07/14 10:54 AM

• This reaction is accompanied by headache, myalgia and fever (treat with antipyretics,
acetaminophen, or NSAIDs).
• Hypersensitivity reactions (true type I anaphylactic reactions are rare; < 0.05%).
• Assume complete cross-allergenicity between penicillins/cephalosporins.
(Continued)
98
Crisp_Sec04_096-110.indd 99 14/07/14 10:54 AM

SECTION 4

Cephalosporins (β-lactam structure, bactericidal; Figure 24)
First-generation cephalosporins
Cephalexin—presurgical prophylaxis, urinary tract infections (UTI)
Second-generation cephalosporins
Cefotetan—disulfiram reaction
Cefamandole—disulfiram reaction
Cefaclor
99
Crisp_Sec04_096-110.indd 99 14/07/14 10:54 AM

Third-generation cephalosporins—enter central nervous system after parenteral administration
Ceftazidime—antipseudomonal activity; high penetration into the subarachnoid space
Ceftriaxone—drug of choice for treatment of gonorrhea and meningococcal meningitis
Cefoperazone—disulfiram-like reaction
Fourth-generation cephalosporins
Cefepime—extended spectrum of activity against gram (+) and gram (−) negative bacteria;
covers pseudomonal infections
(Continued)
99
Crisp_Sec04_096-110.indd 100 14/07/14 10:54 AM

SECTION 4

Cephalosporins (continued)
The beta-lactam antibiotics (penicillins and cephalosporins) bind covalently to penicillin-
binding proteins (PBPs) and inhibit the transpeptidation reaction. This halts all
peptidoglycan synthesis and causes death of the bacterium.
100
Crisp_Sec04_096-110.indd 100 14/07/14 10:54 AM

• Hypersensitivity; partial cross-hypersensitivity with penicillins (about 5%)
• Clostridium difficile colitis
• Disulfiram reaction (cefoperazone, cefamandole, and cefotetan)
(Continued)
100
Crisp_Sec04_096-110.indd 101 14/07/14 10:54 AM

SECTION 4

Cell Wall Synthesis Inhibitors (continued) (Figure 24)
Carbapenems—(plus cilastatin to inhibit metabolism by renal dehydropeptidase) gram-positive
cocci, gram-negative rods, and anaerobes
Imipenem—broad spectrum; used in hospitals for treatment of serious infections such as
necrotizing pancreatitis
Meropenem
Monobactams
Aztreonam—activity against gram-negative rods (parentally available), use in β-lactam allergy
(virtually no cross-allergenicity to penicillins or cephalosporins). Binds to bacterial cell wall
transpeptidases and inhibits cell wall synthesis.
101
Crisp_Sec04_096-110.indd 101 14/07/14 10:54 AM

Bacitracin—inhibits cell wall peptidoglycan synthesis by blocking regeneration of the bactoprenol
carrier.
Cycloserine—prevents cross-linking of the peptidoglycan strands by inhibiting L-alanine racemase
and D-alanine synthetase, enzymes are involved in the incorporation of D-alanine into the
peptidoglycan structure.
Fosfomycin—bactericidal; inactivates pyruvyl transferase and inhibits cell wall synthesis.
(Continued)
101
Crisp_Sec04_096-110.indd 102 14/07/14 10:54 AM

SECTION 4

Cell Wall Synthesis Inhibitors (continued)
Vancomycin
• Bactericidal; used against multi-resistant gram (+) bacteria (MRSA, enterococci, and
Clostridium difficile as backup drug).
• Enterococcal resistance involves change in the muramyl pentapeptide “target,” such that the
terminal D-ala is replaced by D-lactate.
• Inhibits cell wall synthesis by binding to the D-ala-D-ala terminus of the peptidoglycan
peptide and preventing chain elongation and cross-linking.
• In combination with gentamycin, vancomycin is effective against enterococcal endocarditis
in patients with penicillin allergy.
102
Crisp_Sec04_096-110.indd 102 14/07/14 10:54 AM

• Urticarial reactions, flushing (“red-man” syndrome due to histamine release), ototoxicity (can
be permanent), and nephrotoxicity that can be additive with other drugs.
(Continued)
102
Crisp_Sec04_096-110.indd 103 14/07/14 10:54 AM

SECTION 4

Cell Wall Synthesis Inhibitors
Daptomycin
• Similar spectrum to vancomycin and acts as an effective alternate; more rapidly bactericidal.
• Active against vancomycin-resistant strains of enterococci and Staphylococcus aureus.
• Treats skin and soft tissue infections, bacteremia, and endocarditis.
Mechanism of Action
• Binds to the cell membrane by Ca2+-dependent insertion of its lipid tail; causes membrane
depolarization, K+ efflux, and cell death.
103
Crisp_Sec04_096-110.indd 103 14/07/14 10:54 AM

• Myopathy
• Allergic pneumonitis in patients treated >2 weeks
• Daptomycin is blocked by pulmonary surfactant (do not use to treat pneumonia).
(Continued)
103
Crisp_Sec04_096-110.indd 104 14/07/14 10:54 AM

SECTION 4

Protein Synthesis Inhibitors
Tetracyclines—broad-spectrum bacteriostatic drugs
Tetracycline
Doxycycline
Minocycline
• Block tRNA from binding to the 30S ribosomal subunit; inhibit protein synthesis
• Wide spectrum, effective against gram (+) and gram (−) organisms, treat Rickettsia (Rocky
Mountain spotted fever), H pylori, Borrelia burgdorferi (Lyme disease), and prostatitis
• The tetracycline treat infections caused by obligate intracellular organisms (Chlamydia and
Mycoplasma species).
104
Crisp_Sec04_096-110.indd 104 14/07/14 10:54 AM

• Phototoxicity (sensitivity to the sun)
• Discoloration of developing teeth
• Depression of bone growth in children
• Contraindicated in pregnancy and children
(Continued)
104
Crisp_Sec04_096-110.indd 105 14/07/14 10:54 AM

SECTION 4

Aminoglycosides
Amikacin
Gentamicin
Neomycin
Streptomycin
Tobramycin
• The aminoglycosides bind to the 30S ribosomal subunit and induce an error in translation
(misreading of the genetic code), causing the wrong tRNA to bind and the wrong amino
acid to be inserted into the nascent peptide.
• Active against aerobic gram-negative bacilli (Pseudomonas aeruginosa).
• Bactericidal effects are synergistic when administered with an extended-spectrum penicillin
(e.g., ticarcillin, piperacillin) or cephalosporin.
• Post-antibiotic effect, which is a delay in bacterial regrowth following the removal of the
agent.
105
Crisp_Sec04_096-110.indd 105 14/07/14 10:54 AM

• Nephrotoxicity
• Ototoxicity
• Neuromuscular blockade (↓ ACh release)
(Continued)
105
Crisp_Sec04_096-110.indd 106 14/07/14 10:54 AM

SECTION 4

Macrolides—(look for “thro” in the name)
Azithromycin
Erythromycin
Clarithromycin
Dirithromycin
• Broad-spectrum bacteriostatic antibiotics (can also be bactericidal)
• Blocks peptidyl transferase at the 50S ribosomal subunit, preventing attachment of the
nascent peptide and the new amino acid.
• Inhibit ribosomal translocation, leading to inhibition of bacterial protein synthesis
• Treat atypical organisms (Chlamydia, Mycoplasma, H pylori, Legionella).
• Useful in treating lung and chest infections; use in patients with penicillin allergy.
• Community-acquired pneumonias—where atypical pathogens such as Mycoplasma
pneumoniae and Legionella pneumophila are common.
106
Crisp_Sec04_096-110.indd 106 14/07/14 10:54 AM

• Chlamydial infections (Chlamydia pneumoniae pneumonia or Chlamydia trachomatis pelvic
infections, especially in pregnancy.)
• Bordetella pertussis
• Inhibit P450 3A4 (clarithromycin and erythromycin)
• Prolongation of QT interval (torsades)
• Pseudomembranous colitis has been reported with clarithromycin use.
(Continued)
106
Crisp_Sec04_096-110.indd 107 14/07/14 10:54 AM

SECTION 4

Protein Synthesis Inhibitors (continued)
Streptogramins
Quinupristin-Dalfopristin
Mechanism of Action
• Bactericidal antibiotics that inhibit protein synthesis in a manner similar to the macrolides.
• Active against gram (+) cocci (multidrug-resistant strains of streptococci, penicillin-resistant
strains of S pneumoniae and vancomycin-resistant E faecium)
• Treats vancomycin-resistant enterococci (VRE) and Staphylococcus aureus (VRSA)
107
Crisp_Sec04_096-110.indd 107 14/07/14 10:54 AM

14/07/14 10:54 AM
(Continued)
107
• Arthralgia/myalgia syndrome
SECTION 4

Protein Synthesis Inhibitors (continued) p-Aminobenzoic acid
Folic Acid Inhibitors Sulfonamides

Dihydropteroate
− (compete
Sulfonamides synthase
with PABA)
Sulfacetamide
Sulfadiazine Dihydrofolic acid
Sulfamethoxazole
Sulfasalazine Dihydrofolate − Trimethoprim
reductase
Sulfisoxazole
Folate Reductase Inhibitors Tetrahydrofolic acid
Trimethoprim
Trimethoprim-sulfamethoxazole
Purines
DNA
108
Crisp_Sec04_096-110.indd 108 14/07/14 10:54 AM

Mechanism of Action
• Structural analogs of PABA and act by inhibiting dihydropteroate synthase.
• The sulfonamides and trimethoprim are bactericidal and inhibit sequential steps in the
synthesis of folic acid in bacteria.
• Trimethoprim works by inhibiting folate reductase and produces a synergistic effect when
administered with a sulfonamide (sulfamethoxazole).
(Continued)
108
Crisp_Sec04_096-110.indd 109 14/07/14 10:54 AM

SECTION 4

Protein Synthesis Inhibitors (continued)
Fluoroquinolones—(look for “flox” in the name)
Ciprofloxacin
Ofloxacin
Levofloxacin
Norfloxacin
Nalidixic Acid (there’s always one goofball)
• Bactericidal; act as DNA topoisomerase IV inhibitors (DNA gyrase in bacteria). These
enzymes are involved in the repair and replication of DNA.
• These drugs induce a post-antibiotic effect.
• Fluoroquinolones chelate divalent and trivalent cations (Ca2+, Mg2+, and Fe2+).
109
Crisp_Sec04_096-110.indd 109 14/07/14 10:54 AM

• Damage to growing cartilage and cause reversible arthropathy.
• May be used in children in some cases (treatment of pseudomonal infections in patients with
cystic fibrosis).
• Tendonitis in adults and risk of tendon rupture.
• Contraindicated in pregnancy.
(Continued)
109
Crisp_Sec04_096-110.indd 110 14/07/14 10:54 AM

SECTION 4

Miscellaneous Antimicrobial Agents
Metronidazole
Linezolid
Mechanism of Action
• Metronidazole—an antiprotozoal drug with antibacterial action against anaerobes
(Bacteroides and Clostridium species). Drug of choice for Clostridium difficile colitis.
• Metronidazole is taken up by anaerobic cells, reduced by ferredoxin to form metabolic
products that are taken up into the bacterial DNA to form unstable molecules.
• Linezolid is effective against gram-positive bacteria, and treats VRSA, VRE, drug-resistant
Streptococcus pneumoniae, and vancomycin-resistant E faecium infections.
• Linezolid binds to the 23S ribosomal RNA on the 50S subunit to prevent formation of the
ribosome complex that initiates protein synthesis.
110
Crisp_Sec04_096-110.indd 110 14/07/14 10:54 AM

• Linezolid can induce bone marrow suppression (platelets), and peripheral and optic
neuropathy.
• Metronidazole causes a metallic taste in the mouth, dark, red-brown urine, a disulfiram
reaction with ETOH, and Stevens–Johnson syndrome.
110
Crisp_Sec04_096-110.indd 111 14/07/14 10:54 AM

SECTION 5
Pharmacokinetic and Pharmacodynamic Principles
Routes of Cytochrome CYP- CYP- CYP- Drugs Causing a Properties of Review of

Administration P-450 Inducer Inducer Inhibitor Disulfiram-like Charged (Ionized) Logs and
Inducers and Case #1 Case #2 Case Reaction and Uncharged Antilogs
Inhibitors (Unionized)
Drugs
(Continued)
111
Crisp_Sec05_111-128.indd 111 10/07/14 1:05 PM

Pharmacokinetic and Pharmacodynamic Principles (Cont'd.)
Henderson- How do Antibiotics Phase I and Therapeutic High-yield

Hasselbalch and Oral Phase II Index Pharmacological
Equation Contraceptive Metabolism Equations for the
Drugs Interact? USMLE
111
Crisp_Sec05_111-128.indd 112 10/07/14 1:05 PM

SECTION 5
Routes of Administration
Oral (PO)
• Most common route
• First-pass Metabolism—drugs absorbed from the gut may complex with food or be
metabolized by enzymes in the liver before reaching the systemic circulation (Figure 25).
This ↓’s the bioavailability of the drug (bioavailability is the fraction of unchanged drug
reaching the systemic circulation).
Intravenous (IV)
• Drug introduced directly into the circulation (100% bioavailable)
• Can be dangerous; once injected, drug cannot be recalled from the bloodstream
• Potential for the introduction of infection from infected needle
112
Crisp_Sec05_111-128.indd 112 10/07/14 1:05 PM

Sublingual
• Fast-acting route that avoids first-pass metabolism
Inhalational Route
• Fastest route of absorption for aerosolized or nebulized drugs
Intrathecal Route
• Drug introduced in subarachnoid space
• Potential for the introduction of infection
112
Crisp_Sec05_111-128.indd 113 10/07/14 1:05 PM

SECTION 5
Cytochrome P-450 Inducers and Inhibitors

P-450 Inhibitors
• Antiulcer medication: Cimetidine and omeprazole
• Antibiotics: Macrolides, chloramphenicol, erythromycin
• Antifungals: Ketoconazole and itraconazole
• Isoniazid (INH)
• Acute ETOH
• Grapefruit juice
• Ritonavir
• Selegiline
• Clopidogrel
113
Crisp_Sec05_111-128.indd 113 10/07/14 1:05 PM

P-450 Inducers
• Anticonvulsants: Phenytoin, carbamazepine, barbiturates (phenobarbital)
• Chronic ETOH
• Glucocorticoids
• Rifampin
• Atorvastatin
• Cigarette smoking
113
Crisp_Sec05_111-128.indd 114 10/07/14 1:05 PM

SECTION 5
CYP-Inducer Case #1
A 32-year-old woman is taking carbamazepine for seizure control. She and her husband have
decided not to have more children, and she comes in for a checkup and asks for birth control pills.
You recommend oral ethinyl estradiol and norethindrone. Four months later, the patient becomes
pregnant and comes back to see you. She is not happy and asks you what happened.
114
Crisp_Sec05_111-128.indd 114 10/07/14 1:05 PM

You of course realize that despite the fact that this patient is taking oral contraceptives, she is also
taking carbamazepine for seizures. Carbamazepine is a CYP-inducer and increases the metabolism
of estrogen in the patient’s birth control pills. As a result, she conceived and is now pregnant.
How might this situation have been prevented?
114
Crisp_Sec05_111-128.indd 115 10/07/14 1:05 PM

SECTION 5
CYP-Inducer Case #2
Classic P-450 Inducer Case #2
A 67-year-old male receives a kidney transplant and is administered tacrolimus to prevent
organ rejection. The patient has been taking St. John wort for 2 years to treat his depression,
but was embarrassed to admit this to his physician. When he sees his doctor for an 8-week
postoperative follow-up appointment, the physician informs him that his body is rejecting
the transplanted kidney.
115
Crisp_Sec05_111-128.indd 115 10/07/14 1:05 PM

What happened here?
St. John Wort is a CYP-inducer and induces a more rapid metabolism of tacrolimus, causing organ
rejection.
How might this situation have been prevented?
115
Crisp_Sec05_111-128.indd 116 10/07/14 1:05 PM

SECTION 5
CYP-Inhibitor Case
A 57-year-old female recently received a kidney transplant and is being maintained on
cyclosporine. She is also being treated with nitroglycerin, felodipine, and omeprazole,
respectively, for angina, hypertension, and gastroesophageal reflux (GERD). She returns to the
clinic for a postoperative follow-up appointment at 12 months and has a markedly elevated
cyclosporine plasma concentration. This raises the physician’s concern for nephrotoxicity.
116
Crisp_Sec05_111-128.indd 116 10/07/14 1:05 PM

Question: Which other drug was this patient taking that likely caused cyclosporine levels to
become toxic?
Answer: Omeprazole is a proton pump inhibitor that is being used to treat GERD in this patient.
Omeprazole is a classic CYP-inhibitor that decreased the metabolism and clearance of cyclosporine
in this case.
116
Crisp_Sec05_111-128.indd 117 10/07/14 1:05 PM

SECTION 5
Drugs Causing a Disulfiram-like Reaction

Antibiotics (Figure 26)
Metronidazole
Cephalosporins (cefoperazone, cefamandole, and cefotetan)
First-generation Sulphonylureas (Oral Hypoglycemics)
Chlorpropamide
Tolbutamide
Antifungal Agent
Griseofulvin
Symptoms of Disulfiram-like Reaction
Nausea, vomiting, abdominal pain
Throbbing headaches
Vertigo and ataxia
117
Crisp_Sec05_111-128.indd 117 10/07/14 1:05 PM

SECTION 5
Properties of Charged (Ionized) and Uncharged (Unionized) Drugs

Role of pH and pKa of Drugs
• Most drugs are weak acids (HA) or weak bases (HB+).
• Weak acids and weak bases exist as ionized or unionized forms in the body depending upon
the pH of the environment.
• Charged compounds do not readily traverse biological membranes; uncharged drugs do.
• Just as each person has a unique name, each drug has its own pKa (pH value where half the
drug is ionized and the other half is unionized). A low pKa value indicates that the drug is
acidic and will easily give up its proton to a base.
118
Crisp_Sec05_111-128.indd 118 10/07/14 1:05 PM

• Weak acids (HA) donate a proton (H+) to form anions (A–).
HA ↔ H+ + A–
• Weak bases (B) accept a proton to form cations (HB+).
B + H+ ↔ BH+
118
Crisp_Sec05_111-128.indd 119 10/07/14 1:05 PM

SECTION 5
Review of Logs and Antilogs

Before we review the uses of the Henderson–Hasselbalch equation, let us go over the properties of
logs and antilogs.
Review of Logs and Antilogs
Number Log Antilog

0.001 –3 0.001
0.01 –2 0.01
0.1 –1 0.1
1 0 1
10 1 10
100 2 100
1,000 3 1,000
10,000 4 10,000
119
Crisp_Sec05_111-128.indd 119 10/07/14 1:05 PM

SECTION 5
Henderson–Hasselbalch Equation
Henderson–Hasselbalch (H–H) Equation
The H–H equation can be used to describe the behavior of weak acids and weak bases in different
pH environments in the body, and can be written as follows for both weak acids and weak bases:
‘Protonated’
log = pka – pH
‘Unprotonated’
For a weak acid, the following equation is used:
[HA]
log = pka – pH
[A–]
120
Crisp_Sec05_111-128.indd 120 10/07/14 1:05 PM

For a weak base, the following equation is used:
[HB+]
log = pka – pH
[B]
(Continued)
120
Crisp_Sec05_111-128.indd 121 10/07/14 1:05 PM

SECTION 5
Sample Problem on the USMLE
A weak acid with a pKa of 3 has been orally administered. Using the Henderson–Hasselbalch
equation, determine how much of this drug will be absorbed from the stomach (pH = 1) into the
bloodstream.
[HA]
log = pka – pH
[A–]
[HA]
log =3–1
[A–]
[HA]
log = 2 (the antilog of 2 = 100)
[A]
[HA] 100
So, =
[A–] 1
121
Crisp_Sec05_111-128.indd 121 10/07/14 1:05 PM

This means that for every 1% of this weak acid that is charged [A–],
[HA] 100 approximately 99% of the drug is uncharged [HA]. Since the majority
=
[A–] 1 of this drug is in the uncharged form at a pH of 3, it will readily traverse
membranes and be absorbed from the stomach into the bloodstream.
(Continued)
121
Crisp_Sec05_111-128.indd 122 10/07/14 1:05 PM

SECTION 5
A new antihypertensive drug, a weak base with a pKa of 5, is being tested in Phase 1 clinical trials.
Determine if this drug will be more thorougly absorbed from
the stomach (pH = 1) or the small intestine (pH = 7).
122
Crisp_Sec05_111-128.indd 122 10/07/14 1:05 PM

Weak Base in the Stomach:
[HB+]
log = pka – pH
[B]
[HB+]
log =5–1
[B]
[HB+]
log = 4 (antilog of 4 = 10,000)
[B]
At a pH of 1 in the stomach, approximately 99.99% of the weak
[HB+] 10,000 base is charged [HB+] and 0.01% is uncharged [B]. Since the
So, =
[B] 1 majority of the drug is charged at such a low pH, it would not
be readily absorbed from the stomach into the bloodstream.
(Continued)
122
Crisp_Sec05_111-128.indd 123 10/07/14 1:05 PM

SECTION 5
With the same drug as was described in the previous case (weak base with a pKa of 5),
determine the degree of ionization and absorbancy of the antihypertensive agent in the small
intestine (pH = 7).
123
Crisp_Sec05_111-128.indd 123 10/07/14 1:05 PM

[HB+]
log =5–7
[B]
[HB+]
log = –2 (antilog of –2 is 0.01)
[B]
[HB+] 0.01 1 Here, we see that most of this weak base is

= = uncharged in the small intestine and will be
[B] 1 100
readily absorbed into the bloodstream.
123
Crisp_Sec05_111-128.indd 124 10/07/14 1:05 PM

SECTION 5
How do Antibiotics and Oral Contraceptive Drugs Interact?

• The ethinyl estradiol comprising oral contraceptives (OC) cycles through the liver where
it is conjugated and excreted through the bile back to the intestines (Figure 27).
Estradiol-beta-glucuronidase in the gut hydrolyzes the glucuronide moiety,
freeing estrogen to be reabsorbed into the circulation.
• Antibiotics reportedly destroy intestinal bacteria and interrupt enterohepatic
cycling of OCs, resulting in contraceptive failure (Figure 27). The mechanisms
underlying antibiotic-induced contraceptive failure remain speculative.
124
Crisp_Sec05_111-128.indd 124 10/07/14 1:05 PM

• Drugs that increase the enzymatic activity of P-450 (CYP inducers) also reduce the efficacy
and increase the failure rate of OCs (e.g., phenobarbital, carbamazepine, phenytoin, rifampin,
and griseofulvin).
• The American College of Obstetricians and Gynecologists recently concluded that
tetracycline, doxycycline, ampicillin, metronidazole, fluconazole, and fluoroquinolones
do not alter oral contraceptive estrogen levels in women taking combination OCs.
124
Crisp_Sec05_111-128.indd 125 10/07/14 1:05 PM

SECTION 5
Phase I and Phase II Metabolism

Most drugs undergo both Phase I and Phase II biotransformation.
Phase I metabolism includes:
OH
• Oxidation
• Hydroxylation OH
HO
• Dealkylation COOH COOH COOH
• Hydrolysis OCOCH3 OH O O
• Deamination COOH
Aspirin Salicylic acid Glucuronide
125
Crisp_Sec05_111-128.indd 125 10/07/14 1:05 PM

Phase II conjugation mechanisms (mnemonic is “GGAS”) include:
• Glucuronidation
• Glutathione
• Acetylation
• Sulfation
125
Crisp_Sec05_111-128.indd 126 10/07/14 1:05 PM

SECTION 5
Therapeutic Index
The ratio of the lethal dose and effective dose (LD50/ED50) is known as the therapeutic index
(TI). A drug with a high therapeutic index is considered safer than a drug with a low or narrow
therapeutic index. The word “TILE” can be used as a mnemonic to help you remember the
equation for the therapeutic index.
LD50
TI =
ED50
126
Crisp_Sec05_111-128.indd 126 10/07/14 1:05 PM

Drugs with narrow therapeutic indices include: Therapeutic LD50 400
= =4
• Warfarin index: ED50 100
• Theophylline
100
• Cyclosporine
Percentage of individuals responding

Hypnosis Death
• Methotrexate
• Digoxin 80
60
40
ED50 ED99
20
LD1 LD50
0
50 100 200 400 800
Dose (μg/kg)
126
Crisp_Sec05_111-128.indd 127 10/07/14 1:05 PM

SECTION 5
High-yield Pharmacological Equations for the United States Medical Licensing Examination
Volume of Distribution
Pharmacokinetics involves the use of mathematical equations to calculate important
pharmacological parameters, such as volume of distribution (Vd) half-life (t½), clearance (CL),
maintenance dose, and loading dose.
The Vd is a measure of how widely a drug distributes in the body. This is a hypothetical volume
representing a ratio of the amount of drug in the body to the amount of drug in the plasma.
127
Crisp_Sec05_111-128.indd 127 10/07/14 1:05 PM

The apparent Vd reflects a balance between the binding of a drug to tissues and the binding to
plasma proteins.
dose
Vd =
Co
Drugs with small Vd—usually tightly bound to plasma proteins and somewhat restricted to the
plasma compartment.
Drugs with a larger Vd—lipid-soluble drugs that do not stay in the plasma; hemodialysis is
ineffective at clearing drugs with a large Vd.
(Continued)
127
Crisp_Sec05_111-128.indd 128 10/07/14 1:05 PM

SECTION 5
High-yield Pharmacological Equations for the United States Medical Licensing Examination
Important Equations for the USMLE
dose
Vd = Co = drug concentration at time zero (initial concentration of drug in the plasma)
Co
0.693 × Vd
Clearance =
t½
0.693 × Vd
t½ =
CL
128
Crisp_Sec05_111-128.indd 128 10/07/14 1:05 PM

Css × CL
Maintenance dose = (Css = concentration of drug at steady state)
Bioavailability
Loading dose = Vd × Cp (Cp = concentration of drug in the plasma)
128
Crisp_Sec05_111-128.indd 129 10/07/14 1:05 PM

Figures and Tables
Location of Muscarinic, Nicotinic, and Adrenergic (α and β) Receptors
N Parasympathetic
ACh
ACh Cardiac and smooth muscle,
M gland cells, nerve terminals
Medulla
ACh
NN
ACh M
Sympathetic
Sweat glands
ACh N NE
α, β Sympathetic
Cardiac and smooth muscle,
gland cells, nerve terminals
Spinal cord ACh N

D
Sympathetic
D1 Renal vascular smooth muscle
ACh
N Adrenal Epi, NE
medulla NM
Figure 1. (Reproduced, with Somatic
permission, from Katzung BG et al Skeletal muscle
[editors]: Basic & Clinical Pharmacology,
Voluntary motor nerve
12th ed. McGraw-Hill 2012.)
129
Crisp_EM_129-158.indd 129 18/07/14 10:40 AM

iversity of Miami School of Medicine 129.171.150.66] at [02/16/16]. Copyright © McGraw-Hill Global Education Holdings, LLC. Not to be redistributed or modified in any way w
Crisp_EM_129-158.indd 130
Drugs Affecting the Cholinergic Nerve Terminal
Axon
Na+ Hemicholiniums
CHT Choline
AcCoA + Choline
ChAT
Nerve
terminal ACh H+ Vesamicol
VAT
Hetero- Presynaptic
receptor receptors
Calcium
channel ACh
ATP, P Acetylcholine
Ca2+
130
autoreceptor
VAMPs
ACh
Botulinum ATP, P
toxin
SNAPs ACh
Choline
Acetate
Postsynaptic cell
Cholinoceptors Other
receptors
Figure 2. (Reproduced, with permission, from Katzung BG et al [editors]:

18/07/14 10:40 AM
Drugs Affecting the Adrenergic Pharmacology
Axon
Na+
MAO A Tyrosine
Tyr
Tyrosine
Dopa hydroxylase Metyrosine
Nerve MAO
terminal Dopamine H+ Reserpine
VMAT
Hetero- Presynaptic
receptor receptors
Calcium
NE
channel
ATP, P
Autoreceptor
Ca2+
131
VAMPs NE,
ATP, P Cocaine,
Bretylium, NET tricyclic
guanethidine antidepressants
NE
SNAPs
Diffusion
Postsynaptic cell
Adrenoceptors Other
receptors

18/07/14 10:40 AM
Drugs for the Treatment of Glaucoma
Muscarinic Agonists (Carbachol and Pilocarpine) and AChEIs (Demecarium, Physostigmine, and Echothiophate)—treat
glaucoma by increasing the diameter of the Canal of Schlemm.
β-blockers (Timolol, Betaxolol, Carteolol)—treat glaucoma by decreasing the synthesis of aqueous humor.
Carbonic anhydrase inhibitors (Dorzolamide, Acetazolamide Brinzolamide)—Decrease aqueous secretion due to lack of HCO3–
Cornea
Canal of Schlemm Anterior
Figure 4. Structures of the anterior chamber chamber
of the eye. Tissues with significant autonomic Trabecular meshwork
Dilator (α)
functions and the associated ANS receptors are Sphincter (M)
shown in this schematic diagram. Aqueous humor Sclera
is secreted by the epithelium of the ciliary body, Iris
flows into the space in front of the iris, flows
through the trabecular meshwork, and exits via
the canal of Schlemm (arrow). Blockage of the β
adrenoceptors associated with the ciliary epithelium
Lens
causes decreased secretion of aqueous. Blood
vessels (not shown) in the sclera are also under
autonomic control and influence aqueous drainage.
(Reproduced, with permission, from Katzung BG
et al [editors]: Basic & Clinical Pharmacology, 12th ed. Ciliary epithelium (β)
McGraw-Hill 2012.) Ciliary muscle (M)
132
Crisp_EM_129-158.indd 132 18/07/14 10:40 AM

Sites of Action of Major Antihypertensive Drugs
Vasomotor center
Methyldopa
Clonidine
Guanabenz
Guanfacine
Sympathetic nerve terminals

Guanethidine
Guanadrel
Reserpine
Sympathetic ganglia
β-Receptors of heart Mecamylamine
Propranolol and
other β-blockers
133
Angiotensin α-Receptors of vessels Vascular smooth muscle

receptors of vessels Prazosin and Hydralazine Verapamil and other
Losartan and other α1-blockers Minoxidil calcium channel
other angiotensin Nitroprusside blockers
receptor blockers Diazoxide Fenoldopam
β-Receptors of juxtaglomerular
Kidney tubules cells that release renin
Thiazides, etc Propranolol and
other β-blockers
Angiotensin-
converting
enzyme Renin
Angiotensin II Angiotensin I Angiotensinogen
Aliskiren
Captopril and
other ACE inhibitors

18/07/14 10:40 AM
Schematic Site of Antihypertensive Action of Clonidine and α-Methyldopa
IC
Nucleus of the tractus solitarius
Brain- CP
stem
Inhibitory interneurons
X
XI
α-2 adrenoreceptors 1
XII
Figure 6. The antihypertensive
effects of clonidine and
α-methyldopa are mediated at α-2 Vasomotor
adrenoceptors in the brainstem center
Motor fibers 3
(1). A proposed mechanism of
hypotension involves α-2-induced
activation descending inhibitory 2 NE
Spinal
fibers (2), which decreases
cord Autonomic Sympathetic
sympathetic tone and decreases
the release of circulating NE ganglion nerve ending
and EPI in the periphery (3).
(Reproduced, with permission,
from Katzung BG et al [editors]: EPI/NE
Basic & Clinical Pharmacology,
12th ed. McGraw-Hill 2012.) Adrenal medulla
134
Crisp_EM_129-158.indd 134 18/07/14 10:40 AM

Vasodilator
drugs
Decreased
systemic
vascular
resistance
Decreased 1 Decreased Increased

renal arterial sympathetic
Figure 7. Compensatory nervous system
sodium pressure
responses to vasodilators; excretion outflow
basis for combination 2
therapy with β-blockers Increased
and diuretics. renin
1
release 2
(Reproduced, with 2
permission, from Katzung
BG et al [editors]: Basic Increased Increased Increased Decreased
Increased Increased systemic heart cardiac venous
& Clinical Pharmacology, aldosterone angiotensin II vascular rate contractility capacitance
12th ed. McGraw-Hill resistance
2012.)
1 Effect blocked by
diuretics.
Sodium retention, Increased Increased
2 Effect blocked by increased plasma arterial cardiac
β-blockers. volume pressure output
135
Crisp_EM_129-158.indd 135 18/07/14 10:40 AM

Acetylcholine,
bradykinin
Blood
Endothelial
Endoplasmic cell
reticulum
Ca2+ Arginine
CaM eNOS
Ca2+•CaM NO
Vascular
smooth
GTP
Soluble muscle
Ca2+
- guanylyl cell
- PKG cGMP cyclase
Contraction Phosphodiesterase
GMP
Figure 8. Regulation of vasodilation by endothelial-derived nitric oxide (NO). Endogenous vasodilators (e.g., ACh, bradykinin) activate
NO synthesis in the luminal endothelial cells, leading to calcium (Ca2+) efflux from the endoplasmic reticulum into the cytoplasm.
Calcium binds to calmodulin (CaM) which activates endothelial NO synthase (eNOS), resulting in NO synthesis from L-arginine.
NO diffuses into smooth muscle cells, where it activates soluble guanylyl cyclase and cyclic guanosine monophosphate (cGMP)
synthesis from guanosine triphosphate (GTP). cGMP binds and activates protein kinase G (PKG), resulting in an overall
reduction in calcium influx, and inhibition of calcium-dependent muscle contraction. (Reproduced, with permission, from
Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)
136
Crisp_EM_129-158.indd 136 18/07/14 10:40 AM

Inhibitors of Angiotensin (ACEIs and ARBs)
Angiotensinogen Kininogen
Renin Kallikrein
–
Aliskiren Increased
prostaglandin
Angiotensin I Bradykinin
synthesis
Angiotensin-converting enzyme
(kininase II)
–
Angiotensin II Inactive
ACE metabolites
inhibitors
ARBs
– –
Vasoconstriction Aldosterone Vasodilation
Figure 9. Angiotensin converting enzyme secretion
Spironolactone,
(ACE; also known as kininase II) is eplerenone
–
inhibited by ACE inhibitors (ACEIs).
ACEIs prevent the synthesis of angiotensin Increased peripheral Increased sodium Decreased peripheral
II and the release of aldosterone from vascular resistance and water retention vascular resistance
the adrenal cortex. The ARBs block the
action of Angiotensin II at A-1 receptors.
(Reproduced, with permission, from
Katzung BG et al [editors]: Basic & Clinical Increased Decreased
blood pressure blood pressure
Pharmacology, 12th ed. McGraw-Hill 2012.)
137
Crisp_EM_129-158.indd 137 18/07/14 10:40 AM

Diuretics
Proximal NaHCO3 NaCl Ca2+ Distal convoluted
NaCl
convoluted (+PTH) tubule
tubule 1
Proximal
4
straight tubule
7 7 K+
K+ H+
2 Ca2+
Collecting
Glomerulus H2O Mg2+ 7 tubule
Na+
Cortex ? 4 5 NaCl
K+ 3
(+aldosterone)
Outer medulla 2Cl–
K+
Diuretics H+
Thick
1 Acetazolamide ascending 7
2 Osmotic agents (mannitol) limb
H2O 6
Thin
3 Loop agents (e.g., furosemide) descending (+ADH)
Collecting
4 Thiazides limb 2
Figure 10. (Reproduced, duct
with permission, from 5 Aldosterone antagonists 2 H2O
Thin
Katzung BG et al 6 ADH antagonists ascending
[editors]: Basic & Clinical 7 Adenosine Loop of limb
Pharmacology, 12th ed. Inner medulla Henle
McGraw-Hill 2012.)
138
Crisp_EM_129-158.indd 138 18/07/14 10:40 AM

Table 1. Site and Mechanism of Action of the Diuretics
Diuretic Class Site of Action Mechanism of Action
Osmotic diuretics Proximal convoluted Inhibition of H2O reabsorption in kidney tubules.
Mannitol tubule
Urea
Carbonic anhydrase inhibitors Proximal convoluted Inhibition of NaHCO3 reabsorption and ↑ excretion
Acetazolamide tubule of sodium bicarbonate.
Dorzolamide
Loop diuretics Ascending limb of the Block the active Na+/K+/2Cl– co-transport system
Furosemide loop of henle in ascending limb of the Loop of Henle and prevent
Ethacrynic acid the reabsorption of Na+, K+, Cl–, Mg2+, Ca2+ etc.
Bumetanide
Thiazides Early distal Block Na+ reabsorption in the early distal tubule
Hydrochlorothiazide convoluted tubule by inhibition of the Na+/Cl– co-transporter on the
Chlorthalidone luminal membrane (↑ NaCl excretion).
Indapamide
Potassium-sparing diuretics Late distal tubule and Block Na+ reabsorption and K+ and H+ secretion in
Spironolactone cortical collecting duct the late distal tubule and collecting duct.
Amiloride These drugs promote Na+ excretion and K+
Triamterene retention.
139
Crisp_EM_129-158.indd 139 18/07/14 10:40 AM

A: SVT
B: AFL
C: AFib
140
D: VT
1 sec
E: VT-TdP
Figure 11. Electrocardiograms typical of a variety of

arrhythmias. SVT, supraventricular tachycardia; AFL, atrial
18/07/14 10:40 AM
flutter; AFib, atrial fibrillation; VT, ventricular tachycardia.

VT-TdP, ventricular tachycardia of the torsade de pointes type.
0
Phase 0
−20
Phase 3
−40
−60 Phase 4
r
ke
e ma t
−80 c
Pa urre n
c
Na+, Ca2+/ K+
−100
Slow Ca2+ current
Cardiac action potentials in slow-response fibers

Figure 12.
141
Crisp_EM_129-158.indd 141 18/07/14 10:40 AM

Overshoot (phase 1)
0 Plateau
se 0)
(phase 2
−20 )
tion (pha
Ca2+ K+
−40
Repolarization
mV
(phase 3)
Na+
Depolariza
−60 K+
−80 Resting
potential
−100 Fast Na+ current (phase 4)
Slow Ca2+ current
Cardiac action potentials in fast-response fibers

Figure 13.
142
Crisp_EM_129-158.indd 142 18/07/14 10:40 AM

Table 2. Specific Antiarrhythmic Drug Contraindications
Condition Contraindicated/Use with Caution
Heart failure Disopyramide, Flecainide
Sinus or AV node dysfunction Digoxin, Verapamil, Diltiazem, β-receptor antagonists,
Amiodarone
Wolff–Parkinson–White syndrome (risk of Digoxin, Verapamil, Diltiazem, β-blockers (any drug that
extremely rapid rate if atrial fibrillation develops) decreases AV nodal conduction)
History of myocardial infarction Flecainide, Encainide
Prolonged QT interval Quinidine, Procainamide, Disopyramide, Sotalol, Ibutilide,
Amiodarone
Cardiac transplant Adenosine
143
Crisp_EM_129-158.indd 143 18/07/14 10:40 AM

Different Conformational States of Na+ Channels During the Cardiac Action Potential
Resting Activated Inactivated
Extracellular
+ Na+
+ Na +
Na+ +
m m m m m m
+
h
h h +
40 40 40
Intracellular
Intracellular
Intracellular
0 0 0
–40 –40 –40
Threshold
–60 –60 –60
Recovery
Figure 14. A schematic representation of Na+ channels cycling through different conformational states during the cardiac
action potential. Transitions between resting, activated, and inactivated states are dependent on membrane potential and time.
The activation gate is shown as m and the inactivation gate as h. Potentials typical for each state are shown under each channel
schematic as a function of time. The dashed line indicates that part of the action potential during which most Na+ channels
are completely or partially inactivated and unavailable for reactivation. (Reproduced, with permission, from Katzung BG et al
[editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)
144
Crisp_EM_129-158.indd 144 18/07/14 10:40 AM

Compensatory Responses During Congestive Heart Failure
Cardiac output
Carotid sinus firing Renal blood flow
Sympathetic Renin
discharge release
Angiotensin II
Force
Rate
Figure 15. Compensatory responses that occur
during congestive heart failure. Sympathetic discharge Preload Afterload Remodeling
facilitates renin release, and angiotensin II ↑ NE
release by sympathetic nerve endings. (Reproduced,
Cardiac output
with permission, from Katzung BG et al [editors]: Basic
& Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)
(via compensation)
145
Crisp_EM_129-158.indd 145 18/07/14 10:40 AM

Schematic of Drugs for Congestive Heart Failure
Myofibril syncytium
Digoxin
–
Interstitium
Cell membrane
Na+/K +-ATPase NCX Cav–L Cytoplasm
ATP –
Na+ + Ca2+channel blockers
K+
Ca2+ β agonists
Trigger Ca2+
SERCA
ATP
CalS
CalS
Sarcoplasmic Ca2+ Ca2+
Ca2+ reticulum
CalS
CalS CalS
RyR ATP
146
Ca2+
Ca2+
Actin – tropomyosin- Myosin

Z troponin
Sarcomere
Figure 16. Schematic diagram of a cardiac muscle sarcomere with sites

of drug action for treating congestive heart failure.
Na+/K+-ATPase—the sodium pump, is the site of action of cardiac
glycosides.
NCX is the sodium-calcium exchanger.
Cav-L is the voltage-gated, L-type calcium channel.
SERCA (sarcoplasmic endoplasmic reticulum Ca2+-ATPase) is a
calcium transporter ATPase that pumps calcium into the sarcoplasmic
reticulum (SR).
18/07/14 10:40 AM
RyR (ryanodine RyR2 receptor) is a calcium-activated calcium channel

in the membrane of the SR that is triggered to release stored calcium.
(Reproduced, with permission, from Katzung BG et al [editors]: Basic &
Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)
Drugs for the Treatment of Congestive Heart Failure
100
80
LV stroke work (g-m/m2)

Normal range
60
Figure 17. Relation of left ventricular (LV) performance to A + Ino

filling pressure in patients with acute myocardial infarction. Depressed
40 1
The upper line indicates the range for normal, healthy
2
individuals. The heart operates at a stable point (point A)
Vaso B
at a given level of exercise. In CHF, cardiac function
is shifted down and to the right, through points 1 and 2,
finally reaching point B. A “pure” positive inotropic drug 20
(+ Ino) would move the operating point upward by increasing
cardiac stroke work. A vasodilator (Vaso) would move the
Shock
point leftward by reducing filling pressure. Effective therapy
usually results in both effects. (Modified and reproduced with 0
permission, from Swan HJC, Parmley WW: Congestive heart 0 10 20 30 40
failure. In: Sodeman WA Jr, Sodeman TM [editors]: Pathologic
Physiology. Saunders, 1979.) LV filling pressure (mm Hg)
147
Crisp_EM_129-158.indd 147 18/07/14 10:40 AM

Drugs for the Treatment of Congestive Heart Failure
Blood vessel lumen

Nitrates
Nitrites
Capillary eNOS
Arginine Nitric oxide (NO)
endothelial
cells
Ca2+
Interstitium
Guanylyl
cyclase NO
Nitrates
Nitrites
Ca2+ Nesiritide +
Sildenafil
Vascular smooth –
muscle cell GC* PDE
148
GTP cGMP GMP

MLCK*
Myosin
light chains Myosin-LC-PO4 Myosin-LC
(myosin-LC)
Actin
Contraction Relaxation
Figure 18. Mechanism of action of the Nitrovasodilators

(Nitroglycerin, Isosorbide Dinitrate)
The organic nitrates ↑ release of nitric oxide (NO), which activates
guanylyl cyclase and ↑ cGMP. Increased cGMP induces smooth muscle
relaxation by ↑ myosin phosphatase activity, inducing dephosphorylation
of myosin light chain. Relaxation of venous smooth muscle leads to
venous pooling and a ↓ in preload, which will ↓ ventricular volume
18/07/14 10:40 AM
and wall tension, reducing cardiac work and O2 demand. (Reproduced,

with permission, from Katzung BG et al [editors]: Basic & Clinical
Pharmacology, 12th ed. McGraw-Hill 2012.)
GABAA Receptor/Chloride Ionophore Complex
GABA site
Benzodiazepine site Barbiturate site
Steroid site
anesthetics
or anxiogenics
Picrotoxin site
Cl– convulsants
Figure 19. Pharmacologic binding sites on the GABAA receptor.

(Reproduced with permission from Nestler EJ et al [editors]:
Molecular Basis of Neurpharmacology, McGraw-Hill 2001.)
149
Crisp_EM_129-158.indd 149 18/07/14 10:40 AM

Table 3. Clinical Actions of the Benzodiazepines
Benzodiazepines Clinical Indications
Alprazolam Anxiety, panic, and phobias
Diazepam Anxiety, preoperative sedation, muscle relaxation, and ETOH withdrawal
Lorazepam Anxiety, status epilepticus (drug of choice, IV), preoperative sedation,
and ETOH withdrawal
Midazolam Preoperative sedation, anesthesia (intravenous)
Temazepam Sleep disorders
Oxazepam Sleep disorders and anxiety
150
Crisp_EM_129-158.indd 150 18/07/14 10:40 AM

Antipsychotic Potency
100
Chlorpromazine
Clozapine
D2 receptors (nM)
10
KD (affinity) for Molindone
Thiothixene
Fluphenazine
1 Haloperidol
0.1
1 10 100 1000 10000
Average daily clinical dose (mg)
Figure 20. The antipsychotic potency of the typical antipsychotic drugs is correlated
with affinity for D2 receptors.
151
Crisp_EM_129-158.indd 151 18/07/14 10:40 AM

Biogenic Amine Hypothesis of Depression

Serotonergic Noradrenergic
Tryptophan Tyrosine
Tryptophan Tyrosine
hydroxylase hydroxylase
Serotonin Norepinephrine
Presynaptic
axon
MAO-A
βγ
α
5-HT1B Metabolites
α βγ
α β α2
γ
5-HT1A
Serotonin
receptors SSERT NET
Adrenoceptor
152
α
βγ α
Postsynaptic
Gi βγ axon
PLC
Gs
AC
IP3, DAG cAMP
ATP
PKC PKA
Cytoplasm
CREB
Nucleus
Figure 21. The Biogenic Amine Hypothesis of Depression

Depression is associated with decreases in 5-HT and/or NE signaling in
the brain with significant alterations in downstream signal transduction
systems (protein kinases and ion channels). Most antidepressants are
believed to alter the reuptake of 5-HT, NE and/or DA, or block the
metabolism of the biogenic amines (MAO inhibitors). Long-term
18/07/14 10:40 AM
treatment with antidepressants desensitizes presynaptic receptors and

alters the postsynaptic transduction systems of the biogenic amines.
Metabolism of Dopamine
3-O-methyldopa
COMT
Tolcapone
AAAD
Levodopa Dopamine
Periphery Carbidopa
Blood-brain barrier (BBB)
CNS AAAD MAOB

Levodopa Dopamine Metabolites
Selegiline
Tolcapone COMT
3-O-methyldopa
Figure 22. (Modified and reproduced, with permission, from Brunton L et al
[editors]: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th ed.
McGraw-Hill 2011.)
153
Crisp_EM_129-158.indd 153 18/07/14 10:40 AM

Mechanism of Action of Cocaine and Amphetamine
Cocaine Amphetamine
VMAT
Amph
DA
DAT
DAT
DAT
DA DA DA
DA
Cocaine Amph
Figure 23. Mechanism of Action of Cocaine and Amphetamine: (Left) Cocaine inhibits the DA
transporter (DAT) and increases synaptic DA levels. (Right) Amphetamine acts as a substrate for
the DAT (competitively inhibits the DAT). Amphetamine enters the presynaptic neuron through the
DAT and once inside the cell, interferes with the VMAT and impedes DA (and NE) entrance into the
presynaptic storage vesicle. Dopamine (or NE) increases in the cytosol and exits the nerve terminal
via the DAT acting in the reverse (instead of exiting via normal vesicular exocitosis). Amphetamine
and cocaine ↑ synaptic levels of DA or NE. (Reproduced, with permission, from Katzung BG et al
[editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)
154
Crisp_EM_129-158.indd 154 18/07/14 10:40 AM

Overview of Antibiotic Mechanisms
Cell membrane
Folate synthesis inhibitors
inhibitors RNA polymerase • Amphotericin
• Sulfonamides inhibitors • Ketoconazole
• Trimethoprim • Rifampin • Polymyxin
Protein Ribosome
Folate
synthesis
mRNA
DNA
mRNA Protein
synthesis
Cell wall synthesis DNA gyrase Protein synthesis

inhibitors inhibitors inhibitors
• Beta-lactam antibiotics: • Fluoroquinolones • Aminoglycosides
carbapenems, • Chloramphenicol
cephalosporins, • Clindamycin
monobactams, and • Macrolides
penicillins • Mupirocin
• Other antibiotics: • Streptogramins
bacitracin, fosfomycin, • Tetracyclines
Figure 24. Overview of
Antibiotic Mechanisms. and vancomycin
155
Crisp_EM_129-158.indd 155 18/07/14 10:40 AM

First-pass Metabolism
Intravenous
administration
Systemic circulation
Oral
administration
Biotransformation Liver
Hepatic
Figure 25. With first-pass metabolism, drugs portal vein
that are orally administered can be absorbed from
the GI tract (stomach and small intestine). Some
drugs are metabolized by liver enzymes before
reaching the systemic circulation, thus decreasing Intestines
Oral drug
bioavailability (i.e., the fraction of drug reaching
the systemic circulation unchanged).
156
Crisp_EM_129-158.indd 156 18/07/14 10:40 AM

Disulfiram Reaction
Ethanol Acetaldehyde Acetate

Disulfiram
(–)
Alcohol Aldehyde
Figure 26. Disulfiram and other drugs (cephalosporins, metronidazole and

the sulfonylurea hypoglycemics) inhibit the action of aldehyde dehydrogenase.
When these drugs are administered with ethanol, acetaldehyde builds up in
the blood, causing a disulfiram reaction (nausea/vomiting, headache) within
10-30 minutes after alcohol is ingested.
157
Crisp_EM_129-158.indd 157 18/07/14 10:40 AM

Interaction of Antibiotics with Oral Contraceptives
Excretion via bile

Liver
Intestines
Estrogen Estrogen
glucuronide glucuronide
Estrogen Bacterial Antibiotic

enzymes eliminates
Free estrogen can be
bacteria and
Estrogen absorbed into the
interrupts
Reabsorption bloodstream.
enterohepatic
via circulation
cycling
Figure 27. Antibiotics have been shown to interrupt the enterohepatic cycling of the estrogen in
estradiol-containing oral contraceptive agents. This action can decrease the efficacy of estrogen and
result in contraceptive failure.
158
Crisp_EM_129-158.indd 158 18/07/14 10:40 AM

USMLE Step 1 Pharma Flashcards PDF

Uploaded by

Copyright:

Available Formats

You might also like

USMLE Step 1 Pharma Flashcards PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

USMLE Step 1 Pharma Flashcards PDF

Uploaded by

Copyright:

Available Formats

ty of Miami School of Medicine 129.171.150.66] at [02/16/16]. Copyright © McGraw-Hill Global Education Holdings, LLC.

Not to be redistributed or modified in an

Crisp_FM_i-xiv.indd i 18/07/14 10:18 AM

New York / Chicago / San Francisco / Athens / London / Madrid

Crisp_FM_i-xiv.indd iii 18/07/14 10:18 AM

Crisp_FM_i-xiv.indd iv 18/07/14 10:18 AM

eBook conversion by codeMantra

Section 1 Autonomic Pharmacology 1–19

Figures and Tables 129–158

Crisp_FM_i-xiv.indd vii 18/07/14 10:18 AM

Crisp_FM_i-xiv.indd ix 18/07/14 10:18 AM

Crisp_FM_i-xiv.indd x 18/07/14 10:18 AM

Crisp_FM_i-xiv.indd xi 18/07/14 10:18 AM

Crisp_FM_i-xiv.indd xiii 18/07/14 10:18 AM

Crisp_Sec01_001-019.indd 1 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 2 17/07/14 3:02 PM

Location of Muscarinic, Nicotinic and Adrenergic (α and β) Receptors

Crisp_Sec01_001-019.indd 2 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 3 17/07/14 3:02 PM

Drugs Affecting the Cholinergic Nerve Terminal (Figure 2)

Crisp_Sec01_001-019.indd 3 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 4 17/07/14 3:02 PM

Drugs Affecting the Adrenergic Nerve Terminal (Figure 3)

Crisp_Sec01_001-019.indd 4 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 5 17/07/14 3:02 PM

Important Muscarinic Receptor Agonist Actions

Crisp_Sec01_001-019.indd 5 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 6 17/07/14 3:02 PM

Clinical Indications of Muscarinic Agonists (Figure 4)

Crisp_Sec01_001-019.indd 6 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 7 17/07/14 3:02 PM

Clinical Indications of Acetylcholinesterase Inhibitors (Figure 4)

Crisp_Sec01_001-019.indd 7 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 8 17/07/14 3:02 PM

Clinical Indications for Muscarinic Blocking Drugs (Antimuscarinics)

Crisp_Sec01_001-019.indd 8 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 9 17/07/14 3:02 PM

Adverse Drug Reactions of the Antimuscarinics

Crisp_Sec01_001-019.indd 9 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 10 17/07/14 3:02 PM

Effects of α-1 and α-2 Adrenoceptor Activation

Crisp_Sec01_001-019.indd 10 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 11 17/07/14 3:02 PM

Effects of β-1 and β-2 Adrenoceptor Activation

Crisp_Sec01_001-019.indd 11 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 12 17/07/14 3:02 PM

Signal Transduction Mechanisms for α- and β-Adrenoceptors

Crisp_Sec01_001-019.indd 12 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 13 17/07/14 3:02 PM

Clinical Uses of α-1 Adrenergic Agonists

Crisp_Sec01_001-019.indd 13 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 14 17/07/14 3:02 PM

Clinical Uses of α-2 Adrenergic Agonists

Crisp_Sec01_001-019.indd 14 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 15 17/07/14 3:02 PM

Clinical Uses of β-1 and β-2 Adrenergic Agonists

Crisp_Sec01_001-019.indd 15 17/07/14 3:02 PM

Crisp_Sec01_001-019.indd 16 17/07/14 3:02 PM