860/(6WHS
Lionel P. Raymon, PharmD, PhD
Director of Curriculum Integration
Chair of Biochemistry/Pharmacology
V 2.0
Lionel P. Raymon, PharmD, PhD
Director of Curriculum Integration
Chair of Biochemistry/Pharmacology
Steven R. Daugherty, PhD
Director, Faculty and Curriculum at Becker Professional Education
Chicago, IL
Cover Photo: I Dream Stock/SuperStock
The United States Medical Licensing Examination® (USMLE®) is a joint program of the Federation
of State Medical Boards (FSMB) and National Board of Medical Examiners® (NBME®). United States
Medical Licensing Examination, USMLE, National Board of Medical Examiners, and NBME are registered
trademarks of the National Board of Medical Examiners. The National Board of Medical Examiners does
not sponsor, endorse, or support Becker Professional Education in any manner.
© 2013 by DeVry/Becker Educational Development Corp. All rights reserved.
No part of this work may be reproduced, translated, distributed, published or transmitted without the
prior written permission of the copyright owner. Request for permission or further information should
be addressed to the Permissions Department, DeVry/Becker Educational Development Corp.
Table of Contents
Pharmacology
Unit 1
Principles of Pharmacology: Pharmacokinetics and
Pharmacodynamics of Drugs
Chapter 1 Pharmacokinetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-1
2
Routes of Administration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-2
3
Diffusion or Transport of Drug Across Membranes . . . . . . . . . . . . . . . . . . . . . 1-3
4
Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-7
5
Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-10
6
Drug Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-12
7
Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-15
8
Steady State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-20
Chapter 2 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-1
Unit 2
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-1
2
(Quantitative) Dose-Response Curves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-2
3
Population (Quantal) LDR Curves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-7
4
Types of Drug-Responsive Signaling Mechanisms . . . . . . . . . . . . . . . . . . . . . . 2-9
5
Federal Oversight of Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-12
Autonomic and Somatic Pharmacology
Chapter 3 Autonomic and Somatic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . 3-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3-1
2
Blood Pressure Control Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3-3
3
Pupillary Size and Accommodation Mechanisms . . . . . . . . . . . . . . . . . . . . . . . 3-6
Chapter 4 Cholinergic Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-1
2
Muscarinic Receptor Pharmacology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-3
3
Nicotinic Receptor Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-7
Chapter 5 Adrenergic Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-1
1
Adrenergic Synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-1
2
Adrenergic Receptor Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-2
3
Direct-Acting Adrenoceptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-4
© DeVry/Becker Educational Development Corp. All rights reserved.
iii
Table of Contents
Pharmacology
Unit 3
4
Mixed-Acting Agonists: Norepinephrine, Epinephrine, Dopamine . . . . . . . . . . . 5-6
5
Indirect-Acting Adrenergic Receptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . 5-8
6
Adrenergic Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-9
Cardiovascular Pharmacology
Chapter 6 Antiarrhythmics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-1
2
Class I Drugs: Na+ Channel Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-6
3
Class II: ǃ-Adrenergic Receptor Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-9
4
Class III: K+ Channel Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-10
5
Class IV: Ca2+ Channel Blockers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-12
6
Class V: Miscellaneous Antiarrhythmics . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-13
Chapter 7 Antihypertensives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7-1
2
Treatment of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7-3
Chapter 8 Drugs for Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8-1
2
Inotropes: Drugs That Increase Contractility . . . . . . . . . . . . . . . . . . . . . . . . . 8-3
3
Drugs Without Positive Inotropic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8-5
4
Pulmonary Hypertension and Cor Pulmonale . . . . . . . . . . . . . . . . . . . . . . . . . 8-6
Chapter 9 Treatment of Ischemic Heart Disease (IHD) . . . . . . . . . . . . . . . . . . . . . . . . 9-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9-1
2
Angina vs. Myocardial Infarction (MI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9-2
3
Individual Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9-3
Chapter 10 Antihyperlipidemics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10-1
2
Plasma Lipid Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10-1
3
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10-5
Chapter 11 Diuretics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-1
iv
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-1
2
Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-2
© DeVry/Becker Educational Development Corp. All rights reserved.
Table of Contents
Pharmacology
Unit 4
Blood Drugs: Antiplatelet, Anticoagulant, and Thrombolytic Drugs
Chapter 12 Antiplatelet Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12-1
2
Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12-2
Chapter 13 Anticoagulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13-1
2
Heparins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13-3
3
Warfarin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13-4
4
Direct Thrombin Inhibitors: DTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13-5
Chapter 14 Thrombolytics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14-1
Unit 5
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14-1
2
Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14-2
CNS Pharmacology
Chapter 15 Sedative-Hypnotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15-1
1
GABA and Its Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15-1
2
Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15-3
3
Barbiturates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15-6
4
Abuse Liability of Benzodiazepines and Barbiturates . . . . . . . . . . . . . . . . . . . 15-7
5
Other Drugs Used as Anxiolytics or Sedative-Hypnotics . . . . . . . . . . . . . . . . 15–8
Chapter 16 Antiepileptic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-1
2
Phenytoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-2
3
Carbamazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-4
4
Valproic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-5
5
Ethosuximide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-6
6
Lamotrigine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-6
7
Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-6
8
Felbamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-6
9
Antiepileptic Drugs and Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-7
10
Main Indications by Seizure Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-7
© DeVry/Becker Educational Development Corp. All rights reserved.
v
Table of Contents
Pharmacology
Chapter 17 Anesthetic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17-1
2
General Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17-1
3
Local Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17-4
4
Neuromuscular Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17-6
Chapter 18 Central Analgesics: Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-1
2
Endogenous Opioid Peptides and Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . 1-1
3
Pharmacology of Morphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18-2
4
Opioid Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18-3
5
Mixed Agonists-Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18-4
6
Opioid Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18-4
7
Opioid Drugs With Special Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18-5
8
Opioids and Opiates as Drugs of Abuse. . . . . . . . . . . . . . . . . . . . . . . . . . . . 18–5
Chapter 19 Parkinson Disease Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19-1
2
Role of Dopamine in the CNS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19-1
3
Levodopa-Carbidopa. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19-5
4
COMT Inhibitors: Tolcapone and Entacapone . . . . . . . . . . . . . . . . . . . . . . . . 19-5
5
Monoamine Oxidase Type B Inhibitors: Selegiline and Rasagiline . . . . . . . . . . 19-6
6
Dopamine Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19-6
7
Muscarinic Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19-6
8
Amantadine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19-7
Chapter 20 Antipsychotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20-1
vi
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20-1
2
Dopamine Hypothesis of Schizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . 20-1
3
Serotonin Hypothesis of Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20-2
4
Glutamate Hypothesis of Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . 20-2
5
Typical Antipsychotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20-3
© DeVry/Becker Educational Development Corp. All rights reserved.
Table of Contents
Pharmacology
Chapter 21 Antidepressant Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21-1
1
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21-1
2
Monoamine Oxidase Inhibitors (MAOIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . 21-3
3
Tricyclic Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21-4
4
Selective Serotonin Reuptake Inhibitors (SSRIs) . . . . . . . . . . . . . . . . . . . . . 21-5
5
Atypical Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21-7
6
General Considerations About Antidepressants . . . . . . . . . . . . . . . . . . . . . . 21-8
Chapter 22 Drugs for Mania and Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . 22-1
1
Bipolar Disorder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22-1
2
Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22-2
Chapter 23 CNS Stimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23-1
2
ADHD Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23-1
3
Stimulant Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23-2
Chapter 24 Marijuana and Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24-1
Unit 6
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24-1
2
Distribution and Pharmacology of CB Receptors . . . . . . . . . . . . . . . . . . . . . . 24-2
3
Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24-3
4
Drug Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24-3
5
Synthetic Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24-3
Antimicrobial Agents
Chapter 25 Antimicrobial Drugs (or Agents) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25-1
2
Resistance Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25-3
3
Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25-3
Chapter 26 Antibacterials: Cell Wall Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . 26-1
1
Classification of Antibacterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26-1
2
Cell Wall Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26-3
© DeVry/Becker Educational Development Corp. All rights reserved.
vii
Table of Contents
Pharmacology
Chapter 27 Antibacterials: Protein Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . 27-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27-1
2
Aminoglycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27-3
3
Tetracyclines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27-4
4
Tigecycline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27-5
5
Linezolid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27-5
6
Streptogramins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27-5
7
Macrolides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27-6
8
Ketolides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27-6
9
Clindamycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27-6
10
Chloramphenicol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27-7
Chapter 28 Antibactierals: Nucleic Acid Synthesis Inhibitors . . . . . . . . . . . . . . . . . . 28-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28-1
2
Folic Acid Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28-1
3
Direct Nucleic Acid Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . 28-4
Chapter 29 Miscellaneous Antimicrobial Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29-1
1
Metronidazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29-1
2
Polymyxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29-1
3
Mupirocin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29-1
Chapter 30 Antibiotic Choice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30-1
1
Drugs of Choice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30-1
Chapter 31 Antimycobacterial Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31-1
viii
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31-1
2
Treatment for Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31-1
3
Treatment of Leprosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31-4
© DeVry/Becker Educational Development Corp. All rights reserved.
Table of Contents
Pharmacology
Chapter 32 Antifungal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32-1
2
Amphotericin B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32-3
3
Azoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32-4
4
Flucytosine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32-5
5
Echinocandins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32-5
6
Treatment of Superficial Mycoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32-6
Chapter 33 Antiviral Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33-1
2
Treatment of Herpes Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33-2
3
HIV Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33-5
4
Influenza Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33-10
5
Hepatitis Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33-11
Chapter 34 Antiparasitic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34-1
Unit 7
1
Protozoal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34-1
2
Helminthic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34-3
Anticancer Drugs
Chapter 35 Overview of Anticancer Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35-1
1
Cancer in the United States. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35-1
2
Chemotherapy and the Cell Cycle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35-2
3
Common Adverse Effects of Anticancer Drugs . . . . . . . . . . . . . . . . . . . . . . . 35-3
4
Other Treatments for Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35-5
Chapter 36 Anticancer Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36-1
1
Drug Classes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36-1
2
Antimetabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36-2
3
Alkylating Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36-3
4
Plant Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36-5
5
Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36-6
6
Hormonal Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36-7
7
Targeted Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36-9
8
Miscellaneous Anticancer Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36-12
© DeVry/Becker Educational Development Corp. All rights reserved.
ix
Table of Contents
Pharmacology
Unit 8
Endocrine Drugs
Chapter 37 Overview of the Endocrine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37-1
1
The Endocrine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37-1
2
Endocrine Hormones and Associated Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 37-3
Chapter 38 Sex Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38-1
1
Androgens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38-1
2
Estrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38-4
3
Progestins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38-6
Chapter 39 Adrenalcortical Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39-1
2
Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39-2
3
Mineralocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39-6
Chapter 40 Diabetes Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40-1
2
Classification and Pathology of Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . 40-1
3
Diabetes Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40-4
4
Monitoring Diabetic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40-4
5
Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40-5
6
Diabetes Type 2 Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40-7
Chapter 41 Thyroid Disorder Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41-1
2
Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41-2
3
Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41-3
Chapter 42 Drugs Affecting Calcium and Bone Structure. . . . . . . . . . . . . . . . . . . . . . 42-1
x
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42-1
2
Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42-1
© DeVry/Becker Educational Development Corp. All rights reserved.
Table of Contents
Pharmacology
Unit 9
Pharmacology of Immune and Inflammatory Disorders
Chapter 43 Eicosanoids, NSAIDs, and Acetaminophen . . . . . . . . . . . . . . . . . . . . . . . 43-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43-1
2
Eicosanoid Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43-2
3
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) . . . . . . . . . . . . . . . . . . . . . 43-4
4
Selective COX-2 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43-6
5
Acetaminophen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43-6
Chapter 44 Histamines and H1 Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44-1
2
Histamine Pharmacology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44-1
3
H1 Receptor Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44-3
Chapter 45 Therapies for Gastroesophageal Reflux and Peptic Ulcer Disease . . . . . 45-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45-1
2
H2 Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45-2
3
Proton Pump Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45-3
4
Antacids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45-3
5
Cytoprotectants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45-4
6
Helicobacter Pylori Eradication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45-4
Chapter 46 Serotonin Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46-1
2
Serotonin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46-2
3
Carcinoid Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46-3
4
Migraine Headaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46-3
Chapter 47 Asthma and COPD Treatments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47-1
2
Asthma Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47-2
© DeVry/Becker Educational Development Corp. All rights reserved.
xi
Table of Contents
Pharmacology
Chapter 48 Therapies for Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48-1
2
Therapies for Acute Gout Attacks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48-1
3
Prophylaxis of Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48-2
Chapter 49 Disease-Modifying Antirheumatic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 49-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49-1
2
Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49-1
Chapter 50 Immunosuppressants (Anti-rejection Drugs) . . . . . . . . . . . . . . . . . . . . . 50-1
1
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50-1
2
Cyclosporine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50-1
3
Tacrolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50-1
4
Sirolimus (Rapamycin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50-2
5
Mycophenolate Mofetil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50-2
Appendix 1
xii
Toxicology
© DeVry/Becker Educational Development Corp. All rights reserved.
Table of Contents
Pharmacology
Unit 1
Figures
Principles of Pharmacology: Pharmacokinetics and
Pharmacodynamics of Drugs
Chapter 1 Pharmacokinetics
Figure 1–1.0 . . . General Principles of Pharmacokinetics . . . . . . . . . . . . . . . . . . . 1-1
Figure 1–2.0 . . . Oral Route of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . 1-2
Figure 1–3.3A . . Degree of Ionization and Clearance vs. pH Deviation From pKa . . 1-4
Figure 1–3.3B . . Approach to pH/pK Problems. . . . . . . . . . . . . . . . . . . . . . . . . . 1-5
Figure 1–3.4 . . . Renal Clearance of a Drug. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-6
Figure 1–4.1 . . . Plot of Plasma Concentration vs. Time . . . . . . . . . . . . . . . . . . . 1-7
Figure 1–4.2 . . . Comparison of Plasma Level Curves Following IV
vs. Extravascular Administration . . . . . . . . . . . . . . . . . . . . . . . 1-8
Figure 1–4.3 . . . Formulations That Are Not Bioequivalent . . . . . . . . . . . . . . . . . 1-9
Figure 1–5.4 . . . Redistribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-11
Figure 1–6.0A . . Biotransformation of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . 1-12
Figure 1–6.0B . . Two Phases of Drug Metabolism of Acetyl Salicylic Acid . . . . . . 1-12
Figure 1–7.1 . . . Estimation of Concentration at Time Zero (C0). . . . . . . . . . . . . 1-15
Figure 1–7.2 . . . Plots of Zero-Order Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . 1-16
Figure 1–7.3 . . . Plots of First-Order Kinetics. . . . . . . . . . . . . . . . . . . . . . . . . . 1-17
Figure 1–7.4 . . . Plasma Decay Curve—First-Order Elimination . . . . . . . . . . . . . 1-18
Figure 1–7.5 . . . Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-18
Figure 1–8.1A . . Plasma Levels Following IV Bolus Administration
at Intervals Equal to Drug Half-Life . . . . . . . . . . . . . . . . . . . . 1-20
Figure 1–8.1B . . Rate of Infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-20
Figure 1–8.2 . . . Steady-State Concentration . . . . . . . . . . . . . . . . . . . . . . . . . 1-21
Unit 2
Autonomic and Somatic Pharmacology
Chapter 2 Pharmacodynamics
Figure 2–1.0 . . . Drug Effects on Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-1
Figure 2–2.0A . . Full Agonist, Partial Agonist, and Antagonist . . . . . . . . . . . . . . . 2-2
Figure 2–2.0B . . Potency and Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-2
Figure 2–2.0C . . Comparison of LDR Curves for Two Agonists Acting on
the Same Receptor and on Different Receptors . . . . . . . . . . . . . 2-3
Figure 2–2.0D . . Efficacy and Potency of Full and Partial Agonist . . . . . . . . . . . . . 2-3
© DeVry/Becker Educational Development Corp. All rights reserved.
xiii
Table of Contents
Pharmacology
Figures
Figure 2–2.1 . . . Duality of Partial Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-4
Figure 2–2.2A . . Activators and Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-4
Figure 2–2.2B . . LDR Curves of Antagonists and Potentiators . . . . . . . . . . . . . . . 2-5
Figure 2–2.2C . . LDR Curves Using Norepinephrine (NE) and % of
Vasoconstriction Through D1 Receptor Stimulation . . . . . . . . . . . 2-6
Figure 2–3.0A . . Dose-Response Plots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-7
Figure 2–3.0B . . Nortriptyline Dose-Response . . . . . . . . . . . . . . . . . . . . . . . . . . 2-8
Figure 2–5.1 . . . Drug Testing and Development . . . . . . . . . . . . . . . . . . . . . . . 2-13
Figure 2–5.2 . . . Classification of Controlled Substances . . . . . . . . . . . . . . . . . . 2-14
Chapter 3 Autonomic and Somatic Nervous System
Figure 3–1.1 . . . Efferent Pathways of Autonomic and Somatic Nervous System . . 3-2
Figure 3–2.1A . . Nervous Reflexes in the Control of Blood Pressure . . . . . . . . . . . 3-3
Figure 3–2.1B . . Baroreceptor Reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3-3
Figure 3–2.4 . . . Blood Pressure/Heart Rate Tracings . . . . . . . . . . . . . . . . . . . . . 3-5
Figure 3–3.0A . . ANS Modulation of Pupil Size . . . . . . . . . . . . . . . . . . . . . . . . . . 3-6
Figure 3–3.0B . . PANS Modulation of Accommodation . . . . . . . . . . . . . . . . . . . . 3-6
Chapter 4 Cholinergic Pharmacology
Figure 4–1.0 . . . Cholinergic Synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-1
Figure 4–2.3 . . . Effects of Organophosphate on AChE . . . . . . . . . . . . . . . . . . . . 4-5
Figure 4–3.2 . . . Algorithm: Reflex Control of Heart Rate . . . . . . . . . . . . . . . . . . 4-8
Chapter 5 Adrenergic Pharmacology
Figure 5–1.0A . . Adrenergic Neuroeffector Junction . . . . . . . . . . . . . . . . . . . . . . 5-1
Figure 5–1.0B . . Main Metabolites of Catecholamines . . . . . . . . . . . . . . . . . . . . . 5-2
Figure 5–3.1 . . . Effect of D1 Stimulation on Heart Rate and Blood Pressure . . . . . 5-4
Figure 5–3.3 . . . Effect on Nonselective ǃ Agonists on
Heart Rate and Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . 5-5
Figure 5–4.1 . . . Effect of Norepinephrine on Heart Rate and Blood Pressure. . . . . 5-6
Figure 5–4.2A . . Effect of Low-Dose Epinephrine on
Heart Rate and Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . 5-7
Figure 5–4.2B . . Effect of Medium-Dose Epinephrine on
Heart Rate and Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . 5-7
Figure 5–4.2C . . Effect of High-Dose Epinephrine Is Similar to Norepinephrine . . . 5-7
xiv
© DeVry/Becker Educational Development Corp. All rights reserved.
Table of Contents
Pharmacology
Unit 3
Figures
Cardiovascular Pharmacology
Chapter 6 Antiarrhythmics
Figure 6–1.2A . . Action Potential in Fast Response Fibers
(Ventricular, Atrial, Muscle, and His-Purkinje Fibers) . . . . . . . . . 6-2
Figure 6–1.2B . Action Potential in Slow Response Fibers
(SA and AV Nodal Cells) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-3
Figure 6–1.2C . . Autonomic Effects on the SA Node Action Potential . . . . . . . . . . 6-4
Figure 6–1.2D . . Refractoriness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-5
Figure 6–1.2E . . States of Voltage-Dependent Ion Channels . . . . . . . . . . . . . . . . 6-5
Figure 6–2.0A . . State-Dependent Block of Class I Drug . . . . . . . . . . . . . . . . . . . 6-6
Figure 6–2.0B . . Class I Antiarrhythmic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-6
Figure 6–2.1 . . . Torsade de Pointes EKG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-7
Figure 6–3.0 . . . Effects of Class II Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-9
Figure 6–4.1A . . Amiodarone-Induced Skin Changes . . . . . . . . . . . . . . . . . . . . 6-10
Figure 6–4.1B . . Chest X-Ray Showing Pulmonary Fibrosis . . . . . . . . . . . . . . . . 6-11
Figure 6–4.3 . . . Effects of Class III Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-11
Figure 6–5.0 . . . Effects of Class IV Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-12
Chapter 7 Antihypertensives
Figure 7–1.0 . . . Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7-1
Figure 7–2.3A . . Sympatholytic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7-5
Figure 7–2.3B . . Direct Acting Vasodilators . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7-9
Figure 7–2.3C . . Drugs Acting on the Renin-Angiotensin-Aldosterone System . . . 7-11
Figure 7–2.3D . . Antihypertensive Drug Summary and Sites of Action . . . . . . . . 7-13
Chapter 8 Drugs for Heart Failure
Figure 8–1.0 . . . Pathophysiology of Heart Failure and Therapeutic Sites of Action . . 8-1
Figure 8–2.0 . . . Mechanism of Action of Inotropes . . . . . . . . . . . . . . . . . . . . . . 8-3
Chapter 9 Treatment of Ischemic Heart Disease (IHD)
Figure 9–2.0 . . . Progression and Management of Angina and MI. . . . . . . . . . . . . 9-2
Chapter 10 Antihyperlipidemics
Figure 10–2.0 . . Atherosclerosis and Thrombosis. . . . . . . . . . . . . . . . . . . . . . . 10-1
Figure 10–2.1A . Lipid Deposits on Artery Walls . . . . . . . . . . . . . . . . . . . . . . . . 10-2
© DeVry/Becker Educational Development Corp. All rights reserved.
xv
Table of Contents
Pharmacology
Figures
Figure 10–2.1B . Atheroembolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10-2
Figure 10–2.3 . . Manifestations of Hyperlipidemia . . . . . . . . . . . . . . . . . . . . . . 10-3
Figure 10–3.2A . Site of Action of Antihyperlipidemics . . . . . . . . . . . . . . . . . . . 10-5
Figure 10–3.2B . Action of Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10-6
Figure 10–3.2C . Obesity Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10-10
Chapter 11 Diuretics
Figure 11–1.0 . . Diuretic Therapies and Sites of Action . . . . . . . . . . . . . . . . . . 11-1
Figure 11–2.0 . . Therapeutic Targets in the Renal Transport System . . . . . . . . . 11-2
Figure 11–2.2A . Action of Carbonic Anhydrase Inhibitors on
Proximal Tubule Transport. . . . . . . . . . . . . . . . . . . . . . . . . . . 11-3
Figure 11–2.2B . Action of Acetazolamide in Acute Mountain Sickness . . . . . . . . 11-4
Figure 11–2.3A . Action of Loop Diuretics on Proximal Tubule Transport . . . . . . . 11-5
Figure 11–2.3B . Loop Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-5
Figure 11–2.4A . Action of Thiazides on Proximal Tubule Transport . . . . . . . . . . . 11-6
Figure 11–2.4B . Thiazides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-7
Figure 11–2.5A . Action of Potassium-Sparing Diuretics on
Proximal Tubule Transport. . . . . . . . . . . . . . . . . . . . . . . . . . . 11-8
Figure 11–2.5B . Potassium-Sparing Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . 11-9
Figure 11–2.5C . Diuretics and Urinary Electrolytes Algorithm . . . . . . . . . . . . . . 11-9
Unit 4
Blood Drugs: Antiplatelet, Anticoagulant, and Thrombolytic Drugs
Chapter 12 Antiplatelet Drugs
Figure 12–1.0 . . Primary Hemostasis and Site of Action of Antiplatelet Drugs . . . 12-1
Chapter 13 Anticoagulants
Figure 13–1.0 . . The Clotting Cascade and Site of Action of Anticoagulants . . . . 13-1
Figure 13–3.2 . . Transient Protein C Deficiency and Hypercoagulability . . . . . . . 13-4
Chapter 14 Thrombolytics
Figure 14–1.0 . . Pulmonary Embolus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14-1
Figure 14–2.3 . . Site of Action of Blood Drugs. . . . . . . . . . . . . . . . . . . . . . . . . 14-3
xvi
© DeVry/Becker Educational Development Corp. All rights reserved.
Table of Contents
Pharmacology
Unit 5
Figures
CNS Pharmacology
Chapter 15 Sedative-Hypnotic Drugs
Figure 15–1.0A . Metabolic Pathway for GABA . . . . . . . . . . . . . . . . . . . . . . . . . 15-1
Figure 15–1.0B . GABAA Receptor Structure. . . . . . . . . . . . . . . . . . . . . . . . . . . 15-2
Figure 15–2.1 . . Action of Benzodiazepines on GABAA Receptor . . . . . . . . . . . . . 15-3
Figure 15–3.1 . . Action of Barbiturates on GABAA Receptor . . . . . . . . . . . . . . . . 15-6
Chapter 16 Antiepileptic Drugs
Figure 16–1.0 . . Epileptic Seizures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16-1
Figure 16–2.2 . . Effect of Zero-Order Elimination Kinetics of Phenytoin on
Its Plasma Concentration as a Function of Dose. . . . . . . . . . . . 16-2
Figure 16–2.3 . . Teeth and Gums After Long-Term Phenytoin Therapy . . . . . . . . 16-3
Chapter 17 Anesthetic Drugs
Figure 17–2.1 . . Stages of General Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . 17-1
Figure 17–3.0 . . Local Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17-4
Figure 17–4.3 . . TOF Pattern Showing "Fade" . . . . . . . . . . . . . . . . . . . . . . . . . 17-7
Chapter 18 Central Analgesics: Opioids
Figure 18–2.0 . . Opioid Receptor Location and Function . . . . . . . . . . . . . . . . . . 17-1
Chapter 19 Parkinson Disease Drugs
Figure 19–2.1A . Nigrostriatal Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19-2
Figure 19–2.1B . Parkinson Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19-3
Figure 19–2.2 . . Mesolimbic and Mesocortical Pathways . . . . . . . . . . . . . . . . . . 19-4
Figure 19–8.0 . . Site/Mechanism of Action of Combination Therapy
for Parkinson Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19-7
Chapter 20 Antipsychotic Drugs
Figure 20–5.2 . . Extrapyramidal Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . 20-3
Unit 6
Antimicrobial Agents
Chapter 25 Antimicrobial Drugs (or Agents)
Figure 25–1.0A . Medically Important Bacteria. . . . . . . . . . . . . . . . . . . . . . . . . 25-1
Figure 25–1.0B . Bacteriostatic and Bactericidal Drug Effects. . . . . . . . . . . . . . . 25-2
© DeVry/Becker Educational Development Corp. All rights reserved.
xvii
Table of Contents
Pharmacology
Figures
Chapter 26 Antibacterials: Cell Wall Synthesis Inhibitors
Figure 26–1.0 . . Antibacterial Mechanisms of Action . . . . . . . . . . . . . . . . . . . . 26-2
Figure 26–2.0 . . Cell Wall Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . 26-3
Figure 26–2.1A . ǃ–Lactams and Cell Wall Synthesis . . . . . . . . . . . . . . . . . . . . 26-4
Figure 26–2.1B . ǃ–Lactam Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26-4
Figure 26–2.1C . Primary Syphilis Lesion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26-5
Figure 26–2.1D . Secondary Syphilis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26-5
Figure 26–2.1E . Streptococcus Pyogenes (Group A Strep) . . . . . . . . . . . . . . . . 26-6
Figure 26–2.2 . . Cephalosporin Chemical Structure . . . . . . . . . . . . . . . . . . . . . 26-7
Figure 26–2.3 . . Structure of Imipenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26-8
Figure 26–2.4 . . Structure of Aztreonam . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26-9
Chapter 27 Antibacterials: Protein Synthesis Inhibitors
Figure 27–1.0 . . Site of Action of Protein Synthesis Inhibitors . . . . . . . . . . . . . . 27-1
Chapter 28 Antibacterials: Nucleic Acid Synthesis Inhibitors
Figure 28–2.0 . . Action of Folic Acid Synthesis Inhibitors . . . . . . . . . . . . . . . . . 28-1
Figure 28–2.1 . . Pharmacokinetics of Sulfasalazine . . . . . . . . . . . . . . . . . . . . . 28-2
Chapter 31 Antimycobacterial Drugs
Figure 31–1.0 . . Antimycobacterial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . 31-1
Chapter 32 Antifungal Drugs
Figure 32–1.0 . . Site of Action of Antifungal Drugs . . . . . . . . . . . . . . . . . . . . . 32-1
Figure 32–3.0 . . Ergosterol Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32-4
Chapter 33 Antiviral Drugs
Figure 33–1.0 . . Major Sites of Action of Antiviral Drugs. . . . . . . . . . . . . . . . . . 33-1
Figure 33–3.0 . . Mechanism of Action of HIV Drugs . . . . . . . . . . . . . . . . . . . . . 33-5
Unit 7
Anticancer Drugs
Chapter 35 Overview of Anticancer Drugs
Figure 35–2.0 . . Chemotherapeutic Targets in the Cell Cycle. . . . . . . . . . . . . . . 35-2
xviii
© DeVry/Becker Educational Development Corp. All rights reserved.
Table of Contents
Pharmacology
Figures
Chapter 36 Anticancer Drugs
Figure 36–3.0 . . Bifunctional Alkylating Agents . . . . . . . . . . . . . . . . . . . . . . . . 36-3
Figure 36–7.3 . . Mitogen-Activated Protein Kinase Pathway for
Epidermal Growth Factor Receptor and Site
of Action of Targeted Anticancer Agents . . . . . . . . . . . . . . . . 36-11
Unit 8
Endocrine Drugs
Chapter 37 Overview of the Endocrine System
Figure 37–1.0 . . Hypothalamic-Anterior Pituitary Hormones . . . . . . . . . . . . . . . 37-2
Chapter 38 Sex Steroids
Figure 38–1.1A . Regulation of Male Hormone Secretion . . . . . . . . . . . . . . . . . . 38-1
Figure 38–1.1B . Aromatization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38-2
Chapter 39 Adrenalcortical Steroids
Figure 39–2.0 . . Secretion and Action of ACTH and Cortisol . . . . . . . . . . . . . . . 39-2
Figure 39–2.1 . . Steroid Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39-3
Figure 39–2.2 . . Glucocorticoids and Mineralocorticoids . . . . . . . . . . . . . . . . . . 39-4
Figure 39–2.3 . . Cushingoid Side Effects of Glucocorticoids. . . . . . . . . . . . . . . . 39-5
Chapter 40 Diabetes Therapy
Figure 40–2.0A . Type 1 and Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . 40-1
Figure 40–2.0B . Clinical Course of Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . 40-2
Figure 40–5.0 . . Kinetics of Various Insulin Preparation . . . . . . . . . . . . . . . . . . 40-5
Figure 40–6.0 . . Algorithim Based on the American Diabetes Association . . . . . . 40-7
Chapter 41 Thyroid Disorder Therapy
Figure 41–1.0 . . Thyroid Hormone Endocrine Axis . . . . . . . . . . . . . . . . . . . . . . 41-1
Figure 41–2.2 . . Myxedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41-2
Figure 41–3.0 . . Exophthalmos of Graves Disease . . . . . . . . . . . . . . . . . . . . . . 41-3
Unit 9
Pharmacology of Immune and Inflammatory Disorders
Chapter 43 Eicosanoids, NSAIDs, and Acetaminophen
Figure 43–1.0 . . Arachidonic Acid Metabolism and Site of Action of
Key Anti-inflammatory Drugs . . . . . . . . . . . . . . . . . . . . . . . . 43-1
© DeVry/Becker Educational Development Corp. All rights reserved.
xix
Table of Contents
Pharmacology
Figures
Chapter 44 Histamines and H1 Antagonists
Figure 44–2.0 . . Histamine Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44-1
Chapter 45 Therapies for Gastroesophageal Reflux and Peptic Ulcer Disease
Figure 45–1.0 . . Barrett Esophagitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45-1
Chapter 46 Serotonin Pharmacology
Figure 46–1.0 . . Serotonin Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46-1
Chapter 47 Asthma and COPD Treatments
Figure 47–1.0 . . Pathogenesis of Extrinsic Asthma. . . . . . . . . . . . . . . . . . . . . . 47-1
Figure 47–2.0 . . Asthma Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47-2
Figure 47–2.7 . . Asthma Treatment Strategies . . . . . . . . . . . . . . . . . . . . . . . . 47-5
Chapter 48 Therapies for Gout
Figure 48–1.0 . . Gouty Joints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48-1
Figure 48–3.2 . . Action of Xanthine Oxidase Inhibitors . . . . . . . . . . . . . . . . . . . 48-2
xx
© DeVry/Becker Educational Development Corp. All rights reserved.
Table of Contents
Pharmacology
Unit 1
Tables
Principles of Pharmacology: Pharmacokinetics and
Pharmacodynamics of Drugs
Chapter 1 Pharmacokinetics
Table 1–3.1 . . . . Three Basic Modes of Drug Transport Across a Membrane . . . . . . 1-3
Chapter 2 Pharmacodynamics
Table 2–4.3 . . . . G-Protein Coupled Receptors. . . . . . . . . . . . . . . . . . . . . . . . . 2-10
Table 2–5.3 . . . . FDA Classification of Drugs and Pregnancy . . . . . . . . . . . . . . . 2-15
Unit 2
Autonomic and Somatic Pharmacology
Chapter 4 Cholinergic Pharmacology
Table 4–2.0 . . . . Muscarinic Receptor Activation . . . . . . . . . . . . . . . . . . . . . . . . 4-3
Table 4–2.1 . . . . Properties of Direct-Acting Cholinomimetics . . . . . . . . . . . . . . . 4-4
Table 4–2.2 . . . . AChE Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-4
Table 4–2.4 . . . . Antimuscarinics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-6
Table 4–3.1 . . . . Nicotinic Receptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-7
Table 4–3.2A . . . Characteristics of Ganglion Blocking Agents . . . . . . . . . . . . . . . 4-7
Table 4–3.2B . . . Cholinergic Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-8
Chapter 5 Adrenergic Pharmacology
Table 5–2.1 . . . . Adrenergic Receptor Subtypes. . . . . . . . . . . . . . . . . . . . . . . . . 5-3
Table 5–2.2 . . . . Effects of Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-3
Table 5–3.1 . . . . D1 Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-4
Table 5–3.2 . . . . D2 Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-4
Table 5–3.3 . . . . ǃ Agonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-5
Table 5–6.1 . . . . D Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5–9
Table 5–6.2A . . . First- and Second-Generation Drugs. . . . . . . . . . . . . . . . . . . . 5-10
Table 5–6.2B . . . Adrenergic Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . . 5-11
Unit 3
Cardiovascular Pharmacology
Chapter 6 Antiarrhythmics
Table 6–6.3A . . . Antiarrhythmic Indication Summary . . . . . . . . . . . . . . . . . . . . 6-13
Table 6–6.3B . . . Antiarrhythmic Drug Summary . . . . . . . . . . . . . . . . . . . . . . . 6-14
© DeVry/Becker Educational Development Corp. All rights reserved.
xxi
Table of Contents
Pharmacology
Tables
Chapter 7 Antihypertensives
Table 7–1.0 . . . . Blood Pressure Classification . . . . . . . . . . . . . . . . . . . . . . . . . . 7-1
Table 7–2.2A . . . Drug Choice Based on Comorbid Condition . . . . . . . . . . . . . . . . 7-3
Table 7–2.2B . . . Drug Choice Based on Demographic Data . . . . . . . . . . . . . . . . . 7-3
Table 7–2.2C . . . Drugs Used in Hypertensive Emergencies and Urgencies . . . . . . 7-4
Table 7–2.3 . . . . Selectivity of ǃ-Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7-7
Chapter 8 Drugs for Heart Failure
Table 8–1.0A . . . Heart Failure: Symptoms and Causes . . . . . . . . . . . . . . . . . . . . 8-1
Table 8–1.0B . . . Clinical Stages of Heart Failure and Treatment Options . . . . . . . . 8-2
Table 8–4.4A . . . Heart Failure Drug Summary. . . . . . . . . . . . . . . . . . . . . . . . . . 8-7
Table 8–4.4B . . . Pulmonary Hypertension Drug Summary . . . . . . . . . . . . . . . . . 8-7
Chapter 9 Treatment of Ischemic Heart Disease (IHD)
Table 9–3.5 . . . . IHD Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9-4
Chapter 10 Antihyperlipidemics
Table 10–2.4 . . . Framingham Estimated 10-Year Risk of CHD
and Optimal LDL Levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10-4
Table 10–3.2A . . Lipid Lowering Drug Summary. . . . . . . . . . . . . . . . . . . . . . . 10-11
Table 10–3.2B . . Obesity Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . 10-11
Chapter 11 Diuretics
Table 11–2.5 . . . Diuretic Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . 11-10
Unit 4
Blood Drugs: Antiplatelet, Anticoagulant, and Thrombolytic Drugs
Chapter 12 Antiplatelet Drugs
Table 12–2.2 . . . P2Y12 Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12-2
Table 12–2.4 . . . Antiplatelet Drug Summary. . . . . . . . . . . . . . . . . . . . . . . . . . 12-3
Chapter 13 Anticoagulants
Table 13–1.0 . . . Heparins and Coumarins. . . . . . . . . . . . . . . . . . . . . . . . . . . . 13-2
Table 13–4.0A . . Direct Thrombin Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 13-5
Table 13–4.0B . . Anticoagulant Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . 13-5
xxii
© DeVry/Becker Educational Development Corp. All rights reserved.
Table of Contents
Pharmacology
Tables
Chapter 14 Thrombolytics
Table 14–2.0 . . . Thrombolytic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14-2
Table 14–2.3 . . . Thrombolytic Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . 14-3
Unit 5
CNS Pharmacology
Chapter 15 Sedative-Hypnotic Drugs
Table 15–1.0A . . GABA Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15-1
Table 15–1.0B . . GABA Receptor Subunits. . . . . . . . . . . . . . . . . . . . . . . . . . . . 15-2
Table 15–2.4A . . Pharmacokinetics of Anxiolytic Benzodiazepines . . . . . . . . . . . 15-5
Table 15–2.4B . . Pharmacokinetics of Sedative Benzodiazepines . . . . . . . . . . . . 15-5
Table 15–5.2 . . . Sedative-Hypnotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . 15-8
Chapter 16 Antiepileptic Drugs
Table 16–10.0A . Antiepileptics by Seizure Types . . . . . . . . . . . . . . . . . . . . . . . 16-7
Table 16–10.0B . Antiepileptic Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . 16-8
Chapter 17 Anesthetic Drugs
Table 7–2.2 . . . . Inhaled Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17-2
Table 17–3.1 . . . Local Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17-4
Table 17–4.4 . . . Anesthetic Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . . 17-9
Chapter 18 Central Analgesics: Opioids
Table 18–2.0 . . . Opioid Peptides and Receptors. . . . . . . . . . . . . . . . . . . . . . . . 18-1
Table 18–4.0 . . . Agonists and Relative Potencies at P Receptors . . . . . . . . . . . . 18-3
Table 18–6.0 . . . Opioid Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18-4
Table 18–8.0 . . . Opioid Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18-6
Chapter 19 Parkinson Disease Drugs
Table 19–2.4 . . . Predicted Effects of Drugs Interfering With Dopamine . . . . . . . 19-4
Table 19–8.0 . . . Parkinson Disease Drug Summary . . . . . . . . . . . . . . . . . . . . . 19-7
Chapter 20 Antipsychotic Drugs
Table 20–5.4 . . . Typical Antipsychotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20-5
Table 20–5.5A . . Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20-6
Table 20–5.5B . . Antipsychotic Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . 20-6
© DeVry/Becker Educational Development Corp. All rights reserved.
xxiii
Table of Contents
Pharmacology
Tables
Chapter 21 Antidepressant Drugs
Table 21–2.0A . . MAO Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21-3
Table 21–2.0B . . Dietary and Drug Restrictions for MAOIs. . . . . . . . . . . . . . . . . 21-3
Table 21–3.0 . . . Important Tricyclic Antidepressants . . . . . . . . . . . . . . . . . . . . 21-4
Table 21–4.2 . . . Pharmacokinetics and Drug Interactions . . . . . . . . . . . . . . . . . 21-6
Table 21–6.0 . . . Antidepressant Drug Summary . . . . . . . . . . . . . . . . . . . . . . . 21-8
Chapter 22 Drugs for Mania and Bipolar Disorder
Table 22–2.4 . . . Mood Stabilizer Drug Summary . . . . . . . . . . . . . . . . . . . . . . . 22-3
Chapter 23 CNS Stimulants
Table 23–3.2 . . . CNS Stimulants (ADHD Drug) Summary . . . . . . . . . . . . . . . . . 23-2
Chapter 24 Marijuana and Cannabinoids
Table 24–2.0A . . CB Receptor Distribution. . . . . . . . . . . . . . . . . . . . . . . . . . . . 24-2
Table 24–2.0B . . CB1 Stimulation and Effect . . . . . . . . . . . . . . . . . . . . . . . . . . 24-2
Table 24–5.0 . . . Cannabinoid Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . 24-3
Unit 6
Antimicrobial Agents
Chapter 26 Antibacterials: Cell Wall Synthesis Inhibitors
Table 26–2.7 . . Cell Wall Synthesis Inhibitors Drug Summary . . . . . . . . . . . . 26-11
Chapter 27 Antibacterials: Protein Synthesis Inhibitors
Table 27–1.0A . . Mechanism of Action of Protein Synthesis Inhibitors . . . . . . . . . 27-2
Table 27–1.0B . . Main Mechanisms of Resistance for Protein Synthesis Inhibitors . . 27-2
Table 27–10.0 . . Protein Synthesis Inhibitors Drug Summary . . . . . . . . . . . . . . 27-7
Chapter 28 Antibacterials: Nucleic Acid Synthesis Inhibitors
Table 28–2.3 . . . Folic Acid Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . 28-3
Table 28–3.3A . . Direct Nucleic Acid Synthesis Inhibitors . . . . . . . . . . . . . . . . . 28-5
Table 28–3.3B . . Nucleic Acid Synthesis Inhibitors Drug Summary . . . . . . . . . . . 28-5
Chapter 30 Antibiotic Choice
Table 30–1.0 . . . Antibiotic Choice Based on Specific Bacteria Infections . . . . . . . 30-1
Chapter 31 Antimycobacterial Drugs
Table 31–3.0 . . . Antimycobacterial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . 31-4
xxiv
© DeVry/Becker Educational Development Corp. All rights reserved.
Table of Contents
Pharmacology
Tables
Chapter 32 Antifungal Drugs
Table 32–1.0 . . . Presentation and Treatments of Major Systemic Mycoses . . . . . 32-2
Table 32–6.3 . . . Antifungal Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . . 32-6
Chapter 33 Antiviral Drugs
Table 33–1.0 . . . Mechanism of Action and Indication of Major Antiviral Drugs. . . 33-1
Table 33–3.1 . . . NRTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33-6
Table 33–3.2 . . . NNRTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33-7
Table 33–3.3 . . . Action of NNRTIs and PIs on CYP450s . . . . . . . . . . . . . . . . . . 33-8
Table 33–5.2 . . . Antiviral Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . 33-13
Chapter 34 Antiparasitic Drugs
Table 34–1.1A . . Treatment of Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34-1
Table 34–1.1B . . Prophylaxis for Travelers. . . . . . . . . . . . . . . . . . . . . . . . . . . . 34-2
Table 34–1.2 . . . Treatment for Other Protozoal Infections . . . . . . . . . . . . . . . . 34-2
Table 34–2.0 . . . Treatment for Helminthic Infections . . . . . . . . . . . . . . . . . . . . 34-3
Unit 7
Anticancer Drugs
Chapter 35 Overview of Anticancer Drugs
Table 35–1.0 . . . Most Common Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30-1
Table 35–3.1A . . Bone Marrow Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30-3
Table 35–3.1B . . Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30-3
Table 35–3.2 . . . Antiemetics Used in Cancer Chemotherapy . . . . . . . . . . . . . . . 35-4
Chapter 36 Anticancer Drugs
Table 36–2.0 . . . Antimetabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36-2
Table 36–3.0 . . . Alkylating Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36-4
Table 36–4.0 . . . Plant Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36-5
Table 36–5.0 . . . Antibiotics Used in Cancer Treatment . . . . . . . . . . . . . . . . . . . 36-6
Table 36–6.1 . . . Antiestrogen Therapy of ER/PR+ Breast Cancer . . . . . . . . . . . . 36-7
Table 36–6.2 . . . Antiandrogen Therapy of Prostate Cancer . . . . . . . . . . . . . . . . 36-8
Table 36–7.1 . . . Monoclonal Antibodies Used in Cancer Therapy . . . . . . . . . . . 36-10
Table 36–7.2 . . . Important Tyrosine Kinase Inhibitors . . . . . . . . . . . . . . . . . . 36-10
Table 36–8.4A . . Anticancer Drugs and Cell Cycle Phases . . . . . . . . . . . . . . . . 36-12
Table 36–8.4B . . Anticancer Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . 36-13
© DeVry/Becker Educational Development Corp. All rights reserved.
xxv
Table of Contents
Pharmacology
Unit 8
Tables
Endocrine Drugs
Chapter 37 Overview of the Endocrine System
Table 37–2.0 . . . Drugs Related to Hypothalamic and Pituitary Hormones . . . . . . 37-3
Chapter 38 Sex Steroids
Table 38–3.4 . . . Sex Steroid Drugs Summary . . . . . . . . . . . . . . . . . . . . . . . . . 38-7
Chapter 39 Adrenalcortical Steroids
Table 39–3.0 . . . Adrenal Steroid Drug Summary . . . . . . . . . . . . . . . . . . . . . . . 39-6
Chapter 40 Diabetes Therapy
Table 40–2.0 . . . Clinical Features of Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . 40-2
Table 40–5.0 . . . Characteristics of Insulin Preparations . . . . . . . . . . . . . . . . . . 40-5
Table 40–6.2 . . . Sulfonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40-8
Table 40–6.5 . . . Antidiabetic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40-10
Chapter 41 Thyroid Disorder Therapy
Table 41–3.2 . . . Thyroid Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41-4
Chapter 42 Drugs Affecting Calcium and Bone Structure
Table 2–2.6 . . . . Bone Mineralization Disorder Drug Summary . . . . . . . . . . . . . 42-2
Unit 9
Pharmacology of Immune and Inflammatory Disorders
Chapter 43 Eicosanoids, NSAIDs, and Acetaminophen
Table 43–2.1 . . . Leukotrienes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43-2
Table 43–2.2 . . . Important Prostaglandin Analogs Used in Medicine . . . . . . . . . 43-3
Table 43–3.1 . . . Dose-Dependent Action of Aspirin . . . . . . . . . . . . . . . . . . . . . 43-4
Table 43–5.0 . . . Eicosanoids and NSAIDs Summary. . . . . . . . . . . . . . . . . . . . . 43-7
Chapter 44 Histamines and H1 Antagonists
Table 44–2.0 . . . Four G-Protein Coupled Receptors . . . . . . . . . . . . . . . . . . . . . 44-1
Table 44–3.0 . . . Selected H1 Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44-3
Chapter 45 Therapies for Gastroesophageal Reflux and Peptic Ulcer Disease
Table 45–6.0 . . . GERD and PUD Drug Summary . . . . . . . . . . . . . . . . . . . . . . . 45-4
xxvi
© DeVry/Becker Educational Development Corp. All rights reserved.
Table of Contents
Pharmacology
Tables
Chapter 46 Serotonin Pharmacology
Table 46–2.0 . . . Serotonin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46-2
Table 46–4.2 . . . Summary of Drugs Acting on 5-HT Receptors . . . . . . . . . . . . . 46-4
Chapter 47 Asthma and COPD Treatments
Table 47–2.7 . . . Asthma Therapy Drug Summary . . . . . . . . . . . . . . . . . . . . . . 47-6
Chapter 48 Therapies for Gout
Table 48–3.4 . . . Gout Drug Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48-3
Chapter 49 Disease-Modifying Antirheumatic Drugs
Table 49–2.11 . . DMARDs Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49-3
Chapter 50 Immunosuppressants (Anti-rejection Drugs)
Table 50–5.0 . . . Immunosuppressant Drug Summary . . . . . . . . . . . . . . . . . . . 50-2
Appendix 1
Table 51–1.0 . . . Main Antidotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A-1
Table 51–2.0 . . . Main Toxic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A-2
Table 51–3.0 . . . Heavy Metals: Presentation and Chelator Treatment . . . . . . . . . A-3
Table 51–4.0 . . . Chelators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A-4
Table 51–5.0 . . . Select Herbal Preparations and Toxicities . . . . . . . . . . . . . . . . . A-5
© DeVry/Becker Educational Development Corp. All rights reserved.
xxvii
Unit 1
Pharmacokinetics
CHAPTER 1
1
Overview
Pharmacokinetics explores the process of absorption, distribution,
metabolism, and excretion of drugs.
Extravascular Administration
Intravascular Administration
No Absorption
Absorption
USMLE® Key Concepts
Whole Blood or Plasma Drug
For Step 1, you must be able to:
% Protein
ein Bound
X Identify the routes of
administration.
X Explain diffusion,
absorption, distribution,
metabolism, and
elimination.
% Free
X Solve pharmacokinetic
calculations for single and
chronic dosing with drugs.
(Active)
Distribution to Tissues
Lungs
Other
Liver
Fat
Kidney
Metabolism or Excretion
Effects
Therapeutic
Brain
Toxic
cFigure 1–1.0 General Principles of Pharmacokinetics
Chapter 1–1
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRNLQHWLFV
2
Pharmacology
Routes of Administration
Oral (PO):
Most common route of administration
Considerations:
— Bioavailability
— Stomach acid
— Enzymes
— Motility
— Portal circulation and first-pass metabolism by liver
Dose of drug
*
*Sublingual
avoids first
pass
‡ Low pH
‡ Enzymes
‡ Motility
Bioavailability: fraction of
drug in systemic circulation
Liver
First-pass
metabolism
Portal system
*
*Rectal to avoid oral
(vomiting; bitter taste; children)
cFigure 1–2.0 Oral Route of Administration
Intravenous (IV):
Clinical
Application
Introduces drug directly in circulation
No absorption
Invasive
Avoiding first-pass
metabolism:
Intramuscular (IM):
Alternative when IV access difficult
Depot injections for slow release over days to weeks
Subcutaneous (SQ)
Transdermal (skin patch)
Inhalation:
‡ Sublingual nitroglycerin
for angina
‡ IV lidocaine for
arrhythmia
Fastest route of absorption
Requires aerosolized or nebulized drug
Intrathecal: Drug introduced in subarachnoid space
Chapter 1–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRNLQHWLFV
3
Pharmacology
Diffusion or Transport of Drug
Across Membranes
Drugs may diffuse across membranes.
Drugs may be carried by proteins across membranes.
3.1 Modes of Drug Transport Across a Membrane
dTable 1–3.1 Three Basic Modes of Drug Transport Across
a Membrane
Mechanism
DirecƟon
Energy
Required
Carrier
Saturable
Connection to
Physiology
Passive
diffusion
Down gradient
No
No
No
Facilitated
diffusion
Down gradient
No
Yes
Yes
Active
transport
Against gradient
(concentration/
electrical)
Yes
Yes
Yes
For discussion of membrane
transport see Physiology,
chapter 2.
3.2 Diffusion Rate
D v¨C ×
(S.A.)
T
×
SOL
SIZE
Diffusion rate depends on:
'C = Concentration gradient of drug: Only the free and
non-ionized fraction of the drug diffuses down its concentration
gradient.
Two membrane parameters:
S.A. = Surface area: The larger the area, the greater the
diffusion rate.
T = Thickness: The thicker the membrane, the slower the
diffusion rate.
Two drug parameters:
SOL = Solubility:
— Non-ionized drug is more lipid soluble and diffuses better.
— Ionized drug is more water soluble and tends not to
diffuse well.
SIZE = Size of drug molecule:
— Smaller diffuses best.
— Plasma protein binding prevents diffusion.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 1–3
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
!
3.3 Role of pH and pK in Ionization of Drugs
Most drugs are weak acids or weak bases.
Most drugs exist in either non-ionized or ionized forms in an
equilibrium.
This depends on:
pH of the environment
pKa of the drug
For weak acids and weak bases:
Ionized = water soluble/better
excretion
pH is variable
pK belongs to a drug and is constant
pK is the pH value at which the drug is 50% ionized and 50%
non-ionized
100
0
Hepatic
Encephalopathy
20
60
40
50
50
60
40
Weak acid
R-NH
0
-2
80
R-COO
–
+
3
% Ionized
% Non-ionized
Weak base
80
20
Non-ionized = lipid soluble/
better diffusion
Clinical
Application
R-NH2
R-COOH
Important Concept
Gut bacteria metabolize
lactulose to lactic acid,
acidifying the fecal
masses and causing
ammonia (NH3) to become
ammonium (NH4+), which
is ionized and fecally
excreted.
100
-1
0
2
1
pH–pK
pH < pK
More Acidic
Neutral
pH = pK
pH > pK
More Basic
cFigure 1–3.3A Degree of Ionization and Clearance
vs. pH Deviation From pKa
Chapter 1–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
1. Compare pH and pK
pH < pK
pH > pK
Lots of H+, acidic medium
Few H+, basic medium
Drug is protonated
Drug is unprotonated
2. Is the drug . . .
. . . a weak acid?
RCOOH > RCOO–
Big % in ratio
RCOO– > RCOOH
Big % in ratio
. . . or a weak base?
RNH3+ > RNH2
Big % in ratio
RNH2 > RNH3+
Big % in ratio
3. Find the percentage
What is the unit difference between pH and pK?
If 0, pH = pK,
ratio is
If 1, ratio is
If 2, ratio is
If 3, ratio is
50%/50%
90%/10%
99%/1%
99.9%/0.1%
Example: The oral anticoagulant warfarin is a weak acid of pK 5.0.
If stomach pH is 2.0:
1. pH < pK, drug is mainly protonated
2. Weak acidic drug: R-COOH > R-COO–
Big % in ratio
3. Three units between pH and pK:
99.9% R-COOH
0.1% R-COO–
Conclusion: The drug is primarily non-ionized and well absorbed.
cFigure 1–3.3B Approach to pH/pK Problems
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 1–5
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
3.4 Ionization Increases Renal Clearance of Drugs
Only the free drug is filtered by the glomerulus.
Both ionized and non-ionized forms of a drug are filtered.
Whereas a non-ionized drug can be secreted or reabsorbed,
the ionized drug is trapped in the urine.
Acidification of urine o increases ionization of weak bases o
increases renal elimination (R-NH3+ > R-NH2).
Alkalinization of urine o increases ionization of weak acids o
increases renal elimination (R-COOí > R-COOH).
Blood
vessel
d ve
esse
se
el
Free drug
(unbound to protein)
Clinical
Application
Acidification of urine:
‡ 1+4Cl
‡ 9LWDPLQC
‡ &UDQEHUUy juice
Alkalinization of urine:
‡ 1D+&23
‡ Acetazolamide
(historically)
‡ Aspirin overdose and
management
Glomerulus
Glome
N I
Proximal tubule
Filtered
Secretion
N
N
I
I=Ionized Drug
N=Non-ionized Drug
Reabsorption
cFigure 1–3.4 Renal Clearance of a Drug
Chapter 1–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRNLQHWLFV
4
Pharmacology
Absorption
Absorption is the entry of a drug into the systemic circulation from
the site of its administration.
Intravascular administration (e.g., IV): Does not involve
absorption, and there is no loss of drug (bioavailability = 100%).
Extravascular administration: Less than 100% of a dose
may reach the systemic circulation because of variations
in bioavailability.
4.1 Plasma Level Curves
Minimum toxic
Cmax
Time to peak
concentration
Peak level
Important Concept
Elimination is usually biphasic:
1. Rapid decrease in blood
concentration due to tissue
distribution.
Distribution
Therapeutic range
Plasma Drug Concentration
!
2. Slower decrease in blood
concentration due to
metabolism and excretion.
Minimum effective
concentration
E li m
in
at
io
n
Metabolism/excretion
Lag
Tmax
Time
Duration of action
Onset of
activity
Cmax = Maximal drug level obtained from one dose.
Tmax = Time at which Cmax occurs.
Lag time = Time from administration to appearance in blood.
Onset of activity = Time from administration to blood level reaching
minimal effective concentration (MEC).
Duration of action = Time plasma concentration remains greater than MEC.
Time to peak = Time from administration to Cmax.
cFigure 1–4.1 Plot of Plasma Concentration vs. Time
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 1–7
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
4.2 Bioavailability (f)
Bioavailability is the fraction of a dose that reaches the systemic
circulation.
Intravascular doses have 100% bioavailability (f = 1).
Bioavailability is calculated as the ratio of area under the curves
(AUC) of a dose given extravascularly against a dose given by IV.
Plasma Drug Concentration
Intravascular dose
(e.g., IV bolus)
%f=
AUCPO
AUCIV
× 100
0 ” f ” 100%
Extravascular dose
(e.g., oral)
Time
cFigure 1–4.2 Comparison of Plasma Level Curves Following IV
vs. Extravascular Administration
Chapter 1–8
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
4.3 Bioequivalence
Two different formulations of the same drug are bioequivalent if:
They have the same availability.
They have the same rate of absorption.
Bioequivalent formulations can be used interchangeably
(e.g., generic versus trade name of the drug, capsule versus tablet).
Cmax and Tmax depend on the rate of absorption (see Figure 1–4.3).
A faster absorption rate increases Cmax and speeds up Tmax
(nCmax, pTmax)
A slower absorption rate decreases Cmax and delays Tmax
(pCmax, nTmax)
Bioequivalence is most important for drugs with narrow
therapeutic ranges.
Plasma Concentration
Cmax and Tmax are
dependent on the
rate of absorption
Cmax A
Formulation A:
Rapid release
Formulation
Formulatio
on B:
Slow release
rele
ease
Cmax B
Tmax A
Tmax B
cFigure 1–4.3 Formulations That Are Not Bioequivalent
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 1–9
&KDSWHU‡3KDUPDFRNLQHWLFV
5
Pharmacology
Distribution
Distribution is the movement of a drug from the systemic circulation
to organs and tissue. Factors influencing distribution include:
Drug chemistry
Plasma protein binding
Tight versus fenestrated capillaries
Blood-flow rate to organs
5.1 Plasma Protein Binding
Under normal conditions, protein-binding capacity is much larger
than is drug concentration. Consequently, the free faction is
generally constant.
Plasma proteins include:
Albumin
Globulins
Apoproteins
Glycoproteins
Drug + Protein
(Active, free)
֕
Drug-Protein Complex
(Inactive, bound)
Competition between drugs for plasma protein-binding sites
may increase the "free fraction," possibly enhancing the effects
of the drug displaced.
Example: Sulfonamides can displace bilirubin from albumin
binding sites and cause kernicterus in a neonate.
5.2 Special Barriers to Distribution
5.2.1 Placental Barrier
Small and lipid-soluble drugs can easily cross the placental barrier.
In pregnancy, there are two considerations in choosing the safest
drug:
A water-soluble alternative, if available, is the safest.
Example:
— Heparin is large and water soluble.
— Warfarin is small and lipid soluble.
— Heparin is the anticoagulant of choice in pregnancy.
If no water-soluble alternative exists, the drug with the highest
plasma protein binding is the best.
Example:
— Propylthiouracil (PTU) is > 90% bound to plasma protein.
— Methimazole is < 10% bound.
— PTU is always the DOC in hyperthyroidism of pregnancy.
5.2.2 Blood-Brain Barrier
Same principles as placental barrier.
Inflammation disrupts the blood-brain barrier.
Chapter 1–10
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
5.3 Apparent Volume of Distribution (Vd)
A theoretical volume relating the dose given with the blood/
plasma concentration of the drugs.
A concentration is a mass ("the dose, D") over a volume
("the volume of distribution"):
C0 =
D
Vd
C0 is extrapolated from the elimination curve (see topic 7,
"Elimination").
Whereas:
C0 and dose are proportional to each other
C0 and Vd are inversely related
High Vd indicates a drug with large tissue distribution (e.g.,
fluoxetine Vd = 2,500 L/70 kg).
Low Vd indicates a drug primarily found in the blood (e.g.,
furosemide Vd = 7.7 L/70 kg).
High plasma protein binding tends to lower Vd (e.g., furosemide
plasma protein bindings is 99%).
High tissue protein binding tends to increase Vd.
Competition with protein binding will alter Vd:
n Free fraction can diffuse from:
— Blood to tissue and n Vd
— Tissue to blood and p Vd
— Example: Verapamil or quinidine displaces digoxin from
tissue-binding site, p digoxin Vd
!
Important Concept
Know physiological Vd for Step 1:
‡ Total body water: 0.6L/kg
(obesity Ⱥ, lean ȸ)
‡ ECF water: 0.2 L/kg
‡ Blood: 0.08 L/kg
‡ Plasma: 0.04 L/kg
‡ Fat: 0.2 to 0.35 L/kg
5.4 Redistribution
Lipid-soluble drugs redistribute into fat tissues prior to elimination.
In the case of CNS drugs, the duration of action of an initial dose
may depend more on the redistribution rate than on the half-life.
With a second dose, the blood/fat is less; therefore, the rate
of redistribution is less and the second dose has a longer
duration of action.
Redistribution of anesthetics can result in prolonged residual
effects (e.g., propofol, thiopental).
Active
CNS
Rapid
Blood-brain
barrier
Inactive
Blood
Free
Drug (D)
Fat
Slow
Elimination
cFigure 1–5.4 Redistribution
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 1–11
&KDSWHU‡3KDUPDFRNLQHWLFV
6
Pharmacology
Drug Metabolism
The general principle of drug metabolism is the metabolic
conversion of drug molecules to more water-soluble metabolites
that are more readily excreted.
Figure 1–6.0A shows the possible outcomes of metabolism with
respect to pharmacological action.
Drug
Inactive metabolite(s) (most common)
Drug
Active metabolite(s) (most benzodiazepines, SSRIs)
Prodrug
Drug
(Isoniazid, nucleoside analogs as antiviral, or anticancer drugs)
cFigure 1–6.0A Biotransformation of Drugs
Drug metabolism is often divided into phase I and phase II:
Phase I:
— Involves modification of the drug molecule by oxidation,
reduction, and hydrolytic reactions.
— The most common enzymes involved in phase I are the
cytochrome P450 (CYP) enzymes.
Phase II:
— Involves conjugation of the drug molecule with enzymes
known as transferases.
— Examples are acetylation, glucuronidation, glutathionylation,
and sulfation.
!
Important Concept
‡ Phase II reactions usually
result in inactive, more
water-soluble metabolites.
‡ There are few cases of
drugs with active phase II
metabolites (e.g., morphine6-glucuronide).
Some drugs directly
enter phase ll
metabolism.
Drug
Phase I
Oxidation
Hydroxylation
Dealkylation
Deamination
Hydrolysis
Phase II
Derivative
Conjugation
Following phase l, the
drug may be activated,
unchanged, or most
often, inactivated.
Conjugate
Conjugated drug is
usually inactive
OH
HO OH
COOH
OCOCH3
Phase I
Aspirin
COOH
COOH
OH
Phase II
Salicylic acid
O O
COOH
Glucuronide
of salicylic acid
cFigure 1–6.0B Two Phases of Drug Metabolism of Acetyl Salicylic Acid
Chapter 1–12
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
6.1 Cytochrome P450s
Located in the endoplasmic reticulum (microsomal)
Heme-containing proteins
Require NADPH and O2
Found in the liver, gut, kidneys, skin, and lungs
Six enzymes metabolize drugs:
3A4 (50%)
2D6 (30%)
1A2 (~5%)
2C9 (~5%)
2C19 (~5%)
2E1(~5%)
2C9, 2C19, and 2D6 have genetic polymorphisms:
Poor metabolizers
Intermediate metabolizers
Extensive metabolizers
Ultrarapid metabolizers
2C19: 20% of Asians are deficient
2D6: 5%–10% of Caucasians are deficient
Codeine 2D6
o morphine: ultrarapid metabolizers die
Warfarin 2C9
o inactive: poor metabolizers bleed
6.1.1 General Inducers
nGene expression of 3A4 (and generally other P450s), resulting in
faster metabolism of other drugs.
Important examples include:
Anti-seizure drugs:
— Barbiturates
— Phenytoin
— Carbamazepine
Antibiotics: Rifampin
HIV drugs:
— Efavirenz
— Nevirapine
Chronic ethanol
St. John's wort
Glucocorticoids
The list is not complete; detailed information on drugs is covered
in the chapters that follow.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 1–13
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
6.1.2 General Inhibitors
Competitively or allosterically block metabolism of other drugs
by 3A4 (and often other P450s).
Important examples include:
Anti-ulcer drugs:
— Cimetidine
— Proton pump inhibitors (2C19)
Antibiotics:
— Macrolides, except azithromycin
— Protease inhibitors (e.g., ritonavir)
— Azoles (e.g., ketoconazole)
Grapefruit juice
SSRIs (particularly on 2D6)
Acute ethanol
Calcium channel blockers (verapamil, diltiazem)
The list is not complete; detailed information on drugs is covered
in the chapters that follow.
6.2 Glucuronidation
Inducible.
Neonates, premature infants cannot conjugate.
Rarely give active metabolites—a notable exception is morphine6-glucuronide, which is more potent than morphine itself.
6.3 N-Acetylation
Genetic polymorphism
Slow acetylators will have a buildup of drug
Associated with SLE-like syndrome:
† ANAs, † anti-histones, ٓ anti-dsDNA/anti-Sm
Malar rash, hematotoxicity, rarely other SLE-like findings
Most common with:
— Procainamide
— Hydralazine
— Isoniazid
Chapter 1–14
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRNLQHWLFV
7
Pharmacology
Elimination
Elimination is the process of removing drugs from the body (and/or
plasma) and the drugs' kinetic characteristics. The major modes of
drug elimination are:
Biotransformation to inactive metabolites.
Excretion via the kidney.
Excretion via other modes, including the bile duct, lungs, and sweat.
Elimination half-life (t½) is the time needed to eliminate 50% of a
given amount of a drug (or to decrease plasma levels of the drug
to 50% of a former level).
Elimination curves are used to estimate C0.
7.1 Estimation of Concentration at Time Zero (C0)
The volume of distribution (Vd) is calculated by the equation
Vd = dose/C0.
C0 is estimated from the place on the y-axis where the elimination
phase is extrapolated to intersect.
C0 is the hypothetical plasma concentration that would result if
a drug were injected and distributed instantaneously.
10
Drug conc. mg/L
Log Plasma Drug Concentration
100
1
0.1
0.01
Distribution
phase
Elimination phase
Time
cFigure 1–7.1 Estimation of Concentration at Time Zero (C0)
From the pharmacokinetic data in Figure 1–7.1, calculate the Vd
assuming 200 mg of the drug was injected. Extrapolating back to
time zero gives an estimate of the hypothetical drug concentration
if distribution had been achieved instantly.
Vd = Dose/C0
= 200 mg/10 mg/L
= 20 L
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 1–15
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
7.2 Zero-Order Elimination Rate or
Saturation Kinetics
A constant amount of drug is eliminated per unit time.
For example, if 100 mg is administered and 10 mg is eliminated
every hour, the time course of drug elimination is:
1 hr
1 hr
1 hr
1 hr
1 hr
1 hr
100 mg o 90 mg o 80 mg o 70 mg o 60 mg o 50 mg o 40 mg
Graphically, the elimination is linear.
The rate of elimination is independent of plasma concentration
(or amount in the body). It is constant at 10 mg/hr.
Drugs with zero-order elimination have no fixed half-life:
t½ is variable.
In the example, it takes 5 hrs to eliminate 50% of 100 mg, but
4 hrs to eliminate 50% of 80 mg.
Drugs with zero-order elimination include:
Units of Drug
Log Units of Drug
Ethanol (except low blood levels)
Phenytoin (high therapeutic dose)
Salicylates (toxic doses)
Time
Time
cFigure 1–7.2 Plots of Zero-Order Kinetics
Chapter 1–16
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
7.3 First-Order Elimination Rate or
Exponential Kinetics
A constant fraction of the drug is eliminated per unit time.
For example, if 100 mg of a drug is administered and its elimination
half-life = 1 hour, the time course of elimination is:
1 hr
1 hr
1 hr
1 hr
100 mg o 50 mg o 25 mg o 12.5 mg o6.25 mg
Graphically, the elimination is a decaying exponential.
The half-life is a constant.
The rate of elimination is directly proportional to plasma level
(or the amount present):
The higher the amount, the more rapid the elimination.
In the example above, the first hour had an elimination rate
of 50 mg/hr and the second hour had a rate of 25 mg/hr.
Units of Drug
Log Units of Drug
Most drugs follow first-order elimination rates.
Time
Time
cFigure 1–7.3 Plots of First-Order Kinetics
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 1–17
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
7.4 Graphic Analysis
Beware of linear elimination graphs.
Check the y-axis: If a log scale is used, it is a first-order
kinetic plot!
The plot in Figure 1–7.4 can be used to find the t½.
Here t½ = 6 hours.
Note that the slope k, constant of elimination, is inversely
proportional to t½:
t½ =
0.7
k
Plasma Levels (mcg/mL)
k is in "per time" unit.
100
80
60
50
40
30
Slope N
20
t½
10
2
4
6
10
8
12
Time (hr)
cFigure 1–7.4 Plasma Decay Curve—First-Order Elimination
7.5 Clearance
Conceptually better than k, the slope of elimination curve in
per time units!
100 mL of blood
x x
x
x x
x
1 min.
Kidney (renal Cl)
100 mL of blood
Liver (metabolic Cl)
Drug
x x
x
x x
x
In urine (renal Cl)
In bile (metabolic Cl)
cFigure 1–7.5 Clearance
Chapter 1–18
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
Irrespective of the drug concentration, the clearance in
Figure 1–7.5 is 100 mL/min.
Clearance (Cl) represents the volume of blood cleared of drug
per unit of time.
Cl = Vd x k
Volume
per time
Volume
per time
Using t½ = 0.7/k
Cl = Vd × 0.7/t½
t½ = Vd × 0.7/Cl
If a drug is renally cleared, only the free fraction is filtered by
the glomerulus.
Example: Assume that GFR is 120 mL/min. If a drug is 50%
bound to albumin, calculate its renal clearance assuming no
reabsorption, no secretion (Answer: 50% x GFR = 60 mL/min).
Connection to
Physiology
Renal clearance can also be
calculated as:
7.6 Summary of Single-Dose Pharmacokinetics
Clx= Ux ⁄ Px × V
1. C0 = D/Vd
Zero-Order Kinetic:
2. t½ = 0.7/k
Saturation/toxic doses
t½ variable
Rate of elimination is constant
Where:
‡ Ux is urine concentration of X
‡ Px is plasma concentration
of X
‡
‡ V is urine production rate
3. Cl = Vd × k
‡
First-Order Kinetic:
All common situations
t½ constant
Rate of elimination is variable
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 1–19
&KDSWHU‡3KDUPDFRNLQHWLFV
8
Pharmacology
Steady State
Steady state is reached when Rate in = Rate out.
8.1 Plateau Principle
The time to reach steady state is dependent only on the elimination
half-life of a drug and is independent of dose size and frequency
of administration.
Plasma Drug Concentration (mcg/mL)
Consider the example in Figure 1–8.1A: 100 units are given every t½
and t½ = 1 hour.
ss
Cmax
(peak)
200
180
t½
160
t½
t½
t½
ss
Cav
t½
140
120
100
t½
80
88/188
94/194
97/197
75/175
/
60
ss
Cmin
99/199
(trough)
(tro
100/200
100
50/150
40
20
τ
τ
0
1
2
3
4
5
6
7
Time (hr)
cFigure 1–8.1A Plasma Levels Following IV Bolus Administration
at Intervals Equal to Drug Half-Life
Although it takes > 7 t½ to reach mathematical steady state,
by convention clinical steady state is reached at 4–5 t½.
Note: A faster rate of infusion does not
change the time needed to achieve steady
state; only the steady-state concentration,
Css, changes.
Clinical
Application
Time and Steady
State
Plasma Concentration of Drug
Steady-state region
CSS
50% = 1 × half-life
90% = 3.3 × half-life
High rate of infusion
(2 times R0 mg/min)
Low rate of infusion
(R0 mg/min)
95% = 4–5 × half-life
(clinical steady state)
100% = > 7 × half-life
(mathematical steady
state)
0
Start of infusion
cFigure 1–8.1B Rate of Infusion
Chapter 1–20
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
8.2 Steady-State Concentration (Css)
Amount/Time
Rate in
ŀ k0
ŀ MD
CSS =
Amount
Volume
Volume/Time
Rate out
ŀ Cl
cFigure 1–8.2 Steady-State Concentration
Two forms of chronic dosing for rate in:
IV catheter: Rate of Infusion k0 (Rate in = k0)
Multiple discrete doses: Maintenance doses (MD) given at fixed
dosing interval W (Rate in = MD/W)
One parameter for rate out: Clearance
Css =
Rate in (amount/time)
Rate out (volume/time)
=
Amount
Volume
Css = k0/Cl for indwelling catheters
Css = (MD⁄W)/Cl for discrete maintenance doses (i.e., tablets)
Note: Adjust the dose based on bioavailability f.
A loading dose is a single dose that, once distributed, gives a
concentration value equal to Css (i.e., a concentration which is
effective).
Css =
Amount
Volume
=
Loading Dose
Vd
!
Important Concept
For Step 1 only: If the drug is
given every t½ (W = t½), and if
the Css min is also the minimum
effective concentration, the
loading dose is double the
maintenance dose.
Note: Adjust the loading dose based on bioavailability f.
Loading dose may be required for drugs with long t½ or when
efficacy starts with steady-state concentrations and the situation
requires an immediate effect.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 1–21
&KDSWHU‡3KDUPDFRNLQHWLFV
Pharmacology
Consider the following example:
A patient is admitted to the hospital for pneumonia caused by
Pseudomonas aeruginosa. The antibiotic ciprofloxacin is ordered.
The Cl and Vd of ciprofloxacin are 80 mL/min and 40 L, respectively.
If you wish to give an IV loading dose to achieve the therapeutic
plasma concentration of 4 mg/L rapidly, how much ciprofloxacin
should be given?
Loading dose = Vd × Css
= 40 L × 4 mg/L
= 160 mg
Consider the following example:
For the same Pseudomonas aeruginosa patient administered
ciprofloxacin, what maintenance dose should be administered
intravenously every six hours to obtain average steady-state plasma
concentrations of 4 mg/L?
Rate in
= Rate out at steady state
Maintenance dose = Css × Cl × W
Dosage rate
= 4 mg/L × (80 mL/min) x 6 hrs
Convert mL to L and hours to minutes
Dosage rate
= 4 mg/L × (0.08 L/min) W 6 hrs
= 0.32 mg/min
6 x 60 = 360 mins
Calculate for every six hours
= 0.32 mg/min × 360 mins
= 115 mg
8.3 Summary for Steady-State Pharmacokinetics
It takes 4–5 t½ to achieve clinical steady state.
k0
1. Css =
Cl
2. Css =
3. Css =
MD/W
Cl
Loading dose
Vd
Adjust MD and loading doses accordingly with bioavailability f.
Chapter 1–22
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 2
1
Pharmacodynamics
Overview
Pharmacodynamics is the study of how drugs act on the body,
specifically how drugs bind to receptors and their biochemical and
physiological effects. Key concepts in pharmacodynamics include:
Full agonist: A drug that produces a response when it binds
to the receptor.
Partial agonist: A drug that produces a partial response when
it binds to the receptor.
Inverse agonist: A drug that produces an opposite response to
a full or partial agonist when it binds to the receptor.
Antagonist: A drug that does not produce a response when it
binds to the receptor. The drug has an effect only by preventing
an agonist from binding to the receptor.
Affinity: Ability of a drug to bind to the receptor.
Potency: Shows relative doses of two or more agonists to produce
the same magnitude of effect (whether 50% or not).
Efficacy: A measure of how well a drug produces a response
(effectiveness).
Effect
+1
Full agonist
Partial agonist
0
USMLE® Key Concepts
For Step 1, you must be able to:
X Differentiate between full
agonists, partial agonists,
inverse agonists, and
antagonists.
X Explain the use of log
dose-response curves in
determining drug efficacy,
potency, and affinity.
X Describe the types of
drug-responsive signaling
mechanisms.
X Define the role of the FDA
and DEA.
Antagonist
Inverse partial agonist
–1
Inverse full agonist
cFigure 2–1.0 Drug Effects
on Receptors
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 2–1
&KDSWHU‡3KDUPDFRG\QDPLFV
2
Pharmacology
(Quantitative) Dose-Response Curves
Log dose-response curves (LDR) are used to determine the
parameters of efficacy, potency, and affinity.
Efficacy measures the maximal effect a drug can achieve, irrespective
of the dose. It is read on the y-axis of the LDR plot as the height of
the curve.
Full agonist
Effect (%)
100
Partial agonist
50
Antagonist
0
0.1
1
10
100
1,000 10,000
100,000
Concentration or Dose
cFigure 2–2.0A Full Agonist, Partial Agonist, and Antagonist
Potency is generally read on the x-axis of the LDR plot as the dose
or concentration required to achieve 50% of a drug's maximal
effect (ED50 or EC50).
Connection to
Biochemistry
Note the analogy with enzyme
kinetics:
Efficacy
100
‡ Efficacy is similar to Vmax
‡ ED50 or EC50 are similar to KM
Effect
A
B
C
Potency
less
more
Potency: A > B > C
Efficacy: A = B = C
0
Dose, Concentration, or Other
Measure of Exposure
cFigure 2–2.0B Potency and Efficacy
Affinity is often directly related to potency, and the LDR closest
to the y-axis is representing the drug with the highest affinity.
Chapter 2–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRG\QDPLFV
Pharmacology
USMLE tricks in analysis of LDR curves:
A
B
X
100
% Response
% Response
100
50
Y
50
Log Dose of Drug
Log Dose of Drug
cFigure 2–2.0C Comparison of LDR Curves for Two Agonists Acting
on the Same Receptor (left) and on Different Receptors (right)
If curves are not parallel, you cannot compare affinity:
When two drugs interact with the same receptor (same
pharmacologic mechanism), the LDR curves will have parallel
slopes. In Figure 2–2.0C, drugs A and B have the same
mechanism; drugs X and Y do not.
Affinity can be compared only when two drugs bind to the
same receptor. Drug A has a greater affinity than drug B.
In terms of potency, drug A has greater potency than drug B,
and X is more potent than Y.
In terms of efficacy, drugs A and B are equivalent. Drug X has
greater efficacy than drug Y.
If a partial agonist has higher affinity than a full agonist,
then beware of potency statements:
In Figure 2–2.0D, drug Y is a full agonist, and drugs X and Z
are partial agonists.
Y
% Response
100
X
Z
50
Log Dose of Drug
cFigure 2–2.0D Efficacy and Potency
of Full and Partial Agonist
Drug X is more potent than drug Z and drug Y is more potent
than drug Z.
No general comparisons can be made between drugs X and
Y in terms of potency because the former is a partial agonist
and the latter is a full agonist.
At low responses, drug X is more potent than Y, but at high
responses, the reverse is true.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 2–3
&KDSWHU‡3KDUPDFRG\QDPLFV
Pharmacology
2.1 Duality of Partial Agonists
Alone they augment responses, but with a ceiling effect as any
agonist would (solid blue curve in Figure 2–2.1).
In presence of a maximal response from a full agonist, they
behave as antagonists (broken purple curve in Figure 2–2.1),
decreasing the response until the ceiling effect is reached.
Ceiling effects of partial agonists make these drugs safer but
less effective.
Examples include pindolol, acebutolol, buprenorphine, buspirone,
and tamoxifen.
% Response
100
A dose of full agonist
+ Partial agonist
50
Partial agonist alone
Log Dose of Partial Agonist
cFigure 2–2.1 Duality of Partial Agonists
2.2 Antagonism and Potentiation
LDR curves also provide information about antagonism
and potentiation.
Drug
Receptor
Effects
A
B
A+C
promotes
Response
Agonist
inhibits
A alone
A+B
A+D
Competitive
inhibitor
promotes
Log Dose
C
Allosteric
activator
inhibits
D
Allosteric
inhibitor
cFigure 2–2.2A Activators and Inhibitors
Chapter 2–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRG\QDPLFV
Pharmacology
100
Control
% Response
Potentiation
Competitive
Antagonism
Noncompetitive
0
Log Dose of Drug
cFigure 2–2.2B LDR Curves of Antagonists and Potentiators
Pharmacologic antagonism (same receptor):
Competitive antagonists:
— Cause a parallel shift to the right in the LDR curve for agonists.
— Can be reversed by n the dose of the agonist drug.
— Appears to p the potency of the agonist.
— Are always reversibly binding to the same site as the agonist.
Noncompetitive antagonists:
— Cause a nonparallel shift to the right.
— Can be only partially reversed by the dose of the agonist.
— Appear to p the efficacy of the agonist.
— Can be irreversibly (covalently) bound to the active site.
— Can be reversibly bound to an allosteric site.
Physiologic antagonism (different receptor):
Two agonists with opposing action antagonize each other.
Example: A vasoconstrictor (D1 agonist) with a vasodilator
(E2 agonist).
Chemical antagonism:
Formation of a complex between effector drug and another
compound.
Example: Protamine binds to heparin to reverse its action.
Potentiation:
Causes a parallel shift to the left of the LDR curve.
Appears to n the potency of the agonist.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 2–5
&KDSWHU‡3KDUPDFRG\QDPLFV
Pharmacology
NE
+ MAO inhibitors
+ Reuptake blockers
+ Mobile pool releasers
NE
+ 1 antagonists
(prazosin, phentolamine)
% Vasoconstriction
NE
Potentiation
Competitive
antagonism
Noncompetitive
antagonism
NE
+ phenoxybenzamine
Log Dose NE
Figure 2–2.2C LDR Curves Using Norepinephrine (NE) and %
c
of Vasoconstriction Through D1 Receptor Stimulation
Chapter 2–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRG\QDPLFV
3
Pharmacology
Population (Quantal) LDR Curves
Plot the percentage of a population responding to a specified
drug effect versus dose or log dose.
Reveal the range of intersubject variability in the drug response.
Steep LDR curves reflect little variability; flat LDR curves indicate
great variability in patient sensitivity to the effect of the drug.
Estimate ED50, TD50, LD50:
ED50: Effective dose in the 50% of the population studied.
TD50: Toxic dose in the 50% of the population studied.
LD50: Lethal dose in 50% of the animal population or
cell culture studied.
Allows calculation of the therapeutic index (TI):
TI=
% Individuals Responding
100
TD50
ED50
LD50
or
ED50
Cumulative percent
exhibiting
therapeutic effect
Cumulative
percent
exhibiting
toxic
effects
50
Distribution
of doses
resulting in
toxic
effects
Distribution
of doses
resulting in
therapeutic
effects
1.25 2.5
5
10
20
40
80
Cumulative
percent
dead at
each dose
Distribution
of doses
resulting in
lethal
effects
160 320 640
Dose (mg)
ED50
TD50
LD50
Figure 2–3.0A Dose-Response Plots
c
From the data shown in Figure 2–3.0A, TI = 20 = 4
5
Such indices are of most value when toxicity represents an
extension of the pharmacologic actions of a drug. They do not
predict idiosyncratic reactions or drug hypersensitivity.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 2–7
&KDSWHU‡3KDUPDFRG\QDPLFV
Pharmacology
Improvement in Depression Level (%)
In clinical practice, some drugs exhibit unusual dose-response
curves. An example is the "inverted U-shaped" curve of a
nortriptyline dose versus the therapeutic response for treating
major depression (Figure 2–3.0B). In this case, higher doses of
nortriptyline are actually less effective than lower doses and a
target plasma level of approximately 100 —g/L would be optimal.
100
50
0
60
-20
120
180
Nortriptyline Plasma Level (—g/L)
cFigure 2–3.0B Nortriptyline Dose-Response
Chapter 2–8
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRG\QDPLFV
4
Pharmacology
Types of Drug-Responsive
Signaling Mechanisms
Binding of an agonist drug to its receptor activates an effector
or signaling mechanism.
Several different types of signaling mechanisms are known.
4.1 Intracellular Receptors
Lipid-soluble ligands gain access to cytoplasm.
Binding to an intracellular receptor causes translocation to
the nucleus.
Activated receptor binds regulatory DNA regions (enhancers,
silencers).
Responses are due to modulation of gene expression and
are slower in onset but longer in duration.
Examples include intracellular receptors for thyroid hormones,
steroids, vitamin D, and vitamin A.
4.2 Membrane Receptors Directly Coupled
to Ion Channels
Ion channels may be voltage-gated, ligand-gated, or ungated.
Drugs can open or block the channels.
Alteration in ionic conductance may depolarize or hyperpolarize a cell.
Examples:
Nicotinic receptor for acetylcholine (present in autonomic
nervous system ganglia, the skeletal neuromuscular junction,
and the central nervous system) is coupled to an Na+/K+
ion channel. The receptor is a target for nicotine, ganglion
blockers, and skeletal muscle relaxants.
GABAA receptor in the CNS is coupled to a chloride ion channel.
It can be modulated by anticonvulsants, benzodiazepines,
and barbiturates.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 2–9
&KDSWHU‡3KDUPDFRG\QDPLFV
Pharmacology
4.3 G-Protein Coupled Receptors (GPCR)
GPCR are common drug targets.
Sequence of signal transduction:
1. Binding to membrane receptor (7 transmembrane domains)
2. Activation of G-protein:
— Three subunits
— D has GTPase activity
— GTP activates; GDP inhibits
3. Enzyme
4. Second messengers
5. Kinases
dTable 2–4.3 G-Protein Coupled Receptors
Receptor
G-Protein
Enzyme
Second
Messengers Protein Kinases
ǃ1, ǃ2, D1,
glucagon, H2, V2,
LH, FSH, TSH, PTH
Gs
ْAdenylate
cyclase
n cAMP
PKA
D2, M2, D2, opiate,
GABAB, 5-HT1
Gi
ٓAdenylate
cyclase
p cAMP
PKA
Gq
ْPhospholipase
C
n IP3, DAG,
and Ca2+
PKC
D1, M1, M3, AT1,
H1, V1, 5-HT2
4.4 Cyclic GMP and Nitric Oxide Signaling
Nitric oxide (NO) is synthesized from arginine in endothelial
cells and diffuses into smooth muscle. Gq coupled receptor on
endothelium can activate NO synthase.
NO activates guanylyl cyclase, thus increasing cGMP in smooth
muscle.
cGMP is a second messenger in vascular smooth muscle that
facilitates dephosphorylation of myosin light chains, preventing
their interaction with actin and thus causing vasodilation.
Drugs acting via NO include nitrates (e.g., nitroglycerin and
nitroprusside). Endogenous compounds acting via NO include
bradykinin, histamine, and other inflammatory mediators.
Chapter 2–10
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRG\QDPLFV
Pharmacology
4.5 Receptors That Function as Enzymes
or Transporters
There are multiple examples of drug action that depends on
enzyme inhibition, including inhibitors of acetylcholinesterase,
angiotensin-converting enzyme, aspartate protease, carbonic
anhydrase, cyclooxygenases, dihydrofolate reductase, DNA/RNA
polymerases, monoamine oxidases, Na+/K+-ATPase, H+/K+-ATPase,
neuraminidase, and reverse transcriptase.
Examples of drug action on transporter systems include the inhibitors
of reuptake of several neurotransmitters, including dopamine, GABA,
norepinephrine, and serotonin. Many antidepressants block reuptake.
4.6 Receptors That Function as Transmembrane
Enzymes
Two broad types:
Tyrosine kinase receptors
Guanylate cyclase receptors
Ligands dimerize receptors activating the intracellular enzyme
activity of the receptor.
Tyrosine kinase is shared by most growth factor receptors and
the insulin receptor.
Inhibitors are used to treat cancer and often end in "-tinib"
(e.g., imatinib).
Guanylate cyclase is shared by the family of natriuretic peptide
receptors and increases cGMP in cells.
4.7 Receptors for Cytokines
These include the receptors for erythropoietin, somatotropin,
and interferons.
Their receptors are membrane spanning and on activation
can activate a distinctive set of cytoplasmic tyrosine kinases
(Janus kinases, or JAKs).
JAKs phosphorylate signal transducers and activators of
transcription (STAT) molecules.
STATs dimerize and then dissociate, cross the nuclear membrane,
and modulate gene transcription.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 2–11
&KDSWHU‡3KDUPDFRG\QDPLFV
5
Pharmacology
Federal Oversight of Pharmaceuticals
5.1 Drug Development and the Food and Drug
Administration (FDA)
The FDA regulates the safety and efficacy of drugs in the
United States.
The FDA has more limited oversight for nutritional supplements
and herbal remedies.
Multiple steps are involved in the development and approval of
a new drug.
5.1.1 Preclinical Trials
Laboratory experiments and animal studies.
Provide the basis for testing a potential new drug in humans.
5.1.2 Phase 1 Trials
"Is the drug safe?"
Involve healthy volunteers.
Exceptions: trials of highly toxic drugs (e.g., cancer chemotherapy
involving patients with end-stage cancer).
Phase 1 studies work out the toxicity and pharmacokinetics of
the drug.
5.1.3 Phase 2 Trials
"Does the drug work?"
Involve patients.
5.1.4 Phase 3 Trials
"How well does the drug work and what are the most common
side effects?"
Often randomized (treatment or placebo) and double-blind
(neither the physician nor the patient knows what they are getting).
Usually the largest and most expensive phase of clinical trials.
5.1.5 Phase 4 Trials
Post-marketing surveillance studies.
Not required for every drug—may be requested by the FDA to look
for suspected adverse effects.
Chapter 2–12
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRG\QDPLFV
In Vitro
Studies
Pharmacology
Animal
Testing
Clinical
Testing
Phase 1
Marketing
(Is it safe, pharmacokinetics?)
Generics
become
available
20–100
subjects
Biologic
products
Phase 2
(Does it work
in patients?)
100–200
patients
Lead
compound
Chemical
synthesis,
optimization
0
2
Years (average)
Phase 3
Efficacy,
selectivity,
mechanism
(Does it work,
double blind?)
1,000–6,000
patients
Phase 4
(Post–
marketing
surveillance)
Drug metabolism, safety assessment
4
IND
(Investigational
new drug)
8-9
NDA
(New drug
application)
20
(Patent expires
20 years after filing
of application)
cFigure 2–5.1 Drug Testing and Development
5.2 Controlled Substances and the Drug
Enforcement Agency (DEA)
Controlled substances are regulated tightly because of the
potential for abuse liability and causing harm.
The DEA oversees the use of controlled substances.
In the United States, controlled substances are in five categories.
5.2.1 Schedule I Drugs
High abuse liability.
Low or no medical utility.
Available only for highly restricted research studies.
Examples include heroin, marijuana (except in certain states),
lysergic acid diethylamide (LSD), methcathinone ("khat"),
phencyclidine (PCP), mescaline, peyote, and methaqualone.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 2–13
&KDSWHU‡3KDUPDFRG\QDPLFV
Pharmacology
5.2.2 Schedule II Drugs
High potential for abuse.
Can be prescribed under restricted conditions:
Triplicate prescriptions.
No automatic refills.
Examples: opiates, amphetamines, and some short-acting sedatives.
5.2.3 Schedule III Drugs
Lower risk than Schedule II drugs.
Examples: anabolic steroids, dronabinol, and some opiate
preparations.
5.2.4 Schedule IV Drugs
Low potential for abuse.
Can have limited physical and/or psychic dependence.
Examples: benzodiazepines.
5.2.5 Schedule V Drugs
Lowest abuse potential.
Examples: pregabalin and cough medications with low doses
of codeine.
No
medical use
Schedule
Potential
for abuse
I
HIGH
II
Medical
use
acceptable
III
IV
V
LOW
cFigure 2–5.2 Classification of Controlled Substances
Chapter 2–14
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3KDUPDFRG\QDPLFV
Pharmacology
5.3 Teratogenicity
The FDA has classified drugs into five categories: A, B, C, D, and X.
Class A has no risks, and Class X designates absolute
contraindication.
Classification is based on animal studies and, when available,
human studies.
In Class D, the benefits outweigh the risks.
dTable 2–5.3 FDA Classification of Drugs and Pregnancy
Risk
Category
Animals
Humans
A
–
–
B
+/–
–/0
C
+/0
0
D
+
+
X
+
+
– = Studies have proved absence of teratogenicity
0 = No studies available
+ = Studies have proved teratogenicity
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 2–15
Unit 2
CHAPTER 3
1
Autonomic and Somatic Nervous System
Overview
The autonomic nervous system (ANS) is involved in homeostasis of
visceral function without conscious control. It has three subdivisions:
Sympathetic (SANS)
Parasympathetic (PANS)
Enteric
The enteric subdivision comprises two interconnected plexus
(myenteric of Auerbach and submucosal of Meissner) in the gut wall
and is entirely outside the CNS. Coordinated motility of the gut is
modulated by SANS and PANS.
USMLE® Key Concepts
1.1 Efferent Pathways
For Step 1, you must be able to:
The efferent pathways of ANS are best characterized. They comprise
two neurons:
X Describe the anatomic
distribution and physiologic
functions of the cholinergic
and adrenergic receptors
in the sympathetic and
parasympathetic nervous
system.
Preganglionic:
Cell body in CNS
Thinly myelinated
Contains acetylcholine (ACh)
Postganglionic:
Cell body in peripheral ganglia
Unmyelinated
Contains ACh for PANS
Contains norepinephrine (NE) for SANS
© DeVry/Becker Educational Development Corp. All rights reserved.
X Identify agonist and
antagonist drugs of the
major cholinergic and
adrenergic receptors, and
the clinical application of
these drugs.
Chapter 3–1
&KDSWHU‡$XWRQRPLFDQG6RPDWLF1HUYous System
Pharmacology
PANS originates
from:
Brainstem
(cranial nerves
III, VII, IX, X)
SANS originates
from:
T1
Thoracolumbar segments (T1 to L2)
Thoracic splanchnics (T5 to T12)
Lumbar splanchnics (L1 to L2)
Sacral spine
(S2 to S4 pelvic
splanchnics)
L2
CNS
PANS
SANS
Ganglia
CN III
CN VII
CN IX
CN X
S2–S4
T1–L2
Preganglionic
Preganglionic
ACh NN
ACh NN
Effector Cells
Postganglionic
Postganglionic
Sympathetic cholinergic
T8–L1
Preganglionic
Neuroendocrine
System
ACh
M
Smooth muscle
Heart
Glands
NE
ACh
ACh NN Adrenal Epinephrine
medulla
in blood
Smooth muscle
Heart
Glands
M
Sweat glands
Smooth muscle
Heart
Glands
Vessels
Lungs
Metabolism
Motor cortex
Upper motor
neuron
Somatic Nervous
System
Skeletal
muscle
Lower motor
neuron
ACh
NM
cFigure 3–1.1 Efferent Pathways of Autonomic and Somatic Nervous System
1.2 Neurotransmitters
Acetylcholine (ACh) is the neurotransmitter at both nicotinic and
muscarinic receptors in innervated tissues.
Preganglionic and motor efferents use ACh.
Postganglionic transmission in the SANS system may use:
Norepinephrine (NE) at most SANS synapses
Dopamine (DA), causing vasodilation in renal and mesenteric
vascular beds (D1 receptors)
Epinephrine (E), a hormone
Chapter 3–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$XWRQRPLFDQG6RPDWLF1HUYous System
2
Pharmacology
Blood Pressure Control Mechanisms
Connection to
Physiology
ANS and endocrine systems monitor and control BP.
Reflex responses aim at correcting changes in BP.
For discussion of ANS regulation
of blood pressure, see
Physiology, chapter 11, topic 9.
2.1 ANS Control: Baroreceptor Reflexes
Brainstem
Parasympathetics
Heart rate
(CO)
Carotid
sinus
X
Aortic
arch
Sympathetics
IX
Ventricular contractility
(CO)
!
Important Concept
‡ BP = CO ×TPR
‡ CO = HR × SV
1
‡ 735D r4
Arterioles
(e.g., skeletal muscle)
(TPR)
Venoconstriction
(CO)
cFigure 3–2.1A Nervous Reflexes in the Control of Blood Pressure
Both SANS and PANS participate in the acute control of blood
pressure via baroreceptor-mediated reflexes.
A decrease in BP results in SANS firing.
An increase in BP results in PANS firing.
The individual parameters controlled by the ANS include:
—Heart rate (HR)
—Contractility
— Total peripheral resistance (TPR)
BP
CNS
+
ACh NN
ACh + M2
Baroreceptors
Carotid sinus
Aortic arch
–
BP
HR
PANS
SANS
CNS
ACh NN
NE +
HR
TPR
SANS
PANS
cFigure 3–2.1B Baroreceptor Reflexes
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 3–3
&KDSWHU‡$XWRQRPLFDQG6RPDWLF1HUYous System
Pharmacology
Baroreceptor reflexes can be blocked at the ganglionic synapse
with NN receptor antagonists.
Alternatively, a reflex bradycardia can be blocked with muscarinic
antagonists.
A reflex tachycardia can be blocked with ǃ1 antagonists.
2.2 Endocrine Control
Decreases in mean blood pressure (hypotension) result in
decreased renal blood flow.
Decreased renal pressure causes the release of renin, which
promotes the formation of angiotensin II.
Angiotensin II increases aldosterone release from the adrenal
cortex.
Aldosterone causes sodium and water retention, increasing blood
volume.
Increased venous return results in an increase in cardiac output.
Angiotensin II also causes vasoconstriction, resulting in an
increase in TPR.
2.3 Antihypertensive Drugs
Both ANS and endocrine feedback loops are triggered when
patients are treated with antihypertensive drugs.
This may result in tachycardia and salt and water retention.
E-blockers and diuretics are often part of antihypertensive
regimens.
Chapter 3–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$XWRQRPLFDQG6RPDWLF1HUYous System
Pharmacology
2.4 Introduction to Blood Pressure/
Heart Rate Tracings
Blood Pressure
ŀ Increases are seen
as deflections of
the tracing upward
Systolic pressure
Mean blood
pressure
Baseline
(
)
ŀ Decreases are seen
as deflections of
the tracing downward
(
Diastolic pressure
)
ŀ Following mean
blood pressure
changes is enough
(
)
Heart Rate
ŀ Increases are seen
as tighter tracing
Baseline
One beat
(
ŀ Decreases are seen
as wider tracing (
)
)
Example of Drug X Changing Baseline Parameters by
Increasing Mean Blood Pressure and Decreasing Heart Rate
Drug X effect
Baseline
X
cFigure 3–2.4 Blood Pressure/Heart Rate Tracings
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 3–5
&KDSWHU‡$XWRQRPLFDQG6RPDWLF1HUYous System
3
Pharmacology
Pupillary Size and Accommodation
Mechanisms
Iris
Radial muscle
Circular muscle
PANS
+ M3
+
SANS
Constriction of
sphincter muscle:
MIOSIS
Constriction of
radial muscle:
MYDRIASIS
M agonists
antagonists
agonists
M antagonists
cFigure 3–3.0A ANS Modulation of Pupil Size
Ciliary muscle
(M3)
Contraction of
ciliary muscle
Suspensory ligament
Focus for
near vision
Lens
M agonists cause
accommodation
M antagonists prevent
accommodation
(cycloplegia)
Normal
drugs have
no effect on
accommodation
Spasm of
accomodation
cFigure 3–3.0B PANS Modulation of Accommodation
Chapter 3–6
© DeVry/Becker Educational Development Corp. All rights reserved.
Cholinergic Pharmacology
CHAPTER 4
1
Overview
Cholinergic Neuron
Acetyl-CoA + Choline
Choline
acetyltransferase
Hemicholinium
ACh
Na+
Vesamicol
Na+
USMLE® Key Concepts
ATP
ACh
K+
Ca
For Step 1, you must be able to:
X Describe a cholinergic
synapse.
2+
X Differentiate direct vs.
indirect acting drugs.
Exocytosis
Botulinum
toxin
Choline
AChE
AChEIs
M1–5
N
M
ACh
X Identify the effects of
agonists and antagonists of
cholinergic receptors.
Acetate
Agonists
Antagonists
NN or M
Effector Cell
cFigure 4–1.0 Cholinergic Synapse
Choline is accumulated in cholinergic presynaptic nerve endings
via an active transport mechanism linked to a Na+ pump.
Choline uptake is inhibited by hemicholinium. ACh is synthesized
from choline and acetyl-CoA via choline acetyltransferase.
ACh accumulates in synaptic vesicles. The vesicular transport is
blocked by vesamicol.
Presynaptic membrane depolarization opens voltage-dependent
Ca2+ channels, and the influx of this ion causes fusion of the
synaptic vesicle membranes with the presynaptic membrane,
leading to exocytosis of ACh. ACh vesicles may also contain ATP
or VIP as co-transmitters.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 4–1
&KDSWHU‡&KROLQHUJLF3KDUPDFRORJ\
Pharmacology
Botulinum toxin interacts with SNAP-25, a type of SNARE protein
required for vesicle fusion. It prevents ACh release and is used
in blepharospasm, strabismus/hyperhydrosis, dystonia, achalasia,
bruxism, and cosmetics.
Some cholinergic nerve endings have presynaptic autoreceptors
for ACh that, on activation, may elicit a negative feedback of
transmitter release.
Inactivation via acetylcholinesterase (AChE) is the major
mechanism of termination of postsynaptic actions of ACh.
AChE is a target for inhibitory drugs (indirect-acting
cholinomimetics). Note that such drugs can influence cholinergic
function only at innervated sites where ACh is released.
Reversible AChE inhibitors include:
Edrophonium
Physostigmine
Neostigmine
Connection to
Microbiology
The side effects of botulinum
toxin are identical to those
of Clostridium botulinum
ingestion/infection (see Table
3–6.1B, Microbiology, chapter
3, topic 1.1). These effects
are the result of a complete
shutdown of the ANS secondary
to the absence of ganglionic
stimulation by ACh.
Irreversible AChE inhibitors include:
Echothiophate
Malathion
Parathion
Postsynaptic receptors (N and M) activated by ACh are
major targets for both agonists (direct-acting cholinomimetics)
and antagonists.
Chapter 4–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡&KROLQHUJLF3KDUPDFRORJ\
2
Pharmacology
Muscarinic Receptor Pharmacology
There are five receptor subtypes: M1, M2, M3, M4, and M5.
All are GPCRs:
M1, M3, and M5 are Gq-coupled.
M2 and M4 are Gi-coupled.
M receptor activation leads to:
p CV function.
n Secretions.
n Smooth muscle contraction.
M receptor agonists and blockers are generally nonspecific.
dTable 4–2.0 Muscarinic Receptor Activation
Target
Receptor
Response
Cautions
Heart
SA node
AV node
M2
M2
Heart rate(HR): negative chronotropy Arrhythmias (AV block)
Conduction velocity: negative
dromotropy
No effects on ventricles, Purkinje
system
Eye
Sphincter
Ciliary muscle
M3
M3
Contraction: miosis
Contraction: accommodation for
near vision
Blurred vision
Lungs
Bronchioles
Glands
M3
M3
Contraction: bronchospasm
Secretion
Asthma/COPD
M3
Secretion: sweat (thermoregulatory),
salivation, and lacrimation
M3
M1
M3
Motility: cramps
Secretion
Contraction: diarrhea
Peptic ulcer disease
GI distress
Bladder
M3
Contraction (detrusor), relaxation
(trigone/sphincter), and voiding
Urinary incontinence
Sphincters
M3
Relaxation, except lower esophageal,
which contracts
Blood vessels (endothelium)
M3
Dilation (via NO): no innervation, no
effects of indirect agonists
Glands
GI tract
Stomach
Glands
Intestine
Possible baroreceptor
reflex
2.1 Muscarinic Agonists
Direct-acting agonists bind to receptors.
Indirect-acting agonists change levels of ACh in the synapse:
They depend on intact innervation to have an effect.
Although the most commonly reported side effects of muscarinic
agonists are excessive sweating and GI distress, any of the effects
identified as cautions in Table 4–2.0 are possible.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 4–3
&KDSWHU‡&KROLQHUJLF3KDUPDFRORJ\
Pharmacology
dTable 4–2.1 Properties of Direct-Acting Cholinomimetics
Drug
Activity
AChE Hydrolysis
Clinical Uses
ACh
M and N
+++
Short half-life: miotic
agent (cataract
surgery)
Methacholine
M>N
+
Dx: bronchial
hyperreactivity
Bethanechol
M
í
Rx: paralytic ileus
urinary retention
Carbachol
M and N
í
Used as a miotic
agent and in
glaucoma
Pilocarpine
M
í
Rx: glaucoma
(topical), xerostomia
Cevimeline
M3
í
Rx: xerostomia in
Sjögren syndrome
(long-acting)
2.2 Acetylcholinesterase Inhibitors
Blocking AChE increases duration of action of ACh in synaptic
clefts, which results in the stimulation of M and N receptors.
Can be divided into:
Central AChE inhibitors
Peripheral AChE inhibitors
dTable 4–2.2 AChE Inhibitors
Agent
Use
Side Effects/Caution
Central AChE Inhibitors
Rivastigmine
‡ $O]KHLPHUdisease
‡ 3arkinson dementia
Donepezil
Alzheimer disease
Extension of M
pharmacology including rare
AV block
Peripheral AChE Inhibitors
Edrophonium
‡ Dx of myasthenia gravis
‡ DDx cholinergic crisis
Neostigmine
Pyridostigmine
‡ Rx of myasthenia gravis
‡ R
eversal of competitive
neuromuscular blockade
‡ P
ostoperative GI/GU
retention
To decrease excessive M side
effect while diagnosing or
treating myasthenia gravis,
atropine is given
Combined Peripheral and Central AChE Inhibitor
Physostigmine
Life-threatening
anticholinergic toxicity
(i.e., atropine OD)
Can cross blood-brain barrier
Irreversible AChE Inhibitors: Organophosphates
Tabun, sarin, soman
Nerve gases
Malathion,
parathion, diazinon,
chlorpyrifos
Insecticides
‡ See topic 2.3 that follows
‡ Malathion and parathion
are prodrugs of malaoxon
and paraoxon
Echothiophate
Glaucoma
Topical use
Chapter 4–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡&KROLQHUJLF3KDUPDFRORJ\
Pharmacology
2.3 Toxicity of AChE Inhibitors
Memory Aid
2.3.1 Acute Toxicity
AChE inhibitor poisoning:
Dumbbelss
Excessive muscarinic and nicotinic stimulations
Muscarinic effects:
Diarrhea
Urination
Miosis
Bradycardia
Bronchoconstriction
Diarrhea
Urination
Lacrimation
Salivation
Sweating
CNS stimulation
Miosis
Bradycardia
Bronchoconstriction
Excitation (CNS/muscle)
Nicotinic effects:
Lacrimation
Skeletal muscle excitation followed by paralysis
CNS stimulation
Salivation
Sweating
2.3.2 Management
Muscarinic effects: atropine
Regeneration of AChE: pralidoxime (2-PAM)
Time-dependent aging requires use of 2-PAM as soon as possible
(see Figure 4–2.3)
R
Blockade
Aging
P
P
Irreversibly Acting Cholinomimetics
These compounds phosphorylate the esteratic
site on AChE, at serine hydroxyl groups
1. Phosphorylation; reversible by
pralidoxime (2-PAM)
2. Removal of a part of the organophosphate
molecule (aging); complex no longer
reversible by 2-PAM
AChE
R
H2O
AChE
P
2-PAM
Regeneration AChE
R = leaving group
P = organophosphate
cFigure 4–2.3 Effects of Organophosphate on AChE
2.3.3 Chronic Toxicity
Peripheral neuropathy causing muscle weakness and sensory loss.
Demyelination is not due to AChE inhibition.
No treatment.
2.4 Muscarinic Receptor Antagonists
2.4.1 Atropine
Prototype for this class of drug.
As a tertiary amine, it enters CNS.
Other antimuscarinic drugs differ mainly in their pharmacokinetic
properties.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 4–5
&KDSWHU‡&KROLQHUJLF3KDUPDFRORJ\
Pharmacology
Many classes of prescription drugs or OTC preparations have
antimuscarinic side effects. These include:
Antihistamines
Tricyclic antidepressants
Antipsychotics
Quinidine
Amantadine
Meperidine
Antimuscarinics are contraindicated or used with caution in BPH
and narrow-angle glaucoma patients.
The pharmacologic effects of atropine, presented in order of
increasing dose, are:
Decreased secretions (salivary, bronchiolar, sweat)
Mydriasis and cycloplegia
n dose
Hyperthermia (with resulting vasodilatation)
of
Tachycardia
atropine
Sedation
Urinary retention and constipation
Behavioral excitation and hallucinations
Treatment of acute intoxication: Symptomatic ± physostigmine
2.4.2 Other Antimuscarinics
dTable 4–2.4 Antimuscarinics
Drug
Clinical Uses
Characteristics
Atropine
‡ $QWLVSDVPRGLF
‡ $QWLVHFUHWRU\
‡ Management of AChE
inhibitor OD
‡ $QWLGLDUUKHDO
‡ 2SKWKDOPRORJ\
‡ Reversal of AV block
Long action
Tropicamide
Homatropine
Cyclopentolate
Ophthalmology
Topical
Ipratropium
Tiotropium
‡ $VWKPD
‡ &23'
‡ ,QKDODWLRQDO
‡ No CNS entry
‡ No change in mucous
viscosity
Scopolamine
Motion sickness
‡ Causes of sedation
‡ Short-term memory
block
Benztropine
Trihexyphenidyl
‡ 3arkinsonism
‡ Acute extrapyramidal
symptoms induced by
antipsychotics
Lipid soluble (CNS entry)
Oxybutynin
Tolterodine
‡ %ODGGHUspasm
‡ 8ULQDU\incontinence
Dicyclomine
Irritable bowel syndrome
Chapter 4–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡&KROLQHUJLF3KDUPDFRORJ\
3
Pharmacology
Nicotinic Receptor Pharmacology
Nicotine receptors are ligand-gated ion channels.
They are made of five subunits.
Two D subunits are bound by two ACh molecules.
Conductance is to Na+ and K+.
Receptor activation results in depolarization and excitation of cells.
Two broad types:
Neuronal, NN (found in CNS, ANS ganglia, and adrenal medulla)
Skeletal muscle, NM
3.1 Nicotinic Receptor Agonists
dTable 4–3.1 Nicotinic Receptor Agonists
Drug
Use
Comment
Varenicline
Smoking cessation
‡ Risk of suicide, depression
‡ Partial agonist at NN
Succinylcholine
Suxamethonium
Neuromuscular blocker
‡ See chapter 17
‡ Full agonists at NM
3.2 Nicotinic Receptor Antagonists
3.2.1 Ganglion Blocking Agents
Drugs: hexamethonium and mecamylamine.
Reduce the predominant autonomic tone (Table 4–3.2).
Prevent baroreceptor reflex changes in heart rate (Figure 4–3.2).
Most are no longer available clinically because of toxicities.
Used in USMLE ANS problems.
dTable 4–3.2A Characteristics of Ganglion Blocking Agents
Effector
System
Effect of Ganglion Blockade
Arterioles
SANS
Vasodilation, hypotension
Sweat glands
SANS
Anhydrosis
Veins
SANS
Dilation, venous return, CO
Heart
PANS
Tachycardia
Iris
PANS
Mydriasis
Ciliary muscle
PANS
Cycloplegia
GI tract
PANS
p Tone and motility—constipation
Bladder
PANS
Urinary retention
Salivary glands
PANS
Xerostomia
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 4–7
&KDSWHU‡&KROLQHUJLF3KDUPDFRORJ\
CNS
Ganglionic blocking
drugs do not prevent
changes in HR elicited
directly by the drug
(1or M2 agonists).
Pharmacology
Baroreceptors
Vasomotor
center
Blood pressure
change
PANS
SANS
Heart
Blood vessel
Vasoconstrictor
Ganglionic blocking drugs
prevent reflex changes
in heart rate elicited
by vasoconstriction (1)
and vasodilation (2, M3)
Vasodilator
cFigure 4–3.2 Algorithm: Reflex Control of Heart Rate
3.2.2 Neuromuscular Blocking Drugs
See chapter 17, "Anesthetic Drugs"
Curare-like drugs (for example, atracurium)
dTable 4–3.2B Cholinergic Drug Summary
Class
Agent
M Agonists
Acetylcholine
Methacholine
Bethanechol
Carbachol
Pilocarpine
Cevimeline
AChE Inhibitors
Rivastigmine
Donepezil
Edrophonium
Neostigmine
Pyridostigmine
Physostigmine
Organophosphates
M Antagonists
Atropine
Tropicamide
Homatropine
Cyclopentolate
Ipratropium
Tiotropium
Scopolamine
Benztropine
Trihexypherydyl
Oxybutinim
Tolterodine
Dicyclomine
NN Partial Agonist
Varenicline
NN Antagonists
Hexamethonium
Mecamylamine
NM Agonists
Succinylcholine
Suxamethonium
NM Antagonists
Curare-like drugs
Miscellaneous
p Release of ACh
Botulinum toxin
p Vesicular uptake
Vesamicol
p Choline uptake
Hemicholinium
Drugs in red need to be memorized.
Drugs in black … would be good to know!
Chapter 4–8
© DeVry/Becker Educational Development Corp. All rights reserved.
Adrenergic Pharmacology
CHAPTER 5
1
Adrenergic Synapse
Figure 5–1.0A illustrates the important aspects of the adrenergic
synapse.
1
DOPA
Tyrosine
hydroxylase
Tyrosine
DOPA Decarboxylase (aromatic
amino acid decarboxylase)
Dopamine
Vesicular dopamine
Hydroxylase
2
NE
Mobile pool
4
USMLE® Key Concepts
Norepinephrine
MAOA (NE)
3
2
NE 6
5
Receptors
7
Exocytosis
Reuptake
NE
1
COMT
8
Receptors
Metabolites
1
For Step 1, you must be able to:
X Describe an adrenergic
synapse.
X Differentiate direct vs.
indirect acting drugs.
X Identify the effects of
agonists and antagonists of
adrenergic receptors.
Effector Cells
cFigure 5–1.0A Adrenergic Neuroeffector Junction
Tyrosine is actively transported into nerve endings and is
converted to dihydroxyphenylalanine (DOPA) via tyrosine
hydroxylase (No. 1 in Figure 5–1.0A). This step is rate-limiting in
the synthesis of NE.
DOPA is converted to dopamine (DA) via L-aromatic amino acid
decarboxylase (DOPA decarboxylase).
DA is taken up into storage vesicles where it is metabolized to NE
via DA E-hydroxylase (No. 6). Monoamine oxidase (MAO) (No. 2)
may regulate presynaptic levels of transmitter in the mobile pool
(No. 3) but not the NE stored in granules.
Presynaptic membrane depolarization opens voltage-dependent
Ca2+ channels. Influx of this ion causes fusion of the synaptic
granular membranes, with the presynaptic membrane leading
to NE exocytosis into synapse (No. 7).
NE then activates postsynaptic receptors (No. 8), leading to
tissue-specific responses.
Termination of NE actions is mainly due to reuptake (No. 4).
NE released may activate presynaptic D2 receptors (No. 5)
involved in feedback regulation.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 5–1
&KDSWHU‡$GUHQHUJLF3KDUPDFRORJ\
Pharmacology
Metabolism of NE is by catechol O-methyltransferase (COMT)
in the synapse or MAOA in the prejunctional nerve terminal.
Synthesis
Dopamine
Norepinephrine
Epinephrine
Degradation
!
Important Concept
Forms of MAO
MAO
COMT
MAO + COM
T
Dihydroxyphenylacetic acid
Homovanillic acid (HVA)
- 0DLQO\LQOLYer, but
Anywhere
MAO
COMT
MAO + COM
T
Dihydroxymandelic acid
- 0HWDEROL]HV1(+7,
andtyramine
MAO
COMT
MAO + COM
T
Dihydroxymandelilc acid
3-Methoxytyramine
Normetanephrine
‡ 0$O type A:
‡ 0$O type B:
3-Methoxy-4-hydroxymandelic acid (VMA)
- 0DLQO\in Brain
- 0HWDEROL]HVD$
Metanephrine
3-Methoxy-4-hydroxymandelic acid (VMA)
cFigure 5–1.0B Main Metabolites of Catecholamines
Chapter 5–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$GUHQHUJLF3KDUPDFRORJ\
2
Pharmacology
Adrenergic Receptor Pharmacology
There are two receptor subtypes: D and E.
E receptors are more sensitive than D receptors.
All are G protein coupled.
2.1 Receptor Subtypes
dTable 5–2.1 Adrenergic Receptor Subtypes
Receptor
D1
D2
E1
E2
E3
G Protein
Second Messengers
Gq
n IP3, DAG, Ca2+
Gi
p cAMP
Gs
Gs
Gs
n cAMP
2.2 Receptor Activity
dTable 5–2.2 Effects of Stimulation
Receptor
D
1
D
2
E1
E2
Tissue
Response
Vessels:
‡ Arterioles
‡ Veins
Constriction and n
BP
n
TPR, n
afterload, n
diastolic pressure
p
Capacitance, n
preload, n
systolic pressure
Iris radial muscle
Constriction and mydriasis (no cycloplegia)
Kidney
p
Renin release
Liver
n
Glycogenolysis
Genitourinary:
‡ Bladder
‡ 9as deferens
n
Sphincter tone, urinary retention
n
Contraction, emission
Presynaptic
p
Synthesis, p
release of NE
Pancreas
p
Insulin
Platelets
Aggregation
Heart:
‡ SA, AV nodes
‡ Muscle
Heart rate, n
conduction velocity
n
n
Contractility, n
stroke volume, n
systolic pressure
Kidney
n
Renin release
Ciliary body
Aqueous humor
n
Smooth muscle:
‡ Vessels
‡ Bronchioles
‡ 8WHUXV
Relaxation
TPR, p
afterload, p
diastolic pressure
Vasodilation, p
Bronchodilation
Relaxation
Metabolic:
‡ /LYer
‡ $GLSRVH
Glycogenolysis, gluconeogenesis
Lipolysis (E3-mediated)
2.3 Drug Classification
Adrenergic drugs are classified as:
Direct acting: D1, D2, E1, E2 agonists or blockers
Indirect acting: Releasers, enzyme, or uptake inhibitors
Mixed acting: Stimulate or block more than one receptor subtype
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 5–3
&KDSWHU‡$GUHQHUJLF3KDUPDFRORJ\
3
Pharmacology
Direct-Acting Adrenoceptor Agonists
3.1 D1 Agonists
‡ Blood pressure
‡ Potential reflex bradycardia
‡ No change in pulse pressure
α 1 agonist
cFigure 5–3.1 Effect of D1 Stimulation on Heart Rate
and Blood Pressure
dTable 5–3.1 D1 Agonists
Drug
Use
Phenylephrine
Nasal decongestant
Mydriatic
Mephentermine
Metaraminol
Midodrine
Hypotension (in spinal anesthesia, postural, autonomic
insufficiency)
3.2 D2 Agonists
dTable 5–3.2 D2 Agonists
Drug
Use
Clonidine
Methyldopa
Guanfacine
Guanabenz
Hypertension (see cardiovascular section)
Apraclonidine
Brimonidine
Glaucoma
Tizanidine
Muscle relaxant
Spasticity
Chapter 5–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$GUHQHUJLF3KDUPDFRORJ\
Pharmacology
3.3 E Agonists
‡1HR, SV, CO, and
systolic pressure
‡2TPR, diastolic pressure
‡ Pulse pressure
agonists
cFigure 5–3.3 Effect on Nonselective E Agonists on Heart Rate and
Blood Pressure
dTable 5–3.3 E Agonists
Drug
Isoproterenol
Dobutamine
Albuterol*
Metaproterenol
Terbutaline
Receptor
E1= E2
E1
E2
Use
Side Effects
‡ B
radycardia, heart
block (E1)
‡ $VWKPD(E2)
‡ 7achycardia
‡ Hypotension,
flushing,headache
Acute CHF management
‡ Tachycardia
‡ $VWKPD
‡ 3UHPDWXUHlabor
‡ Tremor, anxiety,
restlessness
‡ 3alpitations
‡ Caution in patients
with CV disease
*Asthma medications related to albuterol:
‡ Salmeterol: Long-acting, delayed onset, prophylaxis only.
‡ Formoterol: Long-acting, prompt onset, acute management, and prophylaxis.
‡ Albuterol: Short-acting, prompt onset, acute management.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 5–5
&KDSWHU‡$GUHQHUJLF3KDUPDFRORJ\
4
Pharmacology
Mixed-Acting Agonists: Norepinephrine,
Epinephrine, Dopamine
4.1 Norepinephrine (D1, D2, E1)
Systolic pressure
1,
Mean BP
Diastolic pressure
1
Heart rate
1
Heart rate
if vagal reflex
M2
1
‡ 1: TPR, BP
‡ 1: HR, SV, CO
‡ Pulse pressure
‡ Potential reflex
bradycardia
‡ No effect on
2
cFigure 5–4.1 Effect of Norepinephrine on Heart Rate and Blood Pressure
4.2 Epinephrine (D1, D2, E1, E2)
Effects are dose-dependent:
Low dose: E1, E2
High dose: D1, E1, E2
Low-dose epinephrine is like isoproterenol.
E2-specific effects:
Smooth muscle relaxation: Bronchioles, uterus
Metabolic effects:
— Glycogenolysis (muscle and liver)
— Gluconeogenesis
— Mobilization and use of fat (E3)
High-dose epinephrine is like norepinephrine.
Differentiation of high-dose epinephrine versus norepinephrine:
Epinephrine revHUVDO8VHRID1-blocker to reverse hypertension
to hypotension in a patient receiving too much epinephrine.
Hypertension was due to predominant D1 tone on the
vasculature.
Hypotension results from unmasking E2 receptors.
Chapter 5–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$GUHQHUJLF3KDUPDFRORJ\
Systolic pressure
Pharmacology
1
‡ 1HR, SV, CO
‡ 2TPR, BP
Mean pressure
‡ Pulse pressure
Diastolic pressure
2
Heart rate
1
cFigure 5–4.2A Effect of Low-Dose Epinephrine on Heart Rate and Blood Pressure
Systolic pressure
1
Mean pressure
Diastolic pressure
2+
1
1:
‡
Pulse pressure
‡
2:
TPR, BP
‡
1:
TPR, BP
‡
Heart rate
HR, SV, CO
‡
1 and 2 stimulation
antagonize each other
1
cFigure 5–4.2B Effect of Medium-Dose Epinephrine on Heart Rate and Blood Pressure
6\VWROLFSUHVVXUH
1 1
‡
1:
735 BP
‡ 3RWHQWLDOUHIOH[
EUDG\FDUGLD
0HDQ%3
'LDVWROLFSUHVVXUH
1
+HDUWUDWH
1
+HDUWUDWH
LIYDJDOUHIOH[
M2
+5 69 CO
‡
1:
‡
3XOVHSUHVVXUH
‡ HIIHFWLVPDVNHG
E\ 1SUHGRPLQDQFH
cFigure 5–4.2C Effect of High-Dose Epinephrine Is Similar to Norepinephrine
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 5–7
&KDSWHU‡$GUHQHUJLF3KDUPDFRORJ\
Pharmacology
4.3 Uses of Norepinephrine and Epinephrine
Cardiac arrest
Adjunct to local anesthetic
Hypotension
Anaphylaxis (epinephrine only)
Asthma (epinephrine only)
4.4 Dopamine: D1, E1, D1
Dopamine can be used in shock management.
Effects are also dose dependent:
Low dose (D1):
— D1 in periphery on renal, coronary, and mesenteric vessels.
— Gs-coupled: Stimulation causes vasodilation.
Medium dose (D1, E1): E1 adds inotropic effect to D1
preservation of flow in heart and kidneys.
High dose (D1, E1, D1): D1 can maintain BP.
Fenoldopam is a selective D1 agonist used in hypertension.
5
Indirect-Acting Adrenergic Receptor
Agonists
Releasers:
Displace norepinephrine from mobile pool.
Drug interaction: MAOA inhibitors (hypertensive crisis).
Tyramine (red wine, cheese):
—Oral bioavailability is limited by MAOA metabolism in gut
and liver.
—MAOA inhibition n bioavailability, resulting in hypertensive
crisis.
Amphetamines:
—Clinical use of methylphenidate in narcolepsy and ADHD.
—Psychostimulant due to central release of DA, NE, 5-HT.
!
Important Concept
Denervated effector tissues are
nonresponsive because these
drugs act either to release
transmitter from nerve terminals
or to inhibit neurotransmitter
reuptake.
Ephedrine (cold medication).
Reuptake inhibitors:
Cocaine
Tricyclic antidepressant (in part)
Chapter 5–8
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$GUHQHUJLF3KDUPDFRORJ\
6
Pharmacology
Adrenergic Antagonists
6.1 D Receptor Antagonists
p TPR, p mean BP
May cause reflex tachycardia and salt and water retention
dTable 5–6.1 D Receptor Antagonists
Drug
Phenoxybenzamine
Phentolamine
Prazosin
Terazosin
Doxazosin
Tamsulosin
Receptor
D1, D2
D1, D2
D1
Use
Comments
Pheochromocytoma (DOC)
Irreversible
Hypertension
Reversible
Hypertension
Benign prostatic hyperplasia
Orthostatic
hypotension (see
cardiovascular
section)
Yohimbine
D2
Postural hypotension
Was formerly
used in sexual
dysfunction
Mirtazapine
D2
Antidepressant
DOC in anorexia
nervosa
(see CNS section)
Connection to
Pathology
‡ Pheochromocytoma: see
Pathology, chapter 19, topic
‡ Benign prostatic hyperplasia
%3+ VHHPathology, chapter
1WRSLF
6.2 E Receptor Antagonists
E1 blockade:
p HR p SV, p CO
p Renin release
p Aqueous humor production
E2 blockade:
May precipitate bronchospasm (in asthmatics) and vasospasm
(in patients with vasospastic disorders)
Metabolic effects (caution in diabetics):
—Blocks glycogenolysis and gluconeogenesis
E3 blockade:
Increases blood lipids
Cardioselectivity (E1):
Less effect on vasculature, bronchioles, uterus, and metabolism
Safer in asthma, diabetes, peripheral vascular diseases
Intrinsic sympathomimetic activity (ISA):
Act as partial agonists
Less bradycardia (E1)
Slight vasodilation or bronchodilation (E2)
Minimal change in plasma lipids (E3)
General uses of beta-blockers:
Angina, hypertension, post-MI (all drugs)
Antiarrhythmics (class II: propranolol, acebutolol, esmolol)
Glaucoma (timolol)
Migraine, thyrotoxicosis, performance anxiety, essential tremor
(propranolol)
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 5–9
&KDSWHU‡$GUHQHUJLF3KDUPDFRORJ\
Pharmacology
General clinical considerations:
Chronic use of ǃ-blockers (e.g., in angina, HTN) leads to
receptor upregulation.
During withdrawal from use, it is important to taper dose
to avoid excessive cardiovascular effects (rebound effects)
of endogenous amines.
Additive bradycardia with calcium channel blockers, digoxin,
adenosine.
In ǃ-blocker overdose, glucagon can be used. Glucagon binds
to Gs-coupled receptors and n cAMP causing "reversal" of
ǃ blockade toxicity without interfering with ǃ receptors.
dTable 5–6.2A First- and Second-Generation Drugs
1st Generation:
Nonselective
2nd Generation: E1
Selective
Nadolol
Penbutolol
Pindolol
Propranolol
Sotalol
Timolol
Atenolol
Acebutolol
Bisoprolol
Esmolol
Metoprolol
E-Blocker With ISA
Acebutolol (E1)
Pindolol (E1, E2)
Third-Generation E-Blockers
These E-blockers are also vasodilators.
Nonselective and D1 antagonists: Carvedilol and labetalol are used
in CHF.
Selective E1 and NO release: Nebivolol is used in hypertension.
Chapter 5–10
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$GUHQHUJLF3KDUPDFRORJ\
Pharmacology
dTable 5–6.2B Adrenergic Drug Summary
D1 Agonists
Phenylephrine
Mephentermine
Metaraminol
Midodrine
D2 Agonists
Clonidine
Methyldopa
Guanfacine
Guanabenz
Apraclonidine
Brimonidine
Tizanidine
E Agonists
Isoproterenol (E1= E2)
Dobutamine (E1)
Albuterol (E2)
Formoterol (E2)
Salmeterol (E2)
Terbutaline (E2)
Metaproterenol (E2)
D1 Blockers
Non-selective
Mixed Agonists
Epinephrine (D1, D2, E1, E2)
Norepinephrine (D1, D2, E1)
Dopamine (D1, E1, D1)
Fenoldopam
E Blockers
1st Generation
2nd Generation
3rd Generation
Non-selective
E1 Selective
D1- and E-Blockers
Nadolol
Penbutolol
Pindolol
Propranolol
Sotalol
Timolol
Atenolol
Acebutolol
Bisoprolol
Esmolol
Metoprolol
Labetalol
Carvedilol
D1 Selective
E-Blocker with ISA
NO Release and E-Blocker
Prazosin
Doxazosin
Terazosin
Tamsulosin
Acebutolol (E1)
Pindolol (E1, E2)
Nebivolol
Phentolamine
(reversible)
Phenoxybenzamine
(irreversible)
D1 Agonists
D2 Selective
Yohimbine
Mirtazapine
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 5–11
Unit 3
CHAPTER 6
1
Antiarrhythmics
Overview
Two broad etiologies of arrhythmias:
Abnormal impulse formation (abnormal automaticity)
Alterations in impulse conduction (reentry phenomenon)
Two broad types of tachyarrhythmias:
Supraventricular (SVTs)
Ventricular (VTs)
One major block of conduction: AV block
Symptoms result from decreased cardiac output:
CNS: Syncope, dizziness, convulsions
Heart: Palpitations, sudden cardiac death
Management aims at restoring normal sinus rhythm and canceling
ectopic beats.
Even with the advance of catheter ablation for atrial fibrillation
and ventricular tachycardia, drugs remain an important tool.
For USMLE Step 1, know well:
Mechanism of antiarrhythmic and indication
Proarrhythmic side effects
Antiarrhythmics alter firing rate or prolong refractoriness.
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe the mechanisms
of arrhythmias.
X Describe the effects of
antiarrhythmics on action
potentials of nodal vs.
muscle cells.
X Identify the mechanisms of
action and side effects of
primary antiarrhythmics.
1.1 Classification of Antiarrhythmics
The most commonly used classification system for antiarrhythmic
drugs is the Vaughn Williams classification, which groups drugs
based on their primary mechanism of action.
Class I: Sodium channel blockers
Class II: E-adrenergic receptor blockers
Class III: Potassium channel blockers
Class IV: Calcium channel blockers
Class V: Miscellaneous
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 6–1
&KDSWHU‡$QWLDUUKythmics
Pharmacology
1.2 Physiology of Arrhythmia
mV
1.2.1 Action Potential in Fast Response Fibers
0
1
-50
0
2
3
4
-100
High
Na+
Conductance
Ca++
K+
Low
cFigure 6–1.2A Action Potential in Fast
Response Fibers (Ventricular, Atrial, Muscle,
and His-Purkinje Fibers)
Phase 0:
Na+ channels open, rapid depolarization.
The rate of depolarization depends on the number of channels
opened.
Class I drugs can slow or block phase 0 in fast response fibers.
Phase 1:
Na+ channels are inactivated.
Transient outward K+ current (Ito) and inward Clí current.
No effect of antiarrhythmic drugs on phase 1.
Phase 2:
Plateau phase due to L-type Ca2+ channels.
Inward Ca2+ is balanced by outward K+ through delayed
rectifying K+ channels (IK).
Class III drugs prolong the plateau by blocking IK.
Little effect of Class IV drug in blocking L-type of Ca2+ channels.
Some Na+ comes in through slowly inactivating but persistent
sodium current ("window" Na+ current) and plays a role in
hypoxia-induced arrhythmias.
Class IB drugs block IPNa and decrease the plateau in hypoxic
or depolarized tissues.
Chapter 6–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLDUUKythmics
Pharmacology
Phase 3:
Repolarization phase due to IK.
Inactivation of Ca2+ channels.
Class III drugs and some Class I drugs prolong repolarization
by blocking phase 3.
Phase 4:
Return to resting membrane potential.
Na+/K+ ATPase pump reestablishes Na+-K+ gradients and Na+/
Ca2+ exchange resets the Ca2+ gradient.
Digoxin is in part proarrhythmic through blockade of phase 4.
1.2.2 Action Potential in Slow Response Fibers
Membrane Potential (mV)
+10
0
-10
3
0
Ca2+
permeability
-20
Action
potential
K+
permeability
-30
-40
-50
Ca2+
permeability
4
Ca2+
entry
-60
-70
K+ permeability
accompanied by
slow Na+ entry
4
Slow depolarization:
pacemaker potential
Threshold
Time (ms)
cFigure 6–1.2B Action Potential in Slow Response Fibers
(SA and AV Nodal Cells)
Phase 0:
Na+ channels are inactivated and do not participate in upstroke
of action potential.
Activation of L-type Ca2+ channels is responsible for phase 0.
Class IV drugs block phase 0 in SA, AV nodes.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 6–3
&KDSWHU‡$QWLDUUKythmics
Pharmacology
Phase 3:
Due to K+ channels.
Class III drugs block phase 3.
Phase 4:
Pacemaker current, a composite of inward Na+/Ca2+ and
outward K+ currents.
Confers automaticity. SA node is the normal pacemaker.
ANS controls pacemaker current:
— SANS n slope
— PANS p slope
Class II and Class IV drugs can block phase 4 in SA, AV nodes.
Electrical Potential (mV)
Control
0
-20
-40
NE
-60
-80
ACH
cFigure 6–1.2C Autonomic Effects on the SA Node Action Potential
Chapter 6–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLDUUKythmics
Pharmacology
1.2.3 Refractoriness
Refractoriness is effective as soon as fast Na+ channels are
inactivated.
Duration
The longer the action potential direction, the more prolonged
the refractoriness to pathological stimuli.
RRP
ERP
Membrane Potential (mV)
+20
0
-20
-40
-60
-80
APD
-100
APD = Action Potential Duration
ERP = Effective Refractory Period
RRP = Relative Refractory Period
cFigure 6–1.2D Refractoriness
Any drug that increases APD can n ERP and slow down rhythm.
1.2.4 States of Voltage-Dependent Na+ Channels
At RMP
Closed
Resting
‡5HDG\6WDWHWKHPRUH
QHJDWLYHWKH503LV
WKHJUHDWHUWKHQXPEHU
RIFKDQQHOVLQUHDG\VWDWH
Upon depolarization
DFWLYDWLRQ
Upon repolarization
UHFRYHU\
‡(IIHFWLYH
UHIUDFWRULQHVV
Closed
Inactive
Open
During depolarization
LQDFWLYDWLRQ
‡)DVWNa+
‡6ORZCa2+
‡'HOD\HGK+
cFigure 6–1.2E States of Voltage-Dependent Ion Channels
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 6–5
&KDSWHU‡$QWLDUUKythmics
2
Pharmacology
Class I Drugs: Na+ Channel Blockers
Class I antiarrhythmics block fast sodium channels responsible
for early, rapid depolarization phase of AP (phase 0) in fast
response fibers.
Class I is subdivided in three groups:
Class IA drugs
Class IB drugs
Class IC drugs
The groups are based on state-dependent blockade of Na+ channels.
RMP: -90 mV
Depolarization
Na+
Phase 0
Fast
Slow
Ready State
(closed)
Open, Activated
– IA, IC
Sustained
Depolarization
Repolarization
Closed, Inactivated
Effective Refractoriness
– IB, IC
Class IC are not state-dependent
cFigure 6–2.0A State-Dependent Block of Class I Drug
IA
Quinidine
Procainamide
Disopyramide
IB
Lidocaine
Mexiletine
IC
Flecainide
Propafenone
IB
No significant
change in action
potential tracing
IA
cFigure 6–2.0B Class I Antiarrhythmic
Chapter 6–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLDUUKythmics
Pharmacology
2.1 Class IA Drugs
2.1.1 Quinidine
Antiarrhythmic
Blocks activated Na+ channel.
Prolongs phase 0 and APD.
n ERP in fast response fibers.
Also some K+ channel block and prolongs phase 3.
Used orally in SVTs and VTs.
Proarrhythmic
M and D1 antagonism.
M blockade will speed AV nodal conduction:
— Must digitalize patient in treating SVTs.
M antagonism also prolongs QRS and QT and predisposes
to torsade rhythm (see Figure 6–2.1).
D1 antagonism: p BP and reflex tachycardia.
Side Effects
Cinchonism (due to M and D1 blockage):
— Ocular dysfunction
— GI distress
— Tinnitus
— Vertigo
Also proarrhythmic effects discussed in previous section.
Drug Interaction
Weak base: Antacids will n its absorption and toxicity.
Displaces digoxin from tissue binding site, enhancing digoxin
free fraction and toxicity.
2.1.2 Procainamide
Similar to quinidine (IA).
Procainamide is metabolized by N-acetyltransferase to
N-acetylprocainamide (NAPA), an active metabolite.
Slow acetylators are prone to lupus-like adverse effects.
Procainamide may prolong the QT interval and lead to torsade de
pointes (antimuscarinic).
2.1.3 Disopyramide
Phototake
Same as quinidine (IA).
Stronger anticholinergic.
cFigure 6–2.1 Torsade de Pointes EKG
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 6–7
&KDSWHU‡$QWLDUUKythmics
Pharmacology
2.2 Class IB Drugs
Hypoxia p ATP production and Na+/K+ ATPase activity.
Two issues:
n Intracellular Na+ brings cell close to threshold and causes
abnormal automaticity.
Prolonged depolarization prolongs refractoriness and slows
conduction.
Class IB drugs block inactivated channels, preventing action
potential generation (raise the threshold for excitation).
Class IB drugs block late window Na+ channels, decreasing APD
and speeding up conduction by shortening repolarization.
IB drugs are used in arrhythmias:
Post MI
Digoxin toxicity
Open-heart surgery
2.2.1 Lidocaine
Administered by IV due to first-pass metabolism.
Also used as a local anesthetic.
Can cause CNS side effects:
Drowsiness
Disorientation
Paresthesia
Convulsions in toxic doses
Proarrhythmic effect: Considered the least cardiotoxic of all
conventional antiarrhythmics.
2.2.2 Mexiletine
Mexiletine is an orally available Class IB drug.
2.3 Class IC Drugs
Most potent inhibitors of fast Na+ channel.
Less state-dependent.
Used in:
Life-threatening ventricular tachycardia
Fibrillation
Refractory SVTs
No ANS pharmacology.
Drugs include:
Flecainide
Propafenone
Proarrhythmic effect: Can n sudden cardiac death by p left
ventricular function.
Chapter 6–8
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLDUUKythmics
3
Pharmacology
Class II: E-Adrenergic Receptor Blockers
p SA firing and AV conduction by p phase 4 of AP.
Blunt the sympathetic input into the heart.
Prevent ventricular arrhythmias, especially after myocardial infarction.
Also used in SVTs to protect ventricles from fast atrial rate.
Proarrhythmic effect: Can cause AV block.
Only three drugs are FDA-approved for arrhythmias:
Esmolol: E1 selective, available IV
Metoprolol: E1 selective, available IV or PO
Propranolol: E1 and E2 selective, available IV or PO
Cautions include:
Asthmatics
Peripheral vascular diseases
Diabetics
II
cFigure 6–3.0 Effects of Class II Drugs
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 6–9
&KDSWHU‡$QWLDUUKythmics
4
Pharmacology
Class III: K+ Channel Blockers
Predominantly block the delayed rectifier K+ current and delay
repolarization.
Result in prolongation of the AP and ERP, which manifest as
prolongation of the QT interval.
Proarrhythmic effect: Torsade de pointes.
4.1 Amiodarone
Also has classes IA, II, and IV activity.
Effective against a wide range of atrial and ventricular arrhythmias.
Very long half-life (20–50 days), large Vd.
Amiodarone contains iodine and has high tissue protein binding.
Side effects include:
Pulmonary fibrosis
Liver toxicity (interference with clearance of digoxin, phenytoin,
and warfarin)
Blue-gray discoloration of skin, especially sun-exposed regions
and corneal deposits
Thyroid dysfunction (contains iodine)
Prolongation of QT interval and risk of torsade de pointes
Dronedarone is an alternative to amiodarone, but it n sudden
cardiac death.
!
Important Concept
In addition to amiodarone,
pulmonary fibrosis is caused by
a limited number of other drugs,
including:
‡ %OHRPycin
‡ %XVXOIan
‡ 0HWKRtrexate
Wellcome Photo Library/Custom Medical Stock Photo
‡ Nitrofurantoin
cFigure 6–4.1A Amiodarone-Induced Skin Changes
Chapter 6–10
© DeVry/Becker Educational Development Corp. All rights reserved.
Pharmacology
Wellcome Images
&KDSWHU‡$QWLDUUKythmics
cFigure 6–4.1B Chest X-Ray Showing Pulmonary Fibrosis
4.2 Dofetilide and Ibutilide
Used to convert atrial fibrillation and flutter to sinus rhythm.
Cause torsades de pointes in 3%–5% of patients.
Only administered in a hospital setting.
4.3 Sotalol
Also a beta-blocker: p SA, AV nodal conduction.
Class III: n APD, ERP
Used for life-threatening ventricular tachycardia or atrial fibrillation.
Class III side effect of torsades de pointes, and Class II cautions
and side effects.
III
cFigure 6–4.3 Effects of Class III Drugs
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 6–11
&KDSWHU‡$QWLDUUKythmics
5
Pharmacology
Class IV: Ca2+ Channel Blockers
Verapamil and diltiazem are the only drugs indicated.
p Phase 0 and phase 4 in SA, AV node.
Used in SVTs.
Proarrhythmic effect: AV block.
Side effects of verapamil and diltiazem include:
Reduced blood pressure (especially orthostatic hypotension)
Reduced cardiac output
Lower extremity edema
Constipation (verapamil > diltiazem)
Drug interaction:
Verapamil displaces digoxin, increasing its free function
and toxicity.
Additive AV block with all beta-blockers and digoxin.
Normal
IV
IV
cFigure 6–5.0 Effects of Class IV Drugs
Chapter 6–12
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLDUUKythmics
6
Pharmacology
Class V: Miscellaneous Antiarrhythmics
6.1 Adenosine
Rapidly acting AV nodal blocker administered IV.
Half-life of adenosine is less than 30 seconds.
Adenosine receptors:
A1: Gi-coupled, p SA, AV nodal rate
A2A: Gs-coupled, vasodilate (including coronaries)
A2B: Gq-coupled, bronchoconstriction
Drug of choice for paroxysmal supraventricular tachycardia (PSVTs).
Associated with severe but brief-in-duration shortness of breath,
flushing, and a burning sensation in the chest.
Theophylline (caffeine) antagonizes adenosine receptors.
6.2 Digoxin
Discussed in more detail in topic 2.1, chapter 8.
Used to control ventricular rates in atrial fibrillation and atrial flutter.
Augments parasympathetic activity and slows AV nodal conduction.
Narrow therapeutic index (proarrhythmic).
6.3 Electrolytes
Potassium and magnesium should be normalized in all patients
with arrhythmias, especially ventricular tachycardia.
Magnesium is specifically given to patients with polymorphic
ventricular tachycardia in the setting of prolonged QT
(torsade de pointes).
Potassium is given for digoxin toxicity-induced bradycardia
(when hypokalemia is present).
dTable 6–6.3A Antiarrhythmic Indication Summary
Types of Arrythmia
Class
SVTs
Sinus tachycardia
II, IV
Atrial flutter
IA, IC, II, III, IV, digoxin
PSVTs
Adenosine, same as atrial
flutter above
AV block
Atropine
Ventricular Arrythmias
Ventricular tachycardia
I, III, II (Note: use Class IB
drugs if ischemia, digoxin
toxicity, or open heart surgery
Torsade de pointes
Magnesium, II, IV
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 6–13
&KDSWHU‡$QWLDUUKythmics
Pharmacology
dTable 6–6.3B Antiarrhythmic Drug Summary
Class I
IA
Quinidine
Procainamide
Disopyramide
IB
Lidocaine
Mexiletine
IC
Flecainide
Propafenone
Chapter 6–14
Class II
Propranolol
Esmolol
Acebutolol
Class III
Amiodarone
Dronedarone
Dofetilide
Ibutilide
Sotalol
Class IV
Verapamil
Diltiazem
Class V
Adenosine
Magnesium
Potassium chloride
© DeVry/Becker Educational Development Corp. All rights reserved.
Antihypertensives
CHAPTER 7
1
Overview
Hypertension (HTN) is a common problem that can lead to serious
complications, including:
Hypertensive cardiovascular disease with left ventricular
hypertrophy
Stroke
Dementia
Kidney failure
Antihypertensive agents span a wide range of drug classes.
Based on principles of hemodynamics, most antihypertensives
p BP by p CO or p TPR or the drugs p preload by p blood volume.
Chronic antihypertensive treatment can cause reflex n HR
(n SANS) and n renin with edema formation from n aldosterone.
dTable 7–1.0 Blood Pressure Classification
Category
SBP mmHg
DBP mmHg
Normal
< 120
and
< 80
Prehypertension
120–139
or
80–89
Hypertension stage 1
140–159
and
90–99
Hypertension stage 2
• 160
and
• 100
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe hypertensive
diseases and their
management.
X Differentiate
antihypertensive drugs.
X Identify the key side effects
of antihypertensive drugs.
Key: SBP = systolic blood pressure; DBP = diastolic blood pressure
Source: U.S. Department of Health and Human Services
Hypertension is essential in 95% of cases.
Affects 10%–15% of white adults and 20%–30% of black adults in
the United States.
BP = CO × TPR
‡ CO = SV × HR
1
‡ TPRD
radius4
¨BP (disease)
Baroreceptors
Kidney
ANS
RAAS
cFigure 7–1.0 Hypertension
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 7–1
&KDSWHU‡$QWLKypertensives
Pharmacology
Exacerbating factors include:
Obesity
Sleep apnea
Increased salt intake
Alcohol and smoking
Polycythemia
Chronic NSAIDs use
In 5% of cases, HTN is secondary to renal diseases, with
renal artery stenosis present in 1% to 2% of patients. Primary
hyperaldosteronism, Cushing syndrome, and pheochromocytoma
coarctation are some other causes of 2° HTN.
HTN is asymptomatic but no organ is spared.
Chapter 7–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLKypertensives
2
Pharmacology
Treatment of Hypertension
2.1 Lifestyle Modifications
DASH (Dietary Approaches to Stop Hypertension): A diet rich in
fruits and vegetables and low in saturated fat has been proven to
lower systolic blood pressure by 8–14 mmHg.
Weight reduction decreases systolic blood pressure by 5–20
mmHg for each 10 kg lost.
Sodium restriction lowers systolic blood pressure by 2–8 mmHg.
Regular aerobic activity (30 min brisk walking a day) lowers
systolic blood pressure by 4–9 mmHg.
2.2 Drug Management of Hypertension
Because lifestyle changes only yield modest reduction in BP,
medications are most likely necessary when a patient is diagnosed
with HTN.
Choice is driven by the results of large outcome studies and
existing clinical guidelines.
dTable 7–2.2A Drug Choice Based on Comorbid Condition
HTN and Associated
Disease
Post MI or high CAD
risk
Recommended Drug
Comment
Beta-blockers
Cardioprotective
ACE I
Reduce incidence of heart
failure, MIs, strokes
Diabetes
ACE I
ARBs
Delay progression of
nephropathy
CHF
ACE I
Usually in conjunction with
beta-blockers and diuretics
BPH
D1-blockers
Only time when they may
be used as initial agents
dTable 7–2.2B Drug Choice Based on Demographic Data
Regime
Not Black, < Age 55
Not Black, > Age 55
Black, Any Age
First line
ACE I, ARBs (or CCB
or diuretics)
CCB or diuretics
CCB or diuretics
Second line
Vasodilating betablocker (carvedilol
or nebivolol)
ACE I, ARB,
or vasodilating
beta-blocker
ACE I, ARB,
or vasodilating
beta-blocker
Note: Resistant HTN is the failure to control BP in spite of an appropriate three-drug
regimen which includes a diuretic. In such cases, aldosterone receptor antagonists
should be part of the treatment regimen for all groups.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 7–3
&KDSWHU‡$QWLKypertensives
Pharmacology
dTable 7–2.2C Drugs Used in Hypertensive Emergencies and Urgencies
Drug
Class
Comment
Nicardipine
Clevidipine
L-type calcium channel
blockers
‡ )LUVWchoice
‡ May precipitate MI
Labetalol
Esmolol
Beta- and alpha-blocker
Beta-blocker
Avoid in systolic
dysfunction
Fenoldopam
D1 agonists
Protects kidney function
Other drugs include enalaprilat, furosemide, hydralazine, nitroglycerin, and sodium
nitroprusside.
2.3 Individual Drug Classes
2.3.1 Diuretics
Diuretics (especially thiazide diuretics) are widely used to treat
hypertension.
Most consistently effective HTN drugs in clinical trials.
Most effective in African-Americans, patients over 55, and the obese.
Therapeutic effect:
Initially decrease volume
Chronically decrease TPR
Chlorthalidone has better 24-hour BP control than
hydrochlorothiazide.
Diuretics also are indicated for the treatment of fluid retention in
congestive heart failure, edema (e.g., related to advanced renal
or liver disease), and some electrolyte abnormalities.
More detailed discussion of these agents appears in chapter 11.
Chapter 7–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLKypertensives
Pharmacology
2.3.2 Sympatholytic Agents
Centrally acting agonists +
Gq
Presynaptic:
Indirect acting drugs
Postsynaptic:
Direct acting drugs
Gi
Reserpine –
VMAT
G
NE
NE
NE
G
NET
Guanethidine (G)
GS
Sympatholytic Drugs
cFigure 7–2.3A Sympatholytic Drugs
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 7–5
&KDSWHU‡$QWLKypertensives
Pharmacology
Centrally Acting
D-Methyldopa
Prodrug that is converted to D-methyl-norepinephrine.
The active compound is an agonist at the presynaptic
D2-receptors in the brainstem.
Produces inhibition of CNS sympathetic outflow and a decrease
in blood pressure through decreases in cardiac output (E1)
and vascular tone (D1).
Drug of choice for the treatment of mild to moderate
hypertension in pregnancy.
Adverse effects:
— Autoimmune hemolytic anemia: Up to 20% of patients taking
D-methyldopa will develop a positive Coombs test, but overt
hemolytic anemia is rare.
— Hepatitis.
Clonidine
Activates presynaptic D2-receptors in the vasomotor center
of the brainstem, reducing sympathetic output and decreasing
blood pressure.
Useful in alleviating opiate withdrawal (see chapter 18).
Connection to
Immunology
The direct Coombs test is used
to diagnose IgG antibodies
against red blood cells. It is
performed by taking a sample
of blood from the patient,
adding antihuman globulin
(Coombs serum), and observing
for agglutination. The indirect
Coombs test detects free
antibodies in a patient's serum.
It mixes the patient's serum
with erythrocytes of known
antigenicity, adding Coombs
serum, and observing for
agglutination.
Reserpine
VMAT transports norepinephrine, dopamine, and serotonin
from the cytoplasm of the presynaptic nerve terminal into
storage vesicles for subsequent release.
Reserpine acts by irreversibly blocking the vesicular
monoamine transporter (VMAT).
These neurotransmitters are then broken down.
The net result is a depletion of neurotransmitters and reduced
sympathetic outflow.
Side effects:
— Major depression-like syndrome
— Severe GI complications
Peripherally Acting
These agents act by modulating effects of the sympathetic nervous
system peripherally. They include guanethidine and D- and
E-adrenergic receptor blockers.
Guanethidine
Acts as a "false neurotransmitter."
Norepinephrine transporter (NET) takes guanethidine into
sympathetic nerves.
Concentrated into vesicles, it displaces norepinephrine.
Because guanethidine is inactive at adrenergic receptors,
the result is a decrease in sympathetic transmission.
Tricyclic antidepressants block reuptake and prevent
guanethidine's effect.
Guanethidine is rarely used because of side effects.
Chapter 7–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLKypertensives
Pharmacology
D1-Adrenergic Receptor Antagonists
Include prazosin, doxazosin, and terazosin.
Selective antagonists of peripheral D1-adrenergic receptors.
Reduce blood pressure by relaxing vascular smooth muscle and
decreasing arteriolar resistance.
Uncommonly selected as primary agents to treat hypertension
due to side effects such as orthostatic hypotension (on starting
therapy, "first-dose syncope").
D1-Adrenergic antagonists may be considered in patients with
benign prostatic hyperplasia (BPH) to prevent urinary retention.
Have modest favorable effects on plasma lipids—decreased
low-density lipoprotein (LDL) and increased high-density
lipoprotein (HDL).
E-Adrenergic Receptor Antagonists
Beta-blockers are widely used to treat hypertension.
Often more effective in younger patients (higher resting
sympathetic tone) and in high renin HTN (whites > blacks).
E1 block:
— Heart: p HR, contractility, and CO
— Kidney: p renin and TPR
Side effects:
— Bradycardia
— AV conduction block
— Hypotension
— )atigue
— Sexual dysfunction
— May cause or exacerbate depression
— Abrupt withdrawal of beta-blockers may result in rebound
hypertension and tachycardia
!
Important Concept
E2 blockade aggravates the
following conditions:
‡ $VWKPD
‡ 9asospastic diseases
‡ D
iabetes
Clinical
Application
First-line therapy for
beta-blocker overdose
is intravenous glucagon,
which binds to its receptor
on cardiac cells and
increases intracellular
F$03LQGHSHQGHQWO\
from the E-receptor.
dTable 7–2.3 Selectivity of E-Blockers
Drug
Nonselective E-Blockers
Propanol
Nadolol
Timolol
Nonselective E and D1 Antagonists
Labetalol
Carvedilol
E-Adrenergic Partial Agonists
Acebutolol
Pindolol
E1-Selective Blockers
Atenolol
Betaxolol
Bisoprolol
Metoprolol
E-Blocker and NO release
Nebivolol
© DeVry/Becker Educational Development Corp. All rights reserved.
!
Important Concept
Be able to identify the classes
into which the various betablockers fall.
Chapter 7–7
&KDSWHU‡$QWLKypertensives
Pharmacology
Nonselective Beta-Blockers
These agents block both E1- and E2-receptors. Prototypical agents
in this class include:
Propranolol
Nadolol
Timolol
Used for the treatment of hypertension in cases of active coronary
artery disease.
Nonselective beta-blockers are indicated for other conditions:
Propranolol: hyperthyroidism, phobias
Propranolol and nadolol: portal hypertension and cirrhosis
Timolol: eye-drop treatment for glaucoma
Cardioselective E1-Blockers
Include atenolol, betaxolol, bisoprolol, and metoprolol.
Safer to use with asthmatics, patients with peripheral vascular
disease (PVD), and diabetics.
Mortality and morbidity benefits with metoprolol in patients
with chronic heart failure and post-myocardial infarction.
Third-Generation Beta-Blockers
Also vasodilators.
Nonselective beta-blockers with D1 blocking activities: carvedilol
and labetalol.
Cocaine overdose: Labetalol prevents cocaine's vasoconstrictive
effects.
The cardiac and renal effects of these agents are similar
to those of other beta-blockers.
They also produce vasodilation and reduce peripheral vascular
resistance through Dblockade on vascular smooth muscle.
More effective as antihypertensives compared to other
beta-blockers.
,QGLFDWHGDOVRLQDFXWH&+)PDQDJHPHQW
E-selective blocker with NO release activity: Nebivolol.
2.3.3 Direct Vasodilators
Have no ANS pharmacology:
Will cause reflex tachycardia (add a E1-blocker) and edema
(add a diuretic).
Act directly on the arteriolar smooth muscle, causing a decrease
in systemic vascular resistance and lowering of blood pressure.
Include:
Prodrugs of NO:
— Hydralazine
— Sodium nitroprusside
ATP-dependent K+ channel openers:
— Minoxidil
— Diazoxide
Chapter 7–8
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLKypertensives
Openers: Minoxidil
Diazoxide
Pharmacology
ATP dependent
K+ channels
K+ efflux
Hyperpolarization
+ Protein kinase G
cGMP
GTP
Guanylate
cyclase
+
+ Phosphatase
NO
Myosin light
chain P (active)
Myosin light
chain (inactive)
NO
NO
synthase
Arginine
NO prodrugs
Hydralazine
Nitroprusside
Nitrates
(see angina)
Smooth
muscle
relaxation
Endothelium
cFigure 7–2.3B Direct Acting Vasodilators
Hydralazine
Prodrug of NO
Selective arteriolar dilation
Safe in pregnancy
Used for moderate to severe HTN
Side effects:
— SLE-like syndrome, which is more common in "slow acetylators"
— Reflex tachycardia and fluid retention
!
Important Concept
Hypertension in pregnancy:
‡ Mild: methyldopa
‡ Severe: hydralazine
Sodium nitroprusside
Intravenous medication used for hypertensive emergencies
Metabolized to nitric oxide
Causes venous and arterial vasodilation through cGMP
dependent pathways
No longer a DOC (see Table 7–2.2C)
Nitroprusside is converted to cyanide
Only used in slow infusion
Sodium nitrite followed by sodium thiosulfate is the antidote to
cyanide poisoning and may be administered if toxicity is suspected
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 7–9
&KDSWHU‡$QWLKypertensives
Pharmacology
Minoxidil
Potent direct arteriolar vasodilator that is available orally
and usually reserved for refractory hypertension.
Opens ATP-dependent K+ channels in vascular smooth muscle,
causing hyperpolarization.
Results in smooth muscle relaxation, reduced peripheral
vascular resistance, and decreased blood pressure.
Side effects:
— Hypertrichosis (excess hair growth), which has been
exploited in topical hair products for baldness (e.g., Rogaine)
— Reflex tachycardia and edema
!
Important Concept
‡ $73GHSHQGHQWK+ channels
are also found on E cells of
the pancreas.
‡ 0LQRxidil and diazoxide
suppress insulin release and
are diabetogenic.
‡ Diazoxide is used in insulinoma.
2.3.4 Calcium Channel Antagonists (CCBs)
There are two classes of CCBs:
Dihydropyridines, which all end in "-dipine"
Non-dihydropyridines
Dihydropyridine Calcium Channel Blockers
More commonly used in the treatment of hypertension.
Include:
Amlodipine
)elodipine
Isradipine
Nicardipine
Nifedipine
Nisoldipine
Block L-type Ca2+ channels in vascular smooth muscle,
causing vasodilation and decreased peripheral vascular resistance.
Do not strongly affect cardiac tissue channels and have no effects
on heart rate or contractility.
Adverse effects:
Gingival hyperplasia (consider isradipine)
Hypotension and lower-extremity edema
Reflex tachycardia
Non-dihydropyridine Calcium Channel Blockers
Include verapamil and diltiazem.
Antagonize calcium channels in the heart resulting in decreased
heart rate and contractility.
May be used to control hypertension in patients with angina
who cannot tolerate beta-blockers.
Adverse effects:
AV conduction block
Heart failure
Constipation (with verapamil)
Chapter 7–10
Looking Ahead
Gingival hyperplasia is also
seen with:
‡ $QWLFRQvulsants:
— 3KHQytoin
— Ethosuximide
— Topiramate
— 9alproate
‡ Cyclosporine
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLKypertensives
Pharmacology
2.3.5 Agents Modulating the Renin-AngiotensinAldosterone System
Liver
Angiotensinogen
Renal perfusion
SANS
+
Na+ in DCT
Renin (JG cells)
‡ β1 blockade release
‡ Aliskiren inhibits
Vasodilates
Bradykinin
Angiotensin I
Angiotensin
Converting
Enzyme
‡ ACE inhibitors
(-pril)
A
C
E
Angiotensin II
+
Prostaglandins
Inflammation
Inactive metabolites
Vessels:contraction
AT-1 receptors
‡ ARBs block
(-sartan)
Adrenal cortex: aldosterone secretion
‡ Spironolactone
Eplerenone
– Aldosterone receptors (see Chapter 8)
cFigure 7–2.3C Drugs Acting on the Renin-Angiotensin-Aldosterone System
Angiotensin Converting Enzyme (ACE) Inhibitors:
Captopril Family
Widely used class of agents for the treatment of hypertension.
Include 10 drugs ending in "-pril."
Enalapril is a prodrug; enalaprilat is the active metabolite.
6HH)LJXUH±'DWHQGRIFKDSWHUIRUDFRPSOHWHOLVW
All agents are effective, and differences are mostly related to
pharmacokinetic properties such as half-life and dosing interval.
Multiple clinical trials have demonstrated long-term benefits of
ACE inhibitors in patients with a range of conditions, including:
Left ventricular systolic dysfunction (especially postmyocardial infarction)
Diabetic or hypertensive nephropathy
Heart failure
Stroke
Prevent the conversion of angiotensin I to angiotensin II:
p
Vasoconstrictive effects of angiotensin II peripherally
(afterload reduction) and in the kidney (causing efferent
arteriolar dilation)
Decrease the release of aldosterone:
Prevent sodium and water retention
Increase bradykinin:
Beneficial vasodilatory effects
Contributes to dry cough
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 7–11
&KDSWHU‡$QWLKypertensives
Pharmacology
Angiotensin II Receptor Antagonists (ARBs): Losartan Family
Also commonly used in the treatment of hypertension.
Include seven drugs ending in "-sartan."
See figure 7–2.3D at end of chapter for a complete list.
Directly antagonize the angiotensin II receptor.
ARBs do not affect bradykinin metabolism.
ARBs have similar effectiveness to ACE inhibitors in regard to
blood pressure control, but it is less clear whether these drugs
possess all the long-term benefits shown with ACE inhibitors.
Adverse Effects of ACE Inhibitors and ARBs
Both ACE inhibitors and ARBs can cause hypotension and
hyperkalemia.
Both are contraindicated in bilateral RAS (or in patients who only
have a single functioning kidney with RAS).
Alterations in renal function are the result of a combination of
decreased blood pressure and decreased glomerular filtration
due to efferent arteriolar dilation.
Heavy NSAID use increases the risk of adverse renal effects
related to the use of ACE inhibitors and ARBs.
Both ACE inhibitors and ARBs are contraindicated throughout
pregnancy because of detrimental effects on fetal renal function
(e.g., oligohydramnios and Potter syndrome) and teratogenicity.
Adverse effects of ACE inhibitors > ARBs:
Dry cough usually managed by changing the patient to an ARB
Life-threatening angioedema
Renin Inhibitors: Aliskiren
Newer class of antihypertensive agents, which act by directly
inhibiting the enzyme renin:
Block the conversion of angiotensinogen to angiotensin I.
!
Important Concept
Be able to identify the adverse
effHFWVRI$CE inhibitors and
$5%VDQGZKLFKDGYerse
effHFWVDUHVHHQPRUHZLWK$CE
inhibitorVWKDQZLWK$5%V
(e.g., cough, angioedema).
Adverse effects include hyperkalemia, and, in rare cases,
angioedema.
Aliskiren is contraindicated in pregnancy.
Chapter 7–12
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLKypertensives
Pharmacology
Vasomotor center: α2 agonists
‡ 0HWK\OGRSD
‡ &ORQLGLQH
‡ *XDQDEHQ]
‡ *XDQIDFLQH
Sympathetic
nerve terminals
‡ *XDQHWKLGLQH
‡ *XDQDGUHO
‡ 5HVHUSLQH
-receptors of heart
‡ 3URSUDQRORODQG
RWKHU EORFNHUV
Sympathetic ganglia: NN antagonist
‡ 7ULPHWKDSKDQ
-receptors of vessels
‡ 3UD]RVLQDQG
RWKHU EORFNHUV
Angiotensin Vascular smooth muscle
‡ +\GUDOD]LQH
‡ 9HUDSDPLODQGRWKHU
‡ 0LQR[LGLO
FDOFLXPFKDQQHOEORFNHUV
‡ 1LWURSUXVVLGH ‡ )HQROGRSDP
‡ 'LD]R[LGH
receptors of vessels
‡/RVDUWDQ
‡&DQGHVDUWDQ
‡(SURVDUWDQ
Kidney tubules
‡,UEHVDUWDQ
‡ 7KLD]LGHV
‡2OPHVDUWDQ
‡7HOPLVDUWDQ
‡9DOVDUWDQ
$QJLRWHQVLQ,,
$QJLRWHQVLQ
FRQYHUWLQJ
HQ]\PH
-receptors of juxtaglomerular
cells that release renin
‡ 3URSUDQRORODQG
RWKHU EORFNHUV
$QJLRWHQVLQ,
‡&DSWRSULO
‡%HQD]HSULO
‡(QDODSULO
‡)RVLQRSULO
‡/LVLQRSULO
‡0RH[LSULO
‡3HULQGRSULO
‡4XLQDSULO
‡5DPLSULO
‡7UDQGRODSULO
5HQLQ
$QJLRWHQVLQRJHQ
‡$OLVNLUHQ
cFigure 7–2.3D Antihypertensive Drug Summary and Sites of Action
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 7–13
CHAPTER 8
1
Drugs for Heart Failure
Overview
Five million patients have heart failure in the United States.
Three fourths of patients are older than 65.
dTable 8–1.0A Heart Failure: Symptoms and Causes
Side*
Symptoms
Left-sided
Right-sided
Causes
‡ p CO
‡ n Pulmonary venous
pressure: dyspnea—
exertional o orthopnea
o paroxysmal nocturnal
dyspnea o rest dyspnea
1. Ischemic heart disease
2. Hypertension
3. Cardiomyopathies
4. Valvulopathies
Fluid retention:
‡ Pitting edema of legs
‡ Hepatic congestion
("nutmeg liver")
1. Left-side heart failure
2. Pulmonary disease: cor
pulmonale
USMLE® Key Concepts
For Step 1, you must be able to:
*Note that most patients have symptoms of left- and right-sided heart failure.
X Explain the role of SANS and
RAAS in CHF.
X Contrast drugs that p
remodeling and n survival
with drugs that n inotropy. X Describe the action, use,
and side effects of digoxin.
Passive Congestion
Heart Failure
‡'LXUHWLFV
Loops and thiazides
‡6\PSDWKRPLPHWLFV
‡'LJR[LQ
p CO
pRenal perfusion pressure
Silent baroreceptors
‡E-blockers p release
n SANS
n Renin
n NE
n Angiotensin I
‡$OLVNLUHQ ʥ
‡ Combined D, E blockade:
Labetalol, carvedilol
+ D
1
+E
n Angiotensin II
1
‡ n Afterload by n TPR
‡ n Contractility
‡ nPreload by nYHQRXVUHWXUQ
‡ n Renin
‡$&(LQKLELWRU ʥ
‡$5%V ʥ
+ AT-1
n Afterload by n TPR
n Aldosterone
+ Aldosterone receptors
‡6SLURQRODFWRQH
‡(SOHUHQRQH ʥ
Na+, H2O retention
‡ n Preload
cFigure 8–1.0 Pathophysiology of Heart Failure and Therapeutic
Sites of Action
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 8–1
&KDSWHU‡'UXJVIRU+HDUW)ailure
Pharmacology
dTable 8–1.0B Clinical Stages of Heart Failure and Treatment Options
Stage
Symptoms
A
‡ High risk, but no signs or symptoms
B
‡ Structural heart disease, but no symptoms
C
‡ Structural heart disease with symptoms
D
‡ Heart failure refractory to conventional
therapy
Treatment
‡ Control hypertension, hyperlipidemia, and/
or diabetes
‡ Give diuretics, ACE inhibitors or ARBs
‡ Add digitalis, beta-blocker, aldosterone
antagonists, vasodilators
‡ Cardiac resynchronization
‡ Heart transplant
The pharmacotherapy for heart failure targets:
p Preload: diuretics, ACE inhibitors, ARBs, and venodilators
p Afterload: ACE inhibitors, ARBs, and arteriodilators
n Contractility: digoxin, beta agonists
p Remodeling of cardiac muscle: ACE inhibitors, ARBs,
spironolactone, eplerenone, carvedilol
Whereas digoxin does not improve survival, ACE inhibitors, ARBs,
carvedilol, and spironolactone have been proved beneficial for
congestive heart failure (CHF)
Initial treatment: a diuretic and an ACE inhibitor with the early
addition of a beta-blocker
Clinical
Application
Some treatment may be harmful and should be avoided
in heart failure:
ACE inhibitor + ARB + spironolactone—because of
hyperkalemia
Thiazolidinediones (glitazones)—because they worsen
heart failure
Calcium channel blockers (except amlodipine,
felodipine)
NSAIDs and COX-2 inhibitors—because they worsen
renal function
Chapter 8–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'UXJVIRU+HDUW)ailure
2
Pharmacology
Inotropes: Drugs That Increase
Contractility
Cardiac Cell
! Monitor K+
carefully
Sarcoplasmic reticulum
Digoxin – 2 K
3 Na+
+
Ca2+
Contractility
CO
Ca2+
2H+
3 Na+
Ca2+
+
Ca2+
channel
! Avoid calcium
channel blockers
in heart failure
AMP
+
Via protein
kinase A
activation
Phosphodiesterase – Inamrinone,
Milrinone
ATP
cAMP Adenylyl cyclase (via G protein)
ƹ
s
β1 receptor +
! Chronic stimulation
leads to desensitization
Dobutamine,
isoproterenol
norepinephrine, epinephrine, dopamine
cFigure 8–2.0 Mechanism of Action of Inotropes
2.1 Digoxin
Direct effect: Inhibition of cardiac Na+/K+-ATPase
Results in n intracellular Na+
p Na+/Ca2+ exchange
n Intracellular Ca2+
n Ca2+ release from sarcoplasmic reticulum
n Actin-myosin interaction
n Contractile force
Indirect effect: Inhibition of neuronal Na+/K+-ATPase
Results in n vagal activity:
— p Heart rate
— n Diastolic filling
— n SV
Results in n sympathetic activity:
— n Contractility
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 8–3
&KDSWHU‡'UXJVIRU+HDUW)ailure
Pharmacology
Pharmacokinetics:
Long t1/2 (24–36 hours):
— Need loading dose (LD)
Renal clearance:
— Caution in renal impairment (p dose)
Tissue protein binding (large Vd):
— Displacement by other drugs (can n digoxin by 100%)
— Amiodarone
— Propafenone
— Quinidine
— Verapamil
Therapeutic drug monitoring and potassium level monitoring
required
Uses:
CHF
Supraventricular tachycardias, except Wolff-Parkinson-White
syndrome
Side effects:
Early signs include anorexia, nausea, vomiting, diarrhea
Later signs include disorientation, visual effect disturbances
In toxic doses, any cardiac arrhythmias: ECG shows inverted
T waves, ST depression, and premature ventricular beats
Management of toxicity:
Use of Fab antibodies toward digoxin
Supportive therapy (electrolytes and antiarrhythmics class IB)
Electrolyte interactions:
p K+, p Mg2+, n Ca2+ (all increase digoxin toxicity)
Caution with:
— K+ wasting diuretics
— Loops (p Mg2+)
— Thiazides (n Ca2+)
Clinical
Application
8PMGG1BSLJOTPO8IJUF4ZOESPNF
‡ 7reatment: Block accessory pathway with IA or III
‡ Caution: Do not slow AV conduction (avoid digoxin, beta-blocker,
Ca2+ channel blocker, adenosine)
AV node
SA node
(slow conduction)
Conduction
accessory
pathways
(fast muscle fibers)
Chapter 8–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'UXJVIRU+HDUW)ailure
Pharmacology
2.2 Bipyridines
Inamrinone and milrinone
cAMP phosphodiesterase inhibitors
n cAMP in heart muscle which results in n inotropy
n cAMP in smooth muscle which results in p TPR
2.3 Sympathomimetics
Dobutamine and dopamine
See unit 2, chapter 3 for details
3
Drugs Without Positive Inotropic Effects
Diuretics:
Loops for associated backward failure
Spironolactone to p remodeling (with ACE inhibitors)
ACE inhibitors or ARBs
Metoprolol and carvedilol
Nesiritide:
Recombinant form of human B-type natriuretic peptide (rhBNP)
Binds to natriuretic peptide receptors, activating the receptorassociated guanylate cyclase
The n cGMP vasodilates and n natriuresis, p preload
Used in acutely decompensated CHF
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 8–5
&KDSWHU‡'UXJVIRU+HDUW)ailure
4
Pharmacology
Pulmonary Hypertension and
Cor Pulmonale
WHO classifies pulmonary HTN in five groups based on etiology:
Group 1: Idiopathic/familial/primary
Group 2: Secondary to left-sided heart failure
Group 3: Secondary to hypoxemia of lung diseases
(advanced COPD/RPD)
Group 4: Secondary to chronic thromboembolism
Group 5: Secondary to other causes
First-line therapy includes oral calcium channel blockers and
treatment of underlying disorder
4.1 Endothelin Receptor Antagonists
Block ETA/ETB receptors: bosentan
Block ETA only: ambrisentan
Prevent vasospasm from endothelin
Contraindicated in pregnancy
Side effects are related to vasodilation:
Hypotension
Increased heart rate
Flushing
Headaches
4.2 Phosphodiesterase Type V Inhibitors
Sildenafil and tadalafil
ncGMP
Also used in erectile dysfunction
Avoid with nitrates in angina/MI patients
4.3 Prostacyclin Analogs
Epoprostenol:
Requires continuous IV infusion
Iloprost and treprostinil:
Available by inhalation
4.4 Oral Soluble Guanylate Cyclase Activator
Riociguat
Contraindicated with nitrates or PDE-type V inhibitors
Side effects related to vasodilation
Chapter 8–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'UXJVIRU+HDUW)ailure
Pharmacology
dTable 8–4.4A Heart Failure Drug Summary
Type
Inotropes
Drugs
Na+/K+ ATPase inhibitor: Digoxin
cAMP phosphodiesterase inhibitors:
‡ $PULQRQH
‡ 0LOULQRQH
Sympathomimetics (see chapter 5)
ACE inhibitors (see chapter 7)
p Remodeling
ARBs (see chapter 7)
D- and ǃ-blockers (see chapter 7)
Diuretics (see chapter 11)
Recombinant atrial
natriuretic peptide
Nesiritide
dTable 8–4.4B Pulmonary Hypertension Drug Summary
Type
Drugs
Endothelin receptor antagonists
Bosentan
Ambrisentan
PDE type V inhibitors
Sildenafil
Tadalafil
PGI2 analogs
Epoprostenol
Iloprost
Treprostinil
Soluble guanylate cyclase activator
Riociguat
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 8–7
CHAPTER 9
1
Treatment of Ischemic
Heart Disease (IHD)
Overview
Coronary artery disease (CAD) is the No. 1 cause of death in the
United States and worldwide.
Responsible for one in four deaths each year in the U.S.
(600,000).
Risk factors for CAD include:
Hyperlipidemia
Hypertension
Diabetes
Smoking
Obesity
Family history
Male, sedentary lifestyle
> 16 million Americans with CAD (~6% of population).
USMLE® Key Concepts
For Step 1, you must be able to:
X Identify risk factors for CAD.
X Name drugs that improve
survival in IHD patients.
X Describe action and side
effects of nitrates.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 9–1
&KDSWHU‡7reatment of Ischemic Heart Disease (IHD)
2
Pharmacology
Angina vs. Myocardial Infarction (MI)
Angina: Reversible pain secondary to ischemia
MI: Irreversible cardiac injury (coagulation necrosis) following
ischemia
$FXWHFRURQDU\V\QGURPH
6WDEOHDQJLQD
8QVWDEOHDQJLQD
$FXWH0,
‡3UHFRUGLDOFKHVWSDLQ
SUHFLSLWDWHGE\VWUHVVRUH[HUFLVH
‡6\PSWRPVDWUHVWRUZLWKPLQLPDOH[FHUFLVH
‡5DSLGO\UHOLHYHGE\UHVWRUQLWUDWHV
‡0D\QRWEHUHOLHYHGE\QLWUDWHV
‡Classified based on ECG findings
as STEMI or non STEMI
(ST-segment elevation MI)
‡This distinction is essential for management
(reperfusion therapy or not)
‡0DLQVWD\RIWUHDWPHQW
—Prevention of further
attacks by O2 demand,
‡0DLQVWD\RIWUHDWPHQW
—Antiplatelet drugs
O2 supply
—Anticoagulants
—Nitrates
—Coronary intervention (PCI, CABG)
— -blockers
—Fibrinolysis only in STEMI
—Ca2+ channel blockers
—Antiplatelet drugs
—Risk reduction (treat hyperlipidemia,
diabetes, etc.)
$IWHUDFXWHFRURQDU\V\QGURPH0,
‡
‡
Treatment of complications
(CHF, arrhythmias, etc.)
Survival and
reinfarction
— -blockers
—Antiplatelet drugs
—Statin drugs
—ACE inhibitors/ARBs/spironolactone if CHF
cFigure 9–2.0 Progression and Management of Angina and MI
Chapter 9–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡7reatment of Ischemic Heart Disease (IHD)
3
Pharmacology
Individual Drugs
Decrease oxygen demand by decreasing heart rate, contractility,
afterload, and preload.
Increase oxygen supply by promoting coronary blood flow.
3.1 Nitrates
Mechanism of Action
Nitrates are converted to nitric oxide (NO) inside cells.
NO activates soluble guanylate cyclase, which results in
generation of cGMP.
Cyclic GMP activates myosin light-chain phosphatase via a
cGMP-dependent protein kinase, resulting in vasodilation.
See chapter 7, Figure 7–2.3B.
Large vein dilation p preload and p heart work and O2
consumption.
Arteriolar dilation p afterload and p heart work and O2
consumption.
Dilation of coronary arteries n oxygen supply to cardiac muscle
(minor contributor).
Tachyphylaxis
Acute tolerance: Decreased response with repeated dosing
of a drug.
7o avoid tachyphylaxis, patients should have a nitrate-free
interval of 8–12 hours or more during their dosing cycle to
restore effectiveness.
Formulation
Short-acting nitroglycerin:
— Used when needed
— Sublingual, buccal spray, or IV to avoid first-pass metabolism
Long-acting nitrates:
— Isosorbide mono- or dinitrate
— Oral sustained-release nitroglycerin
— Nitroglycerin ointment, transdermal patch
— All are associated with tachyphylaxis
Side Effects
Flushing
Headache
Hypotension
Drug Interaction: PDE5 inhibitors
3.2 Beta-Blockers
See unit 2, chapter 5 for individual drugs.
Contraindicated in vasospastic angina (see calcium channel
blockers).
Avoid partial agonists.
7KHRQO\DQWLanginal drugs proven to prolong life post MI.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 9–3
&KDSWHU‡7reatment of Ischemic Heart Disease (IHD)
Pharmacology
3.3 Calcium Channel Blockers (CCBs)
Unlike beta-blockers, CCBs have not been proven to p mortality
post infarction.
Dihydropyridine and non-dihydropyridine CCBs can be used for
prevention of angina.
Diltiazem and verapamil reduce heart rate and contractility,
decreasing myocardial oxygen demand.
Dihydropyridines (nifedipine family) decrease afterload, cardiac
work, and also dilate coronary arterioles.
Beneficial in coronary vasospasm: Prinzmetal angina, cocaine
addicts.
See unit 3, chapters 6 and 7 for individual drugs.
3.4 Late Inward Na+ Channel Blocker: Ranolazine
Ischemia and p O2 supply p activity of Na+/K+-A73ase.
n Intracellular Na+ p Na+/Ca2+ exchange.
Ischemia causes:
n Intracellular Ca2+
n Diastolic pressures
p Coronary blood flow
Ranolazine blocks late inward Na+ current and allows p of
intracellular Ca2+ overload.
No effect on BP or HR (safe in combination with nitrates,
beta-blockers).
First-line use for chronic angina treatment (not for acute treatment).
Can n47:
Contraindicated with antiarrhythmic class I or III drugs.
Caution with P450 inhibitors.
1RWLQGLFDWHGLQSDWLHQWVZLWKORQJ47V\QGURPH
Avoid in patients with significant liver or kidney disease.
3.5 Other Drugs
For antihyperlipidemic drugs, see unit 3, chapter 10.
For antiplatelet drugs, see unit 4, chapter 12
For anticoagulants, see unit 4, chapter 13.
For thrombolytic drugs, see unit 4, chapter 14.
dTable 9–3.5 IHD Drug Summary
Type
Drugs
Nitrates
Nitroglycerin
Isosorbide mono- or dinitrate
ǃ-blockers
See chapter 5 for individual drugs.
Calcium channel blockers
See chapters 6 and 7 for individual
drugs.
Late inward Na+ channel blocker
Ranolazine
Chapter 9–4
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 10
1
Antihyperlipidemics
Overview
Dyslipidemia is a major risk factor for a wide range of clinical
disorders, most commonly affecting the cardiovascular and
cerebrovascular system.
Various drugs are available to improve lipid profile and thereby
reduce the risk of cardiovascular complications in patients with
existing cardiovascular disease.
2
USMLE® Key Concepts
Plasma Lipid Abnormalities
Dyslipidemia can manifest in a variety of clinical signs and
symptoms.
The plasma lipid profile is often measured to assess risk for
cardiovascular disease.
70
60
Age
50
40
X Explain the management of
hyperlipidemia.
X Identify lipid lowering drugs.
X Describe side effects of lipid
lowering drugs.
Myocardial infarction
Cerebral infarction
Gangrene of extremities
Abdominal aortic aneurysm
Clinical horizon
Fibrous
plaque
30
20
10
For Step 1, you must be able to:
Complications:
‡7KURPERVLV
‡3ODTXHUXSWXUH
‡+HPRUUKDJH
‡:DOOZHDNHQLQJ
‡&DOFLILFDWLRQ
Fatty
streak
0
cFigure 10–2.0 Atherosclerosis and Thrombosis
2.1
Atherosclerosis and LDL
Atherosclerosis:
A condition in which artery walls thicken due to the
accumulation of lipid.
Secondary inflammatory response in the walls of arteries,
caused by the accumulation of inflammatory cells, such as
macrophages (foam cells).
Promoted by elevated levels of low-density lipoprotein (LDL).
Oxidized LDL are responsible for the initial fatty streak
formation in large arteries.
© DeVry/Becker Educational Development Corp. All rights reserved.
Connection to
Pathology
‡ Biochemistry, chapter
12, topic 6 on lipoprotein
metabolism.
‡ Pathology, chapter 11, topic
2.2 on artherosclerosis.
Chapter 10–1
&KDSWHU‡$QWLKyperlipidemics
Pharmacology
In mg/dL:
Tryglycerides
5
Science Source
LDL cholesterol = Total cholesterol í HDL cholesterol í
cFigure 10–2.1A Lipid Deposits on Artery Walls
2.1.1 Coronary Artery Disease
Plaques narrow the caliber of vessels:
pOxygen delivery and stable angina
Plaques may result in acute coronary syndromes:
Rupture
Secondary thrombus formation
Acute reduction of blood flow
2.1.2 Peripheral Vascular Disease
p Blood flow to organs or limbs:
Caliendo/Custom Medical Stock Photo
Renal artery stenosis
Intermittent claudication
Ischemic foot ulcerations
Atheromatous plaques in large vessels such as the aorta may
embolize:
Digital necrosis and acute limb ischemia (atheroemboli)
cFigure 10–2.1B Atheroembolism
2.1.3 Cerebral Vascular Accidents
Atheroemboli to the cerebral vasculature result in embolic strokes—
in particular, the middle cerebral artery (MCA) territory.
Chapter 10–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLKyperlipidemics
Pharmacology
2.2 Cholesterol Gallstones
Form when bile contains too much cholesterol and not enough
bile salts.
Biliary colic results from blocking bile outflow.
Acute hemorrhagic pancreatitis results from accumulation of
stones in the ampulla of Vater.
2.3 Visible Manifestations of Hyperlipidemia
Extreme hyperlipidemia may have visible manifestations:
Mediscan/Visuals Unlimited, Inc.
Barbara Galati/Phototake
Dr. Ken Greer/Visuals Unlimited, Inc.
Biophoto Associates/Sciene Source
Xanthelasma
Retinal lipid deposits
Tendon xanthomas
Skin xanthomas
cFigure 10–2.3 Manifestations of Hyperlipidemia
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 10–3
&KDSWHU‡$QWLKyperlipidemics
Pharmacology
2.4 Goals of Antilipidemic Therapy
Primary goal is reduction of LDL cholesterol.
Once LDL is at the targeted goal, then other lipids can be addressed.
If patients have very high triglycerides (> 500 mg/dL), prevent
pancreatitis by lowering triglyceride levels.
All patients should be encouraged to initiate therapeutic lifestyle
changes:
Low-fat diet
Increased physical activity
Weight loss
2.4.1 Low-Density Lipoprotein (LDL)
Target LDL is based on coronary heart disease (CHD) risk, with
patients in higher-risk categories having more aggressive
(i.e., lower) LDL goals.
Risk is determined by assessing the absolute 10-year risk of CHD
using the Framingham Risk Score.
CHD risk factors:
Smoking
Hypertension
HDL < 40 mg/dL
Age • 45 in men and • 55 in women
Family history of premature CHD in a first-degree relative
Each risk factor is given a number of points.
The sum of all the points estimates the 10-year risk of CHD in
percentage.
Example: 15 points in men estimates a CHD 10-year risk at 20%.
dTable 10–2.4 Framingham Estimated 10-Year Risk of CHD
and Optimal LDL Levels
Risk
Low
Moderate
Moderately High
High
Framingham
10-year risk
None
< 10%
10%–20%
> 20%
Optimal
LDL (mg/dL)
< 160
< 130
< 130
< 100
2.4.2 High-Density Lipoprotein (HDL)
HDL participates in reverse cholesterol transport and is protective
against CHD.
Very high HDL (> 60 mg/dL) is a "negative risk factor" and low
HDL (< 40 mg/dL) is a predictor of CHD.
There is not a specific goal for raising HDL.
2.4.3 Triglycerides
Target of therapy if triglycerides are > 500 mg/dL.
Aim is to prevent acute pancreatitis:
pTriglyceride (very low-fat diets)
Weight reduction
Increased physical activity
Triglyceride-lowering drug (fibrate or nicotinic acid)
Chapter 10–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLKyperlipidemics
3
Pharmacology
Management
Management of hyperlipidemia typically consists of dietary changes
and pharmaceutical therapy.
3.1 Diet
Cholesterol-lowering diet:
Saturated fat < 7% calories
Cholesterol < 200 mg/day
Diet can p LDL by 25%–30% in some individuals.
3.2 Antihyperlipidemics
Multiple classes of antihyperlipidemics exist.
Statins currently are the most widely used in the United States.
Diet
Hepatocyte
Gut
From dietary
glucose
Acetyl-CoA
HMG-CoA
Statins
Glycerol-3phosphate
Fatty acids
Ezetimibe
Dietary
cholesterol
Cholesterol
+
HMG-CoA reductase
Fat
Mevalonate
Trapped by bile
sequestering
resins
Triglycerides + Cholesterol esters
Niacin
statins
Biliary
excretion
+ ApoB-100
Mipomersen
IDL
Blood VLDL
LPL
Fibrates +
+ CEs
CETP
LDL
+ O2
Turbulence
Oxidized LDL
Plaques
Fat for storage
in adipose
or muscle
LDL receptor
mediated uptake
Familial hypercholesterolemia
LDL receptor number or function
Distribution
to all tissues
including liver
cFigure 10–3.2A Site of Action of Antihyperlipidemics
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 10–5
&KDSWHU‡$QWLKyperlipidemics
Pharmacology
3.2.1 HMG-CoA Reductase Inhibitors ("Statins")
Most important drugs for the treatment of dyslipidemias.
Agents in this class include:
Lovastatin
Simvastatin
Atorvastatin
Rosuvastatin
Fluvastatin
Pravastatin
Pitavastatin
No clear superiority of one statin over others.
Shown to reduce MI and mortality in secondary prevention as well
as in older men free of CHD.
Also reduce the risk of stroke.
Mechanism of Action
Competitive inhibitors of HMG-CoA reductase:
Rate-limiting step in endogenous cholesterol synthesis.
When intrinsic cholesterol synthesis is blocked, the liver increases
uptake of cholesterol from the plasma:
Upregulation of hepatic LDL receptors
pPlasma LDL
Statins also decrease VLDL synthesis:
pPlasma TGLs
3-Hydroxy-3-methylglutaryl-CoA
Statins
HMG-CoA reductase
Mevalonate
Farnesyl pyrophosphate
Squalene
Cholesterol
cFigure 10–3.2B Action
of Statins
Chapter 10–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLKyperlipidemics
Pharmacology
Therapeutic Effects
Decreases in LDL (30%–60%) and VLDL as well as mild increases
in HDL.
Exhibit actions beyond lipid-lowering activity:
Improvement of endothelial function
Modulation of the inflammatory response
Maintenance of plaque stability
Adverse Effects
Hepatotoxicity: n AST (discontinue if > 3x normal).
Myopathy:
Ranges from myalgias (~5%–10%) to myositis (~0.5%) to
overt rhabdomyolysis (< 0.1%).
Risk increases with higher doses and concurrent therapy with
gemfibrozil and nicotinic acid.
Check CK.
Drug Interactions
Inhibitors of P450, including grapefruit juice.
Red yeast rice (monacolin K is identical to lovastatin).
3.2.2 Fibrates
Include gemfibrozil and fenofibrate.
Mechanism of Action
Fibrates are peroxisome proliferator-activated receptor alpha
(PPAR-D) agonists.
PPARs are specific transcription factors controlling carbohydrate
and lipid metabolism.
Fibrates induce lipoprotein lipase, which promotes catabolism
of VLDL.
Therapeutic Effect
Fibrates lower serum triglycerides by 35%–50%.
Fibrates also modestly increase HDL cholesterol.
Adverse Effects
Cholelithiasis
Hepatitis
Myositis (in particular when combined with statins)
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 10–7
&KDSWHU‡$QWLKyperlipidemics
Pharmacology
3.2.3 Bile Acid Sequestrants
Currently available bile acid sequestrants include:
Cholestyramine
Colestipol
Colesevelam
As metabolites of cholesterol, bile acids are one means to
eliminate cholesterol from the body.
Mechanism of Action
Bile acid sequestrants trap bile acids in the intestine:
pEnterohepatic recycling of bile acids secreted by the liver.
Hepatocytes make more bile acids, decreasing the intrahepatic
cholesterol pool.
LDL receptor gene expression increases, which clears LDL from
the plasma.
Therapeutic Effect
Bile acid sequestrants modestly reduce LDL (15%–25%) and may
minimally increase HDL (5%–10%).
Adverse Effects
Fat malabsorption:
Steatorrhea
Nausea
Bloating
Cramping
Malabsorption of lipophilic drugs (such as digoxin and warfarin)
and fat-soluble vitamins (A, D, E, and K).
n VLDL synthesis: contraindicated or used cautiously in patients
with hypertriglyceridemia.
3.2.4 Nicotinic Acid (Niacin)
Actions on plasma lipids unrelated to its mechanism of action as
an essential dietary vitamin:
For lipid-lowering effects, nicotinic acid is given in much higher
doses than are needed as a vitamin.
Nicotinic acid is available in immediate-release and sustainedrelease formulations.
Mechanism of Action
Inhibits the hepatic production of VLDL and consequently its
metabolite LDL.
Affects HDL metabolism by reducing the transfer of cholesterol
from HDL to VLDL and by delaying hepatic HDL clearance.
Therapeutic Effect
Very effective for increasing HDL, and may raise levels by as much
as 30%–35%.
Also causes a 15%–25% decrease in LDL.
First lipid-lowering agent shown to reduce mortality in MI patients.
Chapter 10–8
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLKyperlipidemics
Pharmacology
Adverse Effects
Flushing occurs in 80% of patients.
Pruritus, paresthesia, and nausea occur in about 20% of patients.
Symptoms mediated in part by the release of prostaglandins
from mast cells and can last from 10 minutes up to several hours
after dosing.
Pretreatment with aspirin 30 minutes before dosing minimizes
side effects.
Patients are started at low doses that are titrated slowly upward
to improve compliance and allow tolerance to side effects.
3.2.5 Cholesterol Uptake Inhibitors: Ezetimibe
Mechanism of Action
Impairs absorption of dietary and biliary cholesterol at the brush
border of the intestine.
Therapeutic Effect
Modestly reduces LDL (~15%–20%)
Has not yet been shown to improve clinical outcomes when used
independently of other therapies.
Effective in combination with a statin.
Adverse Effects
Very well tolerated.
Headache, diarrhea, and rare cases of liver damage.
Does not impair the absorption of triglycerides or fat-soluble
vitamins.
3.2.6 Mipomersen
Antisense oligonucleotide against apoB-100 mRNA.
Nuclease resistant (phosphorothioate rather than phosphodiester
bonds).
Currently FDA-approved for homozygous familial
hypercholesterolemia.
Administered by weekly subcutaneous injection.
Adverse effects:
Injection site pain/inflammation
Hepatic fat accumulation (check LFTs)
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 10–9
&KDSWHU‡$QWLK\SHUOLSLGHPLFV
Pharmacology
3.2.7 Weight-Loss Therapies
%RG\0DVV,QGH[%0,
1RUPDO18.5–24.9
2YHUZHLJKW25–29.9
2EHVH!
— &ODVV,±
— &ODVV,,±
— &ODVV,,,!
RI$PHULFDQVDUHREHVH
$VPXFKDVWZRWKLUGVRIREHVLW\PD\EHH[SODLQHGE\JHQH
PXWDWLRQVDIIHFWLQJOHSWLQLWVUHFHSWRUVRUWKHLUVLJQDO
trDQVGXFWLRQSDWKZay.
Obesity Drugs
GLHWDQGH[HUFLVH
Amphetamine
derivatives:
‡ 3KHQWHUPLQH
‡ 'LHWK\OSURSLRQ
‡ n1(UHOHDVH
‡ $QRUH[LDQW
Phentermine
+
Topiramate
Orlistat:
Lorcaserin:
‡ 1R&16HIIHFW
‡ %ORFNVJDVWULFDQG
SDQFUHDWLFOLSDVHV
‡ p)DWDEVRUSWLRQ
‡ 6WHDWRUUKHD
‡ +TFDJRQLVW
‡ +TFUHFHSWRUVDUH
IRXQGLQK\SRWKDODPXV
‡ $QRUH[LDQW
0DQ\DQRUH[LDQWVKDYHEHHQUHPRYHGGXHWRFDUGLRYDVFXODUWR[LFLWLHV
n1(+7 LQFOXGLQJYDOYXORSDWKLHVDQGFDUGLDFILEURVLV
cFigure 10–3.2C Obesity Drugs
Chapter 10–10
‹'H9U\%HFNHU(GXFDWLRQDO'HYHORSPHQW&RUS$OOULJKWVUHVHUYHG
&KDSWHU‡$QWLKyperlipidemics
Pharmacology
dTable 10–3.2A Lipid Lowering Drug Summary
Class
Drugs
HMG-CoA reductase inhibitors
Lovastatin
Atorvastatin
Fluvastatin
Pitavastatin
Pravastatin
Rosuvastatin
Simvastatin
Fibrates
Gemfibrozil
Fenofibrate
Bile sequestering resins
Cholestyramine
Colestipol
Colesevelam
Cholesterol uptake inhibitors
Ezetimibe
Vitamins
Niacin
Antisense therapy
Mipomersen
dTable 10–3.2B Obesity Drug Summary
Class
Drugs
Anorexiants
Phentermine
Lorcaserin
Lipase inhibitor
Orlistat
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 10–11
CHAPTER 11
1
Diuretics
Overview
Diuretics are a class of drugs widely used in clinical practice.
The various classes of diuretics target different segments of the
nephron and differentially affect renal reabsorption and clearance of
electrolytes.
Most diuretics work by increasing Na+ excretion and are therefore
natriuretic.
Osmotic diuretics, which are not natriuretic, are the only drugs
that truly increase urine volume.
Major clinical uses:
USMLE® Key Concepts
Hypertension
Congestive heart failure
Edema
Electrolyte abnormalities
For Step 1, you must be able to:
X Identify the site and
mechanisms of action of
diuretics.
X Describe electrolyte and pH
disturbances associated
with chronic diuretic
therapy.
Diuretics
Drugs that modify
water excretion
Drugs that modify
salt excretion
Proximal
convoluted
tubule
Thick ascending
limb of the loop
of Henle
Carbonic
anhydrase
inhibitors
Distal
convoluted
tubule
Collecting ducts
and connecting
tubules
Osmotic
diuretics
Thiazide
Loop
diuretic
Entire
tubule
k+ sparing
diuretics
cFigure 11–1.0 Diuretic Therapies and Sites of Action
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 11–1
&KDSWHU‡'LXUHWLFV
2
Pharmacology
Diuretics
Five classes:
1. Osmotic diuretics
2. Carbonic anhydrase inhibitors
3. Loop diuretics
4. Thiazides
5. Potassium-sparing diuretics
60% Na+, H2O
2
H2O
Medullary
concentration
gradient
(countercurrent)
10% Na+, Cl–
120
mL/min
>90% HCO3–
4
1
H2O
100
25%
Na+
2Cl–
K+
<5% Na+, H2O
K+
5
H2O
3
ADH
H2O
1–2 mL/min
cFigure 11–2.0 Therapeutic Targets in the Renal Transport System
Diuretics acutely cause salt and water losses.
2° hyperaldosteronism will cause hypokalemia and often metabolic
alkalosis on chronic diuretic therapy.
Upregulation of unaffected pumps cause further electrolyte
disturbances.
Chapter 11–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'LXUHWLFV
Pharmacology
2.1 Osmotic Diuretics: Mannitol
2.1.1 Mechanism of Action
Administered parenterally.
Freely filtered at the glomerulus, and undergoes little or no
reabsorption by the renal tubule.
Increases water (rather than Na+) excretion.
2.1.2 Therapeutic Uses
Reduce intracranial pressure in cerebral edema.
Reduce intraocular pressure during acute attack of glaucoma.
Preserve urine volume in acute oliguric or anuric renal failure.
Increase clearance of toxins (e.g., eliminate myoglobin in
rhabdomyolysis).
2.1.3 Adverse Effects
Acute hypovolemia:
Angina-like chest pain
Nausea
Headache
Hypotension
Prior to diuretic effect, mannitol may cause ICF water shift and
increase ECF volume.
Contraindicated in CHF and pulmonary edema.
2.2 Carbonic Anhydrase Inhibitors
"-zolamide" drugs:
Acetazolamide
Dorzolamide
Proximal tubule
lumen
Peritubular
fluid
Na+
Na+
Glucose
K+
Na+
Amino acid
Glucose
ATP
2Na+
HPO4=
Na+
HCO3– + H+
–
H+ + HCO3–
Carbonic Acetazolamide
anhydrase Dorzolamide
CO2 + H2O
Carbonic
anhydrase
CO2 + H2O
Organic ions
Follow Na+
H2O, K+, Cl–
cFigure 11–2.2A Action of Carbonic Anhydrase Inhibitors
on Proximal Tubule Transport
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 11–3
&KDSWHU‡'LXUHWLFV
Pharmacology
2.2.1 Mechanism of Action
Inhibit carbonic anhydrase in the proximal tubular epithelial cells.
Decrease Na+/H+ antiport.
n Na+ in lumen: Diuretic
p Absorption of bicarbonate: Metabolic acidosis
2.2.2 Therapeutic Uses
Glaucoma:
Most common use
p Aqueous humor production
Administration route:
— Topical: Dorzolamide, brinzolamide
— Oral: Acetazolamide, methazolamide
— IV: Acetazolamide
Acute mountain sickness: Acetazolamide
Altitude
PAO2: Alveolar O2
PaO2: Arterial O2
PAO2
PaO2:
‡ +\SHUYHQWLODWLRQ
UHVSLUDWRU\DONDORVLV
+ Metabolic acidosis
(HCO3– loss)
+\SR[LF
YDVRFRQVWULFWLRQ
$FHWD]RODPLGH
‡ 3XOPRQDU\HGHPD
‡ &HUHEUDOHGHPD
+ Diuretic
cFigure 11–2.2B Action of Acetazolamide in Acute Mountain Sickness
Metabolic alkalosis
Urine alkalinization:
n Clearance of weak acidic drugs
n Clearance of uric acid or cysteine
2.2.3 Adverse Effects
Hyperchloremic metabolic acidosis (RTA type 2-like)
Severe hypokalemia
Phosphaturia and calciuria may precipitate renal stones
(alkaline urine)
Hypersensitivity: Sulfonamide derivative
Drowsiness
Paresthesia
Chapter 11–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'LXUHWLFV
Pharmacology
2.3 Loop Diuretics
Furosemide (most widely used, short half-life of ~90 minutes)
Bumetanide
Ethacrynic acid (not a sulfonamide derivative, no sulfa allergies;
intravenous)
Torsemide
Tubular fluid
Na+
2Cl–
K+
Na+
H+
Peritubular fluid
+
C1–
K+
– Loop diuretics
+
+
Na+
K+
ATP
K+
+
+
+
HCO3–
H+
CO2
Carbonic anhydrase
cFigure 11–2.3A Action of Loop Diuretics on Proximal
Tubule Transport
2.3.1 Mechanism of Action
Inhibit the Na+-K+-2Cl– cotransporter in the thick ascending loop
of Henle
n Na+, Cl– in lumen: Diuretic
p + Lumen potential: K+ loss
Increased excretion of Ca2+, and Mg2+
Also induce expression of COX-2, n PGE2: Vasodilation
Decreased
Urinary
Excretion
Increased
Urinary
Excretion
Na+
Volume of urine
K+
Mg++, Ca++
Cl–
cFigure 11–2.3B Loop Diuretics
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 11–5
&KDSWHU‡'LXUHWLFV
Pharmacology
2.3.2 Therapeutic Uses
Acute pulmonary edema/CHF
Other edematous states
Hypercalcemia, hyperkalemia
Hypertension
Acute renal failure
Anion overdose (bromide, fluoride, iodide)
2.3.3 Adverse Effects
Hypokalemia
Metabolic alkalosis
Hypomagnesemia
Hypocalcemia
Hyperuricemia (weak acids compete with urate for excretion)
Ototoxicity (irreversible with ethacrynic acid, reversible with others)
Sulfa allergy (except ethacrynic acid)
2.3.4 Drug Interactions
NSAIDs p efficacy of loops in hypertension
Digoxin (p K+ p Mg2+)
Additive ototoxicity (aminoglycosides, vancomycin, cisplatin, etc.)
2.4 Thiazides
Hydrochlorothiazide (most commonly used; first-line for
hypertension) and other drugs ending in "-thiazide"
Chlorthalidone
Metolazone
Indapamide
Lumen
Na+
– Thiazides
Na+
Cl–
K+
Na+
ATP
K+
Ca2+
Ca2+
ATP
PTH
3Na+
Ca2+
3Na+
Ca2+
cFigure 11–2.4A Action of Thiazides on Proximal
Tubule Transport
Chapter 11–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'LXUHWLFV
Pharmacology
2.4.1 Mechanism of Action
Inhibit the Na+/Cl– cotransporter in the distal convoluted tubule
n Na+, Cl– excretion: Diuretic
p Calcium excretion, unlike loop: p intracellular Na+ improves
Na+/Ca2+, exchange (dependent on PTH)
Thiazides also open K+ channels (ATP-dependent) found in vessels
(dilate vessels) and in ǃ cells of pancreas (p insulin release)
Decreased
Urinary
Excretion
Increased
Urinary
Excretion
Na+
K+
Ca++
Volume of urine
cFigure 11–2.4B Thiazides
2.4.2 Therapeutic Uses
Hypertension
Congestive heart failure
Renal stones (calcium)
Nephrogenic diabetes insipidus
2.4.3 Adverse Effects
Hypokalemia
Metabolic alkalosis
Hypercalcemia
p Insulin with hyperglycemia and hyperlipidemia (except
indapamide)
Hyperuricemia
Sulfa allergies
Caution:
Diabetes mellitus
Digoxin (p K+, n Ca2+)
© DeVry/Becker Educational Development Corp. All rights reserved.
!
Important Concept
Sulfa allergies with:
‡ Carbonic anhydrase inhibitors
‡ Loop diuretics (except
ethacrynic acid)
‡ Thiazides
‡ Sulfonamides
‡ Sulfonylureas
‡ Thioamides
‡ Celecoxib
‡ Sumatriptan
Chapter 11–7
&KDSWHU‡'LXUHWLFV
2.5
Pharmacology
Potassium-Sparing Diuretics
Luminal
membrane
Basal
membrane
–
–
Amiloride –
–
Triamterene –
–
Na+
–
K+
HPO4=
Free
+
H+
H2PO4–
NH3
+
NH4+
–
–
Aldosterone
Spironolactone
Eplerenone
Aldosterone
receptor
Gene expression
ATPase
Na+
K+
Na+
ATP +H2O
Principal
cell
K+
ECF
H+
HCO3–
–
HCO3–
–
Intercalated
cell
–
– Carbonic
–
Anhydrase
CO2
ABP_01_10.0_V
cFigure 11–2.5A Action of Potassium-Sparing Diuretics
on Proximal Tubule Transport
2.5.1 Ungated Na+ Channel Blockers: Amiloride,
Triamterene
Mechanism of Action
Inhibit sodium channels in late distal convoluted tubule and
collecting ducts
Less Na+ in, less K+ out: K+-sparing
Therapeutic Uses
Adjunct to K+-wasting diuretics
Hyperaldosteronism/hypercortisolism
Lithium-induced nephrogenic diabetes insipidus (amiloride)
Adverse Effects
Hyperkalemia
Acidosis
2.5.2 Aldosterone Receptor Antagonists: Spironolactone
and Eplerenone
Mechanism of Action
Competitive antagonists of aldosterone receptors
Spironolactone also antagonizes androgen receptors
Therapeutic Uses
Adjunct for K+-wasting diuretics
Hyperaldosteronism/CHF: Prevent cardiac remodeling
Hirsutism, acne: Spironolactone only (antiandrogenic)
Chapter 11–8
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'LXUHWLFV
Pharmacology
Adverse Effects
Hyperkalemia
Acidosis
Spironolactone:
Gynecomastia
Impotence
Menstrual irregularities
Drug Interactions
ACE inhibitors, ARBs, NSAIDs (hyperkalemia)
Digoxin
CYP450 inhibitors
Decreased
Urinary
Excretion
Increased
Urinary
Excretion
Na+
K+
cFigure 11–2.5B Potassium-Sparing Diuretics
1 Is Na+ excretion increased?
Yes
Other diuretics
No
Mannitol
2 Is K+ excretion increased?
Yes
K+-wasting diuretic
No
K+-sparing diuretic
3 Is HCO3– excretion increased?
Yes
Carbonic
anhydrase
inhibitors
Antiandrogenic = Spironolactone
No antiandrogenic effect =
Eplerenone
Amiloride
Triamterene
No
4 Is calcium or magnesium excretion increased?
Yes
Loop diuretics
No
Thiazides
cFigure 11–2.5C Diuretics and Urinary Electrolytes Algorithm
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 11–9
&KDSWHU‡'LXUHWLFV
Pharmacology
dTable 11–2.5 Diuretic Drug Summary
Class
Drug
Osmotic diuretics
Mannitol
Carbonic anhydrase inhibitors
Acetazolamide
Dorzolamide
Brinzolamide
Methazolamide
Thiazides
Hydrochlorothiazide
Bendroflumethiazide
Chlorothiazide
Hydroflumethiazide
Methyclothiazide
Chlorthalidone
Metolazone
Indapamide
Loops
Furosemide
Ethacrynic acid
Bumetanide
Torsemide
K+-sparing
Spironolactone
Eplerenone
Amiloride
Triamterene
Chapter 11–10
© DeVry/Becker Educational Development Corp. All rights reserved.
Unit 4
Antiplatelet Drugs
CHAPTER 12
1
Overview
Primary hemostasis recruits platelets in a three-step process:
1.
Adhesion (VWF/GPIb–IX)
2.
Activation (degranulation)
3.
Aggregation (fibrinogen / GPIIb/IIIa)
Antiplatelet drugs are widely used to reduce the risk of myocardial
infarction and other complications of atherosclerosis.
USMLE® Key Concepts
1 Platelet
adhesion
Shape
change
2 Activation
3 Aggregation
(hemostatic
plug)
Granule release
(ADP, TXA2)
For Step 1, you must be able to:
X Describe the mechanism of
action of antiplatelet drugs.
X Describe the clinical
indications for antiplatelet
drugs.
X List the adverse effects
associated with antiplatelet
drugs.
Clopidogrel
Prasugrel
Ticagrelor
Ticlopidine
GPIIb/IIIa
complex
Platelet
Fibrinogen
Abciximab
Eptifibatide –
Tirofiban
Platelet
P2Y12
–
ADP
+
Arachidonate
COX-1
TXA2
Subendothelial
collagen
– Aspirin
GPIb-IX
von
Willebrand
factor
cFigure 12–1.0 Primary Hemostasis and
Site of Action of Antiplatelet Drugs
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 12–1
&KDSWHU‡$QWLSODWHOHW'UXJV
2
Pharmacology
Drugs
2.1 COX Inhibitor: Aspirin
Thromboxane A2 (TXA2) causes platelet activation.
Aspirin blocks production of TXA2 by irreversibly acetylating
cyclooxygenase-1 (COX-1) in platelets.
81 mg daily dose of aspirin ("baby aspirin"):
Prevents MI and recurrence
Prophylaxis in atrial arrhythmias and TIAs
The main adverse effects of aspirin are gastrointestinal upset and
bleeding.
2.2 P2Y12 Antagonists
Twelve types of purinergic receptors: P2Y1 o 12
All are G-protein coupled
Platelets have P2Y1 (Gq) and P2Y12 (Gi)
ADP activates P2Y12 and decreases cAMP in platelets (cAMP inhibits
platelet activation)
Ticlopidine was the first P2Y12 ("ADP receptor") antagonist
Alternative to aspirin (in particular in allergic patients)
Ticlopidine has been associated with hematologic events such as TTP
Other P2Y12 antagonists are less likely to cause hematologic
toxicities
STEMI
Combined with aspirin in all patients with STEM I (prasugrel,
ticagrelor)
dTable 12–2.2 P2Y12 Antagonists
P2Y12 Antagonists
Prodrug
Active Metabolite
Comments
Ticlopidine
Yes
No
Life-threatening
hematologic
toxicity:
‡ $SODVWLFanemia
‡ $JUanulocytosis
‡ 7TP
Clopidogrel
Yes
No
‡ Requires 2C19 for
activation
‡ P
oor metabolizers:
no effect
Prasugrel
Yes
No
Life-threatening
bleeding possible
Ticagrelor
No
Yes
Used synergistically
with aspirin in acute
coronary syndrome
and in maintenance
post-MI
Chapter 12–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLSODWHOHW'UXJV
Pharmacology
2.3 Glycoprotein IIb/IIIa Inhibitors
Glycoprotein (gp) IIb/IIIa is a fibrinogen receptor/integrin
on platelets.
Abciximab: Fab fragment of a humanized monoclonal antibody
directed against the gp IIb/IIIa receptor.
Used in acute coronary syndromes, often in conjunction with PCT,
or post angioplasty.
The major adverse effect is bleeding.
Other GPIIb/IIIa antagonists:
Eptifibatide
Tirofiban
2.4 cAMP/cGMP Phosphodiesterase Inhibitors:
Dipyridamole and Cilostazol
n cAMP in platelet prevents aggregation
n cAMP or n cGMP in arterial smooth muscle promotes vasodilation
Dipyridamole:
Thromboembolism prophylaxis after cardiac valve replacement
Alternative to treadmills for cardiac stress test
Cilostazol:
PDE3 inhibitor
Used in PVD
dTable 12–2.4 Antiplatelet Drug Summary
Class
Drug
COX inhibitor
Aspirin
P2Y12 antagonists
Clopidogrel
Ticlopidine
Prasugrel
Ticagrelor
GPIIb–IIIa antagonists
Abciximab
Eptifibatide
Tirofiban
PDE inhibitors
Dipyridamole
Cilostazol
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 12–3
Anticoagulants
CHAPTER 13
1
Overview
Anticoagulants include:
Heparins
Coumarins
Direct thrombin inhibitors
Common indications include treatment and prophylaxis of:
Deep venous thrombosis
Atrial fibrillation
Mechanical heart valves
Inherited clotting disorders
USMLE® Key Concepts
For Step 1, you must be able to:
Intrinsic Pathway
ÂSurface contact
ÂHMW kininogen
X Describe the mechanism
of action of anticoagulant
drugs.
H
XII
X Explain how anticoagulant
therapy with heparin and
warfarin is monitored and
identify antidotes for these
two drugs.
XIIa
XI
XIa
W
IX
IXa
W
W
Coumarins/warfarin
prevent activation
H
Heparins inactivate
through antithrombin III
Extrinsic Pathway
Tissue factor
+
H
H
X
X Describe the clinical
indications for anticoagulant
drugs.
W
VIIa
Xa
VII
X List the adverse
effects associated with
anticoagulants.
H
W
II
(prothrombin)
H
IIa
(thrombin)
I
(fibrinogen)
– Direct thrombin
inhibitors
Ia
(fibrin)
*Factors II, VII, IX, X, and proteins C and S (not shown)
require γ-carboxylation and Ca2+-binding
cFigure 13–1.0 The Clotting Cascade and Site of Action
of Anticoagulants
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 13–1
&KDSWHU‡$QWLFRDJXODQWV
Pharmacology
dTable 13–1.0 Heparins and Coumarins
Feature
Heparins
Coumarins
Chemistry
Large water-soluble
polysaccharide
Small lipid-soluble
derivatives of vitamin K
Kinetics
‡ ,9, SC
‡ Hepatic and
reticuloendothelial
elimination
‡ Half-life = 2 hours
‡ No placental access
(DOC in pregnancy)
‡ 32
‡ 98% protein bound
‡ /LYer metabolism
‡ Half-life = 30+ hrs
‡ 3ODFHQWDODFFHVV
(contraindicated in
pregnancy)
Mechanism
‡ Catalyzes the binding
of antithrombin III
(a serine protease
inhibitor) to factors IIa,
IXa, Xa, XIa, and XIIa
‡ 5apid inactivation
‡ I n vivo and in vitro
effects
‡ p hepatic synthesis of
vitamin K-dependent
factors II, VII, IX, X,
proteins C/S
‡ Coumarins prevent
J-carboxylation by
inhibiting vitamin K
epoxide reductase
‡ No effect on factors
already present
‡ In vivo effects only
Monitoring
3artial thromboplastin
time (377)
3URWKURPELQWLPH
(37 ,15
Antagonist
3URWDPLQHVXOIDWH
(fast onset)
‡ Vitamin K (slow)
‡ Fresh frozen plasma
(fast)
Uses
Intensive-care
anticoagulation:
‡ 7KURPERHPEROLVP
‡ 8QVWDEOHangina
‡ D
isseminated
intravascular coagulation
(DIC)
‡ 2SHQKHDUWsurgery
‡ 2WKHU
Ambulatory
anticoagulation:
‡ 7KURPERHPEROLVP
post-MI
‡ Heart valve damage
‡ $trial arrhythmias
‡ 2WKHU
Side effects
and cautions/
contraindications
‡ %OHHGLQJ
‡ 2VWHRSRURVLV
‡ H
eparin-induced
WKURPERF\WRSHQLD +,7 ‡ +\SHUVHQVLWLYLW\
‡ %OHHGLQJ
‡ Skin necrosis (if low
protein C)
‡ 'UXJinteractions
‡ 7eratogenic (skeletal
anomalies)
Chapter 13–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLFRDJXODQWV
2
Pharmacology
Heparins
8QIUactionated heparin:
Heterogeneous mixture of sulfated mucopolysaccharides
Most likHO\WRFDXVHKHSDULQLQGXFHGWKURPERF\WRSHQLD +,7
Low molecular weight heparins:
Enoxaparin, dalteparin
Increased bioavailability
Less +,7
Increased activity against Xa
3UHGLFWDEOHSKDUPDFRNLQHWLFVZLWKZHLJKW-based dosing
Levels determined by anti-Xa assa\ QRW377
Limited antagonism by protamine sulfate
Synthetic heparinoids: Fondaparinux
Selective antithrombin III-mediated Xa inhibition
6DIHULQ+,7 RII-label use)
Heparin-induced thrombocytopenia:
Systemic hypercoagulable state
'XHWRDQWLERGLHVDJDLQVWKHSDULQ3ODWHOHW)actor 4
Immune complexes activate platelets by binding to their
surface
< 1%–5% of patients receiving heparin
20% mortality
Direct thrombin inhibitors (argatroban, lepirudin) are the drug
RIFKRLFHLQ+,7
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 13–3
&KDSWHU‡$QWLFRDJXODQWV
3
Pharmacology
!
Warfarin
3.1 Drug Interactions
p Efficacy of warfarin (p37,15 p Absorption with cholestyramine, colestipol, colesevelam (lipid
malabsorption)
p Absorption with antacids (warfarin is a weak acid)
Competition with vitamin K-rich food (green leafy vegetables)
,QGXFWLRQRI&<3JHQHUal inducers (barbiturates,
rifampin, etc.)
Important Concept
‡ Many rodenticides are
coumarins (brodifacoum,
diphenadione, etc.).
‡ Watch for toxicology cases on
the USMLE!
n Efficacy of warfarin (n37,15 ,QKLELWRUVRI&<3JHQHUal inhibitors (cimetidine, azole
antifungals, etc.)
Synergistic bleeding:
— Aspirin
— Heparin
— 7KLUGJHQHUation cephalosporins
Displacement from plasma protein binding: sulfonamides
3.2 Transient Protein C Deficiency
and Hypercoagulability
+IIa
Inactive
VIII
V
VIIIa
Va
Accelerate
clotting cascade
+C/S
Factor
Active C/S
IIa
Xa
IXa
t½
14 hrs
60 hrs
40 hrs
24 hrs
cFigure 13–3.2 Transient Protein C Deficiency
and Hypercoagulability
3URWHLQ&6DUHEUakes in the clotting cascade.
7KH\GHSHQGRQJ-carboxylation to work.
Existing active C/S have a shorter t1/2 than IIa, IXa, and Xa.
On initiation, warfarin causes a transient protein C deficiency
and hypercoagulability from remaining active clotting factors.
Must heparinize patient initially.
Chapter 13–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLFRDJXODQWV
4
Pharmacology
Direct Thrombin Inhibitors: DTIs
Do not require antithrombin III.
Originally derived from leeches (hirudin).
8VHGLQ+,7.
No antidote available in case of bleeding.
dTable 13–4.0A Direct Thrombin Inhibitors
DTIs
Use
Caution
Monitoring
Toxicity
Argatroban
(parenteral)
‡ 3URSKylaxis or
WUHDWPHQWRI+,7
‡ 3&,
‡ /LYer disease
D377
‡ *,bleeding
‡ +HPDWXULD
Lepirudin
(parenteral)
‡ +,7
‡ 5enal disease
D377
‡ +\SHUVHQVLWLYLW\
‡ %OHHGLQJ
Bivalirudin
(parenteral)
‡ 3&,LQ+,7SDWLHQWV
‡ Safe in liver
disease
$&7 DFWLYated
clotting time)
‡ %OHHGLQJ
‡ +\SHUVHQVLWLYLW\
‡ 3ain (back pain
in > 40%)
Dabigatran
(oral)
‡ Stroke/
thromboembolism
‡ Alternative to
warfarin
‡ 5enal disease
None
‡ %OHHGLQJ
dTable 13–4.0B Anticoagulant Drug Summary
Class
Drug
Heparins
Heparin
LMWH:
‡ Enoxaparin
‡ 'DOWHSDULQ
Fondaparinux
Coumarins
Warfarin
Direct thrombin inhibitors
Argatroban
Bivalirudin
Lepirudin
Dabigatran
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 13–5
CHAPTER 14
1
Thrombolytics
Overview
The fibrinolytic system dissolves intravascular clots as a result
of the action of plasmin, an enzyme that digests fibrin.
Thrombolytics are given intravenously for the emergency
management of:
Coronary thromboses
Deep venous thromboses
Pulmonary embolism
Thromboembolic strokes (contraindicated in hemorrhagic strokes)
Tissue plasminogen activator (tPA) preferentially activates
plasminogen bound to fibrin.
Early administration decreases mortality post-MI:
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe the mechanism of
action of thrombolytic drugs.
Within 3 hours: 50% reduction of mortality
Within 12 hours: 10% reduction of mortality
X Identify the clinical
indications for thrombolytic
drugs.
CNRI/Science Source
X Explain the adverse effects
associated with thrombolytic
drugs.
cFigure 14–1.0 Pulmonary Embolus
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 14–1
&KDSWHU‡7KURPERO\WLFV
2
Pharmacology
Drugs
Current fibrinolytics are recombinant tPA drugs.
Streptokinase (ǃ-hemolytic streptococci, antigenic), anistreplase,
and urokinase (human kidney) have been discontinued in the
United States.
dTable 14–2.0 Thrombolytic Drugs
Drug
Nature
Duration
Clot specificity
Allergies
Alteplase
(rtPA)
tPA
5 min
High
0
Reteplase
Deletion
mutant
15 min
High
0
Tenecteplase
Substitution
mutant
20 min
High
+
Streptokinase
Bacteria
20 min
Low
+++
2.1 Adverse Effects
Bleeding and hemorrhage
Additive with antiplatelet drugs or anticoagulants
2.2 Contraindications
Surgery planned within 10 days
Serious gastrointestinal bleed within last 3 months
Active bleeding or hemorrhagic disorder
Previous cerebrovascular accident (e.g., subarachnoid hemorrhage)
Aortic dissection
2.3 Antifibrinolytics
H-aminocaproic acid (EACA) and tranexamic acid competitively
inhibit plasminogen activation.
Tranexamic acid is also used in dental extractions in
hemophilia patients.
Chapter 14–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡7KURPERO\WLFV
Pharmacology
Atherosclerotic Plaque
Plaque rupture
Platelet
adhesion
activation
aggregation
Trapped
blood cells
Fibrin forms the
framework of the
thrombus
Thrombus
Antifibrinolytic Agents
A
-aminocaproic acid
Tranexamic acid
Fibrin
degradation
products
–
Plasminogen
ulants
icoag
Ant
MWHs, warfarin,
in, L
par
mbin inhibitors
He rect thro
)
(di
Is
DT
Antiplat
elet
Age
nts
–
Activation of
clotting factors
(tissue factor XIIa, –
Xa, IIa, etc.)
Plasmin
Fibrinolytic Agents
Alteplase
Reteplase
Tenecteplase
+
Plasminogen
activator
Proactivators in
plasma and
tissues
Vascular
endothelial
cells
cFigure 14–2.3 Site of Action of Blood Drugs
dTable 14–2.3 Thrombolytic Drug Summary
Type
Drug
Fibrinolytics
Alteplase
Reteplase
Tenecteplase
Streptokinase
Anistreplase
Urokinase
Antifibrinolytics
İ-aminocaproic acid
Tranexamic acid
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 14–3
Unit 5
CHAPTER 15
1
Sedative-Hypnotic Drugs
GABA and Its Receptors
Gamma-aminobutyric acid (GABA) is a major inhibitory
neurotransmitter.
Glutamate
G
L-glutamic acid
a d
decarboxylase (GA
(GAD))
B6
GABA
GABA shunt
GABA transaminase
transamin e
Glutamate + Succinic
i
semialdehyde
S
Succinic semialdehyde
d
dehydrogenase
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe GABA and its
receptors.
Succinic
inic acid
bs c
Krebs
cycle
cFigure 15–1.0A Metabolic Pathway for GABA
X Differentiate
benzodiazepines from
barbiturates.
GABA is ubiquitous in the CNS, primarily found in interneurons.
Its role is to modulate the activity of other neurons through
inhibition.
GABA binds to three separate subtypes of receptors:
GABAA
GABAB
GABAC
dTable 15–1.0A GABA Receptors
Name
Type
Comment
GABAA
Ligand-gated ion channel
‡ Allows Cl entry
‡ Results in hyperpolarization
‡ Ligands include
benzodiazepines and
barbiturates
GABAB
G-protein coupled receptor
‡ Gi-coupled (p cAMP)
‡ Results in n K+ efflux and
p Ca2+ entry
‡ Ligands include baclofen
GABAC
Ligand-gated ion channel
‡ Allows Cl– entry
‡ Classified as a type of
GABAA receptor
‡ No effect by benzodiazepines
or barbiturates
‡ Localized to retina, superior
colliculus (vision pathway)
–
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 15–1
&KDSWHU‡6HGDWLYe-Hypnotic Drugs
Pharmacology
GABAA receptors have five subunits arranged across the
membrane around a chloride channel.
Each subunit has four transmembrane domains.
Number
D
D1-6
E
E1-3
J
J1-3
Others
U1-3
GHST
Important Concept
Similar ligand-gated ion
channels:
dTable 15–1.0B GABA Receptor Subunits
Type
!
‡ Q$ChR
‡ +73
Minimum requirement for GABA binding is to have two D and
two E subunits.
Two GABA molecules must bind to open the Cl– channel.
GABA
binding sites
Benzodiazepine
binding site
Barbiturate
binding site
Cell membrane
cFigure 15–1.0B GABAA Receptor Structure
Drugs enhancing GABA inhibitory pharmacology include:
Benzodiazepines
Non-benzodiazepines
Barbiturates
Meprobamate/carisoprodol
Propofol, etomidate
Inhaled general anesthetics
Therapeutic uses include:
Anxiolysis
Sedation
Anti-seizure
Amnesia
Muscle relaxation
Hypnosis
Anesthesia
Chapter 15–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡6HGDWLYe-Hypnotic Drugs
2
Pharmacology
Benzodiazepines
Most frequently prescribed class of sedative-hypnotics.
2.1 Mechanism of Action
Benzodiazepines bind to the GABAA receptor at a site distinct from
the GABA agonist site and enhance the actions of GABA.
Act as positive allosteric modulators.
Benzodiazepines increase the frequency of chloride ion channel
openings produced by GABA.
The increased chloride influx hyperpolarizes the cells and inhibits
the generation of action potentials.
Benzodiazepines cannot open the chloride ion channel without
GABA.
Benzodiazepine binding sites:
These are on the GABAA receptor.
They are based on the subunit composition.
D1 and D5 mediate sedation, ataxia, and amnesia
("BZ1 receptor").
D2 and D3 mediate anxiolysis and anti-seizure activity
("BZ2 receptor").
Benzodiazepines have no activity on D4 or D6.
GABA
alone
Closed
Open
GABA +
Benzo
Closed
Open
Increased frequency
cFigure 15–2.1 Action of Benzodiazepines on GABAA Receptor
2.2 Pharmacokinetics
Benzodiazepines are often classified by their duration of effect.
Most have active metabolites (see Table 15–1.0A) through CYP3A4
and 2C19.
Oxazepam and lorazepam are directly conjugated and have no
active metabolite.
© DeVry/Becker Educational Development Corp. All rights reserved.
Clinical
Application
Drug interaction with:
‡ *HQHUDO&<3LQKLELWors
‡ Other CNS depressants
Chapter 15–3
&KDSWHU‡6HGDWLYe-Hypnotic Drugs
Pharmacology
2.3 Adverse Effects
Daytime drowsiness and sedation (worse with long-acting agents)
Rebound insomnia (worse with short-acting agents)
Motor incoordination
Anterograde amnesia
Coma and respiratory depression when used with other CNS
depressants, alcohol in particular:
Management is supportive.
Flumazenil, a non-selective benzodiazepine site antagonist,
can be used in an overdose situation.
Flumazenil cannot antagonize the depressant effect of
barbiturates or alcohol.
2.4 Clinical Indications
2.4.1 Anxiolytics
All are Class D for pregnancy:
Use in life-threatening emergency
Positive evidence of human teratogenicity
Approved for management of alcohol withdrawal:
Chlordiazepoxide
Clorazepate
Diazepam
Oxazepam
Approved for seizure disorders:
Clonazepam
Clorazepate
Diazepam
Approved for status epilepticus (IV):
Diazepam
Lorazepam
Preoperative sedation and anxiety relief:
Chlordiazepoxide
Diazepam
Lorazepam
Midazolam:
— Used (as is lorazepam) to trigger anterograde amnesia
— Inducer of anesthesia
— FDA black box warning for respiratory depression/respiratory
arrest
Approved to manage panic disorder:
Alprazolam (only benzodiazepine used for anxiety associated
with depression)
Clonazepam
Chapter 15–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡6HGDWLYe-Hypnotic Drugs
Pharmacology
dTable 15–2.4A Pharmacokinetics of Anxiolytic Benzodiazepines
Duration of Action (t½)
Drug
Short-acting (t½ < 6 hours)
‡ Midazolam
‡ 2[D]epam
Intermediate acting (t½ 6–24 hours)
‡ Alprazolam
‡ Lorazepam
‡ &KORUGLD]epoxide
Long-acting (t½ > 24 hours)
‡ Clonazepam
‡ &ORUazepate
‡ 'LD]HSDP
2.4.2 Sedatives
All are Class X for pregnancy except Quazepam, which is Class D
Avoid sudden withdrawal (rebound insomnia)
dTable 15–2.4B Pharmacokinetics of Sedative Benzodiazepines
Duration of Action (t½)
Drug
Short-acting (t½ < 6 hours)
Triazolam
Intermediate acting (t½ < 24 hours)
‡ Temazepam
‡ (VWD]olam
Long-acting (t½ > 24 hours)
‡ Flurazepam
‡ 4XD]epam
2.4.3 Other Benzodiazepine Site Agonists: The "Z Drugs"
Zolpidem, zaleplon, and eszopiclone are not benzodiazepines
Strong affinity for GABAA receptors containing D1 subunits
Reversed by flumazenil
All are Class C for pregnancy (use with caution if benefits
outweigh risks)
All cause drowsiness and motor impairment
Have been linked to parasomnia (somnambulism)
Additive CNS depression and drug interactions are the same as for
benzodiazepines
Pharmacokinetics: All have very short t½ (one hour for zaleplon to
six hours for eszopiclone)
© DeVry/Becker Educational Development Corp. All rights reserved.
!
Important Concept
Zolpidem, zaleplon, and
eszopiclone are the drugs
of choice for the short-term
management of insomnia.
Chapter 15–5
&KDSWHU‡6HGDWLYe-Hypnotic Drugs
3
Pharmacology
Barbiturates
Have been supplanted by benzodiazepines in the treatment of
anxiety and insomnia.
Clinical applications of barbiturates include:
Anticonvulsants (phenobarbital, primidone)
Anesthetic induction (thiopental)
Drug-induced coma for severe brain trauma (pentobarbital)
Component of lethal injection in some states for capital
punishment
3.1 Mechanism of Action
Barbiturates bind to a different site on the GABAA receptor than
benzodiazepines do.
They increase the duration (and not frequency) of chloride ion
channel opening.
They are GABA-mimetic at high dose.
They also block complex I of the electron transport chain.
There is no antidote in case of overdose.
GABA
alone
Closed
Open
GABA +
Closed
Barbiturate Open
Increased duration
cFigure 15-3.1 Action of Barbiturates on GABAA Receptor
3.2 Pharmacokinetics
All barbiturates except secobarbital are general inducers of CYP450.
3.3 Adverse Effects
Powerful CNS and respiratory depression.
Overdose, especially when combined with other CNS depressants,
can easily lead to coma and death.
Chapter 15–6
Looking Back
AvRLG3LQGXFHUs in
porphyria patients!
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡6HGDWLYe-Hypnotic Drugs
4
Pharmacology
Abuse Liability of Benzodiazepines
and Barbiturates
Groups at risk include polydrug abusers and alcoholics.
Polydrug abusers typically combine these drugs with opiates,
in particular methadone.
More than half of ED visits involving alcohol-drug combinations
contain pharmaceuticals: benzodiazepines are involved ~25%
of these cases, close to 150,000 entries (DAWN data, 2011).
>1.2 million ED visits involved pharmaceuticals: anxiolytics,
sedatives, or hypnotics comprised more than 420,000 cases
(DAWN data, 2011).
A rising trend in nonmedical use of benzodiazepines and
barbiturates is documented (an increase of 138% from 2004
to 2011).
Cross-tolerance occurs between all GABAA drugs.
These drugs cause both psychological and physical dependence.
Withdrawal is characterized by excitation, insomnia, and lifethreatening seizures (barbiturates and alcohol more than
benzodiazepines)
The shorter-acting the drug, the worse the withdrawal.
Supportive management of withdrawal includes the use of
IV diazepam/lorazepam for seizures.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 15–7
&KDSWHU‡6HGDWLYe-Hypnotic Drugs
5
Pharmacology
Other Drugs Used as Anxiolytics
or Sedative-Hypnotics
5.1 Buspirone
Anxiolytic, a partial agonist at 5-HT1A receptors.
Side effects include drowsiness, dizziness.
It is contraindicated with MAO inhibitors (hypertensive crisis).
Takes several weeks to work.
5.2 Ramelteon
Sedative, an agonist at melatonin receptors MT1 and MT2 in
suprachiasmatic nucleus of the hypothalamus, both of which
are Gi-coupled.
FDA-approved for insomnia, particularly in patients with delayed
sleep onset.
In contrast to benzodiazepines, ramelteon has not shown issues
with dependence.
Can cause drowsiness, dizziness.
Additive to other CNS depressants.
Contraindicated with fluvoxamine (CYP450-1A2 inhibition).
dTable 15–5.2 Sedative-Hypnotic Drugs
Class
Drug
Benzodiazepines: Anxiolytic
Alprazolam
Chlordiazepoxide
Clonazepam
Clorazepate
Diazepam
Lorazepam
Midazolam
Oxazepam
Benzodiazepines: Sedative
Temazepam
Estazolam
Flurazepam
Quazepam
Triazolam
Non-benzodiazepines
Zolpidem
Zaleplon
Eszopiclone
Melatonin agonist:
Ramelteon
5-HT1A partial agonist
Buspirone
Barbiturates
Phenobarbital
Primidone
Pentobarbital
Secobarbital
Thiopental
Chapter 15–8
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 16
1
Antiepileptic Drugs
Overview
Epilepsy is a recurrent neurologic disorder associated with sensory
or/and motor disturbances with or without loss of consciousness.
Most often idiopathic and incurable but is controllable with drugs.
Occasional seizures can be the result of toxic, metabolic,
traumatic, or infectious insults.
Epilepsy is characterized by prolonged synchronous depolarization
of cortical neurons.
Normal brain activity is asynchronous.
Status epilepticus is now defined as an unremitting seizure lasting
longer than 5 minutes (previously 30 minutes).
Status epilepticus is always a medical emergency.
2/3 convulsive
SEIZURE TYPES
1/3 nonconvulsive
FOCAL
May become
‡ "Partial" seizures previously
‡ Aura: Sensory, autonomic,
psychic, or motor presentation
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe mechanisms of
action and side effects of
primary antiepileptic drugs.
X Identify the drugs indicated
for the major types of
epilepsy.
GENERALIZED
‡721,&&/21,&*5$1'0$/
‡$%6(1&(3(7,70$/
‡2WKHUW\SHVLQFOXGH
7RQLF
&ORQLF
Myoclonic
Atonic
cFigure 16–1.0 Epileptic Seizures
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 16–1
&KDSWHU‡$QWLHSLOHSWLF'UXJV
2
Pharmacology
Phenytoin
Phenytoin is used to treat any seizure type except absence.
2.1 Mechanism of Action
Blocks voltage-gated sodium channels by keeping them in an
inactivated state.
Similar to class 1B antiarrhythmic drugs.
Decreases the conduction of action potentials.
2.2 Pharmacokinetics
Zero-order elimination kinetics.
General inducer of CYP450s.
When the hepatic hydroxylation system becomes saturated, small
increases in the phenytoin dose cause a large increase in the
plasma concentration of the drug.
Plasma Concentration
( mcg/mL)
30
20
Therapeutic
range
10
0
0
400
800
Phenytoin Dosage
(mg/day)
cFigure 16–2.2 Effect of Zero-Order Elimination
Kinetics of Phenytoin on Its Plasma Concentration
as a Function of Dose
Chapter 16–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLHSLOHSWLF'UXJV
Pharmacology
2.3 Adverse Effects
CNS depression:
Drowsiness, fatigue
Ataxia, nystagmus, dysarthria
Unique to phenytoin:
Gingival hyperplasia
Hirsutism
Interference with vitamins:
Folate: megaloblastic anemia
Vitamin D: rickets, osteomalacia
Non-dose related:
Allergies, including rashes
SLE-like reactions
Pseudolymphoma (lymphadenopathy, fever, rash)
Overdose:
Coma, respiratory depression
Cardiovascular collapse: hypotension and bradycardia
Teratogenic: fetal hydantoin syndrome
Cleft lip/palate
Microcephaly with low-set ears, short neck, epicanthal folds,
broad nasal bridge
Small or absent nails, hypoplasia of distal phalanges
Congenital heart defects: VSD, pulmonary stenosis,
transposition of the great arteries
Clinical
Application
Drugs other than
phenytoin that cause
gingival hyperplasia
include:
‡ Cyclosporine
E.H. Gill/Custom Medical Stock Photo
‡ Dihydropyridine calcium
channel blockers
cFigure 16–2.3 Teeth and Gums After
Long-Term Phenytoin Therapy
2.4 Fosphenytoin
Water-soluble prodrug of phenytoin.
Can be rapidly infused without the adverse effects associated with
the highly alkaline phenytoin intravenous solution.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 16–3
&KDSWHU‡$QWLHSLOHSWLF'UXJV
3
Pharmacology
Carbamazepine
Clinical
Application
Similar therapeutic uses to phenytoin.
Drug of choice for trigeminal neuralgia.
Used to treat bipolar mania.
Gabapentin:
Unclear mechanism of
action
3.1 Mechanism of Action
Carbamazepine has a similar mechanism of action to phenytoin.
3.2 Pharmacokinetics
‡ More commonly used
for management of
chronic pain
‡ Pregabalin, a related
drug, also is commonly
used for chronic pain
General inducer
Induces its own metabolism
3.3 Adverse Effects
CNS depression:
Dizziness, drowsiness
Nausea, vomiting
Unique to carbamazepine: SIADH (frank "water intoxication"
presentation)
Non-dose related:
Rashes, including Stevens-Johnson
Aplastic anemia
Both are FDA black box warnings
Teratogenicity:
Neural tube defects
Cleft lip/palate
Cardiac and urinary tract defects
Chapter 16–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLHSLOHSWLF'UXJV
4
Pharmacology
Valproic Acid
Used for all types of seizures including absence
Prophylaxis of migraine
Used to treat bipolar mania
4.1 Mechanism of Action
Inhibits GABA-transaminase: n GABA
Inhibits T-type Ca2+ channels (see ethosuximide)
Inhibits voltage-gated Na+ channels (see phenytoin/
carbamazepine)
Inhibits histone deacetylase: Orphan drug status in treatment of
colorectal polyposis
Clinical
Application
Vigabatrin:
‡ Inhibitor of GABAtransaminase
‡ Associated with weight
gain
4.2 Pharmacokinetics
Not an inducer of P450S
Inhibits CYP2C9
4.3 Adverse Effects
CNS depression
Unique to valproate:
Alopecia
Pancreatitis (rare but potentially fatal)
Hepatotoxicity (black box warning)
Non-dose related:
Thrombocytopenia
n Bleeding time
Teratogenicity: neural tube defects
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 16–5
&KDSWHU‡$QWLHSLOHSWLF'UXJV
5
Pharmacology
Ethosuximide
This antiepileptic is only used for absence seizures.
5.1 Mechanism of Action
T-type Ca2+ channel blocker
T is for "Transient"
Associated with burst of thalamic neuron activity
5.2 Adverse Effects
CNS depression
Blood dyscrasias
Unclear teratogenic risk (class C)
6
Lamotrigine
Blocks voltage-gated sodium channels
Inhibits glutamate release
Used as adjuvant therapy
Also used to treat bipolar disorder
Severe rash possible
Pregnancy: Class C but cleft lip/palate are reported
7
Topiramate
Anticonvulsant:
Blocks AMPA/kainate receptors
Carbonic anhydrase inhibitor
Migraine prophylaxis
Obesity when used in combination with phentermine
8
Felbamate
NMDA receptor blocker
Aplastic anemia potential
Chapter 16–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLHSLOHSWLF'UXJV
9
Pharmacology
Antiepileptic Drugs and Pregnancy
Most are teratogenic.
Inducers p efficacy of oral contraceptive pills.
No particular DOC identified.
Best drug is the one most likely to be effective and well tolerated
for the particular woman's seizure type.
General guidelines include:
Attempt to decrease pharmacotherapy to monotherapy.
Taper dosages to lowest possible dose.
Attempt complete withdrawal in women seizure-free for the
past two to five years.
Supplement folate at 4 mg/day.
Check maternal D-fetoprotein levels during pregnancy.
10
Main Indications by Seizure Types
dTable 16–10.0A Antiepileptics by Seizure Types
Seizure Type
Drug
Tonic-clonic (grand mal)
‡ Phenytoin
‡ &DUEDPD]epine
‡ 9alproic acid
‡ 3KHQREDUELWDOSULPLGRQH
Absence (petit mal)
‡ Ethosuximide
‡ 9alproic acid
‡ /DPRWULJLQH
Status epilepticus
‡ Lorazepam
‡ 'LD]epam
‡ 3KHQytoin/fosphenytoin
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 16–7
&KDSWHU‡$QWLHSLOHSWLF'UXJV
Pharmacology
dTable 16–10.0B Antiepileptic Drug Summary
Class
Drug
Voltage-dependent Na+ channel blockers
Phenytoin
Carbamazepine
Oxcarbazepine
Lamotrigine
Topiramate
GABAA enhancers
Phenobarbital
Primidone
Lorazepam
Diazepam
GABA transaminase inhibitors
Valproate
Vigabatrin
T-type Ca2+ channel blockers
Ethosuximide
Valproate
NMDA antagonists
Felbamate
AMPA antagonists
Topiramate
Perampanel
Chapter 16–8
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 17
1
Anesthetic Drugs
Overview
Two classes of anesthetic drugs:
General anesthetics
Local anesthetics
Most general anesthetics work by enhancing GABA activity.
Local anesthetics inhibit voltage-gated sodium channels.
2
USMLE® Key Concepts
General Anesthetics
For Step 1, you must be able to:
X Differentiate between
general and local
anesthetics.
2.1 Stages of General Anesthesia
General anesthesia is a state of reversible, controlled
unconsciousness.
Produced by drugs causing:
Muscle paralysis
Amnesia
Sedation
Analgesia
X Explain specialized
pharmacokinetic
parameters of gases.
X Differentiate competitive
vs. non competitive
neuromuscular blockers.
Four main stages (see Figure 17–2.1).
Awake
Awake
Recovery from anesthesia
Deepening anesthesia
Stage 1: Analgesia
‡$QDOJHVLD GHSHQGVRQDJHQW
‡$PQHVLD
‡(XSKRULD
Stage 2: Excitement
‡([FLWHPHQW
‡'HOLULXP
‡&RPEDWLYHEHKDYLRU
Stage 3: Surgical Anesthesia
‡8QFRQVFLRXVQHVV
Commence
surgery
‡5HJXODUUHVSLUDWLRQ
‡'HFUHDVLQJH\HPRYHPHQW
Surgery
completed
Stage 4: Medullary Depression
‡5HVSLUDWRU\DUUHVW
‡&DUGLDFGHSUHVVLRQDQGDUUHVW
‡1RH\HPRYHPHQW
cFigure 17–2.1 Stages of General Anesthesia
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 17–1
&KDSWHU‡$QHVWKHWLF'UXJV
Pharmacology
2.2 Inhaled General Anesthetics
2.2.1 Minimal Alveolar Concentration (MAC)
A measure of anesthetic potency
Defined as the concentration of gas in the lungs that is able to
prevent movement in 50% of patients in response to a surgical
stimulus or pain
Analogous to ED50
A higher MAC indicates lower potency
MAC values are additive
2.2.2 Blood-Gas Partition Coefficient
A measure of the solubility of the anesthetic in the blood.
A higher coefficient means that more of the inhaled anesthetic
dissolves in the blood.
The more soluble an anesthetic is in blood, the longer it takes to
exert action in the brain.
A small blood-gas ratio results in more rapid onset or recovery
from anesthesia.
2.2.3 Inhaled Anesthetics
dTable 7–2.2 Inhaled Anesthetics
Gas
MAC
Blood/Gas
Key Points
Nitrous oxide
105%
0.45
‡ " Laughing gas"/abuse
potential
‡ N
o metabolism
‡ U
sed to relieve pain of
childbirth, trauma, dental
extraction
Chlorofluorocarbons
("Halothane" family)
1%–6%
0.45 (desflurane) ‡ M
alignant hyperthermia risk
to 1.4 (isoflurane) ‡ P
ungency/respiratory irritation:
— Sevoflurane, least likely
— Desflurane, most likely:
avoid in induction
— Opioids p risk of respiratory
irritation
2.3 Intravenous Anesthetics
Preparation includes the use of midazolam or dexmedetomidine,
an D agonist, to sedate the patient and antimuscarinic drugs to dry
out secretions (atropine).
2.3.1 Propofol
Induction and maintenance of anesthesia
"Looks like milk"; poorly water soluble
Propofol infusion syndrome:
ICU patients
Severe metabolic acidosis, hyperkalemia
Rhabdomyolysis, renal failure
Cardiovascular collapse
Chapter 17–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QHVWKHWLF'UXJV
Pharmacology
2.3.2 Thiopental, Methohexital
Ultra-short-acting barbiturate
Uses:
Induction and maintenance of anesthesia
To lower intracranial pressure
GABAA enhancers:
Prolong duration of opening of Cl– channel
Severe respiratory depression potential
2.3.3 Ketamine
Noncompetitive antagonist of NMDA glutamate receptor
Analogue of phencyclidine (PCP)
Dissociative anesthetic: Causes analgesia and amnesia
Frequently used in emergent trauma to induce/maintain
anesthesia
Minimal CNS or CV suppression (may n BP, HR)
Adverse effects:
Vivid dreams and hallucinations
n Intracranial pressure: Avoid in head trauma
Also an abused drug
2.3.4 Etomidate
Used in induction of anesthesia
>10% adrenal suppression:
Blocks steroidogenesis
Off-label use in Cushing syndrome
Not analgesic
Minimal CV effects
2.3.5 Opioids
Central analgesics
Discussed in Chapter 18, "Central Analgesics: Opioids"
Include:
Fentanyl and derivatives
Meperidine (pethidine)
Tapentadol
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 17–3
&KDSWHU‡$QHVWKHWLF'UXJV
3
Pharmacology
Local Anesthetics
Block conduction of action potential by binding to voltage-gated
Na+ channel.
Three-step process:
1. Cross the cell membrane: Weak bases (require alkaline pH
to be unionized).
2. From inside the cell, bind within Na+ channel: Cationic form
is the active drug.
3. Once bound to the channel, stabilize the inactivated state of
the Na+ channel: Similar to class IB antiarrhythmics.
The higher the firing rate, the greater the local anesthetic effect.
C-fibers
Pain
Time
Increasing
and
increasing
conduction
velocity
A
Temperature
Touch
Deep pressure
Fiber type
A
A
A
Motor function
cFigure 17–3.0 Local Anesthetics
3.1 Pharmacokinetics of Local Anesthetics
dTable 17–3.1 Local Anesthetics
Type
Esters
Amides
Nomenclature
x-caine
Example: Co-caine
x-i-x-caine
Example: L-i-do-caine
Metabolism
‡ 3ODVPDesterases
‡ *HQRW\SLFpolymorphism
‡ +\SHUVHQVLWLYLW\(PABA)
‡ /LYer P450s
‡ Toxicity in liver disease
Duration of action
(short, medium, long)
‡ 3URFDLQH
‡ &RFDLQH
‡ 7etracaine
‡ 3ULORFDLQH
‡ /LGRFDLQH
‡ %XSLYacaine
Vasoconstrictors are added to minimize absorption into systemic
circulation:
Keep drugs localized
n Duration of action
p Systemic toxicity
p Bleeding from procedure
Epinephrine:
— D1 stimulation: Vasoconstriction
— D2 stimulation: Spinal anesthesia (p substance P release)
D2 Agonist: Dexmedetomidine and clonidine
Cocaine does NOT require epinephrine:
— Intrinsic sympathomimetic activity
— NE reuptake blockade
Chapter 17–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QHVWKHWLF'UXJV
Pharmacology
3.2 Toxicity of Local Anesthetics
CNS toxicity:
Depression of cortical inhibitory pathway resulting in lifethreatening seizures
Followed by general CNS depression and death
To avoid seizures when using high doses of local anesthetics,
a parenteral benzodiazepine is coadministered
Cardiovascular toxicity:
Direct effect on heart (IB-like): p Activity
Direct effect on smooth muscle: Dilation
Rare CV collapse
Cocaine has sympathomimetic activity:
Vasoconstriction
Hypertension
Ischemia
Allergies from esters: PABA analogues
3.3 Natural Toxins
Tetrodotoxin and saxitoxin:
Marine toxins
Block the activated Na+ channel
Effects resemble local anesthetic
Used in physiology to identify fast Na+ channels
Batrachotoxin and ciguatoxin:
Binds within channel
Prevents inactivation: Prolong Na+ entry
Batrachotoxin can cause hallucinations
Ciguatoxin is associated with "ciguatera"
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 17–5
&KDSWHU‡$QHVWKHWLF'UXJV
4
Pharmacology
Neuromuscular Blockers
Used during surgical anesthesia to cause muscle relaxation
and immobility
Block the nicotinic acetylcholine receptor at the neuromuscular
junction
Two groups: Nondepolarizing and depolarizing
4.1 Nondepolarizing Neuromuscular Blockers
Competitive antagonists at the skeletal muscle nicotinic
acetylcholine receptor
Can be reversed using acetylcholinesterase inhibitors such as
neostigmine
Cause progressive paralysis:
Face
Limbs
Respiratory muscles
Do not affect cardiac or smooth muscle
Do not alter consciousness
Prototype: Tubocurarine, which is isolated from the skin of a
poison dart frog
4.1.1 Mivacurium
Shortest duration of action of all curare-like drugs (metabolized by
plasma cholinesterase)
Slow onset of action
Can cause significant histamine release
4.1.2 Atracurium
Intermediate-acting
Spontaneous inactivation: Hofmann degradation
Production of laudanosine
Results in seizures
4.1.3 Steroid Neuromuscular Blocking Agents
Include pancuronium and vecuronium
Longer acting
No hormonal effect
Pancuronium is also a muscarinic antagonist
Chapter 17–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QHVWKHWLF'UXJV
Pharmacology
4.2 Depolarizing Neuromuscular Blockers
Succinylcholine is an agonist of nicotinic receptors.
Two distinct phases at the neuromuscular junction:
Phase 1:
— Depolarization
— Possible fasciculations
— Augmented by acetylcholinesterase inhibitors
Phase 2:
— Desensitization and possible channel blockade
— Can be antagonized by AChE inhibitors
Succinylcholine also stimulates ANS ganglia and
muscarinic receptors.
Rapidly metabolized by plasma and liver cholinesterases:
Avoid in patients with poor cholinesterase metabolism.
Prolonged duration could require longer intubation and
mechanical ventilation.
4.3 Train-of-Four Pattern: TOF
Four successive stimuli applied at 2 Hz
TOF ratio: Strength of fourth contraction/strength of first
contraction
TOF ratio = 1:
No drug, or
Phase I of depolarizing block (but diminished strength)
TOF ratio < 1:
Nondepolarizing block or
Phase II of depolarizing block
Called "fade"
cFigure 17–4.3 TOF Pattern Showing "Fade"
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 17–7
&KDSWHU‡$QHVWKHWLF'UXJV
Pharmacology
4.4 Spasmolytic Drugs
Decrease muscle tone and spasm
Useful in stroke, spinal injury, cerebral palsy, and multiple
sclerosis
CNS depressants
4.4.1 Baclofen
GABAB agonist
Hyperpolarizes neurons and muscle cells by activating potassium
channels
Sedation and respiratory depression, coma at toxic doses
4.4.2 Dantrolene
Binds to ryanodine receptor channel RyR1:
Blocks calcium release from the sarcoplasmic reticulum inside
a muscle cell
Minimal effect on heart and smooth muscle (RyR2 channel)
Antidote to malignant hyperthermia:
Rare autosomal dominant mutation of RyR1 or of Ca2+ transport
back into sarcoplasmic reticulum
Prolonged release of Ca2+ is triggered by depolarizing drugs
(succinylcholine) and chlorofluorocarbons (e.g., enflurane)
— Massive contraction
— Lactic acidosis
— Increased body temperature
Chapter 17–8
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QHVWKHWLF'UXJV
Pharmacology
dTable 17–4.4 Anesthetic Drug Summary
Class
Drug
General anesthetics (inhaled)
Nitrous oxide
Chlorofluorocarbons: Halothane
Enflurane
Desflurane
Sevoflurane
Isoflurane
General anesthetics (intravenous)
Midazolam
Dexmedetomidine
Thiopental
Methohexital
Propofol
Ketamine
Etomidate
Opioids (e.g., fentanyl)
Local anesthetics (esters)
Procaine
Cocaine
Tetracaine
Benzocaine
Local anesthetics (amides)
Lidocaine
Bupivacaine
Prilocaine
Ropivacaine
Neuromuscular blockers (nondepolarizing)
Mivacurium
Atracurium
Pancuronium
Vecuronium
Neuromuscular blockers (depolarizing)
Succinylcholine
Spasmolytics
Baclofen
Dantrolene
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 17–9
CHAPTER 18
1
Central Analgesics: Opioids
Overview
Central analgesics are the mainstay of pain management.
Morphine is the prototype P agonist.
2
Endogenous Opioid Peptides
and Receptors
USMLE® Key Concepts
Three families, three receptor subtypes with splice variants.
All three receptors are Gi-protein coupled.
For Step 1, you must be able to:
dTable 18–2.0 Opioid Peptides and Receptors
X Describe prototype P
agonist morphine.
P
E-endorphins
Receptor
Peptide
X Identify opioid receptors.
N
G
Dynorphins
Enkephalins
X Differentiate full and partial
agonists and antagonists of
Preceptors.
Note: New peptide nociceptin (orphanin FQ) binds to NOP receptor.
+
Opioid receptor
Gi
X Explain the abuse
potential of opiates and its
management.
K+ out
K+ channel
opening
Opioid receptor
+
Gi
Neurotransmitter
release
Ca2+
channel
closure
cFigure 18–2.0 Opioid Receptor Location and Function
Stimulation of opioid receptors decreases neurotransmitter release:
Presynaptic inhibition (p Ca2+ entry)
Or/and hyperpolarization of neuron (n K+ exit)
The receptors are scattered throughout the CNS, and modulate
the activity of neuronal pathways.
P Receptors are the most abundant but all three receptors can
mediate spinal and supraspinal analgesia:
Dorsal horn of spinal cord: Inhibition of ascending pain pathways
Midbrain periaqueductal gray substance and rostral ventral
medulla: Disinhibition of modulatory descending pathways
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 18–1
&KDSWHU‡&HQWUal Analgesics: Opioids
3
Pharmacology
Pharmacology of Morphine
3.1 CNS Effects
Analgesia: Dissociative effect (p affective aspect of pain)
Euphoria: Basis for abuse potential
Sedation
Respiratory depression: Dose limiting
p Activity of brainstem pCO2 centers
No effect on peripheral pO2 centers
Giving O2 to a patient with opioid-induced respiratory
depression is lethal without proper ventilation support
Can be reversed with IV naloxone
Cough suppression: Independent of P agonist activity
Nausea and vomiting: Activation of CTZ in area postrema
Miosis: Decreased NE release in iris
Minimal tolerance to miosis effect
Markers of opioid overdose triad:
— Coma
— Respiratory depression
— Pinpoint pupils
3.2 Peripheral Effects
Minimal CV Effects
Possible vasodilation involving histamine release (in part)
In CNS, n pCO2 causes dilation and an n ICP
GI Tract
Constipation
Minimal tolerance
p Peristalsis but n spasms
Basis for use as antidiarrheal
Major problem in management of chronic pain
Can be blocked by methylnaltrexone, an antagonist that does
not enter the CNS
Biliary tract: Aggravate biliary colics by n spasms and
constricting Oddi sphincter
Neuroendocrines
n ADH release
n Prolactin
n GH
p LH
Pruritus: Flushing due to n histamine release
Chapter 18–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡&HQWUal Analgesics: Opioids
4
Pharmacology
Opioid Agonists
dTable 18–4.0 Agonists and Relative Potencies
at P Receptors
Drug
Potency
Comments/Uses
Morphine
‡ Analgesia
‡ Pulmonary edema
‡ Diarrhea
Meperidine
0.3
‡ A
lso a strong
antimuscarinic:
— Tachycardia
— No miosis
— No GI/GU/biliary spasms
‡ P450 metabolite
normeperidine is an SSRI,
can cause seizures
Methadone
‡ Used for maintenance of
opiate addicts and analgesia
‡ Also blocks NMDA receptors
‡ Long t½ (1–3 days)
‡ Additive respiratory
depression with heroin
Hydrocodone
Oxycodone
Hydromorphone
Oxymorphone
1
1.5
5
7
‡ Analgesia
‡ Commonly abused
Alfentanil
Fentanyl
Remifentanil
Sufentanil
20
100
200
1,000
‡ Primarily used in anesthesia
‡ Sufentanil is the most
potent analgesic used
in humans
Codeine
0.1
‡ Considered a partial agonist
‡ Used in combination with
NSAIDs for analgesia
‡ Antitussive
Tramadol
0.1
‡ Also NE and 5-HT reuptake
blocker
‡ Can cause seizures
‡ Neuropathic pain
management
Tapentadol
0.1
Also NE reuptake blocker
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 18–3
&KDSWHU‡&HQWUal Analgesics: Opioids
5
Pharmacology
Mixed Agonists-Antagonists
Partial agonists at P receptors: Can precipitate withdrawal
in opiate addicts or in patients taking chronic full agonists for
pain management.
N receptor stimulation causes dysphoria: May limit abuse
potential.
Examples
Nalbuphine
Butorphanol
Pentazocine
Buprenorphine
Partial agonist at P receptors and N antagonist.
Slow dissociations from P receptors.
Effective in detoxifications and maintenance of opiate addicts:
—Less respiratory depression than methadone.
—Available with naloxone to avoid IV abuse.
6
Opioid Antagonists
dTable 18–6.0 Opioid Antagonists
Drug
Comments/Uses
Naloxone
‡ IV use to reverse opioid overdose
‡ Precipitates withdrawal in opiate
addicts
Naltrexone
‡ PO, long acting
‡ Used in alcohol and opiate dependence
‡ Decreases craving
Methylnaltrexone
‡ Does not cross blood-brain barrier
‡ Does not precipitate withdrawal
‡ SQ, to treat constipation from opioid
drugs
‡ Alvimopan available, PO
Chapter 18–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡&HQWUal Analgesics: Opioids
7
Pharmacology
Opioid Drugs With Special Indications
OTC preparations
Antidiarrheal: loperamide
Antitussive: dextromethorphan
8
Opioids and Opiates as Drugs of Abuse
Heroin involved in > 250,000 ED visits in 2011 (DAWN data).
Third most commonly abused drug after cocaine and marijuana.
Narcotic pain relievers caused more than 400,000 ED visits in
2011 (DAWN data).
Tolerance to all effects occur except for miosis and constipation.
Psychological and physical dependence occur.
Abstinence is therefore associated with craving and physical
symptoms.
Classic example of negative reinforcement as a theory for
addictive behavior.
Characteristics of opioid withdrawal:
Restlessness, agitation, anxiety
Pupillary dilation, sweating, tachycardia, hypertension
Diarrhea, spasms
Centrally originating pain
Connection to
Behavioral Science
See Behavioral Science,
Chapter 9, "Substance Abuse,"
for discussion of negative
reinforcement as a theory for
addictive behavior.
Management of withdrawal:
Acute detoxification:
— Methadone
— Clonidine to decrease the autonomic symptoms
Long-term management:
— Methadone
— Buprenorphine with naloxone
— Naltrexone
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 18–5
&KDSWHU‡&HQWUal Analgesics: Opioids
Pharmacology
dTable 18–8.0 Opioid Drug Summary
Class
Drug
Agonists
Morphine
Meperidine
Methadone
Hydrocodone
Oxycodone
Hydromorphone
Oxymorphone
Alfentanil
Fentanyl
Remifentanil
Sufentanil
Codeine
Tramadol
Tapentadol
Mixed agonists-antagonists
Nalbuphine
Butorphanol
Pentazocine
Buprenorphine
Antagonists
Naloxone
Naltrexone
Methylnaltrexone
Alvimopan
OTC opioid drugs
Dextromethorphan
Loperamide
Chapter 18–6
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 19
1
Parkinson Disease Drugs
Overview
Parkinson disease is characterized classically by:
Resting tremor
Bradykinesia
Rigidity
The goal of the treatment is to manage symptoms and improve
patient mobility.
2
USMLE® Key Concepts
Role of Dopamine in the CNS
Four distinct pathways:
Nigrostriatal
Mesolimbic
Mesocortical
Tuberoinfundibular
Five subtypes of dopamine receptors:
D1-like:
— Gs-coupled
— D1 and D5
D2-like:
— Gi-coupled
— D2, D3, and D4
© DeVry/Becker Educational Development Corp. All rights reserved.
For Step 1, you must be able to:
X Describe the role of DA in
the CNS.
X Explain the pathology of
Parkinson disease.
X Describe the use of
dopaminergic and
antimuscarinic drugs in
Parkinson disease therapy.
Connection to
Anatomy
For discussion of basal ganglia,
see Anatomy, chapter 19.
Chapter 19–1
&KDSWHU‡3arkinson Disease Drugs
Pharmacology
2.1 Nigrostriatal Pathway
Control of movement initiation.
Cell bodies are in substantia nigra pars compacta.
Output is to the striatum (caudate and putamen).
Movement
initiation
Striatum
Direct
pathway
D1-like (Gs)
Indirect
pathway
D2-like (Gi)
DA
DA
ACh from
MGq striatum
Substantia
nigra
cFigure 19–2.1A Nigrostriatal Pathway
Dopamine stimulates the direct pathway through D1-like receptors
(Gs-coupled) and inhibits the indirect pathway through D2-like
receptors (Gi-coupled).
Acetylcholine stimulates the indirect pathway and inhibits initiation
of movement through Gq-coupled muscarinic receptors.
Pathophysiology of Parkinson disease:
Parkinson disease results from degeneration of dopaminergic
neurons in the substantia nigra and the striatum.
The goal of therapy is to increase dopamine activity and/or
decrease cholinergic activity.
Chapter 19–2
© DeVry/Becker Educational Development Corp. All rights reserved.
Pharmacology
ISM/Phototake
&KDSWHU‡3arkinson Disease Drugs
cFigure 19–2.1B Parkinson Disease
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 19–3
&KDSWHU‡3arkinson Disease Drugs
Pharmacology
2.2 Mesolimbic and Mesocortical Pathways
Amygdala
Hippocampus
Medial prefrontal cortex
Glutamate
Nucleus accumbens
DA
Medial
forebrain
bundle
Reward
Pleasure
Positive reinforcement
Impulsivity
Ventral
tegmental
area
GABA
Ventral pallidum
Substantia nigra
Pontine reticular formation
MFB
DA
Frontal lobes
Emotions
Cognition
Motivation
Learning
cFigure 19–2.2 Mesolimbic and Mesocortical Pathways
Drug addiction and schizophrenia have similar changes in
mesolimbic and mesocortical pathways.
Positive symptoms of psychosis and abuse liability are associated
with excess dopamine transmission in both pathways.
2.3 Tuberoinfundibular Pathway
Mediates neuroendocrine role of dopamine
Dopamine p prolactin and GnRH
Dopamine p growth hormone release in acromegaly
2.4 Drugs Interfering With Dopamine
dTable 19–2.4 Predicted Effects of Drugs Interfering With Dopamine
Drug
Nigrostriatal
Mesolimbic/Cortical
Tuberoinfundibular
Agonist
n Movement
(Huntington-like)
‡ (XSKRULD
‡ 3V\chosis
Hypoprolactinemia
Antagonist
p Movement
(Parkinson-like)
‡ '\VSKRULD
‡ $QWLSV\chosis
‡ +\SHUSURODFWLQHPLD
‡ *\QHFRPDVWLD
Other dopamine effects include:
p Food intake
Loss of temperature control
Stimulation of nausea, vomiting center
Peripheral vasodilation
Chapter 19–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3arkinson Disease Drugs
3
Pharmacology
Levodopa-Carbidopa
L-dopa is a prodrug: Converted to dopamine by the enzyme dopa
decarboxylase, which is also known as aromatic L-amino acid
decarboxylase (AAAD).
Dopamine does not cross the blood-brain barrier.
Given with carbidopa: Irreversible inhibitor of peripheral AAAD.
Adverse effects:
On-off effects: dyskinesia due to dopamine level fluctuations
Psychosis, hallucinations, agitation
Nausea, vomiting
Hypotension, edema
Efficacy decreases as pathology progresses
4
COMT Inhibitors: Tolcapone
and Entacapone
Catechol-O-methyltransferase (COMT) degrades dopamine to
3-O-methyldopa (3OMD)
Inhibition of COMT:
n t½ of L-dopa
n Fraction reaching CNS
Tolcapone is hepatotoxic (FDA black box warning)
Side effects are those of n dopamine
Combination drugs: L-dopa + carbidopa + entacapone
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 19–5
&KDSWHU‡3arkinson Disease Drugs
5
Pharmacology
Monoamine Oxidase Type B Inhibitors:
Selegiline and Rasagiline
Monamine oxidase (MAO) type B catalyzes the enzymatic breakdown
of dopamine to dihydroxyphenylacetic acid (DOPAC).
5.1 Selegiline
Selective inhibitor of MAO type B
No tyramine interactions
Used as adjunct to L-dopa
Metabolized to amphetamine (sympathomimetic)
Can produce positive amphetamine screens in drug tests
5.2 Rasagiline
Irreversible inhibitor of the MAO type B enzyme
No amphetamine metabolites
6
Dopamine Agonists
6.1 Bromocriptine
D2 receptor agonist
Adjunct or alternative therapy to levodopa
Dopamine-related adverse effects: dyskinesias, hallucinations,
and psychosis
Other uses: hyperprolactinemia and acromegaly
6.2 Pramipexole, Ropinirole, and Rotigotine
Pramipexole is also a D3 agonist.
Antioxidant properties may p progression of disease.
Also used to treat restless legs syndrome (RLS).
All three drugs have antidepressant effects.
7
Muscarinic Antagonists
The loss of dopaminergic signaling in the basal ganglia leads to a
relative excess of muscarinic signaling.
Antimuscarinic agents that penetrate the blood-brain barrier are
used to reduce tremor and rigidity.
Benztropine and trihexyphenidyl.
Atropine-like side effects.
Chapter 19–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡3arkinson Disease Drugs
8
Pharmacology
Amantadine
Antiviral agent
n Synthesis, release of DA
ٚ reuptake of DA
ٚ muscarinic receptors
Causes livedo reticularis
Reuptake
Selegiline,
rasagiline
Amantadine
3-OMD
3-OMD
COMT
Tolcapone
L-dopa
AAAD
Dopamine
MAOB
DOPAC
Blood-brain
barrier
COMT
AAAD
L-dopa
Dopamine
Tolcapone,
Carbidopa
entacapone
‡,UUHYHUVLEOH
‡3HULSKHUDO
$QWLPXVFDULQLFGUXJV%HQ]WURSLQH
WULKH[\SKHQLG\O
cFigure 19–8.0 Site/Mechanism of Action of Combination
Therapy for Parkinson Disease
dTable 19–8.0 Parkinson Disease Drug Summary
Class
Drug
Levodopa (L-dopa)/carbidopa
COMT inhibitors
Entacapone
Tolcapone
MAO type B selective inhibitors
Selegiline
Rasagiline
Dopamine receptor agonists
Bromocriptine
Pramipexole
Ropinirole
Rotigotine
Muscarinic antagonists
Benztropine
Trihexyphenidyl
Amantadine
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 19–7
CHAPTER 20
1
Antipsychotic Drugs
Overview
Schizophrenia: Problems with thought processes and emotional
responsiveness.
Two types of symptoms:
Positive Symptoms
— Thought disorders
— Paranoia
— Delusions
— Hallucinations
— Bizarre behavior
Negative Symptoms
— Social withdrawal
— Flat affect (absence of emotional response)
— Poverty of speech
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe positive and
negative symptoms of
schizophrenia.
X Differentiate dyskinesias
due to antipsychotics.
2
Dopamine Hypothesis of Schizophrenia
X Differentiate typical from
atypical antipsychotics.
"Excessive" dopaminergic activity in limbic system:
Drugs that n DA in limbic system cause symptoms of
psychosis or aggravate existing schizophrenia (e.g., cocaine,
amphetamines, levodopa, bromocriptine).
Postmortem studies show n number of DA receptors in
untreated schizophrenia (D1-like and D2-like).
The increased number of receptors may be the consequence
of diminished dopamine synthesis or release in limbic and
cortical areas.
Connection to
Behavioral
Science
For discussion of schizophrenia,
see Behavioral Science, chapter
10, "Psychiatric Diagnoses and
Related Treatments."
TYPICAL ANTIPSYCHOTICS ANTAGONIZE D2 (and D1) RECEPTORS:
Improve positive symptoms of schizophrenia.
Worsen negative symptoms by causing dysphoria.
Have limiting side effects of dyskinesia (extrapyramidal
symptoms) and hyperprolactinemia.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 20–1
&KDSWHU‡$QWLSV\chotic Drugs
3
Pharmacology
Serotonin Hypothesis of Schizophrenia
Hallucinogens such as LSD and mescaline mimic findings of
schizophrenia by stimulating 5-HT2A receptors.
Serotonin modulates dopamine (and glutamate) neurotransmission:
Overall 5-HT inhibits DA release through 5-HT2A.
5-HT2A antagonism is expected to increase DA.
The net effect is different depending on the brain area and the
receptor densities.
Serotonin inhibits dopamine release in nigrostriatal pathway
through 5-HT2A: Basis for decreased extrapyramidal symptoms
with 5-HT2A antagonism.
Tuberoinfundibular pathways are similarly affected: 5-HT2A
antagonism increases dopamine release and opposes the
hyperprolactinemia of typical D2 antagonists.
Mesocortical pathways have more 5-HT2A receptors than
D2-like receptors: Blockade of 5-HT2A increases dopamine levels
and overcomes the dysphoric effect of D2 blockade, improving
negative symptoms of schizophrenia.
Mesolimbic pathways have more D2-like receptors than 5-HT2A
receptors: blockade of 5-HT2A does not increase dopamine
levels to the point of overcoming the effects of D2 blockade
which decrease the positive symptoms of schizophrenia.
ATYPICAL ANTIPSYCHOTICS ARE WEAK D2 ANTAGONISTS BUT
STRONG 5-HT2A BLOCKERS:
Improve negative symptoms
Still decrease positive symptoms
Have fewer extrapyramidal effects
Have fewer hyperprolactinemia effects
4
Glutamate Hypothesis of Schizophrenia
Phencyclidine (PCP) and ketamine cause psychosis and block
NMDA receptors.
NMDA receptors are found on GABA neurons: Their stimulation
n GABA release.
Schizophrenia is associated with decreased NMDA signaling
("hypofunction") and decreased inhibitory influences from GABA.
Newer drugs are being developed to n NMDA function or regain
the normal inhibitory influences of GABA.
Chapter 20–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLSV\chotic Drugs
5
Pharmacology
Typical Antipsychotics
Block D2 receptors in mesolimbic pathway: Decrease positive
symptoms.
Chlorpromazine is the prototype.
5.1 Side Effects From Dopamine Blockade
Dopamine blockade unfortunately blocks D2 in other
dopaminergic pathways:
Mesocortical:
Worsens negative symptoms
Dysphoria p compliance
Nigrostriatal:
Causes extrapyramidal symptoms
p Compliance also
Tuberoinfundibular:
n Prolactin
Gynecomastia, menstrual irregularities
n Eating: weight gain
5.2 Extrapyramidal Symptoms (EPS)
Six syndromes:
Four are early onset
Two are late onset
Time scale
Onset of treatment
1–5 days
Acute dystonic reactions
1 week–1 month
Drug-induced parkinsonism
Weeks–2 months
Akathisia
Weeks–months
Neuroleptic malignant syndrome
Months–years
Perioral tremors
TARDIVE DYSKYNESIA
cFigure 20–5.2 Extrapyramidal Symptoms
Acute dystonic reaction:
Muscle spasms of tongue, face, neck, back
Treated with antimuscarinic drugs (e.g., benztropine,
diphenhydramine)
Parkinsonism:
Bradykinesia, rigidity, resting tremor
Treated with antimuscarinic drugs
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 20–3
&KDSWHU‡$QWLSV\chotic Drugs
Pharmacology
Akathisia:
Motor restlessness
Treated with dose reduction of antipsychotics
Non selective beta-blockers, antimuscarinic drugs,
or benzodiazepines help
Neuroleptic malignant syndrome:
Catatonia, stupor, high fever, cardiovascular instability,
myoglobinemia
Dantrolene + bromocriptine are considered antidotes
Stop antipsychotics immediately
Perioral tremor:
"Rabbit syndrome"
Antimuscarinic drugs may help
Tardive dyskinesia:
Often irreversible
Upregulation and sensitization of D2 receptors
Oral and facial dyskinesia with chorea and athetosis
No treatment
Atypical antipsychotics are less likely to cause tardive dyskinesia
5.3 Other Pharmacology of Typical Antipsychotics
Muscarinic antagonism:
Atropine-like
3 Cs: Coma, Convulsion, Cardiotoxicity
— Lower seizure threshold
— Can cause torsade de pointes
D1 antagonism:
Prazosin-like
Orthostatic hypotension, reflex tachycardia
Sexual dysfunction
H1 antagonism:
Sedation
Weight gain (in part)
Chapter 20–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLSV\chotic Drugs
Pharmacology
5.4 Typical Antipsychotics
dTable 20–5.4 Typical Antipsychotics
Drugs
Comments
Phenothiazines:
Chlorpromazine
‡ Prominent ANS side effects
Thioridazine
‡ Strongest antimuscarinic: most likely to
cause torsades
‡ But "autotreats" acute EPS
Fluphenazine
‡ Exists in depot form (IM)
Butyrophenones:
Haloperidol
‡ 3otent D2 blockade
‡ C
auses severe EPS, including neuroleptic
malignant syndrome and tardive dyskinesia
‡ U
sed IV in acute management of psychosis
and mania
Diphenylpiperidines:
Pimozide
Used in Tourette syndrome and tic disorders
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 20–5
&KDSWHU‡$QWLSV\chotic Drugs
Pharmacology
5.5 Atypical Antipsychotics
Growing class of medications.
Currently first-line therapy.
Complex pharmacology but all share 5-HT2A antagonism more
than D2 receptor action.
dTable 20–5.5A Atypical Antipsychotics
Drugs
Comments
Clozapine
‡ 6WURQJD4 and 5-HT2A blockade
‡ No tardive dyskinesia
‡ Agranulocytosis (weekly blood test)
‡ Weight gain, seizures
‡ Hypersalivation ("wet pillow syndrome")
Olanzapine
‡ 6WURQJ5-HT2A blockade
‡ Weight gain, seizures
‡ Improves negative symptoms
Risperidone
‡ 6WURQJ5-HT2A blockade
‡ +\SRWHQVLRQfrom D1 blockade
Aripiprazole
‡ Partial agonist of D2 receptors
‡ +72A antagonist
‡ +71A partial agonist
‡ Approved also for mania, autism
Quetiapine
‡ 6WURQJH1 and D1 antagonism
‡ No antimuscarinic antagonism
Ziprasidone
‡ Strong 5-HT pharmacology at 5-HT1,2,6,7
receptors
‡ Also blocks all subtypes of DA receptors
‡ Blocks 5-HT and NE reuptake
dTable 20–5.5B Antipsychotic Drug Summary
Class
Drug
Typical
Chlorpromazine
Thioridazine
Fluphenazine
Haloperidol
Pimozide
Atypical
Clozapine
Olanzapine
Aripiprazole
Quetiapine
Ziprasidone
Chapter 20–6
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 21
1
Antidepressant Drugs
Depression
Characteristics include:
Intense sadness, despair
Mental slowing, loss of concentration
Pessimistic worry
Lack of pleasure
Self-depreciation
Agitation, hostility
1.1 Amine Hypothesis of Depression
Reserpine, an antihypertensive known to deplete DA, NE,
and 5-HT, centrally is associated with severe depression
and suicide ideation.
Drugs decreasing central NE effects such as beta-blockers and D2
agonists cause or aggravate depression.
The acute mechanism of action of antidepressants is to increase
NE, 5-HT and/or DA in the CNS.
Therapeutic effects take weeks to develop.
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe the various
biochemical hypotheses for
depression.
X Contrast the various
families of antidepressants.
1.2 Neurotrophic Hypothesis of Depression
Brain-derived neurotrophic growth factor (BDNF) is critical for
nerve survival and neural plasticity.
Stress and pain are associated with p BDNF in brain areas such
as the cingulate cortex (emotion, attention) and hippocampus
(memory and regulation of hypothalamic-pituitary-adrenal axis).
Direct BDNF administration in rodents acts as an antidepressant.
Imaging shows atrophy (p brain volume) in hippocampus and
cingulate cortex of depressed patients.
Antidepressants n BDNF levels in the CSF of depressed patients
through changes in gene expression.
1.3 Neuroendocrine Factors in Depression
Depression is associated with n cortisol secondary to n CRF
production.
Patients who take steroids or who have hypercortisolism have
mood disorders and cognitive deficits.
Sex steroids, in particular estrogen deficiency, have a role in
depression (post partum, post menopause).
Low testosterone in men is associated with depression.
Abnormal thyroid function is seen in a quarter of depressed patients.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 21–1
&KDSWHU‡$QWLGHSUHVVDQW'UXJV
Pharmacology
1.4 Treatment
Treated with a combination of pharmacotherapy and psychotherapy.
Electroconvulsive therapy (ECT) is used for patients who are
refractory to pharmacotherapy.
Four main classes of antidepressants:
Monoamine oxidase inhibitors (MAOIs)
Tricyclic antidepressants (TCAs)
Selective serotonin reuptake inhibitors (SSRIs)
Atypical antidepressants
Onset of therapeutic effects takes weeks to months.
Chapter 21–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLGHSUHVVDQW'UXJV
2
Pharmacology
Monoamine Oxidase Inhibitors (MAOIs)
MAO enzymes: mitochondrial (outer membrane)
dTable 21–2.0A MAO Enzymes
Enzyme
MAOA
MAOB
Location
‡ 1HXURQV
‡ /LYer
‡ *,
‡ 1HXURQV
‡ 3ODWHOHWV
Substrates
‡ 1(
‡ (SL
‡ +7
‡ '$
‡ 7yramine
‡ '$
‡ 3KHQylethylamine
MAO inhibitors:
Third line after SSRIs/atypicals or TCAs
Refractory depression or refractory panic disorders only
Nonselective MAO inhibitors include phenelzine and
tranylcypromine
n Levels of all three amines: NE, 5-HT, and DA
Major drug and food interactions
dTable 21–2.0B Dietary and Drug Restrictions for MAOIs
Tyramine-Rich Foods and Beverages
Drug Interactions
‡ Cheese, except cream cheese, fresh yogurt,
cottage cheese
‡ Red wine, sherry, vermouth, cognac, beer, ale
‡ Soy sauce, shrimp paste
‡ 6DXHUNUaut
‡ Liver, fermented or aged meats (bologna,
salami)
‡ Meat and yeast extracts
‡ Broad beans, fava beans
‡ 0RUH
Hypertensive crisis: n NE
‡ D agonists (cold medications)
‡ 7CAs
‡ $Qy sympathomimetic
Serotonin syndrome: n 5-HT
‡ 6SRIs
‡ 7CAs
‡ 0HSHULGLQH
‡ 'H[WURPHWKRUSKDQ
‡ St. John's wort
Selegiline (MAOB-selective) is available as a skin patch:
%\SDVVHV*,DQGGLHWDU\UHVWULFWLRQV
Primarily n DA
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 21–3
&KDSWHU‡$QWLGHSUHVVDQW'UXJV
3
Pharmacology
Tricyclic Antidepressants
Second-line agent in depression management
Block NE and 5-HT reuptake
Also block D, M, and H1 receptors: similar to typical antipsychotics
Often require therapeutic drug monitoring
Classic anticholinergic toxicity: 3 Cs
TCAs are metabolized by P450 enzymes: drug interactions
Additive anticholinergic effects
Additive sympathomimetic effects
Antagonism with D2 agonists
dTable 21–3.0 Important Tricyclic Antidepressants
Drug
Transporter
Indication
Imipramine
5-HT > NE
Enuresis
Clomipramine
5-HT > NE
Obsessive-Compulsive Disorder (OCD)
Amitriptyline
5-HT, NE
Neuropathic pain, migraine
Amoxapine
NE > 5-HT, DA
Psychotic depression
Desipramine
NE > 5-HT
Cocaine craving and withdrawal
Chapter 21–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLGHSUHVVDQW'UXJV
4
Pharmacology
Selective Serotonin Reuptake Inhibitors
(SSRIs)
SSRIs and atypicals are first-line agents (chronic) for:
Depression
Panic
*HQHUalized anxiety disorders
Bulimia
OCD
Post-traumatic stress disorder
SSRIs have fewer autonomic side effects therefore less toxicity
than TCAs (particularly cardiovascular toxicity).
Paroxetine and citalopram (not escitalopram) are anticholinergic.
SSRIs include:
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Citalopram
Escitalopram
4.1 Adverse Effects
n+7LQ*,*,XSVHW
Diarrhea
Nausea, vomiting (5-HT3) bruxism
n 5-HT in spinal cord/raphe: sexual dysfunction
5-HT2A exerts inhibitory action on orgasm: anorgasmia
p Libido, p arousal
PDE type 5 inhibitors help (one hour before)
Alternatives:
— Cyproheptadine
— Adjunctive bupropion
n 5-HT in CNS: stimulant effect
Insomnia, headache
Anxiety
Agitation
Coadminister a benzodiazepine initially (e.g., alprazolam)
n 5-HT in platelets: bleeding abnormalities
Caution with blood drugs (aspirin, warfarin)
Less with sertraline or citalopram
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 21–5
&KDSWHU‡$QWLGHSUHVVDQW'UXJV
Pharmacology
Weight gain reported with paroxetine (5-HT2C)
Serotonin syndrome:
In overdose of SSRIs or from drug interactions with:
— TCAs
— MAOIs
— Meperidine
— Dextromethorphan
— St. John's wort
Characterized by:
— Rigidity
— Hyperthermia
— Autonomic instability
— Myoclonus
— Confusion, delirium
— Coma and death
Treatment:
— Sedation with benzodiazepines
— Intubation, ventilation
— Consider cyproheptadine, a 5-HT2 antagonist,
or chlorpromazine
4.2 Pharmacokinetics and Drug Interactions
SSRIs are powerful inhibitors of P450 enzymes.
Citalopram is not an inhibitor of P450 enzymes.
dTable 21–4.2 Pharmacokinetics and Drug Interactions
SSRI
Active Metabolite
P450 Inhibitor
Comment
Fluoxetine
Yes
2D6
3A4
n Alprazolam,
carbamazepine
Fluvoxamine
Yes
1A2
2C19
3A4
n TCAs
Paroxetine
No
2D6
Most potent
SSRI—strong
antimuscarinic
Sertraline
Yes
Minimal
Second most
potent SSRI;
second most
selective SSRI
Citalopram
Yes
N/A
Most selective SSRI
Chapter 21–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLGHSUHVVDQW'UXJV
5
Pharmacology
Atypical Antidepressants
Miscellaneous pharmacology
Often newer agents
5.1 Serotonin Norepinephrine Reuptake
Inhibitors (SNRIs)
SNRIs include:
Venlafaxine
Desvenlafaxine
Duloxetine
Milnacipran
Duloxetine and milnacipran are approved for treatment of
fibromyalgia (pregabalin, a CNS voltage-dependent Ca2+ channel
blocker, is the third drug approved for this condition).
No autonomic (D, M) side effects.
No H1 blockade.
Favored over TCAs for depression or neuropathic pain.
5.2 Serotonin 2A Antagonists and Reuptake
Inhibitors (SARIs)
SARIs include trazodone and nefazodone.
Also block D1 receptors causing hypotension, arrhythmias,
and priapism.
Trazodone also blocks H1 and is sedative.
5.3 Noradrenergic and Specific Serotonergic
Antidepressants (NaSSAs)
NaSSAs include mirtazapine
Mirtazapine is an D2 antagonist:
D2 Antagonism n NE synthesis and release
NE from locus coeruleus neurons in turn activate raphe 5-HT
neurons through D1: n 5-HT release
Mirtazapine also blocks 5-HT2A, 5-HT2C, 5-HT3, and H1 receptors:
Blockade of H1 causes sedation
Blockade of 5-HT2C and H1 is associated with weight gain
(possible indication for anorexia nervosa)
Blockade of 5-HT2A means no sexual dysfunction
Blockade of 5-HT3 means no nausea, vRPLWLQJ*,XSVHW
Leaving 5-HT to stimulate 5-HT1A means good anxiolysis
(like buspirone)
5.4 Bupropion
n DA and NE:
Blocks reuptake
Enhances release
Can cause seizures.
Is used for smoking cessation:
Varenicline, a partial agonist of nicotinic receptors in the CNS,
is an alternative.
Its main active metabolite, hydroxybupropion, is a potent inhibitor
of P450 2D6.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 21–7
&KDSWHU‡$QWLGHSUHVVDQW'UXJV
6
Pharmacology
General Considerations About
Antidepressants
SSRIs are most commonly prescribed as a first choice but there
is no true drug of choice.
Drug and food interactions are an issue.
If the response is poor, switching or combination therapy are
required:
An adequate washout time is required before switching,
typically two to three weeks
Allow four to five weeks between SSRIs and MAOIs
No washout time required within group
Adding lithium, atypical antipsychotics, buspirone, or thyroid
hormones helps in refractory cases.
ECT remains the most effective treatment of severe depression.
Pregnancy and antidepressants:
Safest SSRI are fluoxetine, sertraline, and citalopram
Safest TCAs are amitriptyline, nortriptyline, and desipramine
Safest atypical is bupropion
dTable 21–6.0 Antidepressant Drug Summary
MAO Inhibitors
Phenelzine
Tranylcypromine
Selegiline
Isocarboxazid
SARIs
Nefazodone
Trazodone
Chapter 21–8
Tricyclic
Antidepressants
SSRIs
Amitriptyline
Amoxapine
Clomipramine
Desipramine
Imipramine
Nortriptyline
Fluoxetine
Paroxetine
Sertraline
Citalopram
Fluvoxamine
Escitalopram
NaSSA
Atypical
Mirtazapine
SNRIs
Venlafaxine
Duloxetine
Desvenlafaxine
Milnacipran
Bupropion
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 22
1
Drugs for Mania and
Bipolar Disorder
Bipolar Disorder
Characterized by mood shifts:
Mania
Major depression
Hypomania
Mixed mood states
High comorbidity with substance abuse (cocaine in particular)
Mania is characterized by:
Elevation of mood with hyperactivity, irritability, flight of ideas,
little need for sleep, grandiosity
Activities may be later regretted (excessive spending,
resignation, alienation of a friend, etc.)
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe bipolar disorder.
1.1 Types
Bipolar I: Depressive and manic episodes
Bipolar II:
Depressive and hypomanic episodes
Known as cyclothymic disorders
X Explain the side effects of
lithium.
X Identify alternative drug
therapies to lithium.
Bipolar III: Mania when treated with antidepressant for a
depressive episode
1.2 Treatment
Acute manic or hypomanic symptoms respond to lithium or
valproate within days of treatment.
Monotherapy or adjunctive therapy with atypical antipsychotics
is increasing:
Olanzapine, risperidone, or aripiprazole
Reduce dosage as lithium is started
Clonazepam is also used to manage acute cases (no extrapyramidal
effects).
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 22–1
&KDSWHU‡'UXJVIRU0DQLDDQG%LSRODU'LVRUGHU
2
Pharmacology
Lithium
Lithium decreases frequency and severity of acute manic or depressive
attacks in 70% of patients.
2.1 Mechanism of Action
In a healthy individual, lithium is neither a depressant, a euphoriant,
nor a sedative!
Involves signaling cascade:
Li+ blocks inosine 5'-monophosphatase: p inositol (Gq-coupled
receptor pathway)
Li+ stabilizes the trimeric (D E J, inactive) forms of Gs and Gi
Li+ decreases protein kinase function including PKC, which is
involved in synaptic plasticity
2.2 Pharmacokinetics
PO, readily absorbed from duodenum
Salt: No significant protein binding (unlike most CNS drugs)
Vd close to Total Body Water
95% renal cleared:
An alkali like Na+, K+, 80% of filtered Li+ is reabsorbed in PCT
Na+ loading enhances excretion
Na+ depletion promotes reabsorption
Chronic diuretic therapy will cause decreased Li+ clearance
and n toxicity
NSAIDs facilitate PCT reabsorption and cause Li+ toxicity
Same with ACE inhibitors
Because a small amount of Li+ is also reabsorbed distally,
triamterene or amiloride can n clearance of Li+
2.3 Side Effects
Narrow therapeutic index:
1 to 1.5 mEq/L therapeutic acutely, < 1 mEq/L chronically
Toxic > 2 mEq/L
Mild GI symptoms: Take with food
Tremors: Add propranolol if persistent
Polyuria:
Clinical
Application
Due to decreased ADH response (Gs-coupled)
Causes polydipsia (secondary to high renin)
Fluid + calories in fluid may cause weight gain
If frank diabetes insipidus: Amiloride will n Li+ clearance and
p toxicity
Thyroid dysfunction:
Due to decreased TSH response
Hypothyroidism in ~10% of patients
Treated with thyroid hormones
Glucose intolerance
Leukocytosis (unrelated to infection)
Chapter 22–2
In contrast to central
diabetes insipidus (e.g.,
hypothalamic or pituitary
injury leading to a lack
of ADH secretion),
nephrogenic diabetes
insipidus is an inability
to respond to ADH.
Lithium-induced diabetes
insipidus can be managed
by amiloride, not
thiazides, which would Ⱥ
Li+ clearance.
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'UXJVIRU0DQLDDQG%LSRODU'LVRUGHU
Pharmacology
2.4 Teratogenicity
Li+ causes cardiac anomalies:
Ebstein anomaly (septal tricuspid valve leaflet displaced toward
apex of right ventricle)
Large right atrium, small right ventricle
Often with Wolff-Parkinson-White syndrome
Lamotrigine is an alternative in pregnancy
Gabapentin and clonazepam are safe as anti-panic medication
in pregnancy
dTable 22–2.4 Mood Stabilizer Drug Summary
Type
Drug
Lithium
Anticonvulsants
Valproate
Carbamazepine
Lamotrigine
Atypical
antipsychotics
Quetiapine
Olanzapine
Risperidone
Aripiprazole
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 22–3
CHAPTER 23
1
CNS Stimulants
Overview
Indications include:
Attention deficit hyperactivity disorder (ADHD)
Narcolepsy
Obesity (anorexiant)
Obstruction/sleep apnea (respiratory stimulant)
High abuse potential
2
USMLE® Key Concepts
ADHD Therapy
For Step 1, you must be able to:
Prefrontal NE and mesocortical DA mediate:
Attention
Arousal
Concentration
Motivation
Interest
Other cognitive functions
DA and NE dysfunction are implicated in ADHD and other cognitive
disorders such as Alzheimer disease and other dementias.
X Explain the use of
amphetaminic drugs to treat
ADHD.
X Describe the abuse liability
of psychostimulants.
2.1 Amphetaminic Drugs
Most commonly used drugs.
Include:
D/L-amphetamine
Methylphenidate
Dexmethylphenidate
Lisdexamfetamine (prodrug of D-amphetamine)
Methamphetamine
Amphetaminic drugs n release of DA, NE (and 5-HT) from mobile
pool and block the reuptake of these amines.
Side effects are primarily those associated with increased NE:
Anxiety
Cardiovascular: palpitations, hypertension
Mydriasis
Loss of appetite
2.2 Atomoxetine
Atomoxetine is a selective NE reuptake inhibitor (NRI):
Suicidal ideation (FDA black box warning)
Unlike amphetaminic drugs:
No abuse potential
No problem with withdrawal
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 23–1
&KDSWHU‡&166WLPXODQWV
3
Pharmacology
Stimulant Abuse
3.1 Cocaine
More than half a million visits to emergency departments in 2011
No. 1 cause of ED visits involving illicit drugs
Smoked or injected
Blocks DA, NE, 5-HT reuptake
No effect on mobile pool (unlike amphetamines)
Also blocks voltage-dependent Na+ channel (see chapter 17,
topic 2, Local Anesthetics)
3.2 Amphetamines
See topic 2 above.
Abused amphetaminic drugs include a growing number of
designer drugs:
Substituted cathinones with cocaine or amphetamine-like
pharmacology are called bath salts.
Cathinone comes from khat, a shrub native to eastern Africa
and the Arabian Peninsula (equivalent to cocaine from the
coca plant, native to South America).
Examples include methylone and mephedrone.
Produced as "legal substitutes" of cocaine, methamphetamine,
or MDMA
No routine screen for bath salts.
Presentation:
— Agitation, violent behavior
— Hypertension, tachycardia, mydriasis
— Hallucinations, seizure
— Rhabdomyolysis and acute renal failure
Management is supportive
As of February 2014, close to 50 different compounds are
identified as "bath salts."
dTable 23–3.2 CNS Stimulants (ADHD Drug) Summary
Type
Drug
Releasers of Mobile Pool
D/L amphetamine
Methylphenidate
Dexmethylphenidate
Lisdexamfetamine
Methamphetamine
NE Reuptake Blocker
Atomoxetine
Chapter 23–2
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 24
1
Marijuana and Cannabinoids
Overview
Cannabis sativa contains > 70 cannabinoids.
Endogenous cannabinoids are derived from membrane
phospholipids (similar to arachidonic acid).
Two are well characterized:
Anandamide (N-arachidonoylethanolamine)
2-Arachidonoylglycerol (2-AG)
Two established cannabinoid receptors:
CB1 and CB2
Both are Gi-coupled
Tetrahydrocannabinol (THC) is the most psychoactive cannabinoid
from marijuana.
THC is a CB1 > CB2 agonist.
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe the pharmacology
of THC and its receptors.
X Identify the FDA-approved
indications of dronabinol
and nabilone.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 24–1
&KDSWHU‡0DULMXDQDDQG&DQQDELQRLGV
2
Pharmacology
Distribution and Pharmacology
of CB Receptors
dTable 24–2.0A CB Receptor Distribution
Receptor
CB1
CB2
Distribution
Neuronal > peripheral
Peripheral > neuronal
High
‡ &RUWLFROLPELFareas
‡ %DVDOganglia
‡ &HUHEHOOXP
‡ 6SOHHQ
‡ 7onsils
‡ 7Kymus
Moderate
‡ Dorsal root of spinal cord
‡ Periaqueductal gray substance
‡ +\SRWKDODPXV
‡ %ORRGcells
‡ 0DVWcells
The absence of CB receptors in the medulla correlates with a lack
of respiratory and cardiovascular suppression from cannabis use.
dTable 24–2.0B CB1 Stimulation and Effect
Mechanism
Effect
Established Use
p 5-HT release in CTZ
p6WLPXODWLRQRI+73
‡ $QWLQDXVHDQW
‡ $QWLHPHWLF
p Leptin release in
hypothalamus
n Appetite
Rx of anorexia or cachexia
of cancer$,'6
Two oral cannabinoids, dronabinol and nabilone, are available
for these indications.
Relatively well-confirmed potential indications:
Neuromuscular diseases: spasticity, multiple sclerosis
(central decrease in GABA/glutamate/ACh/glycine)
Analgesia: p neuropeptide release in spinal cord and activation
of TRPV1 receptors
— TRPV1 are the target of capsaicin, an established topical
analgesic
Asthma
Glaucoma
0HGLFDOFDQQDELVXVHLVOHJDOL]ed in 20 states and the District of
Columbia, but is not FDA approved or recognized at the federal level.
Chapter 24–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡0DULMXDQDDQG&DQQDELQRLGV
3
Pharmacology
Adverse Effects
Cautions in heart disease:
Dizziness from hypotension
Palpitations from reflex tachycardia
Cautions in substance abuse patients:
Euphoria, confusion
Cautions in psychiatric patients:
Aggravates or precipitates psychosis
Paranoia, hallucinations
4
Drug Interactions
AdditivH&16GHSUHVVLRQ
Opioids for pain management
Alcohol
Additive CV toxicity:
Amphetamines
Antimuscarinics
TCAs
Antipsychotics
Opposes effects of E-blockers (n risk of ischemic heart disease)
5
Synthetic Cannabinoids
New designer drugs of abuse
0DQy times more potent than THC
6DPHLVVXHVDVZLWKEDWKVDOWV
"Legal" highs
n ER visits
No routine screening
No antidote
dTable 24–5.0 Cannabinoid Drug Summary
Drug
Dronabinol
Nabilone
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 24–3
Unit 6
Antimicrobial Drugs (or Agents)
CHAPTER 25
1
Overview
Antimicrobial agents comprise a diverse array of compounds used
to combat the microorganisms responsible for infectious disease.
Classification:
Antibacterial
Antifungal
Antiviral
Antiparasitic
Non-Gram staining
Gram staining
USMLE® Key Concepts
For Step 1, you must be able to:
Gram
Gram
cocci
Gram
rods
X Define minimum
inhibitory and bactericidal
concentrations.
cocci
Gram
rods
X Differentiate bactericidal
agents from bacteriostatic
agents.
X Explain the role of
combination therapy.
Mycobacterium
Chlamydiaceae
Rickettsiae
Mycoplasma
Spirochetes
Anatomically gram
Anatomically gram
cFigure 25–1.0A Medically Important Bacteria
Minimum Inhibitory Concentration (MIC):
Lowest concentration of drug needed to inhibit bacterial growth
in vitro.
Stronger bacteriostatic agents have lower MICs, which differ
from organism to organism.
Minimum Bactericidal Concentration (MBC): Lowest
concentration of a drug needed to kill 99.99% of microorganisms in
a colony count.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 25–1
Pharmacology
Exponential
growth
No
ef
fec
t(
res
Number of Colonies
ist a n
c e)
&KDSWHU‡$QWLPLFURELDO'UXJV RU$JHQWV Bacteriostatic
Bactericidal
Time
Inoculation
Drug
cFigure 25–1.0B Bacteriostatic and Bactericidal Drug Effects
Combination Therapies:
Synergistic: 1 + 1 = 3
— Example: Aminoglycosides, normally inactive against grampositive organisms, are used together with penicillin or
cephalosporin to treat Enterococcus infections.
Additive: 1 + 1 = 2
— Example: Ciprofloxacin and metronidazole to treat aerobic
and anaerobic gut flora.
Antagonistic: 1 + 1 = 0
— Example: Tetracyclines and penicillin cannot be administered
concurrently because tetracyclines decrease the synthesis of
penicillin-binding proteins.
Chapter 25–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLPLFURELDO'UXJV RU$JHQWV 2
Pharmacology
Resistance Mechanisms
Will be reviewed separately with each class of antimicrobial drug
Three types:
Intrinsic: Mycoplasma has no cell wall and is unaffected
by cell wall synthesis inhibitors
Chromosomal: Alteration of structural proteins like PBP
and methicillin resistance
Plasmid-mediated: Enzymes modifying the antibiotic
structure, such as E-lactamases
3
Adverse Effects
Direct toxicityLQFOXGLQJRUJDQGDPDJH H[DPSOHDPLQRJO\cosides
causing nephrotoxicity and ototo[LFLW\
+\SHUVHQVLWLYLW\UHDFWLRQV YLUWXDOO\DOODQWLELRWLFV
InterDFWLRQVZLWKRWKHUGUXJV GXHWR3HIIHFW
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 25–3
CHAPTER 26
1
Antibacterials: Cell Wall
Synthesis Inhibitors
Classification of Antibacterials
By intended effect:
Bactericidal: No need for host immune response
— All cell wall disruption or synthesis inhibitors
— Aminoglycosides, ketolides
— Quinolones, nitrofurantoin
— Sulfonamides + DHF reductase inhibitors
— Metronidazole
Bacteriostatic: Host must be immune competent
— All protein synthesis inhibitors except aminoglycosides
and ketolides
— Sulfonamides alone
By spectrum of activity:
Broad versus narrow spectrum
Specific family, genus, or species of bacteria
Specific characteristic such as shape (cocci vs. rods) or
metabolic profile (aerobe vs. anaerobes) or simply staining
profile (gram-positive vs. gram-negative)
By mechanism/site of action:
Cell wall disruption or synthesis inhibitors
Protein synthesis (translation) inhibitors
Nucleic acid synthesis inhibitors:
— Direct acting: Transcription or replication inhibitors
— Indirect acting: Folate inhibitors
USMLE® Key Concepts
For Step 1, you must be able to:
X Classify antibacterials by
mechanism of action.
X Describe all classes of cell
wall synthesis inhibitors.
X Explain empirical spectrum
of activity of cell wall
synthesis inhibitors.
X Identify resistance
mechanisms of cell wall
synthesis inhibitors.
X Describe key side effects
and drug interactions or
combinations of cell wall
synthesis inhibitors.
!
Important Concept
Bactericidal agents are
preferred over bacteriostatic
agents in most clinical
situations involving severely ill or
immunocompromised patients.
Chapter 26–1
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLEDFWHULDOV&HOO:all Synthesis Inhibitors
Interference
with cell wall
synthesis
Disruption
of cell
membrane
Bacitracin
-lactams
Glycopeptides
Daptomycin
Colistin
Polymyxin B
Triclosan
Pharmacology
!
Important Concept
E-lactams include:
‡ 3enicillins
Bacterial cell
Cell wall
Cell membrane
DNA
Para-aminobenzoic acid
(PABA)
Tetrahydrofolate
(THF)
RNA
Transcription
c
Protein
Translation
l
‡ &HSKDORVSRULQV
‡ &DUEDSHQHPV
‡ $]WUHRQDP
‡ E-lactamase inhibitors
But not vancomycin, which is a
glycopeptide.
Dihydrofolate
(DHF)
Inhibition
of folic acid
synthesis
Sulfonamides
Trimethoprim
Interference
with DNA
structure and
function
Quinolones
Nitrofurantoin
Inhibition
of RNA
synthesis
Inhibition
of protein
synthesis
Rifamycins
Aminoglycosides
Lincosamides
Macrolides
Tetracyclines
Ketolides
Chloramphenicol
Streptogramins
Linezolid
Spectinomycin
cFigure 26–1.0 Antibacterial Mechanisms of Action
Chapter 26–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLEDFWHULDOV&HOO:all Synthesis Inhibitors
2
Pharmacology
Cell Wall Synthesis Inhibitors
Bactericidal agents
Target cell walls of bacteria
Include penicillins, cephalosporins, aztreonam, carbapenems,
and vancomycin
-lactams
Others
Penicillins
-lactamase resistant
-lactamase sensitive:
‡Natural penicillins
‡Amino penicillins
‡Extended-spectrum
penicillins
Cephalosporins : 4 generations
Glycopeptides : Vancomycin
Telavancin
Lipopeptides : Daptomycin
Nonclassified
: Bacitracin
Cycloserine
Monobactams : Aztreonam
Carbapenems : Imipenem family
Clavulanic acid
-lactamase inhibitors
Sulbactam
Tazobactam
cFigure 26–2.0 Cell Wall Synthesis Inhibitors
2.1 Penicillins
2.1.1 Mechanism of Action
Bind penicillin-binding proteins (PBPs)
Prevent transpeptidation
Inhibit cross-linking of bacterial cell wall
© DeVry/Becker Educational Development Corp. All rights reserved.
!
Important Concept
$OOE-lactams share the same
mechanism of action.
Chapter 26–3
&KDSWHU‡$QWLEDFWHULDOV&HOO:all Synthesis Inhibitors
Porin
Porin
Pharmacology
Porin
Outer
membrane
Cell
wall
Peptidoglycan
Periplasmic
space
-lactamase
Cytoplasmic
membrane
PBP
PBP
PBP
-lactams site of action
cFigure 26–2.1A E-Lactams and Cell Wall Synthesis
2.1.2 Pharmacokinetics
Most penicillins are excreted unmetabolized in the kidney by
filtration and secretion—adjust dosage in renal dysfunction.
The exceptions are nafcillin, oxacillin, and dicloxacillin, which
undergo biliary excretion.
2.1.3 Resistance Mechanisms
Degradation by bacterial penicillinases (also known as
ǃ-lactamases), which cleave the four-membered lactam ring.
Mutation of PBPs to weaken penicillin binding (also known as
methicillin resistance).
Down-regulation of porins that allow entry of penicillins (gram ٚ
only).
Upregulation of efflux channels.
H
N
R
The "R" group is variable
among individual drugs.
It determines stability as
well as the antibiotic spectrum.
O
S
N
O
O
OH
The -lactam ring is squareshaped and is the site of
cleavage by penicillinases
cFigure 26–2.1B E-Lactam Ring
Chapter 26–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLEDFWHULDOV&HOO:all Synthesis Inhibitors
Pharmacology
2.1.4 Spectrum of Activity
The spectrum of activity varies depending on agent and the potential
for resistance.
2.1.5 Adverse Effects
Hypersensitivity reactions (any type)
Assume cross reactivity between individual penicillins
GI upset including pseudomembranous colitis (ampicillin)
Skin rashes with ampicillin and amoxicillin are not allergic and
occur when treating a viral illness (e.g., mononucleosis)
2.1.6 Penicillin Additives
Some drugs are coadministered with penicillins to enhance activity by
preventing resistance or slowing excretion:
ǃ-Lactamase Inhibitors:
Suicide inhibitors of bacterial lactamases
Include clavulanic acid, sulbactam, and tazobactam
Added to E-lactamase-sensitive penicillins
Probenecid:
Blocks the secretion of penicillins into urine
Prolongs half-life
2.1.7 Natural Penicillins: E-Lactamase-Sensitive Narrow
Spectrum
Penicillin G:
Used mainly for syphilis
Benzathine penicillin is a depot form
Wellcome Images/Custom Medical Stock Photo
tĂƚŶĞLJŽůůĞĐƚŝŽŶͬWŚŽƚŽƚĂŬĞ
cFigure 26–2.1C Primary
Syphilis Lesion
cFigure 26–2.1D Secondary
Syphilis
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 26–5
&KDSWHU‡$QWLEDFWHULDOV&HOO:all Synthesis Inhibitors
Pharmacology
Penicillin V: Used to treat group A streptococci infection
DŝĐŚĂĞů'ĂďƌŝĚŐĞͬsŝƐƵĂůƐhŶůŝŵŝƚĞĚ͕/ŶĐ͘
cFigure 26–2.1E Streptococcus Pyogenes (Group A Strep)
2.1.8 E-Lactamase-Resistant Penicillins
Known as anti-staphylococcal penicillins
Methicillin:
Prototype
Not used clinically due to risk of interstitial nephritis
Laboratory testing to detect whether Staphylococcus aureus is
sensitive or resistant to methicillin ("methicillin-resistant Staph
aureus," or MRSA)
Nafcillin, oxacillin, and dicloxacillin: Used for S. aureus
2.1.9 Aminopenicillins: E-Lactamase-Sensitive Broad
Spectrum
!
Important Concept
The main options for the
WUHDWPHQWRI056$DUH
vancomyFLQOLQH]ROLGDQG
quinupristin/dalfopristin.
Ampicillin:
Action against gram-positive and gram-negative organisms
Poor absorption
Administered IV for gram ٚ infections (empirically for
suspected Listeria meningitis)
Nonallergic rash when given during certain viral illness such as
infectious mononucleosis
Amoxicillin:
Excellent oral absorption
Used for otitis media, community-acquired pneumonia,
sinusitis, and GI and GU infections
Combination With Other Drugs:
Aminoglycosides (e.g., gentamicin):
— Synergy
— p Resistance
— Important for bacterial endocarditis (including enterococcal)
!
Important Concept
Combination therapy of
amoxicillin and clavulanic
acid is the clinically preferred
prophylactic treatment for dog,
cat, and human bites.
E-lactamase inhibitors:
— Ampicillin + sulbactam
— Amoxicillin + clavulanic acid
— Increases spectrum and efficacy of aminopenicillins
Chapter 26–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLEDFWHULDOV&HOO:all Synthesis Inhibitors
Pharmacology
2.1.10 Extended Spectrum Penicillins: E-Lactamase
Sensitive
Also known as "antipseudomonal penicillins"
Carboxypenicillins: carbenicillin, ticarcillin
Ureidopenicillins: piperacillin, azlocillin
Primarily used for severe nosocomial infections
Added to aminoglycosides and E-lactamase inhibitors
2.2 Cephalosporins
2.2.1 Mechanism of Action
Similar mechanism of action to penicillins
Bactericidal
2.2.2 Pharmacokinetics
Generally excreted unmetabolized by the kidney
Cefoperazone and ceftriaxone are excreted through the bile
2.2.3 Resistance Mechanisms
These are similar to penicillins.
6HPLV\QWKHWLFFHSKDORVSRULQVDUHSUHSDUHGE\
DWWDFKLQJGLIIHUHQWFKHPLFDOJURXSVDW51DQG52
ǃODFWDPULQJ
R1
C
H
N
H
C
H
C
H
S
C
H
C
O
C
N
O
C
6LWHRIFOHDYDJHE\EDFWHULDO
ǃODFWDPDVHVRUE\DFLG
CH2
R2
COOH
$PLQRFHSKDORVSRUDQLFDFLG
cFigure 26–2.2 Cephalosporin Chemical Structure
2.2.4 Spectrum of Activity
Four Generations:
First and second generation: limited activity against
gram-negatives
Third and fourth generation: greater activity against
gram-negatives
First-Generation Cephalosporins:
Cephalexin and cefazolin
Gram †cocci, E. coli, K. pneumoniae
Cefazolin is used parenterally for surgical prophylaxis
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 26–7
&KDSWHU‡$QWLEDFWHULDOV&HOO:all Synthesis Inhibitors
Pharmacology
Second-Generation Cephalosporins:
Cefuroxime, cefoxitin, and cefotetan
Active against lactamase-producing H. influenzae, K.
pneumoniae, and penicillin-resistant streptococci
Active against anaerobes including Bacteroides
Third-Generation Cephalosporins:
Cefotaxime, ceftazidime, ceftriaxone, cefixime, cefpodoxime,
ceftizoxime
Extended spectrum
Important in empirical management of sepsis and meningitis
Not effective in treating Listeria, atypicals, MRSA and enterococci
Can be combined with aminoglycosides
Fourth-Generation Cephalosporins:
Cefepime
Resistant to most E-lactamases
2.2.5 Adverse Effects
Hypersensitivity reactions
Classically, 10% of patients with life-threatening allergic reaction
to penicillins also are allergic to cephalosporins
Consider macrolides or aztreonam (gram ٚrods only)
Cefamandole, cefotetan (second generation) and
cefoperazone cause:
Bleeding diathesis (p Factor II)
Disulfiram-like effects
Associated with methylthiotetrazole group
2.3 Carbapenems
Most potent lactam antibiotics: severe nosocomial infections
Imipenem/Cilastatin:
Cilastatin inhibits renal dehydropeptidase, which is responsible
for nephrotoxic metabolite of imipenem
Can cause seizures
Other Carbapenems:
Meropenem, doripenem, ertapenem
Do not require cilastatin
Less likely to cause seizure
NH
OH
H
H3C
H
NHCH
S
H
O
N
COOH
cFigure 26–2.3 Structure of Imipenem
Chapter 26–8
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLEDFWHULDOV&HOO:all Synthesis Inhibitors
Pharmacology
2.4 Monobactams: Aztreonam
Gram ٚrods only, including Pseudomonas
No cross-allergenicity to penicillins or cephalosporins
S
NH2
N
N
O
OH
HN
O
CH3
OH
N
O
SO2H
cFigure 26–2.4 Structure of Aztreonam
2.5 Glycopeptide: Vancomycin and Telavancin
2.5.1 Mechanism of Action
Binds D-Ala-D-Ala muramyl pentapeptide
Inhibits transglycosylation
Prevents elongation of peptidoglycan
No effects on PBPs
Telavancin also disrupts bacterial cell membrane
2.5.2 Pharmacokinetics
Poor absorption
Administered IV except for C. difficile induced colitis
Eliminated renally
2.5.3 Spectrum of Activity
MRSA
Enterococci
2.5.4 Resistance Mechanisms
Enterococci switch D-Ala-D-Ala to D-Ala-D-Lactate (VRE)
Some VRSA have similar resistance mechanism
2.5.5 Adverse Effects
"Red man" syndrome:
Involves an erythematous rash on face and upper torso along
with a drop in blood pressure
Mediated by histamine release from mast cell
Common when vancomycin is infused too quickly
Slow infusion and premedication with diphenhydramine can
lessen symptoms
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 26–9
&KDSWHU‡$QWLEDFWHULDOV&HOO:all Synthesis Inhibitors
Pharmacology
Ototoxicity
Nephrotoxicity
Additive with other nephrotoxic or ototoxic agents
2.6 Lipopeptide: Daptomycin
Similar spectrum of action to vancomycin
Gram-positive cocci
2.6.1 Mechanism of Action
Bactericidal
Inserts lipid portion of molecule in bacterial cell membrane:
Decanoic acid (C10:0)
Disrupts membrane
2.6.2 Pharmacokinetics
Renal clearance
Poor absorption: IV use
2.6.3 Resistance Mechanisms
Minimal
Alternative to vancomycin
2.6.4 Spectrum of Activity
MRSA, other Staph, Strep
VRE
2.6.5 Adverse Effects
Allergic (serious skin rash)
Rhabdomyolysis (monitor CK)
2.7 Bacitracin
2.7.1 Mechanism of Action
Cell wall synthesis inhibitor
Prevents dephosphorylation of a lipid carrier used to transport
peptidoglycan building blocks
2.7.2 Pharmacokinetics
Predominantly used as a topical agent.
2.7.3 Spectrum of Activity
Gram † bacteria, particularly skin flora.
2.7.4 Adverse Effects
Severe nephrotoxicity when given IV.
Chapter 26–10
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLEDFWHULDOV&HOO:all Synthesis Inhibitors
Pharmacology
dTable 26–2.7 Cell Wall Synthesis Inhibitors Drug Summary
Subclass
Natural Penicillins
Narrow spectrum
ǃ-lactamase susceptible
Penicillin G
Penicillin V
ǃ-lactamase resistant penicillins
Nafcillin
Oxacillin
Broad spectrum (+/–)
ǃ-lactamase inhibitor
Ampicillin
Amoxicillin
Antipseudomonal penicillin
Piperacillin
Ticarcillin
Carbenicillin
Cephalosporins
First generation
Cefazolin, cephalexin, others
Second generation
Cefotetan
Cefoxitin
Cefuroxime
Activity Spectrum
and Clinical Uses
Streptococcal and
meningococcal infections;
syphilis
Staphylococcal infections
Surgical prophylaxis
‡ Skin, soft tissue
‡ UT infections
‡ S. pneumoniae and
H. influenzae; B. fragilis
(cefotetan)
Pharmacokinetics
and Interactions
Toxicities
Hypersensitivity
Rapid renal elimination;
short half-lives necessitate reactions (~5%–6%
incidence); assume
frequent dosing
complete crossSome biliary clearance of reactivity;GI distress
and maculopapular
nafcillin and oxacillin
rash (ampicillin)
‡ Oral use for older drugs
‡ Mostly IV for newer
drugs; renal elimination
‡ Short half-lives
Hypersensitivity
reactions (~2%
incidence); assume
complete crossreactivity between
cephalosporins; partial
with penicillins; GI
distress
Third generation
Ceftriaxone
Cefotaxime
Ceftazidime
Fourth generation
Cefepime
Many uses including
pneumonia, meningitis,
and gonorrhea
Carbapenems
Imipenem-cilastatin
Meropenem
Ertapenem
Doripenem
Broad spectrum (not
MRSA), gram-negative rods
(Pseudomonas)
Parenteral; cilastatin
inhibits renal metabolism
of imipenem; renal
elimination
Partial cross-reactivity
with penicillins;
CNS effects include
confusion and seizures
Monobactams
Aztreonam
Gram ٚ rods only:
Klebsiella, Pseudomonas,
and Serratia
Parenteral use; renal
elimination
GI upsets, headache,
vertigo; no crossallergenicity with
ǃ-lactams
Glycopeptides
Vancomycin
Telavancin
Gram † activity includes
MRSA and PRSP strains
Parenteral (oral for
C. difficile colitis); renal
elimination IV only, long
half-life
"Red man" syndrome,
nephrotoxicity,
ototoxicity
Lipopeptide
Daptomycin
‡ Gram †activity; used in
endocarditis and sepsis
‡ Vancomycin alternative
Renal elimination
‡ Rhabdomyolysis;
monitor CK
‡ Allergies
Bacitracin
Gram †
Topical use
Third-generation drugs
enter CNS: empirical use
for sepsis meningitis
Broad activity, ǃ-lactamaseresistant
Creatine kinase (CK); methicillin-resistant Staphyloccus aureus (MRSA); penicillin-resistant Streptococcus pneumoniae
(PRSP); urinary tract (UT).
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 26–11
Antibacterials: Protein
Synthesis Inhibitors
CHAPTER 27
1
Overview
Block translation.
Slow or stop the growth of bacteria.
Require the host's immune system to defeat the infection.
Protein synthesis inhibitors are generally bacteriostatic.
Aminoglycosides are bactericidal.
Clindamycin,
macrolides
Chloramphenicol
USMLE® Key Concepts
Translocation
Linezolid
P site
A site
P site
Met
Ile
Arg
A site
Streptogramins
Next Trp
Peptidyltransferase
50S
mRNA
5'
Aminoglycosides
UAC
AUG
tRNA
AUC
AUC
P
A
GGG
tRNA
tRNA
AGA
UGG
P
A
UAA
3'
Tetracyclines
For Step 1, you must be able to:
X Describe various classes of
translation inhibitors.
X Explain empirical spectra
and modes of resistance for
translation inhibitors.
X Identify the main adverse
effects of translation
inhibitors.
30S
Gly
Ile
Met
Protein
N-terminus
cFigure 27–1.0 Site of Action of Protein Synthesis Inhibitors
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 27–1
&KDSWHU‡$QWLEDFWHULDOV3URWHLQ6ynthesis Inhibitors
Pharmacology
dTable 27–1.0A Mechanism of Action of Protein Synthesis Inhibitors
Type
Drug
30S inhibitors
50S inhibitors
Binding Site
Effect
Aminoglycosides
P site
‡ Inhibit initiation complex
(bacteriostatic)
‡ C
ause misreading
(bactericidal)
Tetracyclines
A site
‡ Inhibit elongation
(bacteriostatic)
‡ P
revent incorporation of
next amino acid
Linezolid
P site
Prevent initiation complex
formation (bacteriostatic)
Streptogramins
A site
‡ Inhibit elongation
(bacteriostatic)
‡ C
ause premature release
of peptide
Chloramphenicol
Peptidyltransferase
Inhibit peptide bond
formation (bacteriostatic)
Macrolides and
clindamycin
P site
‡ Inhibit translocation
(bacteriostatic)
‡ C
ause premature
dissociation of
aminoacyl-tRNA
dTable 27–1.0B Main Mechanisms of Resistance for Protein
Synthesis Inhibitors
Drug
Mechanisms
Aminoglycosides
1. TransferDVHV
‡ &RQMXJDWHdrug
‡ &DXVHinactivation
2. AlterDWLRQLQSRULQFKDQQHOV
‡ 'HFUHDVHentry
3. &KDQJHLQU51$
‡ Prevents 30S P site binding
Tetracyclines
1. Pumps increasing efflux
2. Changes in ribosome binding site
3. Inactivates enzymes
Macrolides
1. Methylation of 50S rRNA by methylases
2. Efflux pump
Chapter 27–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLEDFWHULDOV3URWHLQ6ynthesis Inhibitors
2
Pharmacology
Aminoglycosides
Drugs LQFOXGH
Amikacin
Gentamicin
Kanamycin
Neomycin (topical use)
Streptomycin
Tobramycin
Require an O2-dependent uptake to enter bacteria and block
SURWHLQV\QWKHVLV
Only active against gram ٚaerobes and some facultative
anaerobic bacilli
Inactive against gram ٚanaerobes
Streptomycin is used in tuberculosis and bubonic plague.
8VHGLQFRPELQDWLRQIRUV\QHUJ\DQGGHFUHDVHGUHVLVWDQFH
Ampicillin + gentamicin against E. faecalis
Vancomycin + gentamicin against E. faecium
Antipseudomonal penicillin or third-generation cephalosporin or
carbapenem + aminoglycosides against Pseudomonas
Ampicillin + aminoglycosides against Listeria
2.1 Pharmacokinetics
Water soluble, available IV, no CNS entry.
Once-daily dosing decreases to[LFLW\
ConcentrDWLRQGHSHQGHQWNLOOLQJ2QHGRVHDGDy allows for a
higher dose to be used.
Time-dependent to[LFLW\2QHGRVHDGDy allows a peak
concentration, not a steady presence of drug.
Requires therapeutic drug monitoring (TDM).
Renal exFUHWLRQ'HFUHDVHGRVHLQUHQDOG\VIXQFWLRQ
2.2 Adverse Effects
2WRWR[LFLW\
Auditory and vestibular
Irreversible
Additive with other ototoxic agents including loop diuretics
Nephrotoxicity
1HXURPXVFXODUEORFNDGHDWKLJKGRVHFXUare-like, can cause
respiratory paralysis
Dermatitis for neomycin
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 27–3
&KDSWHU‡$QWLEDFWHULDOV3URWHLQ6ynthesis Inhibitors
3
Pharmacology
Tetracyclines
Drugs LQFOXGH
Doxycycline
Minocycline
Tetracycline
Demeclocycline
Entry through passivHGLIIXVLRQ
Broad spectrum antibiotics
Gram †, gram ٚ, anaerobes, atypicals
Protozoa
Doxycycline is more lipid soluble and better distributed, which
makHVLWDGUXJRIFKRLFHLQ
Vibrio sp.
Spirochetes (Rickettsia, Borrelia)
Mycoplasma
Chlamydiae
Brucella (with rifampin)
3.1 Pharmacokinetics
Absorption is impaired by food (less for doxycycline).
Absorption is prevented by chelation of divalent cations
(Ca2+, Mg2+, Fe2+) and by Al3+
Avoid dairy products, antacids, mineral supplements.
Will bind to teeth and bones and cause damage.
Contraindicated in children and during pregnancy.
Minocycline is very wDWHUVROXEOH
High concentration in saliva and tears.
Used to eradicate asymptomatic meningococcal carrier state.
Doxycyline is lipid soluble and not renally eliminated (no dosage
DGMXVWPHQWLQUHQDOIDLOXUH 3.2 Adverse Effects
Direct to[LFLW\WR*,QDXVHDYomiting, diarrhea
Alteration of gut flora, including Clostridium overgrowth and colitis
%RQHDQGWHHWK interferes with growth, causes enamel dysplasia
and discoloration
Hepatotoxicity, in particular during pregnancy or with preexisting
condition
Photosensitivity
Reversible vestibular ototoxicity
Demeclocycline is an ADH receptor function blockHU
Causes nephrogenic diabetes insipidus
Used to treat SIADH
Chapter 27–4
!
Important Concept
Photosensitization occurs with:
‡ 7etracyclines
‡ 4XLQRORQHV
‡ 6XOIonamides
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLEDFWHULDOV3URWHLQ6ynthesis Inhibitors
4
Pharmacology
Tigecycline
A glycylcycline similar to tetracyclines in structure and mechanism
of action
FDA black box warning for n mortality risk
Administered IV, liver cleared
8VHGLQDKRVSLWDOVHWWLQJIRU
Staphylococci including MRSA, VISA, and VRSA
Penicillin- or vancomycin-resistant enterococci (VRE)
Other resistant microorganisms
Not effective against Pseudomonas or Proteus
5
Linezolid
An oxazolidinone antibiotic
Approved IRU
VRE
Nosocomial pneumonia
Skin infections
Reserved for nosocomial, multiple drug-resistant infections
Hematoto[LF
Reversible thrombocytopenia
Anemia, neutropenia
Drug interDFWLRQ
Serotonin syndrome with SSRIs
Linezolid is a weak MAO inhibitor
6
Streptogramins
Quinupristin/dalfopristin
8VHGLQFRPELQDWLRQIRUV\QHUJ\
Dalfopristin binds first
Causes a change in shape of A site
Increases affinity for quinupristin 100-fold
Vancomycin-resistant E. faecium
Not effective against E. faecalis
Skin infections with S. aureus and S. pyogenes
4XLQXSULVWLQGDOIRSULVWLQDUHLQKLELWRUVRI3$GUXJLQWHUactions
To[LFLW\LVLQIXVLRQUHODWHG
PDLQDWLQMHFWLRQVLWH
Flu-like symptoms
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 27–5
&KDSWHU‡$QWLEDFWHULDOV3URWHLQ6ynthesis Inhibitors
7
Pharmacology
!
Macrolides
Drugs LQFOXGH
Important Concept
Remember "thro" in the names
for macrolides:
Erythromycin
Clarithromycin
Azithromycin
‡ (UyTHROmycin
‡ &ODULTHROmycin
Broad spectrum similar to tetracyFOLQHV
Gram † cocci
Gram †URGCorynebacterium diphtheriae (DOC)
At\SLFDOVMycoplasma, Chlamydia, Mycobacterium,
Legionella (DOC)
Gram ٚ, including Neisseria, Campylobacter (DOC), H. pylori
‡ $]LTHROmycin
7.1 Pharmacokinetics
Liver/bile clearDQFH
Inhibit P450 3A4 except azithromycin
Azithromycin has elimination t½ of several da\V
Once-a-day dosing
A single 1 g dose is as effective as a 7-day course of
doxycycline for Chlamydia
7.2 Adverse Effects
GI:
Macrolides stimulate motilin receptors
Clarithromycin causes less GI upset
Liver: Cholestasis with erythromycin salts
Heart: QT prolongation
8
Ketolides
Telithromycin
Related to macrolides
Effective in macrolide-resistant strains
3ULPDU\XVHFRPPXQLW\-acquired pneumonia
Inhibitor of P450 3A4
9
Clindamycin
Active on gram-positive cocci and anaerobes.
Good distribution to bone, skin, and tendons.
First drug known to be associated with C. difficile colitis.
DOC for aspiration pneumonia (adult outpatient).
Chapter 27–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLEDFWHULDOV3URWHLQ6ynthesis Inhibitors
10
Pharmacology
Chloramphenicol
Broad spectrum antibiotic
Black box wDUQLQJIDWDOEORRGG\VFUasias
No longer first-line agent
Associated with gra\EDE\V\QGURPH
IneffectivHFRQMXJDWLRQLQQHRQDWHV
Chloramphenicol requires glucuronidation
P450 inhibitor
dTable 27–10.0 Protein Synthesis Inhibitors Drug Summary
Subclass
Activity and
Clinical Uses
Mechanism of Action
Pharmacokinetics
and Interactions
Toxicities
Aminoglycosides
Amikacin
Gentamicin
Kanamycin
Neomycin
Streptomycin
Tobramycin
‡ Bind 30S P site
‡ %DFWHULFLGDO
IV, renal elimination
‡ Gram ٚ aerobes
‡ 7%
‡ Used in combination
with cell wall
synthesis inhibitors
‡ Nephrotoxicity
‡ O
totoxicity
‡ N
euromuscular
blockade
Tetracylines
Tetracycline
Doxycline
Minocyline
Tigecycline
‡ B
ind 30S A site
‡ B
acteriostatic
‡ T
igecycline has
broadest spectrum
and resistance is
less common
‡ Chlamydia,
Mycoplasma,
Rickettsia,
spirochetes, H.
pylori
‡ Treatment of acne
(low dose)
‡ Oral, IV
‡ Renal and biliary
clearance
‡ G
I upset
‡ D
eposition in
developing bones
and teeth
‡ P
hotosensitivity
‡ S
uperinfection
Macrolides
Erythromycin
Azithromycin
Clarithromycin
Telithromycin
‡ B
ind 50S
‡ B
acteriostatic
‡ L
east resistance to
telithromycin
Community acquired
pneumonia, pertussis,
corynebacteria,
chlamydial infections,
and Legionella
‡ Oral, IV
‡ Hepatic clearance
‡ Azithromycin has
long half-life
‡ G
I upset
‡ H
epatic dysfunction
‡ Q
T elongation
‡ C
YP450 inhibition
(not azithromycin)
Lincosamide
Clindamycin
‡ Bind 50S
‡ Bacteriostatic
‡ Skin, soft tissue
‡ Anaerobic infections
‡ Oral, IV
‡ Hepatic clearance
‡ GI upset
‡ C. difficile colitis
Streptogramins
Quinupristin/
dalfopristin
‡ Binds 50S A site
‡ Bactericidal
‡ Staphylococcal
infections
‡ VRE
‡ IV
‡ Renal clearance
Infusion-related
arthralgia and
myalgia
Chloramphenicol
‡ Binds 50S
‡ Bacteriostatic
‡ Wide spectrum
‡ Backup drug
‡ Oral, IV
‡ Hepatic clearance
‡ Blood dyscrasia
‡ Gray baby
syndrome
Linezolid
‡ Binds 23S RNA of
50S P site
‡ Bacteriostatic
‡ MRSA
‡ PRSP
‡ VRE strains
‡ Oral, IV
‡ Hepatic clearance
‡ Dose-related
anemia
‡ Serotonin syndrome
with SSRIs
Methicillin-resistant Staphylococcus aureus (MRSA); penicillin-resistant Streptococcus
pneumoniae (PRSP); selective serotonin reuptake inhibitors (SSRIs); vancomycinresistant enterococci (VRE)
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 27–7
CHAPTER 28
1
Antibacterials: Nucleic Acid
Synthesis Inhibitors
Overview
There are two classes of nucleic acid synthesis inhibitors:
Indirect acting: Folic acid synthesis inhibitors
Direct acting: Replication or transcription inhibitors
2
Folic Acid Synthesis Inhibitors
USMLE® Key Concepts
Paraaminobenzoic acid (PABA) + Pteridine
Dihydropteroate
synthase
For Step 1, you must be able to:
Sulfonamides
Dihydropteroic acid
+ Glutamate
Dihydrofolic acid
NADPH
Dihydrofolate
reductase
Trimethoprim,
pyrimethamine
NADP
Tetrahydrofolic acid
X Describe folate inhibitors
and direct nucleic acid
synthesis inhibitors.
X Explain empirical spectra
and resistance mechanisms
of folate inhibitors and
direct nucleic acid synthesis
inhibitors.
X Idenitfy adverse effects and
drug interactions of folate
inhibitors and nucleic acid
synthesis inhibitors.
cFigure 28–2.0 Action of Folic Acid
Synthesis Inhibitors
THF is used for T, A, and G synthesis.
Folate synthesis inhibitors p DNA and RNA synthesis in
microorganisms.
Humans do not make folate (vitamin B9).
2.1 Sulfonamides
Broad spectrum: gram †, gram ٚ, Chlamydia.
Bacteriostatic.
As PABA analogs, they block dihydropteroate synthase
competitively.
They do not affect mammalian cells.
Resistance is common:
Altered affinity for dihydropteroate synthase
n Efflux or p permeability
n Production of PABA (e.g., staphylococci)
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 28–1
&KDSWHU‡$QWLEDFWHULDOV1XFOHLF$FLG6ynthesis Inhibitors
Pharmacology
2.1.1 Pharmacokinetics
Rapidly absorbed orally, with the following exceptions:
6LOYer sulfadiazine:
— Topical use in burn patients
— 6LOYer is toxic to bacteria
6XOIDVDOD]LQHXVHGLQXOFHUative colitis or regional enteritis.
Sulfasalazine
Gut bacteria
Sulfapyridine + 5-aminosalicylic acid
‡ Active sulfonamide
‡ Absorbed
‡ NSAID
‡ Local in gut
cFigure 28–2.1 Pharmacokinetics of Sulfasalazine
High albumin binding:
Can displace bilirubin in neonates and cause fatal kernicterus.
Drug interactions with:
— Oral anticoagulants
— 6XOIRQylureas
— Hydantoin anticonvulsants
Good distribution to all tissues.
Liver metabolism by N-acetylation (conjugation).
Parent and metabolites are renally excreted:
Crystalluria with sulfamethoxazole in acidic urine
2.1.2 Adverse Effects
Hypersensitivity reactions:
Higher rates in HIV patients
6NLQDQGPXFRVDH6WHYHQV-RKQVRQV\QGURPH
Photosensitivity
Acute hemolysis in G6PD patients
Chapter 28–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLEDFWHULDOV1XFOHLF$FLG6ynthesis Inhibitors
Pharmacology
2.2 Dihydrofolate (DHF) Reductase Inhibitors
Looking Ahead
Trimethoprim: prokaryotes
Pyrimethamine: protozoa
May precipitate bone marrow suppression in folate-deficient
patients
Methotrexate is an
antineoplastic drug which blocks
eukaryotic DHF reductase.
2.3 Combination Sulfonamide + DHF Reductase
Inhibitor
6ynergy
Decreased resistance
2.3.1 Trimethoprim-Sulfamethoxazole (TMP-SMX)
DOC for suspected or proven:
Haemophilus (respiratory infections, otitis)
Nocardia (respiratory and cutaneous mycetomas)
Pneumocystis jiroveci (prophylaxis and suppression)
UTIs/gastroenteritis (Enterobacteriaceae)
Community-acquired 056A
2.3.2 Pyrimethamine-Sulfadiazine
This combination is the DOC for toxoplasmosis (prophylaxis
and suppression).
dTable 28–2.3 Folic Acid Synthesis Inhibitors
Subclass
‡ Trimethoprimsulfamethoxazole
‡ Pyrimethaminesulfadiazine
Mechanism of AcƟon
AcƟvity and
Clinical Uses
‡ 87,V
‡ 6ynergistic
‡ 5espiratory
inhibition of folic
‡ Ear and sinus
acid synthesis
infections
‡ C
ombination is
‡ P. jiroveci
bactericidal
pneumonia
‡ 6XOIRQDPLGHVLQKLELW
‡ 1RFDUGLRVLV
dihydropteroate
synthase
‡ T
rimethoprim and
pyrimethamine
inhibit dihydrofolate
reductase
© DeVry/Becker Educational Development Corp. All rights reserved.
PharmacokineƟcs
and InteracƟons
‡ High protein binding
‡ $FHW\ODWLRQ
‡ 5enal clearance
‡ Kernicterus in
neonates
ToxiciƟes
‡ Hypersensitivity
(rDVKHV6-6 ‡ Bone marrow
suppression
‡ High incidence
of adverse effects
LQ$,'6
‡ *,upsets
‡ Acute hemolysis in
G6PD deficiency
Chapter 28–3
&KDSWHU‡$QWLEDFWHULDOV1XFOHLF$FLG6ynthesis Inhibitors
3
Pharmacology
Direct Nucleic Acid Synthesis Inhibitors
3.1 Quinolones
3.1.1 Mechanism of Action
Block topoisomerase II (DNA gyrase) in most gram ٚbacteria
Block topoisomerase IV in most gram † bacteria:
Topoisomerase II introduces negative supercoils
Topoisomerase IV keeps sister chromatids separated
Quinolones block replication (and transcription)
Bactericidal
Resistance is increasing:
Change in topoisomerases
Efflux pump
3.1.2 Pharmacokinetics
Distributed to all tissues, including bones.
Renal clearance: adjust in renal dysfunction.
Multivalent cations decrease absorption.
Inhibition of P450 1A2: n TCAs, clozapine, theophylline.
3.1.3 Adverse Effects
Tendonitis, tendon rupture:
Contraindicated in children/pregnancy
May affect chondrogenesis
n QT: levofloxacin, gemifloxacin, moxifloxacin
GI upset
Photosensitivity
&16LQVRPQLDKHDGDFKHUarely hallucinations and seizures
3.1.4 Spectrum of Activity
UTIs and gastroenteritis:
Alternative to TMP-60;
'2&LQ6KLJHOOD
Osteomyelitis, septic arthritis, skin infections due to gramnegative (and gram-positive):
Diabetes
6LFNOHFHOOSDWLHQWV
Ciprofloxacin is the DOC in anthrax
Used in combination for drug-resistant pneumococci
Mycoplasma, Chlamydia, and Rickettsia:6HFRQGOLQHDIWHU
macrolides or tetracyclines
No longer recommended for gonorrhea (resistance): thirdgeneration cephalosporin + macrolide or tetracycline is first choice
Chapter 28–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLEDFWHULDOV1XFOHLF$FLG6ynthesis Inhibitors
Pharmacology
3.1.5 Individual Drugs
Memory Aid
Nalidixic acid: prototype
Norfloxacin: weakest
Ciprofloxacin, ofloxacin, levofloxacin: gram ٚ > gram †
Gemifloxacin and moxifloxacin:
All quinolones have "flox" in
their names:
‡ Ciprofloxacin
Greater gram † activity
,QFOXGLQJFLSURIOR[DFLQUHVLVWDQW6SQHXPRQLDH
"Respiratory quinolones"
‡ Levofloxacin
‡ Gatifloxacin
‡ Moxifloxacin
3.2 Nitrofurantoin
Antiseptic used for UTIs.
Prodrug: Bacteria produce active metabolites (DNA damage).
Activity against E. coli and enterococci.
Most Enterobacter, Proteus, Pseudomonas, or Klebsiella
are resistant.
Colors the urine brown.
May precipitate hemolysis in G6PD patients.
3.3 Rifamycins
These drugs include rifampin (see chapter 31,
"Antimycobacterial Drugs").
dTable 28–3.3A Direct Nucleic Acid Synthesis Inhibitors
Subclass
Ciprofloxacin
Norfloxacin
Ofloxacin
Levofloxacin
Moxifloxicin
Gemifloxacin
AcƟvity and
Clinical Uses
PharmacokineƟcs
and InteracƟons
‡ 87,V
‡ *DVWURHQWHULWLV
‡ Bone/tissue
infections
‡ Respiratory
diseases
‡ p Absorption with
cations
‡ ٚ 1A2
‡ 5enal clearance
Mechanism of AcƟon
‡ I nhibits DNA
replication
‡ B
locks
topoisomerases II
and IV
‡ %DFWHULFLGDO
‡ R
esistance:
alteration of
topoisomerases and
pumps
ToxiciƟes
‡ *,upset
‡ &16HIIHFWV
(dizziness,
headache)
‡ Tendinitis/tendon
rupture
‡ Avoid in young
children and in
pregnancy
‡ 3KRWRVHQVLWLYLW\
‡ n QT
dTable 28–3.3B Nucleic Acid Synthesis Inhibitors Drug Summary
Type
Drug
Folic acid synthesis ٚ
Trimethoprim-sulfamethoxazole
Pyrimethamine-sulfadiazine
Nucleic acid synthesis ٚ
Quinolones
Ciprofloxacin
Norfloxacin
Ofloxacin
Levofloxacin
Moxifloxicin
Gemifloxacin
Nitrofurantoin
Rifamycins
Rifampin
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 28–5
CHAPTER 29
1
Miscellaneous Antimicrobial Drugs
Metronidazole
Antiprotozoal: DOC in Giardia, Trichomonas, and Entamoeba
Antibacterial:
DOC for Bacteroides
DOC for Clostridium difficile
Good anaerobe coverage
Active against H. pylori and Campylobacter
Prodrug: forms nitro radicals that kill anaerobic microorganisms
Adverse effects:
Metallic taste
Glossitis, stomatitis
Dysuria, cystitis
Neuropathies (possibly irreversible)
Hypersensitivity: SJS with mebendazole coadministration
Disulfiram-like effect
Tinidazole is a related antiprotozoal drug
2
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe the target
organisms, mechanism of
action, and adverse effects
of metronidazole.
X Identify topical
antimicrobials.
Polymyxins
Basic peptides against gram ٚbacteria
Act like detergents: disrupt membranes
Used topically
Include:
Polymyxin B
Polymyxin E (colistin)
3
Mupirocin
Pseudomonic acid: produced by P. fluorescens
Used topically
Active against gram † cocci, including MRSA:
Blocks isoleucyl-tRNA synthetase of S. aureus
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 29–1
Antibiotic Choice
CHAPTER 30
1
Drugs of Choice
Antibiotic susceptibility will alter DOC.
Alternative drugs are available as substitutes for DOC.
Acid-fast rods are discussed in chapter 31, except for Nocardia
(DOC = TMP-SMX).
dTable 30–1.0 Antibiotic Choice Based on Specific
Bacteria Infections
Type
Gram † cocci
Gram ٚcocci
Gram † rods
Bacteria/Infection
DOC
Staphylococci
‡ 1RQǃ-lactamase +
‡ ǃ-lactamase +
‡ 0HWKLFLOOLQresistant
‡ 9ancomycin resistant
Penicillin G/V
1DIFLOOLQRxacillin
Vancomycin
Streptogramins, linezolid
Streptococci
S. pneumoniae:
‡ 2WLWLVmedia
‡ 3QHXPRQLD
‡ 0HQLQJLWLV
Amoxicillin +/í clavulanic acid
Macrolides +/í quinolones
Third-generation cephalosporins
Enterococci
‡ E. faecalis
‡ E. faecium
‡ 95(
Ampicillin +/í gentamicin
Vancomycin +/í gentamicin
Linezolid or streptogramins
Neisseria meningitidis
Lactam antibiotic
N. gonorrhoeae
Ceftriaxone + azithromycin,
doxycycline
Moraxella catarrhalis
Cefuroxime or quinolones, macrolides
Actinomyces
Penicillin or tetracycline
Bacillus anthracis
Ciprofloxacin or doxycycline
Clostridium
Metronidazole, clindamycin
Listeria
Ampicillin +/– aminoglycoside
Corynebacterium
diphtheriae
Macrolide
USMLE® Key Concepts
For Step 1, you must be able to:
X Identify the drug or
combination of choice for
empirical bacterial infection
management.
(continued on next page)
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 30–1
&KDSWHU‡$QWLELRWLF&KRLFH
Pharmacology
dTable 30–1.0 Antibiotic Choice Based on Specific
Bacteria Infections (continued)
Type
Gram ٚ rods
Bacteria/Infection
Enterobacter
Carbapenems
Serratia
Carbapenems
E. coli:
‡ 6HSVLV
‡ 87,
Spirochetes
DOC
Third-generation cephalosporin or
carbapenems
TMP-SMX, quinolones
H. pylori
Amoxicillin + clarithromyFLQ33,
or bismuth + tetracycline
+ metronidazole
C. jejuni
Macrolides
Haemophilus:
‡ 0HQLQJLWLV
‡ 5espiratory or ear
infection
Third-generation cephalosporins
TMP-SMX
Klebsiella sp.
Cephalosporins
Proteus mirabilis
Proteus vulgaris
Ampicillin
Third-generation cephalosporins
Pseudomonas
aeruginosa
Piperacillins + tazobactam,
or third-generation cephalosporin
+ aminoglycoside,
or carbapenems + aminoglycosides
Borrelia burgdorferi or
B. recurrentis
Doxycycline
Treponema pallidum or
T. pertenue
Penicillin
Leptospira
Penicillin
0\FRSODVPD
Macrolides
&KODP\GLD
Doxycycline
5LFNHWWVLD
Doxycycline
Chapter 30–2
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 31
1
Antimycobacterial Drugs
Overview
Antimycobacterial agents
Drugs used in
tuberculosis
First-line drugs
Drugs used
in leprosy
Alternative drugs
Drugs used for
atypical mycobacteria
Drugs for major
infections
Drugs for minor
infections
cFigure 31–1.0 Antimycobacterial Agents
2
USMLE® Key Concepts
For Step 1, you must be able to:
X Name combination
therapies for tuberculosis.
Treatment for Tuberculosis
Combination drug therapy is required.
Multidrug-resistant strains require drug-resistance testing.
Primary drugs for treating tuberculosis include:
Isoniazid
Rifampin
Pyrazinamide
Ethambutol
X Identify individual
antimycobacterial drugs and
their mechanism of action.
X Identify the key side effects
of each antimycobacterial
drug.
Secondary drugs for tuberculosis, which are generally used for
drug-resistant strains or for patients who cannot tolerate one or
more of the primary drugs, include:
Streptomycin
Cycloserine
Quinolones
2.1 Isoniazid
Bactericidal
Cell wall synthesis inhibitor
Prodrug:
Activated by catalase-peroxidase (KatG) of TB
Inhibits mycolic acid synthesis
Irreversibly blocks enoyl-acyl carrier protein reductase (InhA)
and ǃ-ketoacyl-ACP synthase (KasA)
Resistance mechanisms:
Mutations in KatG gene: p activation
Mutations in InhA or KasA gene: altered target
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 31–1
&KDSWHU‡$QWLPycobacterial Drugs
Pharmacology
Adverse effects:
Hepatitis and peripheral neuropathy: give B6
Precipitates seizures in epileptic patients (p B6, p GABA)
Most common cause of iatrogenic sideroblastic anemia
SLE-like syndrome in slow acetylators
Hemolysis in G6PD patients
2.2 Rifampin and Other Rifamycins
Bactericidal
Active against all mycobacteria except M. fortuitum
Synergy with isoniazid and streptomycin
Blocks DNA-dependent RNA polymerase:
Nucleic acid synthesis inhibitor
Blocks transcription
Binds to the ǃ subunit of prokaryotic RNA polymerase
Has no effect on eukaryotic RNA polymerases
Pharmacokinetics:
Well-distributed, including CNS
Liver-metabolized
Gives an orange-red color to urine, saliva, tears, and sweat
Adverse effects:
Hepatotoxicity
Inducer of P450s: multiple drug interactions
Other rifamycins include:
Rifabutin: used with macrolides and ethambutol in M. aviumintracellulare complex
Rifabutin has less P450 induction effect
Rifapentine has a long t½ (once-weekly dosing)
Clinical
Application
‡ Rifampin is also used
in the eradication
of asymptomatic
meningococcal carrier
state and in H. influenzae
meningitis.
‡ Combined with
ơ-lactams or vancomycin
against staphylococcal
endocarditis or
osteomyelitis.
2.3 Pyrazinamide
Converted by mycobacterial enzymes to a toxic metabolite:
pyrazoic acid
Kills bacteria at low pH in lysosomes
Adverse effects:
Hepatotoxicity
Gout: inhibits urate excretion
Chapter 31–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLPycobacterial Drugs
Pharmacology
2.4 Ethambutol
Inhibits arabinosyltransferase
Prevents arabinogalactan synthesis (cell wall)
Bacteriostatic
Adverse effects:
Optic neuritis with red/green color blindness and blurry vision
2.5 Other Antitubercular Drugs
Cycloserine:
Inhibits mycobacterial cell wall synthesis by blocking peptide
formation.
Central nervous system side effects include seizures.
Capreomycin:
Inhibits RNA synthesis.
Similar adverse effects to aminoglycosides.
2.6 Tuberculosis Regimens
2.6.1 Prophylaxis Regimens
High-risk patients:
Immunocompromised
Very young or very old
Patients with recent PPD (skin test) conversion
Isoniazid for six months
2.6.2 Treatment of Active Tuberculosis
Initial four-drug regimen: isoniazid, rifampin, pyrazinamide, and
ethambutol until sensitivity of the strain is known.
After sensitivity is known, treatment must include at least two
drugs to which the tuberculosis strain is sensitive in vitro.
Common regimens are:
Isoniazid + rifampin + pyrazinamide for six months
Isoniazid + rifampin for nine months
2.6.3 Treatment of Tuberculosis During Pregnancy
The following are considered safe during pregnancy:
Isoniazid
Rifampin
Ethambutol
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 31–3
&KDSWHU‡$QWLPycobacterial Drugs
3
Pharmacology
Treatment of Leprosy
Sulfones: dapsone
Same pharmacology as sulfonamides
dTable 31–3.0 Antimycobacterial Agents
Drugs
Mechanism
of Action
Activity
Pharmacokinetics
and Interactions
Toxicities
Isoniazid (INH)
‡ Requires
bioactivation
‡ Inhibits mycolic
acid synthesis
‡ Resistance:
mutations in
KatG, InhA, and
KasA
Bactericidal
‡ Oral, IV forms
‡ H
epatic clearance
(fast and slow
acetylators)
‡ +HSDWRWRxicity
‡ Peripheral
neuropathy (use B6)
‡ Hemolysis in G6PD
deficiency
Rifamycins
Rifampin
Rifabutin
Rifapentine
Inhibit DNAdependent RNA
polymerase
Bactericidal
General inducer of
P450s
‡ /LYer toxicity
‡ 2Uange fluids
Ethambutol
Inhibits formation of
arabinoglycan
Bacteriostatic
‡ 5enal elimination
‡ R
educe dose in
renal dysfunction
Optic neuritis
Pyrazinamide (PYR)
Requires
bioactivation via
hydrolytic enzymes
to form pyrazoic
acid (active)
Bacteriostatic
Hepatic and renal
elimination (reduce
dose in dysfunction)
‡ +HSDWRWRxicity
‡ +\SHUXULFHPLD
‡ 0\algia
‡ Polyarthralgia (40%
incidence)
Streptomycin (SM)
‡ Binds 30S
‡ Inhibits protein
synthesis
Bactericidal
‡ 3arenteral
‡ 5enal elimination
‡ 2WRWRxicity
‡ 1HSKURWRxicity
Chapter 31–4
© DeVry/Becker Educational Development Corp. All rights reserved.
Antifungal Drugs
CHAPTER 32
1
Overview
Systemic mycosis may affect normal individuals; the endemic
fungi responsible for these infections include:
Histoplasma
Blastomyces
Coccidioides
More often, mycoses are severe in immunocompromised patients;
the opportunistic pathogens responsible for these infections
include:
Aspergillus
Pneumocystis
Candida
Cryptococcus
Mucor
USMLE® Key Concepts
For Step 1, you must be able to:
Superficial fungal infections are generally treated with topical drugs.
The primary drugs are:
Azoles
Amphotericin B/nystatin
Echinocandins
X Contrast the site and
mechanisms of action of
antifungal drugs.
X Compare polyenes and
azoles and their toxicity
profiles.
X Describe the major
systemic mycoses and their
treatments of choice.
Cell Wall
Cell membrane:
Amphotericin B/nystatin
DNA:
Flucytosine
Glucans: Caspofungin
Micafungin
Anidulafungin
Echinocandins
Ergosterol
synthesis:
Azoles, terbinafine
Microtubules:
Griseofulvin
cFigure 32–1.0 Site of Action of Antifungal Drugs
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 32–1
&KDSWHU‡$QWLIXQJDO'UXJV
Pharmacology
dTable 32–1.0 Presentation and Treatments of Major Systemic Mycoses
Systemic Mycosis
Pathology
Drug of Choice
Histoplasmosis
Blastomycosis
Coccidioidosis
‡ )XQJDOpneumonia
‡ May disseminate to skin, mucosae, joints,
meninges
1. Itraconazole (non-meningeal
disease)
2. Amphotericin B (more severe/CNS
involvement)
Aspergillosis
‡ Lungs: necrotizing pneumonia
‡ Sinuses
‡ Brain
‡ Invasive in immunosuppressed and CGD
patients
1. Voriconazole
2. Amphotericin B
3. Caspofungin
Pneumocystosis
Interstitial plasma cell pneumonia
1. TMP-SMX
2. Primaquine + clindamycin
3. Pentamidine
4. Atovaquone
Candidiasis
‡ Mucosal
‡ Disseminated
1. )OXFRQD]ole
2. Caspofungin, micafungin, or
anidulafungin
‡ Endocarditis
Amphotericin B + flucytosine
Cryptococcosis
)XQJDOPHQLQJLWLV
1. Amphotericin B + fluconazole
2. Amphotericin B + fluconazole +
flucytosine
3. Maintenance on fluconazole in AIDS
patients
Zygomycosis (Mucor,
Rhizopus, Absidia,
Cunninghamella)
Rhinocerebral
1. Control of underlying disease and
surgery, 30%–50% mortality rate for
localized disease
2. Posaconazole
Chapter 32–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLIXQJDO'UXJV
2
Amphotericin B
Widest spectrum, but very toxic
)XQJLFLGDO
2.1 Mechanism of Action
Binds to ergosterol in the fungal cell membrane
Causes artificial pores
Disrupts integrity of the fungal membrane
Pharmacology
Clinical
Application
‡ Nystatin is only used
topically.
‡ Swish and swallow
in candidiasis (no
absorption).
2.2 Resistance Mechanisms
Resistance is caused by low ergosterol content in cell membranes.
2.3 Pharmacokinetics
Oral: poor absorption
IV: no CNS entry
Intrathecal
t½ = two weeks
2.4 Adverse Effects
Acute-infusion-related:
)ever, chills, muscle rigor, and hypotension (due to histamine
release)
Prophylaxis with NSAIDs, antihistamines, and corticosteroids
+ slow infusion
Dose-dependent:
Nephrotoxicity (RT$JORPHUXODUGDPDJH&5)DQGDQHPLD
Liposomal amphotericin B improves efficacy and reduces
toxicity
Combination with azoles, flucytosine allows lower
amphotericin B dose
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 32–3
&KDSWHU‡$QWLIXQJDO'UXJV
3
Pharmacology
Azoles
Two groups:
Imidazoles:
— Ketoconazole
— Miconazole (topical only)
— Clotrimazole (topical only)
Triazoles:
— Itraconazole
— )OXFRQD]ROH
— Voriconazole
— Posaconazole
Triazoles are metabolized more slowly and have less effect on
human steroid synthesis.
Squalene
epoxidase Squalene
Squalene
epoxide
Terbinafine
Lanosterol
14 -sterol
demethylase
Azoles
Ergosterol
cFigure 32–3.0 Ergosterol Synthesis
3.1 Mechanism of Action
Azoles inhibit fungal CYP450 enzymes:
Block 14D-sterol demethylase
Accumulation of 14D-methyl sterols disrupts fungal
phospholipids in membrane
)XQJLVWDWLFSRVVLEO\IXQJLFLGDODWKLJKGRVHV
Broad spectrum
3.2 Resistance Mechanisms
Mutations in ERG 11, 14D-sterol demethylase gene in Candida
confer cross-resistance to all azoles
Increased efflux through ATPase pumps
3.3 Pharmacokinetics
All azoles are effective orally
Also available IV except for ketoconazole and posaconazole
&6)SHQHWUDWLRQIOXFRQD]ROHRQO\
All azoles are general inhibitors of CYP450s
Chapter 32–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLIXQJDO'UXJV
Pharmacology
3.4 Adverse Effects
Well tolerated, GI upset, nausea
p Synthesis of androgens and cortisol
p Libido, gynecomastia
Ketoconazole is used for Cushing disease
Rare hepatotoxicity
Drug interactions
4
Flucytosine
4.1 Mechanism of Action
Activated by fungal cytosine deaminase to 5-fluorouracil )8 disrupts RNA synthesis
)8DOVREORFNVWKymidylate synthase: disrupts DNA synthesis
)8LVDOVRXVHGDVDQDQWLFDQFHUGUXJ
4.2 Resistance Mechanisms
)OXF\WRVLQHLVQHYer used alone due to rapid emergence of resistance.
4.3 Pharmacokinetics
8VHGorally
Combined with amphotericin B
Enters &6)
4.4 Adverse Effects
Bone marrow suppression
5
Echinocandins
Include:
Caspofungin
Micafungin
Anidulafungin
Cell wall synthesis inhibitors: block ǃ-glucan synthase
)XQJLFLGDO
IV only
Well tolerated
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 32–5
&KDSWHU‡$QWLIXQJDO'UXJV
6
Pharmacology
Treatment of Superficial Mycoses
Dermatophytes
Onychomycosis
6.1 Terbinafine
Given orally or topically
Inhibits fungal squalene epoxidase, blocking ergosterol synthesis
GI distress, hepatotoxicity
6.2 Griseofulvin
)XQJLVWDWLF
Interferes with fungal mitosis
Given orally
Distributes in newly formed keratin
Disulfiram-like effect
Induces P450s
6.3 Miconazole and Clotrimazole
dTable 32–6.3 Antifungal Drug Summary
Type
Drugs
Polyenes
Amphotericin B
Nystatin
Azoles
Ketoconazole
Miconazole
Clotrimazole
Itraconazole
)OXFRQD]ole
Voriconazole
Posaconazole
Pyrimidine analog
)OXF\WRVLQH
Echinocandins
Caspofungin
Micafungin
Anidulafungin
Miscellaneous
Terbinafine
Griseofulvin
Chapter 32–6
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 33
1
Antiviral Drugs
Overview
Viruses: obligate intracellular parasites
Drugs affect viral replication cycle: may damage host cells
Many are nucleoside/nucleotide analogs: antimetabolites
1. Attachment
Virus
Polymerase
inhibitors
Amantadine
4. DNA/RNA
synthesis
2. Penetration
Fusion
inhibitors
3. Uncoating
Protease
inhibitors
5. Protein
synthesis
6. Assembly
USMLE® Key Concepts
Neuraminidase
inhibitors
For Step 1, you must be able to:
7. Release
X Describe the mechanism of
action of antiviral drugs.
X Classify antiviral drugs
based on their spectrum of
activity.
Interferons
Host cell
cFigure 33–1.0 Major Sites of Action of Antiviral Drugs
dTable 33–1.0 Mechanism of Action and Indication of Major Antiviral Drugs
Mechanism
Drug
Indication
Block absorption and entry
‡ Enfuvirtide
‡ 0DUaviroc
‡ 3alivizumab
HIV
HIV
RSV
Block uncoating
‡ Amantadine
‡ 5LPDQWDGLQH
Influenza A
Influenza A
Block viral DNA polymerase
‡ Acyclovir
‡ *DQFLFORvir
‡ )oscarnet
‡ $GHIRvir
‡ /DPLYXGLQH
‡ (QWHFDvir
HSV, VZV
CMV
CMV, HSV, VZV
HBV
HBV
HBV
Block viral RNA polymerase
‡ Ribavirin
‡ )oscarnet
RSV
CMV, HSV, VZV
Block viral reverse transcriptase
‡ NRTIs: zidovudine family
‡ NNRTIs: nevirapine family
HIV
HIV
Block viral aspartate protease
3URWHDVHLQKLELWRUVVDTXLQDvir family
HIV
Block viral release
Neuraminidase inhibitors
Influenza A and B
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 33–1
&KDSWHU‡$QWLYLUal Drugs
2
Pharmacology
Treatment of Herpes Viruses
Include HSV 1 and 2, VZV, and CMV
Most drugs are nucleoside analogs:
3URGUXJ
RHTXLUHNLQDVHVWREHFRPHQXFOHRWLGHDQDORJV
*HWLQFRUSRUated into viral DNA
/DFND 2+DQGSUHYent attachment of next nucleotide by viral
polymerase
Cause chain termination
Block viral DNA polymerase
2.1 HSV and VZV Treatment
Connection to
Biochemistry
For discussion of nucleoside
analogs, see Biochemistry,
chapter 2, pp. 2–10.
2.1.1 Acyclovir
Mechanism of Action
*XDQRVLQHDQDORJSURGUXJ
5HTXLUHVYLUDOWK\PLGLQHNLQDVH 7. )LUVWSKRVSKRU\ODWLRQVWHS
Cellular kinases: guanosine triphosphate analog
2QO\LQ+69+69DQG9=9
Chain terminator
Resistance:
Absence or pSURGXFWLRQRIYLUDO7.
Cross-resistance with:
— Valacyclovir
— )amciclovir
— *DQFLFORvir
No cross-resistance with:
— )oscarnet
— Cidofovir
— Trifluridine
Pharmacokinetics
Topical, oral, IV
*RRGGLVWULEXWLRQLQERG\IOXLGVLQFOXGLQJ&6)
Short t½ WRKRXUV
Renally excreted
Valacyclovir is a prodrug of acyclovir givHQ32
*,OLYer
Valacyclovir
acyclovir
Hydrolases
n Bioavailability of acyclovir 3- to 5-fold
Approximates IV levels
Chapter 33–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLYLUal Drugs
Pharmacology
Adverse Effects
Well tolerated
2Ual: nausea, diarrhea, headache
IV:
Nephrotoxicity
Neuroto[LFLW\ FRQIXVLRQVHL]XUHV
Severe thrombocytopenia with valacyclovir
Indications
HSV 1 and 2:
p Virus shedding, symptoms, and time to heal
p Recurrence when used prophylactically
VZV:
$FXWHWUHDWPHQW ZLWKKRXUVRIUDVKRQVHW
No effect on postherpetic neuralgia
CMV:
Inactive on established CMV infection
Used for prophylaxis of CMV immunocompromised patients
2.1.2 Famciclovir
3URGUXJ
Converted to penciclovir after oral administration
3enciclovir is available for topical use
*XDQRVLQHanalog:
RHTXLUHV7.IRUDFWLYation
Inhibits viral DNA polymerase
Not a chain terminator
2.2 CMV Treatment
2.2.1 Ganciclovir
Mechanism of Action
*XDQRVLQHDQDORJSURGUXJ
RHTXLUHVYLUDOSKRVSKRWUDQVIHUDVH8/ &09 )LUVWSKRVSKRU\ODWLRQVWHS
&DQXVH7.LQ+69
Cellular kinases: ganciclovir triphosphate
Chain terminator
RHVLVWDQFHWKURXJKFKDQJHVLQ8/RU7.
Pharmacokinetics
2Ual, IV, intraocular implant
Valganciclovir is a prodrug of ganciclovir:
32only
n Bioavailability of ganciclovir
)ood n bioavailability further
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 33–3
&KDSWHU‡$QWLYLUal Drugs
Pharmacology
Adverse Effects
%RQHPDUURZVXSSUHVVLRQ GRVHOLPLWLQJ UHFRPELQDQW*&6)
ILOJUDVWLP PDy help
CNS toxicity: headache to convulsions
Indications
CMV retinitis prophylaxis and treatment:
Immunocompromised patients
Transplant recipients
Relapses and retinal detachment still occur
!
Disseminated CMV
Important Concept
Acyclovir, valacyclovir, and
famciclovir have good
activity against HSV and VZV,
but generally poor activity
against CMV. Ganciclovir and
valganciclovir have much better
activity against CMV than
acyclovir or famciclovir.
2.2.2 Foscarnet
Inorganic pyrophosphate analog
Blocks viral DNA and RNA polymerases
Not a prodrug
Resistance: point mutation in DNA polymerase
,9RQO\ LQIXVLRQSXPS
Nephrotoxicity and symptomatic hypocalcemia:
Arrhythmia, tetany, seizures
IV pentamidine n risk of severe hypocalcemia
Used for ganciclovir-resistant CMV or acyclovir-resistant HSV/VZV
infections
&KDSWHU±
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLYLUal Drugs
3
Pharmacology
HIV Treatment
According to the CDC:
An estimated 1.2 million people in the United States have HIV.
~20% of cases are undiagnosed.
Estimated annual incidence: 50,000 cases
)LYe major classes of drugs:
Nucleoside reverse trDQVFULSWDVHLQKLELWRUV 157,V
Non-nucleoside reverse trDQVFULSWDVHLQKLELWRUV 1157,V
3URWHDVHLQKLELWRUV 3,V
IntegrDVHLQKLELWRUV ,,V
Entry inhibitors:
— )XVLRQLQKLELWRUV ),V
— &KHPRNLQHUHFHSWRUDQWDJRQLVWV &5$V
Combination therapy:
Synergy
p Resistance
gp120env
p17 gag
p24 gag
gp41env
Enfuvirtide (FI)
binding to CD4
CCR5 Maraviroc (CRA)
CXCR4
Reverse
transcriptase pol
NRTIs/NNRTIs
Integrase pol
Aspartate pol
protease
Raltegravir
(II)
Elvitegravir
PIs
p7p9 gag
cFigure 33–3.0 Mechanism of Action of HIV Drugs
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 33–5
&KDSWHU‡$QWLYLUal Drugs
Pharmacology
3.1 NRTIs
Competitive inhibitors of reverse transcriptase
Nucleoside analog activated by host cell kinases
Chain terminators
Active against HIV-1 and HIV-2
Mitochondrial toxicities:
/DFWLFacidosis
Hepatitis
3ancreatitis
3eripheral neuropathies
Bone marrow suppression
Myopathy
NRTIs are not substrDWHVRI&<3V
Resistance occurs—cross-resistance confined to drugs with similar
structure
Some of the least toxic NRTIs are also used for HBV:
Emtricitabine
/DPLYXGLQH
Tenofovir
If comorbid HIV/HBV cessation would result in exacerbation of
hepatitis due to rebound HBV replication
dTable 33–3.1 NRTIs
NRTI
Analog
Important Point
ZidoYXGLQH ='9
T
‡ Bone marrow suppression
‡ 0\opathy
‡ /LYer toxicity
StaYXGLQH G7
T
‡ 3eripheral neuropathy
‡ Associated with fat wasting
+,9OLSRG\VWURSK\V\QGURPH
‡ Avoid didanosine:
— Additive neuropathy
—3otentially fatal pancreatitis
‡ Avoid zidovudine: compete for
activation
(PWULFLWDELQH )T&
C
‡ 2QHRIOHDVWWRxic NRTIs:
— Hyperpigmentation of skin
/DPLYXGLQH 7&
C
‡ /HDVWWRxic
‡ $YRLG)7&DQG7&
combinations
(continued on next page)
Chapter 33–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLYLUal Drugs
Pharmacology
dTable 33–3.1 NRTIs (continued)
NRTI
Analog
Important Point
'LGDQRVLQH G',
A
‡ 3HULSKHUDOQHXURSDWK\
‡ 3DQFUHDWLWLV
‡ AvRLGG7: additive toxicity
TenofoYLU 7')
A
‡ Nucleotide analog
‡ 3URGUXJ
Tenofovir disoproxil fumarate
p Hydrolase
Tenofovir
p.LQDVH
Tenofovir phosphate
‡ nG',$8&E\!
— Should not be used together
— Blocks dDI metabolism
AbacaYLU $%&
*
Hypersensitivity ± ‡ 8QLTXHSRWHQWLDOO\IDWDO
‡ )HYHUDEGRPLQDOSDLQDQG
rDVKZLWKLQVL[ZHHNVUHTXLUHV
immediate discontinuation
‡ Restarting ABC causes shock
and death
‡ /LQNHGWR+/$% 3.2 NNRTIs
Noncompetitive inhibitors of reverse transcriptase: allosteric site
binding changes conformation
Not prodrugs
Rapid resistance if used alone
2QO\DFWLYe on HIV-1
Associated with skin rash, including Stevens-Johnson syndrome
0HWDEROL]HGE\&<3GUXJLQWHUDFWLRQV HJZLWK3,V
dTable 33–3.2 NNRTIs
NNRTI
P450
Important Point
Nevirapine
$
‡ , QGXFHURI$LQFOXGLQJLWV
own metabolism
‡ /LYer toxicity
Efavirenz
2B6
$
‡ CNS, nightmares, psychosis
‡ Teratogenic: two modes of
ELUWKFRQWUROUHTXLUHG
‡ ,QGXFHURI$
Delavirdine
$
‡ ,QKLELWRURI$
Etravirine
$
‡ ,QGXFHURI$
‡ ,QKLELWRURI&
Rilpivirine
$
‡ Depression, insomnia: less
than efavirenz
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU±
&KDSWHU‡$QWLYLUal Drugs
Pharmacology
3.3 Protease Inhibitors
+,9DVSDUW\OSURWHDVHLVUHTXLUHGWRFOHDvH3RODQG*DJ
polypeptides into functional proteins
3,VFDQFRPSHWLWLYely inhibit the enzyme
$OO3,VFDXVHLQVXOLQUHVLVWDQFH
n/LSLGV
n*OXFRVH
Cushingoid appearance
/HDVWUHVLVWDQFHZLWKDWD]DQDvir
$OO3,VDUHKHSDWLFDOO\FOHDUHG
$OOEXWQHOILQDYLUDUHVXEVWUDWHVRI$
Nelfinavir is metabolizHGE\&
Drug interactions are the main issue
0RVWLQKLELW$ULWRQDYLUWKHPRVW
Ritonavir in combination can allow decreased dosage of other
+,9GUXJV HJ, ritonavir/lopinaYLU
Inhibition of glucuronidation:
Atazanavir, indinavir, tipranavir
Hepatotoxicity, n indirect bilirubin
Inhibit 8*7$
3,Vinclude:
Atazanavir
Darunavir
)osamprenavir
Indinavir
/RSLQDvir/ritonavir
Nelfinavir
Ritonavir
6DTXLQDvir
Tipranavir
dTable 33–3.3 Action of NNRTIs and PIs on CYP450s
P450
1A2
2C19
2D6
3A4
Inducers
Ritonavir
N/A
N/A
‡ Efavirenz
‡ Nevirapine
‡ Etravirine
Inhibitors
N/A
N/A
Ritonavir
‡ Ritonavir > all
other PIs
‡ Delavirdine
Substrates
N/A
Nelfinavir
N/A
‡ All other PIs
‡ NNRTIs
3.4 Entry Inhibitors
3.4.1 Enfuvirtide
%LQGVWRJS
3UHYents fusion with membrane
HIV-1 activity only
*LYHQVXEFXWDQHRXVO\LQMHFWLRQVLWHUHDFWLRQ SDLQLQGXUDWLRQ
Chapter 33–8
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLYLUal Drugs
Pharmacology
3.4.2 Maraviroc
CCR5 antagonist
HIV-1 activity only:
CCR5-tropic
RHTXLUHVWURSLVPWHVWLQJ
Inactive against HIVZLWK&;&5RUPL[ed tropism
SubstrDWHIRU&<3$
Adverse effects:
Upper respiratory infections
Hepatoxicity
3.5 Integrase Inhibitors
3UHYent proviral cDNA integration in human genome
Two drugs:
Raltegravir
ElvitegraYLU LQFRPELQDWLRQ
MetabolizHGE\JOXFXURQLGDWLRQ QRW&<3
Adverse effects:
0\RSDWK\UKDEGRP\RO\VLV FKHFN&.
*,distress
3.6 Combination Therapy for HIV and Clinical
Considerations
2QO\FRPELQDWLRQVZLWKWZRRUWKUHHGUXJVGHFUHDVHYLUal load
below detection threshold.
Most common initial therapy includes tenofovir/emtricitabine plus
any of the four options below:
Efavirenz or rilpivirine
Atazanavir or darunavir with ritonavir boosting
ElvitegraYLUZLWKFRELFLVWDWERRVWLQJ ٚ$
Raltegravir
HIV risk for healthcare professionals:
Needle stick: 1 in 300 if blood is from HIV patient
Testing:
— Immediate for negative baseline
— Six weeks
— Three months
— Six months
Zidovudine + lamivudine for four weeks p convHUVLRQE\
3UHYenting perinatal transmission of HIV:
Zidovudine administration to the mother during pregnancy,
labor, and delivery and to the newborn decreases the rate of
transmission by 2/3.
Almost as effective if started during labor or when only
DGPLQLVWHUHGWRWKHLQIDQWZLWKLQKRXUVRIELUWK
Combination therapy may decrease the risk further.
Breast-feeding increases the rate of transmission by 10%–20%
and should be avoided.
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU±
&KDSWHU‡$QWLYLUal Drugs
4
Pharmacology
Influenza Treatment
Vaccination is preventive measure.
Influenza A causes pandemics:
16 hemagglutinins
neuraminidases
Examples:
— H5N1: avian flu
— +1VZLQHIOX6SDQLVKIOX — +1+RQJ.RQJIOX Influenza B and C are less common.
4.1 Amantadine and Rimantadine
Inhibit uncoating of influenza A RNA: block M2 proton channel
of virus.
Rimantadine is more potent.
May decrease duration of active flu by 1 to 2 days.
H1N1 and H3N2 are resistant.
Adverse effects:
Atropine-like
/LYHGRUHWLFXODULV
$OVRXVHGLQ3DUNLQVRQGLVHDVH EORFNV0UHFHSWRUVDQGnGRSDPLQH 4.2 Zanamivir and Oseltamivir
Inhibit neuraminidases of influenza A and B:
Analogs of sialic acid
Compete with hemagglutinin binding
3URSKylaxis mainly: may decrease duration of flu by 3 to
GDys.
2VHOWDPLYLULV32SURGUXJDFWLYated by hepatic esterases.
Zanamivir is administered by inhalation.
H1N1 is resistant to oseltamivir, not zanamivir.
Chapter 33–10
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLYLUal Drugs
5
Pharmacology
Hepatitis Treatment
5.1 HBV
*RDOVRIWKHUapy:
Suppression of HBV DNA
Seroconversion to negative HBeAg/HBsAg
RHGXFWLRQRI$/T/AST
p Cirrhosis and hepatocellular carcinoma risk
Two classes of drugs:
Nucleoside/nucleotide analogs
Interferon D
Several HBV drugs are also used for HIV
)LUVW-line agents are:
3HJ\ODWHGLQWHUIHURQD
(QWHFDYLU (79
Tenofovir disoproxil fumarate 7')
(PWULFLWDELQH )7&
/DPLYXGLQHWHOELYXGLQHDQGDGHIRvir are second and third line
5.1.1 Entecavir (ETV)
*XDQRVLQHanalog
ٚ HBV DNA polymerase
Well tolerated:
32, nausea, fatigue
f = 1 on empty stomach
5.1.2 Pegylated Interferon D-2a
/RQJHUt½WKDQ,)1D
*LYen subcutaneously
Complex antiviral, antiproliferative, and immunomodulating effects
,QWHUIHURQVDFWLYDWH-$.67$7SDWKZD\V
/HDGWRH[SUHVVLRQRIPRUHWKDQGLIIHUHQWSURWHLQV
Interference with viral translation is the major effect
Induce phosphodiesterases that cleave viral RNA
,QGXFHH[SUHVVLRQRI0+&,WRHQKDQFH&7/
Adverse effects:
Acute influenza-like symptoms
%RQHPDUURZVXSSUHVVLRQ p WBCs, pSODWHOHWV
Neuroto[LFLW\ VRPQROHQFHFRQIXVLRQVHL]XUHV
Alopecia
Thyroid dysfunction
Contraindications:
Autoimmune disorders
Hepatic decompensation
Cardiac arrhythmia
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 33–11
&KDSWHU‡$QWLYLUal Drugs
Pharmacology
5.2 HCV
*RDOLVYLUal eradication
Treatments include:
,)1D SHJ\ODWHGRUQRW
Ribavirin
Boceprevir
5.2.1 Ribavirin
*XDQRVLQHanalog
Ribavirin monophosphate EORFNV,03GHK\GURJHQDVH
NAD
IMP
NADH
IMPDH
Xanthine MP
GTP
Ribavirin
monophosphate
p*73GHSHQGHQWHQGFDSSLQJRIYLUal mRNA
Indications:
+&9 ZLWK,)1D
569 EURQFKLROLWLVSQHXPRQLWLV
/DVVDIHYHU Arenaviridae, hemorrhagic fevHU
+DQWDYLUXV Bunyaviridae, hemorrhagic fevHU
Adverse effects:
Bone marrow suppression
Upper airwa\LUULWDWLRQ DHURVROXVHGIRU569
Teratogenicity
5.2.2 Boceprevir and Telaprevir
+&916$SURWHDVHLQKLELWRU
8VHGLQFRPELQDWLRQZLWK,)1Dand ribavirin
Chapter 33–12
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLYLUal Drugs
Pharmacology
dTable 33–5.2 Antiviral Drug Summary
Type
Drug
Antiherpetics
Acyclovir
Valacyclovir
)amciclovir
3enciclovir
*DQFLFORYLU
Valganciclovir
)RVFDUQHW
HIV drugs
NRTIs:
Zidovudine
Stavudine
Emtricitabine
/DPLYXGLQH
Tenofovir
Didanosine
Abacavir
NNRTIs:
Nevirapine
Efavirenz
Delavirdine
Etravirine
Rilpivirine
Protease Inhibitors:
Atazanavir
Darunavir
)osamprenavir
Indinavir
/RSLQDvir/ritonavir
Nelfinavir
Ritonavir
6DTXLQDvir
Tipranavir
Integrase Inhibitors:
Raltegravir
Elvitegravir
Chemokine Receptor Antagonist:
Maraviroc
Fusion Inhibitor:
Enfuvirtide
Influenza drugs
Amantadine
Rimantadine
2VHOWDPLYLU
Zanamivir
Hepatitis B/C drugs
3HJ\ODWHG ,QWHUIHURQD
HBV:
Entecavir
Tenofovir
Emtricitabine
/DPLYXGLQH
HCV:
Ribavirin
Boceprevir
Telaprevir
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 33–13
CHAPTER 34
1
Antiparasitic Drugs
Protozoal Infections
1.1 Malaria
Affects 500 million humans
2 million deaths per year
Plasmodium falciparum: most severe disease
P. vivax and P. ovale: relapses from liver hypnozoites
dTable 34–1.1A Treatment of Malaria
USMLE® Key Concepts
Type of Malaria
Drugs of Choice
Non-falciparum
Chloroquine
Vivax/ovale
Chloroquine + primaquine (if normal G6PD)
Uncomplicated falciparum
‡ C
entral America/Hispaniola
Chloroquine or sulfadoxine/pyrimethamine
‡ O
ther endemic countries
Artemisinin-based combinations or quinine
Severe malaria
‡ IV Artesunate
‡ IV Quinine
‡ IV Quinidine
For Step 1, you must be able to:
X Describe the treatment or
prophylaxis of chloroquine
sensitive or resistant
malaria.
X Identify the drugs of choice
for protozoal infections.
Quinine and derivatives:
Include:
— Chloroquine
— Hydroxychloroquine
— Halofantrine
— Amodiaquine
— Many others
Oxidize plasmodia in RBCs
Primaquine also destroys liver forms of plasmodia
Side effects include cinchonism
Hemolysis in G6PD patients
Artemisinin and derivatives:
Include:
— Artemether
— Artesunate
— Dihydroartemisinin
No cross-resistance with other drugs
Enhanced activity on chloroquine-resistant malaria
Extremely well tolerated
Teratogenic in animals
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 34–1
&KDSWHU‡$QWLSDUasitic Drugs
Pharmacology
Other drugs used in combinations
Antibiotics:
— Doxycycline
— Sulfadoxine/pyrimethamine
Atovaquone + proguanil (Malarone):
— Atovaquone: ٚcytochrome b/c1 complex of ETC
— Proguanil: ٚDHF reductase/thymidylate synthase
dTable 34–1.1B Prophylaxis for Travelers
Type of Malaria
Drugs
Chloroquine-sensitive P. falciparum
Chloroquine
Chloroquine-resistant P. falciparum
Mefloquine
Multidrug-resistant P. falciparum
Malarone or doxycycline
3YLYD[3RYDOH
Primaquine
1.2 Other Protozoal Infections
dTable 34–1.2 Treatment for Other Protozoal Infections
Protozoa
*LDUGLD
(QWDPRHED
Drug
Metronidazole or tinidazole
Comments
‡ Luminal amebicide: diloxanide
‡ Trichomonas: treat all partners
7ULFKRPRQDV
%DEHVLD
Quinine + clindamycin or atovaquone +
azithromycin
7R[RSODVPDJRQGLL
Sulfadiazine + pyrimethamine
&U\SWRVSRULGLXP
No effective agent: nitazoxanide approved
,VRVSRUD
TMP-SMX
7U\SDQRVRPDFUX]L
Nifurtimox or benznidazole
Chagas disease:
‡ Nifurtimox (GI and CNS toxicity)
‡ Benznidazole (bone marrow suppression,
peripheral neuropathy)
7EUXFHL
‡ Pentamidine or eflornithine (CNS) +/nifurtimox
‡ $UVHQLFDOV
— Suramin
— Melarsoprol
Sleeping sickness:
‡ Pentamidine (immediate p BP)
‡ Eflornithine (bone marrow suppression)
‡ Arsenicals:
— Seizure, coma, death
— Kidney + liver toxicity
— GI distress
/HLVKPDQLD
‡ $QWLPRQLDOVstibogluconate
‡ $QWLIXQJDOV
‡ Antimonials (cutaneous)
‡ Amphotericin B (visceral)
Chapter 34–2
Immunocompromised patients
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLSDUasitic Drugs
2
Pharmacology
Helminthic Infections
dTable 34–2.0 Treatment for Helminthic Infections
Protozoa
Nematodes (e.g.,
pinworms, ascaris, filaria)
Cestodes (tapeworms) and
trematodes (flukes)
Drug
Comments
Albendazole
Mebendazole
Thiabendazole
‡ p Microtubule polymerization by binding
to ǃ-tubulin
‡ p Glucose uptake
‡ ETC uncouplers
‡ Mild GI side effects
Pyrantel pamoate
‡ Depolarizing neuromuscular blocking agent
Ivermectin
‡ Paralysis through an invertebrate Cl– channel
Praziquantel
‡ n Ca2+ influx
‡ Causes spastic paralysis
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 34–3
Unit 7
CHAPTER 35
1
Overview of Anticancer Drugs
Cancer in the United States
Cancer is the second most common cause of death in the
United States.
In 2012, more than 1.6 million cases were diagnosed and close to
600,000 people died from cancer.
dTable 35–1.0 Most Common Cancers*
Rank
Males
Females
1.
Prostate (29%)
Breast (29%)
2.
Lung (14%)
Lung (14%)
3.
Colorectal (9%)
Colorectal (9%)
4.
Bladder (7%)
Uterus (6%)
5.
Melanoma (5%)
Thyroid (5%)
* American Cancer Society, 2012
Death rates are decreasing for the four most common types of
cancer—according to the ACS (2012) and the CDC, between 2004
and 2008 rates fell:
>1.8% per year for men
>1.6% per year for women
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe the epidemiology
of common cancers.
X List the adverse effects
associated with cancer
chemotherapy.
X Describe the management
of the adverse effects of
cancer chemotherapy.
Reduction of mortality results from a broad strategy of:
Prevention
Detection
Treatment
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 35–1
&KDSWHU‡2Yerview of Anticancer Drugs
2
Pharmacology
Chemotherapy and the Cell Cycle
Many chemotherapeutic agents target the cell cycle
Mytosis
M
G0
G2
ter ha
p
I
n
se
G1
S
Nondividing
permanent cells
‡ Cardiac myocyte
‡ Neuron
Quiescent
stable cells
‡ Hepatocytes
‡ Renal tubule cells
‡ Endocrine cells
DNA synthesis
Continuously cycling
labile cells
‡ Epithelia (skin; GI)
‡ Bone marrow stem cells
cFigure 35–2.0 Chemotherapeutic Targets in the Cell Cycle
Log-kill hypothesis:
Cytotoxic actions follow first-order kinetics.
A fixed percentage of tumor cells are killed, not a fixed number.
Combination therapy achieves addition or synergy.
Growth fraction:
Not all cells in a tumor actively divide.
The percentage that divides is the growth fraction.
The higher the growth fraction, the more aggressive the tumor,
and the better the efficacy of anticancer drugs.
Drugs can be classified as cell-cycle specific and non-cell-cycle
specific.
Chapter 35–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡2Yerview of Anticancer Drugs
3
Pharmacology
Common Adverse Effects
of Anticancer Drugs
Before chemotherapy:
CBC with differential
Liver and kidney test
3.1 Bone Marrow Toxicity
dTable 35–3.1A Bone Marrow Toxicity
Granulocytes (cells/ʅL)
Platelets (cells/ʅL)
Chemotherapy
(% of full dose)
> 2,000
> 100,000
100%
1,000–2,000
75,000–100,000
50%
< 1,000
< 50,000
0%
Growth factors can be used to stimulate the bone marrow but side
effects limit their use:
Studies have shown lower outcomes when erythropoiesis agents
have been used in potentially curable head and neck, breast, and
cervical cancers.
Management of chemotherapy-induced thrombocytopenia is
limited (only modest improvement).
Granulocyte colony-stimulating factors are recommended when
there is a 20% chance of febrile neutropenia.
dTable 35–3.1B Growth Factors
Growth Factor
Epoetin D
Darbepoetin D
Indication
Toxicities
Anemia (Hb < 10 g/dL)
‡ Hypertension
‡ Thrombotic events
‡ n Risk of tumor
progression or recurrence
Oprelvekin
(recombinant IL-11)
Thrombocytopenia
‡ N
ausea, vomiting
‡ Fluid retention
‡ Heart failure
‡ Arrhythmias
Filgrastim (G-CSF)
Neutropenia
‡ B
one pain
‡ Splenomegaly
‡ Leukocytosis
Sargramostim (GM-CSF)
Myeloid lineage
reconstitution
‡ Bone pain
‡ Myalgia
‡ Fluid retention
‡ SVTs
‡ Systemic capillary leak
syndrome (rare):
— Peripheral edema
— Pleural and pericardial
effusions
© DeVry/Becker Educational Development Corp. All rights reserved.
!
Important Concept
‡ On the Boards, do not be
fooled by an option for wholeblood transfusion (essentially
never transfused in the U.S.).
‡ Transfusion therapy involves
fractions of whole blood:
platelets, plasma, and
packed red blood cells.
Chapter 35–3
&KDSWHU‡2Yerview of Anticancer Drugs
Pharmacology
3.2 Nausea and Vomiting (N+V)
Due to stimulation of central 5-HT3 and neurokinin subtype 1
(NK1) receptors
Highly emetogenic cancer drugs (N+V in > 90% of patients)
include:
Cisplatin
Carmustine
Cyclophosphamide
dTable 35–3.2 Antiemetics Used in Cancer Chemotherapy
Mechanism
Drugs
5-HT3 antagonism ‡ 2QGDQVHWURQ ,9RU32 'UXJVLQVDPHIDPLO\LQFOXGH
granisetron, dolasetron, tropisetron, and palonosetron
‡ Palonosetron is long acting: for acute and delayed N+V
‡ Adding dexamethasone improves efficacy
NK1 antagonism
‡ Aprepitant32RUIRVDSUHSLWDQW,9
‡ Used in combination with 5-HT3 blockers
Lorazepam and prochlorperazine are two other antiemetics commonly
used to treat nausea and vomiting caused by chemotherapy.
3.3 Gastrointestinal Toxicity
Mucosa from mouth:
Soreness to frank ulcerations of mouth
Diarrhea
Most likely with:
— 5-Fluorouracil (5-FU)
— Methotrexate
— Cytarabine
Recombinant keratinocyte growth factor: palifermin
Diarrhea:
Most associated with:
— 5-FU
— Capecitabine
— Irinotecan
— Tyrosine kinase inhibitors
— Epithelial growth factor receptor inhibitors
Managed with loperamide
3.4 Skin Toxicity
Adverse effects include:
Hyperpigmentation
Alopecia
Erythema
Photosensitivity
General rashes
Acral erythema is known as hand-foot syndrome: painful blistering
palms and soles
2Ual pyridoxine (B6) may prevent
Chapter 35–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡2Yerview of Anticancer Drugs
4
Pharmacology
Other Treatments for Cancer
4.1 Surgery
Used for cancers that are fully resectable.
To debulk large tumors prior to chemotherapy or radiation
therapy.
Chemotherapy following surgery is called adjuvant chemotherapy.
Chemotherapy prior to surgery is called neoadjuvant therapy.
4.2 Radiation Therapy
Used in approximately 50% of all cancer patients.
Some tumors are very sensitive to radiation therapy:
Seminomas may be cured by radiation therapy alone.
Used to shrink tumors in conjunction with surgery/chemotherapy.
4.3 Blood Separation Technology
Apheresis: The blood of a patient or donor is passed through a
device that separates red blood cells, platelets, plasma, or white
blood cells, and returns the remainder to the circulation.
Leukapheresis: The removal of white blood cells is sometimes
used in the treatment of leukemias.
Plasmapheresis: The removal of high levels of IgM
that can cause hyperviscosity syndrome in Waldenström
macroglobulinemia.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 35–5
CHAPTER 36
1
Anticancer Drugs
Drug Classes
The main chemotherapy drug classes include:
Antimetabolites
Alkylating agents
Plant alkaloids
Antibiotics
Hormones
Immunotherapy/targeted therapy
Miscellaneous
USMLE® Key Concepts
For Step 1, you must be able to:
X Identify the main classes of
chemotherapeutic drugs.
X Describe the mechanism
of action and common
therapeutic uses of cancer
chemotherapy agents.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 36–1
&KDSWHU‡$QWLFDQFHU'UXJV
2
Pharmacology
Antimetabolites
Antimetabolites target the S phase of the cell cycle by interfering
with replication.
Bone marrow suppression (BMS) is a common side effect.
Three groups:
Folate antagonists
Pyrimidine analogs
Purine analogs
dTable 36–2.0 Antimetabolites
Drug
Mechanism of Action
Toxicities
Antifolates
‡ ٚ DHF reductase:
p T, A, G
p Ser, Met
‡ BMS, N+V, mucositis, diarrhea
‡ Pneumonitis, hepatic fibrosis
‡ Pruritic rDVK SHPHWUH[ed)
‡ NSAIDs, penicillins n to[LFLW\E\pUHQDOH[cretion
‡ Leucovorin rescue p side effects
‡ )OXRURXUacil (IV)
‡ &DSHFLWDELQH(PO)
‡ ٚ Thymidylate synthase (after
activation to FdUMP)
‡ BMS, N+V, mucositis, diarrhea
‡ +DQGIRRWsyndrome
‡ Neuroto[LFLW\ FHUHEHOOXPVSLQDOFRUG
‡ &\WDUabine (ArD&
‡ ٚ
DNA polymerase after
phosphorylation and incorporation
in DNA
‡ BMS, N+V, mucositis, diarrhea
‡ Neuroto[LFLW\ FHUHEHOODUDWD[LD
‡ +HSDWRWR[LFLW\
‡ *HPFLWDELQH
‡ ٚ DNA polymerase like ArD&
‡ ٚ
Ribonucleotide reductase as a
diphosphate
‡ BMS, N+V, mucositis, diarrhea
‡ ,QWHUVWLWLDOpneumonitis
‡ Progressive HUS requires discontinuation
‡ A
ctivated by HGPRTase to
monophosphate
‡ ٚ
PRPP amidotransferase (first step
in de novo purine synthesis)
‡ BMS, N+V, mucositis, diarrhea
‡ Hyperpigmentation of skin
‡ Immunosuppression (azathioprine is a prodrug
of mercaptopurine)
‡ 0HWKRWUH[DWH
‡ 3HPHWUH[ed
‡ 3UDODWUH[DWH
Pyrimidine analogs
Purine analogs
‡ 0HUFDSWRSXULQH
‡ Thioguanine
Chapter 36–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLFDQFHU'UXJV
3
Pharmacology
Alkylating Agents
1RQFHOOF\cle specific: G1, S, G2 most likely
Alkylation of DNA:
Single strDQGRUFURVVOLQNLQJERWKVWUands if bifunctional agent
N7 of guanine: most common site
— 0LVFRGLQJ*T base pairing
— Depurination and strand scission
O6 of guanine o*&FURVVOLQNV
Alkylating agents are carcinogenic: n risk of leukemia/lymphoma
Alkylating agents are vesicants: "mustard" gas of World War I
T
C
G
G
A
G
C
Sugar-phosphate
backbone
C
A
T
G
C
Bifunctional alkylating agents can cause
intrastrand linking and cross-linking
cFigure 36–3.0 Bifunctional Alkylating Agents
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 36–3
&KDSWHU‡$QWLFDQFHU'UXJV
Pharmacology
dTable 36–3.0 Alkylating Agents
Drugs
Toxicities
Nitrogen mustards
‡ &\clophosphamide
‡ ,IRVIDPLGH
‡ %06, N+V
‡ +HPRUUKDJLFcystitis:
Due to acrolein
MESNA is protective
PHUFDSWRHWKDQHVXOIRQDWHVRGLXP
‡ Mechlorethamine
‡ Severe N+V, severe vesicant
‡ %06
Platinum analogs
‡ &LVSODWLQ
‡ &DUERSODWLQ
‡ 2[DOLSODWLQ
‡ 1HSKURWR[LFLW\
Give amifostine
‡ 6HYere N+V:
Give ondansetron
‡ 2WRWR[LFLW\
‡ 3eripheral neuropathies
‡ %06
‡ Hypersensitivity to platinum
‡ Carboplatin is less to[LFWKDQFLVSODWLQ
‡ 2[DOLSODWLQKDVQRQHSKURRWRWR[LFLW\
Methylhydrazines
‡ Procarbazine
‡ %06
‡ 'LVXOILUDPOLNe effect
‡ Metabolite is MOA inhibitor:
Caution with tyrDPLQHFRQWDLQLQJIRRGV7CA,
MAOIs
Nitrosoureas
‡ &DUPXVWLQH(BCNU)
‡ Lomustine (CCNU): crosses
EORRGEUain barrier
Chapter 36–4
‡ %06, N+V
‡ ,QWHUVWLWLDOpneumonitis
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLFDQFHU'UXJV
4
Pharmacology
Plant Alkaloids
There are four groups:
1. Vinca alkaloids:
Catharanthus roseus, Madagascar periwinkles
2. Taxanes:
Taxus brevifolia, Pacific yew
Taxus baccata, European yew
3. Camptothecin analogs:
Camptotheca acuminata ("happy tree" or "tree of life")
4. Epipodophyllotoxins:
Podophyllum peltatum, Mayapple or wild mandrake
dTable 36–4.0 Plant Alkaloids
Drug
Mechanism of Action
Toxicities
Vinca alkaloids
‡ 9LQEODVWLQH
‡ 9LQFULVWLQH
‡ 9LQRUHOELQH
0SKDVHVSHFLILF
‡ Inhibition of microtubule
polymerization
‡ Arrest in metaphase
‡ %06H[FHSWYLQFULVWLQH
‡ 3eripheral neuropathies
‡ &RQVWLSDWLRQ
‡ 6,$'+
0SKDVHVSHFLILF
‡ Inhibition of microtubule
depolymerization (promote
assembly)
‡ Arrest in prophase
‡ +\SHUVHQVLWLYLW\
‡ BMS, N+V, mucositis,
diarrhea
‡ 3eripheral neuropathies
Taxanes
‡ 3DFOLWD[el
‡ 'RFHWD[el
‡ &DED]LWD[el
Camptothecin analogs
‡ ,ULQRWHFDQ
‡ 7opotecan
‡ 6SKDVHspecific:
Inhibition of topoisomerase I
‡ %06, N+V
‡ $VWKHQLD
‡ 6SKDVHspecific:
Inhibition of topoisomerase II
‡ %06, N+V
‡ +\SHUVHQVLWLYLW\
‡ +\SRWHQVLRQ
Epipodophyllotoxins
‡ (WRSRVLGH
‡ 7eniposide
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU±
&KDSWHU‡$QWLFDQFHU'UXJV
5
Pharmacology
Antibiotics
Isolated from Streptomyces sp.
Include:
Actinomycin D (dactinomycin)
Anthracyclines (daunorubicin, do[orubicin)
Bleomycin
dTable 36–5.0 Antibiotics Used in Cancer Treatment
Drug
Mechanism of Action
Toxicities
Actinomycin D
ٚ RNA polymerase:
‡ Binds to dsDNA
‡ I ntercalates between
DGMDFHQW*&EDVHSDLUV
‡ B
MS, N+V, mucositis,
diarrhea
‡ Hyperpigmentation of skin
‡ +HSDWRWR[LFLW\
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
‡ Intercalate in DNA
‡ Free radical formation
‡ Block topoisomerase II
‡ BMS, N+V, mucositis,
diarrhea
‡ RHGRUange urine color
‡ 'RVHGHSHQGHQW
cardioto[LFLW\
Acute: arrhythmia
Chronic: dilated
‡ Cardiomyopathy and CHF:
Due to free radicals
'H[UD]R[DQH prevents it by
chelating iron
Bleomycin
G2SKDVHVSHFLILF
‡ Binds to iron
‡ Forms free radicals
‡ Causes strand scission
‡ Pulmonary fibrosis
‡ 6NLQreaction:
Rash/striae
Hyperpigmentation
‡ +\SHUVHQVLWLYLW\
Chapter 36–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLFDQFHU'UXJV
6
Pharmacology
Hormonal Therapy
Targeting estrogens and androgens:
+RUPRQHGHSHQGHQWEUHDVWDQGSURVWDWHFDQFHUV
Glucocorticoids:
Suppress mitosis in lymphocytes
Acute leukemia and lymphoma
6.1 Antiestrogen Therapy
Selective estrogen receptor modulators (SERMs)
SelectivHHVWURJHQUHFHSWRUGRZQUHJXODWRUV 6(5'V
Aromatase inhibitors
dTable 36–6.1 Antiestrogen Therapy of ER/PR+ Breast Cancer
Drugs
Mechanism
Toxicities
‡ Competitive ٚ of estradiol
binding to ER in breast tissue
‡ $JRQLVWDFWLYLW\LQQRQEUHDVW
tissue
‡ Hot flashes
‡ Vaginal mucosal atrophy
‡ Vaginal bleeding, discharge
‡ Endometrial hyperplasia:
n
5LVNRIHQGRPHWULDOFDUFLQRPDWRIROG
Worse in postmenopausal women
‡ Rarely thromboembolism
‡ Slows development of osteoporosis:
Basis for ralo[LIHQHXVH
‡ Lowers total cholesterol, LDL:
p Risk of MI
‡ Pure ER antagonist
‡ 3UHYents dimerization
‡ Enhances degradation of
receptor
‡ Nausea, headache
‡ Hot flushes
SERMs
‡ Tamo[LIHQ
‡ Toremifene
SERDs
‡ Fulvestrant
Aromatase inhibitors
‡ A
nastrozole
‡ L
etrozole
‡ B
inds to heme of CYP19
aromatase
‡ &RPSHWLWLYe ٚ
‡ ([emestane
‡ ,UUHYersible ٚ
‡ Hot flushes
‡ Hypercholesterolemia
‡ Osteoporosis
‡ Joint and muscle pain
Androstenedione
Testosterone
Aromatase
Estrone
Anastrozole Estradiol
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 36–7
&KDSWHU‡$QWLFDQFHU'UXJV
Pharmacology
6.2 Antiandrogen Therapy
GnRH agonists and antagonists
Androgen receptor (AR) blockers
dTable 36–6.2 Antiandrogen Therapy of Prostate Cancer
Drug
Mechanism of Action
Toxicities
‡ Initial surge in LH, FSH:
Can be blocked by AR blocker (2–4 weeks)
‡ Followed by ٚ of GnRH release:
p Testosterone production
"Chemical" castration
‡ +RWflashes
‡ p Libido
‡ E
rectile
dysfunction
‡ *\QHFRPDVWLD
‡ 2VWHRSRURVLV
GnRH analogs
‡ /HXSUROLGH
‡ *RVHUHOLQ
‡ 7riptorelin
GnRH antagonists
‡ 'HJDUHOL[
‡ No surge in LH, FSH
‡ Chemical castration within one week
AR blockers
‡ )OXWDPLGH
‡ 1LOXWDPLGH
‡ %LFDOXWDPLGH
‡ (Q]DOXWDPLGH
Chapter 36–8
‡ Competitive antagonists
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLFDQFHU'UXJV
7
Pharmacology
Targeted Therapy
Drugs in this category do not fit classification
Novel agents target specific proteins in tumor
Three classes are emerging:
Monoclonal antibodies
Tyrosine kinase inhibitors
Mammalian target of rapamycin (mTor) inhibitors
7.1 Monoclonal Antibodies
Single species of antibody recognizes a specific tumor antigen
Methodology:
Immunize mouse with human tumor antigen.
Fuse splenic cells with myeloma cell lines, which creates a
hybridoma.
Screen for cell line that produces specific antibody.
Isolate and purify.
Murine antibodies cause immune response and have short t½.
Chimeric or "humanized" mouse antibodies:
'1$VHTXHQFHRIPRXVHELQGLQJSRUWLRQRIDQWLERG\LVVSOLFHG
with human DNA sequence of antibody in lymphocytes.
Transgenic mice can be used to produce fully human
antibodies.
Nomenclature:
— [LPDEFKLPHULF
— XPDEKXPDQL]HG
Monoclonal antibodies can also be engineered with a to[LQRUD
radioactive moiety: e.g., gemtuzumab ozogamicin targets CD33
and has an antitumor antibiotic attached to it (AML).
Mechanism for cell killing:
$QWLERG\GHSHQGHQWFHOOXODUF\WRWR[LFLW\ $'&&
&RPSOHPHQWGHSHQGHQWF\WRWR[LFLW\ &'&
Direct induction of apoptosis
6LGHHIIHFWVLQFOXGHLQIXVLRQUHODWHGIHYer, rash and dyspnea, and
hematologic to[LFLWLHV
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 36–9
&KDSWHU‡$QWLFDQFHU'UXJV
Pharmacology
dTable 36–7.1 Monoclonal Antibodies Used in Cancer Therapy
Drug
Target
Indication
Rituximab
‡ CD20 (B cell)
‡ Sensitizes B cell to chemotherapy:
Used in combination therapy
‡ NHL and CLL
‡ $XWRLPPXQHdisorders:
Wegener granulomatosis
Microscopic polyangiitis
ITP
Rheumatoid arthritis
Alemtuzumab
‡ &'
Normal PMNs and lymphocytes
Most lymphomas (B and T cell)
&DXVHVP\HORDQGLPPXQHVXSSUHVVLRQ
‡ CLL: used as a single agent
Trastuzumab
‡ ErbB2:
EGF receptor
aka Her 2/neu
‡ 0HWDVWDWLFErbB2 † breast cancer
‡ Metastatic ErbB2 † gastric or
gastroesophageal adenocarcinoma
Cetuximab
‡ E
rbB1:
EGF receptor
aka Her 1 or EGFR
‡ (*)5† metastatic colorectal cancer:
±RI&5&H[SUHVV(UE%
Bevacizumab
‡ V
EGF:
Prevents its binding to VEGF receptors
‡ 9(*)H[SUHVVLRQLVn in many tumor
types
‡ 8QLTXHWR[LFLWLHV
Hypertension/CHF
Proteinuria
GI perforation and hemorrhage
‡ Metastatic colorectal cancer
‡ 1RQVPDOOFHOOOXQJFDQFHU
‡ (UE%ٚ breast cancer
‡ Metastatic renal cell carcinoma
‡ *OLREODVWRPD
7.2 Tyrosine Kinase Inhibitors (TKIs)
Critical transducers of growth signaling:
Can be part of a membrDQHERXQGUHFHSWRU
Can be cytoplasmic enzymes
Can be nuclear enzymes
Close to 20 different drugs in 2014 are TKIs.
dTable 36–7.2 Important Tyrosine Kinase Inhibitors
Drug
Target TK
Indication
Imatinib
bcrabl
c.LW
PDGFR
‡ &0/
‡ Gastrointestinal stromal tumors
‡ +\SHUHRVLQRSKLOLFsyndrome
Gefitinib
ErbB1 (EGFR)
1RQVPDOOFHOOOXQJFDQFHU
Erlotinib
‡ 1RQVPDOOFHOOOXQJFDQFHU
‡ 3ancreatic cancer
Sorafenib
Multiple receptor tyrosine kinases
(RTKs)
‡ Renal cell cancer
‡ +HSDWRFHOOXODUcancer
‡ 7Kyroid cancer
Sunitinib
Multiple RTKs
‡ Metastatic renal cell cancer
‡ *,67s
‡ Pancreatic neuroendocrine tumors
Chapter 36–10
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLFDQFHU'UXJV
Pharmacology
7.3 mTOR Inhibitors
mTOR is a serine/threonine kinase:
3NLQDVHUHODWHGNLQDVHIDPLO\.
Regulates cell growth, proliferation, and motility.
Rapamycin, an immunosuppressant, inhibits mTOR.
Rapamycin is also known as sirolimus:
Used in transplant rejection
Coronary stent coating to prevent restenosis
mTOR inhibitors have been associated with pneumonitis, bone
marrow suppression, and immunosuppression.
Temsirolimus and everolimus are primarily used in advanced renal
cell carcinoma.
1
2 EGF receptor
dimerization
EGF
P
Cetuximab
(ErbB1)
Trastuzumab
(ErbB2)
Erlotinib
Gefitinib
Sorafenib
P
4 Docking
proteins
P
3 Receptor
tyrosine kinase
autophosphorylates
EGFR
SH2
domain
proteins
5 Activation of Ras (+GTP)
P
5 Activation of
PI3 kinase
Akt
(Protein kinase B)
Temsirolimus
6 Activation
Everolimus
of mTOR
Rapamycin
Kinases in cell
(RAF/MEK/MAPK)
6 Activation of specific
transcription factors
(Myc, CREB, etc.)
Cell
survival
7
Adhesion
Replication
Migration
Cell proliferation
cFigure 36–7.3 Mitogen-Activated Protein Kinase Pathway for Epidermal Growth Factor
Receptor and Site of Action of Targeted Anticancer Agents
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 36–11
&KDSWHU‡$QWLFDQFHU'UXJV
8
Pharmacology
Miscellaneous Anticancer Drugs
8.1 L-Asparaginase
Lymphoid tumors require asparagine from plasma
Hydrolysis to aspartate and ammonia deprives tumor
Used in ALL advanced lymphoma
7R[LFLW\GXHWRp protein synthesis:
Hyperglycemia (p insulin)
Pancreatitis
Hemorrhagic/thrombotic events (p clotting factors)
8.2 All-Trans-Retinoic Acid (ATRA)
AML03H[SUHVVHVDEQRUPDOYLWDPLQ$UHFHSWRU W +LJKGRVH$TRA (vitamin A) forces differentiation of promyelocytes
Retinoic acid syndrome:
Fever, dyspnea, weight gain
Pulmonary, pleural, and pericardial effusions
Mental confusion, death
8.3 Bortezomib
Binds to 20S core of 26S proteasome:
Inhibits protease activity
'HFUHDVHVGHVWUXFWLRQRI,ljB:
— ,lj%LVWKHLQKLELWRURIQXFOHDUIDFWRUNDSSD% 1)ljB)
—1)ljB is involved in inducing genes for cyFOLQVEFO9(*), etc.
— 0RUH,lj%PHDQVOHVVDFWLYLW\RI1)ljB
Used in multiple myeloma and mantle cell lymphoma
Associated with neuropathies, BMS, and cardiac and pulmonary
to[LFLWLHV
8.4 Hydroxyurea
6SKDVHspecific
Ribonucleotide reductase ٚ
dTable 36–8.4A Anticancer Drugs and Cell Cycle Phases
Cell Cycle Specific
Non-Cell Cycle Specific
‡ S phase
Antimetabolites
Camptothecin analogs
Epipodophylloto[LQV
‡ G2 phase: Bleomycin
‡ M phase
Vinca alkaloids
TD[DQHV
‡ Alkylating agents
Nitrogen mustards
Platinum analogs
Nitrosoureas
‡ Hormonal agents
‡ Antitumor antibiotics
‡ Targeted therapy
Chapter 36–12
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$QWLFDQFHU'UXJV
Pharmacology
dTable 36–8.4B Anticancer Drug Summary
Antimetabolites
Antifolates
0HWKRWUH[DWH
PHPHWUH[ed
PrDODWUH[DWH
Pyrimidine analogs
IOXRURXUacil
Capecitabine
Cytarabine
Gemcitabine
Purine analogs
Mercaptopurine
Thioguanine
Platinum analogs
Cisplatin
Carboplatin
2[DOLSODWLQ
Methylhydrazines
Procarbazine
Nitrosoureas
Carmustine
Lomustine
Taxanes
3DFOLWD[HO
'RFHWD[el
&DED]LWD[el
Camptothecin analogs
Irinotecan
Topotecan
Epipodophyllotoxins
Etoposide
Teniposide
Alkylating Agents
Nitrogen mustards
Cyclophosphamide
Ifosfamide
Mechlorethamine
Plant Alkaloids
Vinca alkaloids
Vinblastine
Vincristine
Vinorelbine
Antitumor Antibiotics
Actinomycin D
Bleomycin
Anthracyclines
Daunorubicin
Do[orubicin
Epirubicin
Idarubicin
Hormonal Therapy
Antiandrogen
GnRH analogs
Leuprolide
Goserelin
Triptorelin
GnRH antagonists
'HJDUHOL[
AR blockers
Flutamide
Nilutamide
Bicalutamide
Enzalutamide
Antiestrogen
SERMs
7DPR[LIHQ
Toremifene
SERDs
Fulvestrant
Aromatase inhibitors
Anastrozole
Letrozole
([emestane
Targeted Therapies
Monoclonal antibodies
5LWX[LPDE
Alemtuzumab
Trastuzumab
&HWX[LPDE
Bevacizumab
Tyrosine kinase inhibitors
Imatinib
Gefitinib
Erlotinib
Sorafenib
Sunitinib
mTOR inhibitors
Temsirolimus
Everolimus
Miscellaneous
/DVSDUDJLQDVH
$OOWUDQVUHWLQRLFDFLG
Bortezomib
Hydro[\XUHD
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 36–13
Unit 8
CHAPTER 37
1
Overview of the Endocrine System
The Endocrine System
The endocrine system consists of glands and hormones secreted
in blood acting at distant targets:
Peptide/proteins (water soluble)
Catecholamines (water soluble)
Iodothyronines (lipid soluble)
Steroids (lipid soluble)
Three pathophysiology patterns:
Deficiency
Excess
Resistance
One major axis of the endocrine system is the hypothalamicpituitary axis.
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe the organization of
the endocrine system.
X Identify the analogs of
hypothalamic and pituitary
hormones and their
indications.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 37–1
&KDSWHU‡2Yerview of the Endocrine System
Pharmacology
Hypothalamus
N eur
osecretorycells
Median Eminence
eminence
+
GHRH*
í
Somatostatin
Somatotrophs
í
Dopamine
+
GnRH**
+
TRH
+
CRH
Gonadotrophs
Thyrotrophs
Corticotrophs
+
TRH***
Lactotrophs
GH
LH/FSH
TSH
ACTH
PRL
50%
í
<10%
20%
í
Anterior Pituitary SHUFHQWDJHRIFHOOV
Liver
Other
tissues
IGF-1
Thyroid
Female
‡(VWURJHQ
77
‡3URJHVWHURQH
‡,QKLELQ
OXT
Posterior Pituitary
Gonads
Male
ADH
Breast
WLVVXHí
milk
synthesis
Adrenal
cortex
‡5HQDO
FROOHFWLQJ
duct
‡9DVFXODU
smooth
muscle
‡8WHUXV
‡%UHDVW
‡&RUWLVRO
‡$QGURJHQ
‡7HVWRVWHURQH
‡'LK\GURWHVWRVWHURQH
‡,QKLELQ
$&7+ DGUHQRFRUWLFRWURSLFKRUPRQHRUFRUWLFRWURSLQ
$'+ DQWLGLXUHWLFKRUPRQH
&5+ FRUWLFRWURSLQUHOHDVLQJKRUPRQH
)6+ IROOLFOHVWLPXODWLQJKRUPRQH
*+ JURZWKKRUPRQH
*+5+ JURZWKKRUPRQHUHOHDVLQJKRUPRQH
*Q5+ JRQDGRWURSLQUHOHDVLQJKRUPRQH
/+ OXWHLQL]LQJKRUPRQH
2;7 R[\WRFLQ
35/ SURODFWLQ
75+ WK\URWURSLQUHOHDVLQJKRUPRQH
76+ WK\URLGVWLPXODWLQJKRUPRQHRUWK\URWURSLQ
0DLQFRQWUROOLQJIDFWRU
SXOVHKRXUIDYRUV/+SXOVHKRXUVIDYRUV)6+
2QO\KLJKOHYHOV K\SRWK\URLGLVP KDYHDVLJQLILFDQWHIIHFW
cFigure 37–1.0 Hypothalamic-Anterior Pituitary Hormones
Another important axis is the renin-angiotensin-aldosterone
system, which is discussed in Unit III of this book.
Endocrine regulation involves two forms of feedback:
Physiological response-driven:
—Blood glucose controls secretion of insulin and glucagon
Endocrine axis-driven:
—Negative and positive feedbacks from the target tissue
hormones on pituitary and hypothalamic factors
Chapter 37–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡2Yerview of the Endocrine System
2
Pharmacology
Endocrine Hormones and Associated
Drugs
dTable 37–2.0 Drugs Related to Hypothalamic and Pituitary Hormones
Hormone
Drug
Indication and Comments
Posterior pituitary and hypothalamus
ADH
Desmopressin
(V2-selective, Gs-coupled
n in cAMP)
‡ Neurogenic diabetes insipidus:
– n H2O permeability of collecting ducts
– p Urine volume
– p Plasma osmolarity
– Adverse effects: headaches, fatigue
‡ Hemophilia A and von Willebrand disease:
– n Release of VIII-vWF
– p aPTT and p bleeding time
‡ Primary nocturnal enuresis
Oxytocin
Oxytocin
Labor induction
Anterior pituitary and hypothalamus
Dopamine (PIH)
Bromocriptine
Cabergoline
‡ Hyperprolactinemia, acromegaly (p GH)
‡ $GYerse effects:
– Nausea
– Hypotension, headache
– Hallucinations, psychosis
‡ Also used in Parkinson disease
GH
Somatropin (purified recombinant GH)
Growth failure, pituitary dwarfism
Somatostatin
Octreotide
(SST receptors are all Gi-coupled)
‡ $FURPHJDO\JLJDQWLVPp GH and IGF-1
‡ Pancreatic and GI endocrine tumors:
– Carcinoid: p 5-HT
– VIPoma: p VIP
– Gastrinoma: p gastrin
– Glucagonoma: p glucagon
‡ Esophageal variceal bleeding:
– p Splanchnic flow
– p Portal hypertension
FSH and LH
Hypogonadal states
ACTH
Cosyntropin
Infantile spasms
GnRH
Leuprolide
Goserelin
Prostate cancer (depot form)
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 37–3
CHAPTER 38
1
Sex Steroids
Androgens
The major androgen in humans is testosterone.
Dihydrotestosterone (DHT) is a metabolite of testosterone:
Produced by 5D-reductase
Most potent
androgen for hair
follicles and the
prostate gland
(–)
Hypothalamus
GnRH
1.1 Testosterone
and DHT
These hormones are
secreted by Leydig cells
of the testes in response
to luteinizing hormone
(LH) from the anterior
pituitary gland.
1.1.1 Cellular Actions
Metabolic actions of
testosterone:
Spermatogenesis
(Sertoli cells)
Anabolic effect
on muscle
Bone growth
n RBC production
USMLE® Key Concepts
For Step 1, you must be able to:
(–)
Anterior
pituitary
X Describe the therapeutic
uses of androgen, estrogen,
and progestin drugs.
FSH
LH
Inhibin
Testosterone
DHT
Estrogen
X Explain the adverse effects
of androgen, estrogen, and
progestin drugs.
Testis
Leydig
cell
Metabolic actions of DHT:
Sebaceous gland
activity (acne)
Male pattern
baldness
Prostatic hyperplasia
Male external
structure
development in fetus
Most puberty changes
()
(–)
Sertoli
cell
Testosterone
DHT
Estrogen
Testosterone
DHT
5Dreductase
fFigure 38–1.1A
Regulation of Male Hormone
Secretion
© DeVry/Becker Educational Development Corp. All rights reserved.
DHT
Aromatase
Estrogen
Peripheral
tissues
Chapter 38–1
&KDSWHU‡6H[6WHURLGV
Pharmacology
Conversion to estrogens:
Aromatization
Can cause gynecomastia and azoospermia
O
O
Androstenedione
Aromatization
O
OH
A
HO
Estrone
OH
Testosterone
Aromatization
HO
O
A
17E-Estradiol
fFigure 38–1.1B Aromatization
1.1.2 Therapeutic Uses
Male hypogonadism, which is commonly caused by:
Acquired damage or removal of testes (trauma, surgery, infection)
Decline in testosterone production with aging
Genetic (e.g., Klinefelter syndrome: 47,XXY)
Testosterone esters (e.g., testosterone enanthate):
Transdermal patches
Long-acting intramuscular "depot" injections
Adverse effects: see Topic 1.2, Anabolic Steroids
1.2 Anabolic Steroids
Androgen derivatives
Legitimate clinical uses, but are also used illicitly to boost
athletic performance
Testosterone derivatives:
Methyltestosterone
Nandrolone
DHT derivatives:
Oxandrolone
Stanozolol
Chapter 38–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡6H[6WHURLGV
Pharmacology
Adverse effects:
Cardiovascular:
— n Heart rate (ٚ MAO)
— Hypertension, polycythemia
— p HDL and n LDL
Hepatic:
— p factors II, V, VII, and X; n PT
— Peliosis hepatitis (blood-filled cysts)
— Adenoma
— n AST/ALT
Endocrine:
— Gynecomastia
— Glucose intolerance
— Testicular atrophy
— Amenorrhea in females
Urologic:
— n risk or worsening of BPH
Skin:
— Acne
— Male pattern baldness
CNS:
— Aggressiveness
— Dependence
— Abuse
Teratogenicity:
— Masculinization of female fetus
1.3 Treatment of Prostate Disorders
Dihydrotestosterone stimulates growth:
Role in BPH
Role in cancer (see chapter 36 for discussion of GnRH analog
leuprolide, GnRH antagonist degarelix, and AR blocker
flutamide)
5D-reductase inhibitors:
Finasteride and dutasteride
Block production of dihydrotestosterone
Treatment of benign prostatic hypertrophy and to stimulate
hair growth in male pattern baldness
Adverse effects: antiandrogenic
© DeVry/Becker Educational Development Corp. All rights reserved.
Looking Back
D1 antagonists are also used to
improve symptoms of BPH—see
Unit II.
Chapter 38–3
&KDSWHU‡6H[6WHURLGV
2
Pharmacology
Estrogens
The most potent natural estrogen is 17E-estradiol.
2.1 Overview of Estrogen Actions
Normal sexual maturation in females
Uterine growth (myometrium and endometrium)
Breast growth
p Bone resorption (bone protection)
n HDL, p LDL
Blood clotting
2.2 Clinical Uses
Oral contraceptives (either alone or in combination with
progestogens)
Hormone replacement therapy in postmenopausal women
Female hypogonadism:
Acquired (e.g., surgical removal of ovaries)
Congenital (e.g., Turner syndrome: 45,XO)
Dysmenorrhea
Abnormal uterine bleeding
2.3 Adverse Effects
Nausea
Bloating
Headache
Mastalgia
Thromboembolism:
Synthetic estrogens such as ethinyl estradiol are much more
thrombogenic than endogenous estradiol.
Risk of abnormal clotting is increased if other risk factors
for thrombosis are present (e.g., factor V Leiden, cigarette
smoking, aging).
n Risk of breast cancer: ductal and lobular hyperplasia
n Risk of endometrial cancer: endometrial hyperplasia
n Risk of gallstones
Chapter 38–4
!
Important Concept
Diethylstilbestrol (DES)
use by mothers resulted in
vaginal adenocarcinoma in
daughters and hypospadia and
cryptorchidism in sons.
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡6H[6WHURLGV
Pharmacology
2.4 Contraindications
Thromboembolic disease
Genetic mutation increasing risk of abnormal clotting:
Factor V Leiden
Protein C deficiency
Protein S deficiency
Prothrombin variant
Cerebral vascular disease
Myocardial infarction
Coronary artery disease
Congenital hyperlipidemia
Cigarette smoking (particularly if over the age of 35)
Carcinoma of the breast
Carcinoma of the female reproductive tract
Abnormal vaginal bleeding of unknown cause
Known or suspected pregnancy
Liver tumors or impaired liver function
2.5 Clinically Prescribed Estrogens
Conjugated equine estrogens: hormone replacement therapy
Ethinyl estradiol, mestranol: in oral contraceptive pills
See Unit VII on anticancer drugs for discussion of SERMs,
SERDs, and aromatase inhibitors (tamoxifen, fulvestrant, and
anastrozole, respectively)
Raloxifene:
SERM
Used to treat osteoporosis
Does not increase the risk of estrogen-dependent breast and
endometrial cancers
Clomiphene:
SERM
Blocks peripheral estrogens' negative feedback of GnRH, FSH,
and LH
n Ovulation
n Multiple births
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 38–5
&KDSWHU‡6H[6WHURLGV
3
Pharmacology
Progestins
Clinical
Application
Produced by the adrenal glands, ovaries, placenta, and testes
Natural progestins include:
Pregnenolone
17D-hydroxypregnenolone
Progesterone
17D-hydroxyprogesterone
The adverse effects of
progestins resemble
common symptoms of
polycystic ovary syndrome.
Synthetic derivatives of progesterone are commonly used clinically
3.1 Overview of Progestins
Precursors to the androgens, estrogens, and glucocorticoids
Progesterone is the major progestin active at the progesterone
receptor
Biological effects include:
Maturation of endometrium
LH surge
Breast growth (alveolar-lobular)
3.2 Clinical Uses
Combination with estrogen hormone replacement to decrease the
risk of estrogen-sensitive cancers (breast, endometrium)
Progestin-only oral contraceptive:
Recommended for lactating women
However, increased incidence of breakthrough menstrual
bleeding
Combination oral contraceptives (progestin and estrogen
together): Reduces breakthrough menstrual bleeding
3.3
Adverse Effects
Weight gain
Hirsutism
Acne
Tiredness
Depression
Glucose intolerance
n LDL, p HDL
Chapter 38–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡6H[6WHURLGV
Pharmacology
3.4 Oral Contraceptive Pills (OCP)
Suppress midcycle LH surge
Side effects are those of estrogens and progestins
Drug interactions: P450 inducers p efficacy of OCP
Benefits:
p Risk of endometrial and ovarian cancer
p Endometriosis
p PID
p Osteoporosis
n Risk of hepatic adenoma
Synthetic progestins include desogestrel, norgestrel, and
norethindrone
dTable 38–3.4 Sex Steroid Drugs Summary
Type
Drugs
Androgens
Testosterone
Methyltestosterone
Nandrolone
Oxandrolone
Stanozolol
5D-reductase inhibitors
Finasteride
Dutasteride
Estrogens
Conjugated equine estrogens
Ethinyl estradiol
Mestranol
SERMs
Raloxifene
Clomiphene
Progestins
Desogestrel
Norgestrel
Norethindrone
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 38–7
CHAPTER 39
1
Adrenalcortical Steroids
Overview
The adrenal cortex can synthesize the full range of steroid
hormones: androgens, estrogens, progestins, glucocorticoids,
and mineralocorticoids.
Corticosteroids, which include glucocorticoids and
mineralocorticoids, have widespread effects throughout the body:
Metabolism (carbohydrate, protein, and lipids)
Blood pressure, salt retention
Immune system
Central nervous system
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe the therapeutic
uses of glucocorticoid and
mineralocorticoid drugs.
X Explain the adverse effects
of glucocorticoid and
mineralocorticoid drugs.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 39–1
&KDSWHU‡$GUHQDOFRUWLFDO6WHURLGV
2
Glucocorticoids
The major endogenous glucocorticoid is
cortisol.
Clinically used glucocorticoids are
synthetic derivatives of cortisol.
Glucocorticoid secretion is regulated
by corticotropin-releasing hormone
(CRH) from the hypothalamus and
adrenocorticotropin-releasing hormone
(ACTH) from the anterior pituitary.
Pharmacology
HYPOTHALAMUS
CRH
Anterior
lobe
Posterior
lobe
Proopiomelanocortin
2.1 Therapeutic Uses
Management of inflammatory disorders
(see Unit IX)
Immunosuppressants
Congenital defects in steroid synthesis:
Congenital adrenal hyperplasia refers
to a variety of autosomal recessive
disorders that involve mutations in
enzymes in the steroid synthesis
pathway.
Clinical symptoms depend on
gender, which enzyme is
affected, and the severity of
the mutation.
Treatment includes
chronic glucocorticoid and
mineralocorticoid therapy, and
sex steroid supplementation.
ACTH
Pituitary gland
Adrenal gland
ACTH
Cholesterol
Pregnenolone
Desmolase
Progesterone
Adrenal cortex
Immunosuppressant
Cortisol
Anti-inflammatory
Gluconeogenesis
fFigure 39–2.0 Secretion and Action
Cortisol
Protein
breakdown
of ACTH and Cortisol
Chapter 39–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$GUHQDOFRUWLFDO6WHURLGV
Pharmacology
17 -Hydroxylase
(P450c17)
Cholesterol
3 -Dehydrogenase
5
, 4-isomerase
NAD+
Pregnenolone
17-Hydroxypregnenolone
Progesterone
17-Hydroxyprogesterone
11-Deoxycorticosterone
11 -Deoxycortisol
21 -Hydroxylase
(P450c21)
11 -Hydroxylase
(P450c11)
Looking Ahead
17,20-Lyase
Dehydroepiandrosterone
(DHEA)
-Androstene3,12-dione
4
Testosterone
Aromatase
Corticosterone
Cortisol
Estradiol
Glucocorticoid
pathway
Androgen and
estrogen pathway
The corticosteroids play a major
role in asthma therapy. Inhaled
corticosteroids commonly
used to treat asthma include
budesonide, beclomethasone,
fluticasone, and mometasone.
Systemic corticosteroids used
include prednisone (oral) and
prednisolone (intravenous).
Aldosterone
Mineralocorticoid
pathway
cFigure 39–2.1 Steroid Synthesis
Treatment of glucocorticoid deficiency:
Autoimmune adrenal disease
Damage to the hypothalamus or the pituitary gland
(affecting CRH and/or ACTH)
6KRFNLQIHFWLRQRUWUauma affecting the adrenal gland
Fetal lung maturity:
6WLPXODWHIHWDOOXQJGHYelopment and the production of
surfactant
Betamethasone, dexamethasone, or hydrocortisone are
typically given to pregnant women who are predicted
to deliver prematurely (e.g., before 32 weeks' gestation)
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 39–3
&KDSWHU‡$GUHQDOFRUWLFDO6WHURLGV
Pharmacology
2.2 Clinically Used Glucocorticoids
Compared with cortisol, synthetic glucocorticoids are designed for
good oral bioavailability, longer half-life, and less mineralocorticoid
activity.
The most common systemic glucocorticoids are hydrocortisone,
prednisolone, prednisone, and betamethasone.
Glucocorticoids
Short-acting
(1–12 hours)
Anti-inflammatory
effect
Salt-retaining
effect
Hydrocortisone 1
1
Cortisone 0.8
0.8
4
0.8
5
Prednisolone
Intermediate-acting
0.8
(12–36 hours)
5
Methylprednisolone
0.25
5
Triamcinolone
0
Prednisone
Long-acting
(36–55 hours)
Betamethasone
Dexamethasone
35
0
30
0
Mineralocorticoids
Fludrocortisone
10
200
cFigure 39–2.2 Glucocorticoids and Mineralocorticoids
2.3 Adverse Effects
Drug-induced Cushing syndrome:
Altered fat deposition
Muscle weakness/atrophy
6WULDH
Bruising
Acne
Hyperglycemia due to gluconeogenesis
Osteoporosis
Electrolyte imbalance
6XSSUHVVLRQRIVNeletal growth in children
Decreased wound healing
6XSSUHVVLRQRIWKHLPPXQHV\VWHP n infections, candidiasis)
Varied central nervous system effects (depression,
psychosis, etc.)
ACTH suppression:
Adrenal cortical atrophy
Chronic glucocorticoids should be tapered gradually to allow
patients to restore adrenal function
6XGGHQZLWKGUawal can result in shock
Chapter 39–4
!
Important Concept
Chronic glucocorticoid therapy,
particularly in high doses,
should never be abruptly
withdrawn because of the risk of
acute adrenal insufficiency and
shock state (Addisonian crisis).
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$GUHQDOFRUWLFDO6WHURLGV
Signs
Facial plethora
Hirsutism
Moon face
Acne
Cataracts
Buffalo hump
Central obesity
Abdominal striae
Bruising
Skin atrophy
Muscle weakness
Pharmacology
Associated diagnoses
Avascular necrosis of bone
Glaucoma
Growth failure
Hypercalciuria
Hyperglycemia
Hypertension
Hypogonadism
Infection
Myopathy
Osteoporosis
Pancreatitis
Peptic ulcer disease
Psychological disturbances
Impaired wound healing
cFigure 39–2.3 Cushingoid Side Effects of Glucocorticoids
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 39–5
&KDSWHU‡$GUHQDOFRUWLFDO6WHURLGV
3
Pharmacology
Mineralocorticoids
Important in fluid and electrolyte balance
Main endogenous mineralocorticoid: Aldosterone
Cortisol also has mineralocorticoid effects
Fludrocortisone: Used in patients with adrenal insufficiency
(patients showing signs of low aldosterone; e.g., low plasma
sodium levels)
dTable 39–3.0 Adrenal Steroid Drug Summary
Chapter 39–6
Type
Drugs
Glucocorticoids
Hydrocortisone
Cortisone
Prednisone
Prednisolone
Methylprednisolone
Triamcinolone
Betamethasone
Dexamethasone
Mineralocorticoids
Fludrocortisone
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 40
1
Diabetes Therapy
Overview
According to the CDC, 25.8 million people in the United States
had diabetes in 2011 (8.3% of the population).
~ One million have type 1 diabetes
~ 1,000 have genetic defects of beta cell function or insulin
action
> 23.5 million have type 2 diabetes
Diabetes is the seventh leading cause of death.
< It is the No. 1 cause of:
Kidney failure
Non-traumatic lower limb amputation
New cases of blindness
USMLE® Key Concepts
For Step 1, you must be able to:
X Explain the therapeutic
approaches used to manage
type 1 and 2 diabetes.
It is a major cause of heart disease and stroke.
2
Classification and Pathology of Diabetes
X Identify the adverse effects
of insulin and oral therapies
for diabetes.
Syndrome of disordered carbohydrate, lipid, and protein metabolism:
Characterized by hyperglycemia:
— • 126 mg/dL on two separate occasions after an overnight fast
— • 200 mg/dL two hours after 75 g oral glucose
Hypertension, dyslipidemia, and atherosclerosis are often
associated
Pathogenesis:
Type 1: Immune-mediated destruction of beta cells
Type 2: Insulin resistance
Type 1
Type 2
Age of onset
Usually during
childhood or puberty
Frequently over age
35
Nutritional status
at time of onset
Frequently
undernourished
Obesity usually
present
Prevalence
5% to 10% of
diagnosed diabetics
90% to 95% of
diagnosed diabetics
Genetic
predisposition
Moderate
Very strong
Defect or
deficiency
B cells are destroyed,
eliminating the
production of insulin
Inability of B cells to
produce appropriate
quantities of insulin;
insulin resistance;
other defects
© DeVry/Becker Educational Development Corp. All rights reserved.
eFigure 40–2.0A Type 1 and
Type 2 Diabetes
Chapter 40–1
&KDSWHU‡'LDEHWHV7KHUapy
Pharmacology
dTable 40–2.0 Clinical Features of Diabetes
Presentation
Type
Often asymptomatic
2
Polyuria, polydipsia
1>2
Polyphagia, but with weight loss
1
Nocturnal enuresis
1
Weakness, fatigue
1>2
Recurrent blurred vision
2>1
Peripheral neuropathy
2>1
Vulvovaginitis or pruritus
2>1
Impaired
glucose
tolerance
Normal
Type 2 diabetes
0í5
years
R
el
at
iv
e
No
treatment
ab
ili
ty
to
Diet
se
cre
te
5í15
years
More
than
15 years
ins
uli
n
Diet plus Combination Multiple
metformin
therapy
injections
of insulin
Increasing severity of disease
cFigure 40–2.0B Clinical Course of Type 2 Diabetes
Chapter 40–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'LDEHWHV7KHUapy
Pharmacology
Nonconventional type 2 diabetes:
Uncommon form of diabetes
Presents like type 2 diabetes
Occurs at a young age: maturity-onset diabetes of the
young (MODY)
Include mutations in:
— Glucokinase (MODY 2)
— Nuclear transcription factors that regulate beta cell gene
expression (MODY 1, 3–6)
— Insulin or IRS receptor
— Glucose transporters
Metabolic syndrome:
Syndrome x or insulin resistance syndrome
Cluster of metabolic risk factors:
— n BP
— n Blood lipids (n TGL, n LDL, p HDL)
— Central obesity
— Hyperglycemia (• 100 mg/dL)
n Overall cardiovascular disease risk
~35% of the U.S. population is affected (source: American
Heart Association)
Grouping these disorders as a syndrome reminds clinicians that
therapeutic goals are not only to control hyperglycemia
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 40–3
&KDSWHU‡'LDEHWHV7KHUapy
3
Pharmacology
Diabetes Management
Cornerstone of initial diabetes management is diet modification
and exercise routines.
Weight loss can alleviate the symptoms of type 2 diabetes.
Type 1 diabetics eventually require insulin replacement.
Type 2 diabetics are managed with oral hypoglycemics with
or without insulin.
4
Monitoring Diabetic Therapy
Plasma glucose measurements provide a single time point
of glucose control.
Glycosylated hemoglobin (HbA1c) provides a measure of glucose
control over a several-month period (life of erythrocyte).
Current data recommend relatively tight control aiming for HbA1c
of 7% or less (equating to an average blood glucose of 150 mg/dL
or less).
Chapter 40–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'LDEHWHV7KHUapy
5
Pharmacology
Insulin
Main therapy in type 1 diabetes and ketoacidosis.
Also used in late stages of type 2 diabetes.
Variety of insulin preparation is available, ranging in onset
and duration of action.
dTable 40–5.0 Characteristics of Insulin Preparations
Preparation
Onset
Peak
Duration
Lispro
Aspart
Glulisine
5–15 minutes
1–1.5 hours
3–4 hours
Human
regular
30–60 minutes
2 hours
6–8 hours
Human NPH
2–4 hours
6–7 hours
10–20 hours
Glargine
1.5 hours
Flat
~24 hours
Detemir
1 hour
Flat
17 hours
Premixed insulin exists (e.g., 70% regular/30% NPH)
Insulin glulisine
Insulin aspart, insulin lispro
Relative Plasma
Insulin Level
Regular insulin
NPH insulin
Insulin glargine (20–24 hrs)
Insulin detemir (12–24 hrs)
0
6
12
18
24
cFigure 40–5.0 Kinetics of Various Insulin Preparations
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 40–5
&KDSWHU‡'LDEHWHV7KHUapy
Pharmacology
Administration:
Syringes/needles SQ/IV
Pen injector devices
Insulin pumps
Mechanism of action:
Insulin receptor stimulation activates receptor tyrosine kinase
Phosphorylation of insulin receptor substrate (IRS)
Activation of PI–3 kinase pathway or MAP kinase pathway
Upregulation of GLUT4 n glucose uptake
n Glucose utilization in liver and muscle:
— n Glycolysis
— n Glycogen synthesis
— n Fatty acid synthesis and VLDL synthesis
— n Fat storage in adipose (n LPL)
— p Conversion of fatty acids and amino acids to ketones
— p Gluconeogenesis
Looking Back
Adverse effects:
Hypoglycemia
Insulin allergy: p with human insulins
Lipodystrophy at injection site
Chapter 40–6
‡ M agonists and E2 agonists
n insulin release
‡
D2 agonists p insulin release
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'LDEHWHV7KHUapy
6
Pharmacology
Diabetes Type 2 Therapy
Six main classes of drugs:
Metformin (biguanides)
Sulfonylureas
Thiazolidinediones
GLP-1 agonists
DPP-4 inhibitors
Insulin
Weight loss + Exercise + Metformin
HbA1c > 7%
Metformin + Other agent
HbA1c > 7%
Metformin + 2 other agent
Minor classes of drugs:
HbA1c > 7%
D-Glucosidase inhibitors
Amylinomimetics
Meglitinide derivatives
6.1 Metformin
All of the above + Insulin preparation
cFigure 40–6.0 Algorithm
Based on the American Diabetes
Association
A biguanide, given PO
Does not cause hypoglycemia: "euglycemic"
Does not cause weight gain
n Tissue sensitivity to insulin:
n Glucose uptake and utilization in muscle and fat
p Hepatic gluconeogenesis
Does not n insulin release by pancreas
Actions mediated in part by AMP-activated protein kinase
Used in combination with other agents
Adverse effects:
Lactic acidosis (rare, but potentially fatal)
GI upset (common)
Decrease absorption of folate and B12
6.2 Sulfonylureas
Mechanism of action:
n Insulin release
Block ATP-dependent K+ channels in beta cells of pancreas:
— n K+ depolarizes beta cells
— Depolarization allows Ca2+ entry
— Ca2+ initiates insulin release
n Insulin decreases glucagon release from alpha cells
Adverse effects:
Hypersensitivity:
— Skin rashes (sulfa allergy)
— Hematological toxicity (rare)
Hypoglycemia
Weight gain
Drug interactions:
— High plasma protein binding
— P450 metabolism
© DeVry/Becker Educational Development Corp. All rights reserved.
!
Important Concept
The sulfonylureas are the oral
hypoglycemic agents that can
commonly cause hypoglycemia.
This is due to the mechanism
of action involving more
insulin release as opposed to
facilitating better response to
existing insulin.
Chapter 40–7
&KDSWHU‡'LDEHWHV7KHUapy
Pharmacology
dTable 40–6.2 Sulfonylureas
Drug
Comments
First generation
Chlorpropamide
Disulfiram-like effect, SIADH
Acetohexamide
Active metabolite
Tolbutamide
Safest in elderly diabetics
Tolazamide
Second generation
!
Important Concept
Glipizide
p Dose in liver dysfunction
Other insulin secretagogues
include meglitinide analogs:
Glyburide
p Dose in renal dysfunction
‡ Repaglinide and nateglinide
‡ ٚ
KATP in beta cells such as
sulfonylureas
Glimepiride
Glibenclamide
6.3 Thiazolidinediones
Stimulate PPAR-J altering expression of insulin-responsive genes:
Sensitize tissues to insulin
p Hepatic gluconeogenesis
Similar in effects to metformin
Rosiglitazone and pioglitazone are available:
Used in monotherapy
Used in combination with metformin or sulfonylureas
Adverse effects and risks:
Edema: 3%–4%
CHF: 6% (FDA black box warning)
May n risk of bladder cancer (pioglitazone)
May nrisk of angina/MI (rosiglitazone)
Chapter 40–8
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'LDEHWHV7KHUapy
Pharmacology
6.4 Drugs Interacting With Glucagon-like
Peptide 1 (GLP-1)
GLP-1:
Released by the gut after oral delivery of glucose
Called an incretin: glucose-dependent insulinotropic peptide,
GIP is the second incretin
n Insulin, p glucagon, delays gastric emptying
Metabolized by dipeptidyl peptidase-4 (DPP-4)
Two groups of drugs:
GLP-1 receptor agonists
DPP-4 inhibitors
6.4.1 GLP-1 Agonists
GLP-1 secretion is decreased in type 2 diabetics
Exenatide and liraglutide are full agonists: given SQ
Adverse effects:
Pancreatitis
n Risk of medullary carcinoma of thyroid: contraindicated in MEN2
Nausea (most common)
6.4.2 DPP-4 Inhibitors
Prolong action of endogenous GLP-1
Four "-gliptins" available:
Sitagliptin
Saxagliptin
Alogliptin
Linagliptin
Used in combination therapy
Adverse effects:
Hypersensitivity
Pancreatitis
NASH
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 40–9
&KDSWHU‡'LDEHWHV7KHUapy
Pharmacology
6.5 Miscellaneous Antidiabetic Drugs
D-Glucosidase inhibitors: miglitol and acarbose
Work in the GI
p Absorption of glucose by p starch metabolism
p Insulin demand
Adverse effects: flatulence, GI distress
Pramlintide:
Synthetic analog of amylin given SQ
Delays gastric emptying, p appetite
Used for diabetes type 1 or 2
Sodium-glucose cotransporter 2 (SGLT2) inhibitors:
Canagliflozin
p Renal proximal tubule reabsorption of glucose
Adverse effects include n risk of UTIs
dTable 40–6.5 Antidiabetic Drugs
Class
Drug
Insulin preparations
Biguanides
Metformin
First Generation
Chlorpropamide
Acetohexamide
Tolbutamide
Tolazamide
Sulfonylureas
Second Generation
Glipizide
Glyburide
Glimepiride
Glibenclamide
Chapter 40–10
Thiazolidinediones
Rosiglitazone
Pioglitazone
GLP-1 agonists
Exenatide
Liraglutide
DPP-4 inhibitors
Sitagliptin
Saxagliptin
Alogliptin
Linagliptin
D-Glucosidase inhibitors
Acarbose
Miglitol
Amylinomimetic
Pramlintide
SGLT2 inhibitor
Canagliflozin
Meglitinide analogs
Repaglinide
Nateglinide
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 41
1
Thyroid Disorder Therapy
Overview
Hypothyroidism is typically treated by thyroid hormone replacement.
Hyperthyroidism requires drugs or surgery.
Effects of thyroid hormones:
n Basal metabolic rate:
— n O2 consumption
— n Temperature
Permissive actions on catecholamines:
—n E receptor number and sensitivity
Permissive actions on ovarian cycle and spermatogenesis
n Gut motility and glucose absorption
Needed for carotene conversion to vitamin A
Hypothalamus
TSH
Thyroid gland
For Step 1, you must be able to:
X Identify the treatment
strategies for managing
hypothyroidism and
hyperthyroidism.
X Explain the adverse effects
of hypothyroidism and
hyperthyroidism therapies.
TRH
Anterior pituitary
USMLE® Key Concepts
‡ TRH provides stimulus
for TSH secretion
‡ TSH stimulates thyroid function:
—Gs-coupled receptors
—n T4 ,T3 synthesis
—n Degradation of thyroglobulin
—n Size of gland: goiter
‡ T4 and T3 cause negative feedback
T4
T3
cFigure 41–1.0 Thyroid Hormone Endocrine Axis
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 41–1
&KDSWHU‡7Kyroid Disorder Therapy
2
Pharmacology
Hypothyroidism
Autoimmune thyroiditis (e.g., Hashimoto thyroiditis)
Thyroid gland ablation (by radioiodine or surgery)
Iodine deficiency
Drug toxicity (lithium, amiodarone)
Pituitary dysfunction (lack of TSH)
Hypothalamic dysfunction (very rare)
2.1 Symptoms
Weight gain
Lethargy
Depression
Cold intolerance
Myxedema
Slow heart rate
Constipation
Menorrhagia
Hoarseness
Yellowish, dry skin
Clinical
Application
Myxedema Crises
‡ High mortality
‡ Severe hypothermia,
hypoventilation
2.2 Treatment
‡ Severe hypoglycemia,
hypotension
Dr. Koshy Johnson/Phototake
Treatment of hypothyroidism is with thyroid hormone replacement:
levothyroxine (T4).
cFigure 41–2.2 Myxedema
Chapter 41–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡7Kyroid Disorder Therapy
3
Pharmacology
Hyperthyroidism
Biophoto Associates/Science Source
Graves disease (antibodies to TSH receptor)
Thyroid adenoma
Toxic multinodular goiter
Thyroiditis (usually transient)
Iodine excess
Amiodarone
TSH-secreting tumor (rare)
TRH-secreting tumor (very rare)
cFigure 41–3.0 Exophthalmos of Graves Disease
3.1 Symptoms
Tachycardia
Nervousness, anxiety
Sweating
Weight loss
Heat intolerance
Loose stools
Warm, moist skin
Stare
Tremor
In Graves disease:
Goiter
Exophthalmos
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 41–3
&KDSWHU‡7Kyroid Disorder Therapy
Pharmacology
3.2 Treatment
3.2.1 Propylthiouracil (PTU) and Methimazole
Thyroid peroxidase inhibitors
Block the formation of thyroid hormone in the thyroid gland
Propylthiouracil also inhibits the peripheral conversion of T4 to T3
Slow onset
Common maculopapular rash
Agranulocytosis
Cross placental barrier:
PTU is safest in pregnancy
Higher plasma protein binding
3.2.2 Propranolol
Blocks the conversion of T4 to T3 in the periphery
Used for symptomatic relief in Graves disease
Initial drug of choice in thyroid storm
3.2.3 Radioactive Iodine
131I destroys thyroid gland
Harmful to fetus/children
Worsens Graves ophthalmopathy (contraindicated)
3.2.4 Surgery
As with radioiodine ablation, the patient is maintained on thyroid
hormone replacement following surgery.
dTable 41–3.2 Thyroid Drug Summary
CondiƟon
Drugs
Hypothyroidism
Levothyroxine
Hyperthyroidism
Propranolol
Propylthiouracil
Methimazole
131
I (radioactive iodine)
Chapter 41–4
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 42
1
Drugs Affecting Calcium and Bone
Structure
Overview
Indications:
Osteoporosis
Osteomalacia/rickets
Paget disease
2
Drugs
USMLE® Key Concepts
2.1 Calcium Supplementation
For Step 1, you must be able to:
Adequate dietary calcium in childhood and young adult years is
important in building bone mineral density.
Calcium supplementation is used to maintain bone density or
at least minimize bone density loss.
2.2 Vitamin D
X Identify the drugs available
for the treatment of bone
disorders.
X Explain the adverse effects
of bone disorder therapies.
Textto limited sunlight
Deficiency is common in Western countries due
exposure and low vitamin D intake in diet.
Deficiency can lead to hypocalcemia and secondary
hyperparathyroidism, which causes calcium loss from bones.
Supplementation:
Rickets
Osteomalacia
Hypoparathyroidism
Vitamin D has no effect on osteoporosis (p bone matrix
causes p minerals)menhorragia
Mineralization
2.3 Bisphosphonates
Bisphosphonates stabilize hydroxyapatite bone structure:
Analogs of pyrophosphate
ٚBone resorption by osteoclasts
Therapeutic uses:
Drugs include:
Paget disease
Osteoporosis
Malignancy-associated
hypercalcemia
Alendronate
Risedronate
Ibandronate
Pamidronate
Adverse effects:
Inflammation and erosions of the stomach and esophagus
Osteonecrosis of the jaw
n Risk of esophageal adenocarcinoma
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 42–1
&KDSWHU‡'UXJV$IIHFWLQJ&DOFLXPDQG%RQH6WUXFWXUH
Pharmacology
2.4 Calcitonin
Hypocalcemic peptide hormone produced by parafollicular C cells
of the thyroid gland
Inhibits osteoclastic bone resorption
Administered as intranasal spray:
Postmenopausal osteoporosis
Hypercalcemia of malignancy
2.5 Teriparatide
PTH analog
Taken once daily:
6WLPXODWHVosteoblasts
Continuous administration would stimulate osteoclasts
n Risk of osteosarcoma: only approved for a two-year course
Can cause hypercalcemia: avoid glucocorticoids, thiazides, Ca2+
supplements
2.6 Denosumab
Monoclonal antibody against receptor activator of nuclear factor
kappa B ligand (RANKL):
Osteoclasts express receptor activator of nuclear factor
kappa B (RANK)
RANK is activated by RANKL, which is located on osteoblasts:
—It is n by PTH
Osteoprotegerin is the endogenous RANKL decoy receptor:
—It is n by estrogens
Denosumab mimics osteoprotegerin
Prevents RANK/RANKL binding and inhibits osteoclast activation
Given 64
Can cause hypocalcemia
dTable 42–2.6 Bone Mineralization Disorder Drug Summary
Drugs
Calcium
Vitamin D
Bisphosphonates
Alendronate
Pamidronate
Etidronate
Ibandronate
Teriparatide (PTH analog)
Calcitonin
Denosumab (RANKL inhibitor)
Chapter 42–2
© DeVry/Becker Educational Development Corp. All rights reserved.
Unit 9
Eicosanoids, NSAIDs, and Acetaminophen
CHAPTER 43
1
Overview
Cell membrane phospholipids
Glucocorticoids
Zileuton
5-Lipoxygenase
5-HETEs
Leukotriene B4
Phospholipases A2
Arachidonic acid
NSAIDs
Cyclooxygenases
COX-1/COX-2
Celecoxib,
glucocorticoids
5-HPETE
Leukotriene A4 (LTA4)
Prostaglandin G2 (PGG2)
USMLE® Key Concepts
Prostaglandin H2 (PGH2)
For Step 1, you must be able to:
Leukotriene C4 (LTC4)
Receptors
blocked by
zafirlukast
and
montelukast
Leukotriene D4 (LTD4)
Leukotriene E4 (LTE4)
Thromboxane A2
TXA2
Prostacyclin PGI2
PGD2
PGE2
PGF2
cFigure 43–1.0 Arachidonic Acid Metabolism and Site of Action of Key
Anti-inflammatory Drugs
X Describe the arachidonic
acid cascade.
X Explain the effects of
prostaglandins and
leukotrienes.
X Differentiate aspirin from
other NSAIDs.
X Describe the uses of
leukotriene inhibitors.
X Differentiate
acetaminophen from other
anti-inflammatory drugs.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 43–1
&KDSWHU‡(LFRVDQRLGV16$,'VDQG$FHWDPLQRSKHQ
2
Pharmacology
Eicosanoid Pharmacology
Eicosanoids include:
Arachidonic acid metabolites:
Leukotrienes
Prostaglandins
Prostacyclin
Thromboxane A2
Lipid mediators produced on demand
2.1 Leukotrienes
Produced by lipooxygenase action on arachidonic acid
5-lipooxygenase (5-LOX) is found in leukRF\WHVPDVWFHOOVDQG
dendritic cells
Associated with DVWKPDDQDSK\OD[LV
dTable 43–2.1 Leukotrienes
Type
Effect
LTB4
Chemokine for neutrophils
LTC4
LTD4
Potent bronchoconstriction
‡ n Vascular permeability
‡ n Mucus secretion in airways
Zileuton inhibits 5-LOX
Zafirlukast and montelukast block leukotriene LTD4 receptors
Both groups of drugs are used in asthma prophylaxis
(see chapter 47)
2.2 Cyclooxygenase Products
Two cyclooxygenases: COX-1 and COX-2
COX-1 is constitutively expressed in most cells
COX-2 is inducible:
Expressed at sites of inflammation
Brain and kidney
PGI2 is produced by COX-2
Actions of prostanoids:
6PRRWKPXVFOH YHVVHOVDLUZa\VXWHUXV — Relaxation: PGI23*'23*(2 (high concentrations)
— Constriction: TXA23*)2D3*(2 (low concentrations)
Platelets:
— 6WDELOL]DWLRQ3*,23*'23*(2 (high concentrations)
— Aggregation: TXA23*(2 (low concentrations)
GI (cytoprotective):
— n Mucus and HCO3– secretion
— n Motility
Chapter 43–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡(LFRVDQRLGV16$,'VDQG$FHWDPLQRSKHQ
Pharmacology
&16
—PGE2 causes fever
—Wakefulness
—ٚ1(UHOHDVHIURP6$16
—6HQVLWL]es pain pathways
Eye:
²3*(DQG3*)GHULYatives p intraocular pressure
—n Aqueous humor outflow
All prostanoid receptors are G protein-coupled (Gs*iRU*q)
16$,'VEORFNV\QWKHVLVRIDOOSURVWDQRLGV
dTable 43–2.2 Important Prostaglandin Analogs Used in Medicine
Drug
Type
Indication and Comments
Misoprostol
Alprostadil
PGE1
PGE1
‡ 16AIDs-induced ulcers
‡ Maintains patency of ductus
arteriosus
‡ Used in male impotence supplanted
by PDE5 inhibitors
‡ Both are contraindicated in
pregnancy
Epoprostenol
Iloprost
Treprostinil
PGI2
Pulmonary hypertension
Latanoprost
Bimatoprost
Travoprost
Tafluprost
3*)2
‡ Treatment of glaucoma
‡ Cause brown pigmentation of iris
and eyelashes
Dinoprostone
Carboprost
PGE2
3*)2D
‡ 2[\WRFLF
— Induce labor at term
— Abortion
— Hydatidiform mole
‡ Antiprogestin mifepristone +
misoprostol are also used to
produce early termination of
pregnancy
D
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 43–3
&KDSWHU‡(LFRVDQRLGV16$,'VDQG$FHWDPLQRSKHQ
3
Pharmacology
Nonsteroidal Anti-inflammatory
Drugs (NSAIDs)
1RQVHOHFWLYe competitive inhibitors of COX-1 and COX-2
Aspirin is the exception: irreversible inhibitor of COX-1 and COX-2
)our indications:
Analgesic
Antipyretic
Anti-inflammatory
Antiplatelet aggregant
3.1
Acetylsalicylic Acid (Aspirin)
Irreversible inhibitor of COX-1 and COX-2:
Acetylation of serine OH group near active site
Covalent bond
dTable 43–3.1 Dose-Dependent Action of Aspirin
Dose
80 mg
Action
Antiplatelet:
‡ Post MI prophylaxis
‡ p TIA risk
300 mg
Analgesic
Antipyretic
3–5 g
Anti-inflammatory
Effect on uric acid elimination:
Low to moderate doses p urate secretion and cause
hyperuricemia
High anti-inflammatory doses p urate reabsorption and
cause uricosuria
$VSLULQLVWKHRQO\16AID that behaves as an ETC uncoupler:
'HSHQGVRQDPRXQWLQJHVWHGDQGVL]e of patient:
— < 1 g can be very toxic in a toddler
— > 10–15 g for significant toxicity in an adult
3–5 g in adult causes mild uncoupling:
— p A73V\QWKHVLVn ETC and metabolic rate
— n O2 consumption: hyperventilation and respiratory alkalosis
— Energy of ETC dissipated as heat: fever
— n TCA rate: metabolic acidosis
— Result: compensated state
Toxic levels (suicide/accident/child):
— ppp ATP synthesis
— 1HXURPXVFXODUGHSUHVVLRQUHVSLUatory acidosis
— Uncoupling and n metabolic rate: metabolic acidosis and
hyperthermia
— Result: life-threatening combined acidosis
Overdose management:
— 6XSSRUWLYe (no antidote)
— $ONDOLQL]DWLRQRIXULQHn aspirin clearance: historical use of
DFHWD]olamide
Chapter 43–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡(LFRVDQRLGV16$,'VDQG$FHWDPLQRSKHQ
Pharmacology
Common adverse effects of chronic aspirin use:
GI irritation:JDVWULWLV38'n bleeding risk (consider misoprostol)
Exacerbation of bronchospasm in asthmatics:
— Due to arachidonate metabolism by LOX to leukotrienes
— Avoid use in asthmatics
Hypersensitivity:
— &URVVVHQVLWLYLW\EHWZHHQ16AIDs
— &RPPRQDQJLRHGHPDUashes
— More likHO\LQWULDGRIDVWKPDQDVDOSRO\SVDQGUKLQLWLV
Renal toxicity: analgesic nephropathy due to p prostaglandins
and ischemia
6DOLF\OLVP
— 7LQQLWXVYertigo
— )LUVWVLJQRIWRxicity
Reye syndrome:
— Aspirin use in children to treat fever of viral origin
— 8QFRXSOLQJFDXVHVPXOWLSOHRUJDQIDLOXUHQRWDEO\OLYHUDQG&16
— Reversible
n Bleeding time
Drug interactions:
Ethanol (livHUGDPDJH Zarfarin (anticoagulant): n bleeding
6XOIRQ\OXUHDVwarfarin: n free fraction and toxicity
Methotrexate:
— p Renal clearance secondary to vasoconstriction by aspirin
— n Hematotoxicity of methotrexate
3.2 Other NSAIDs
CompetitivHQRQVHOHFWLYe inhibitors of COX-1 and COX-2
$QDOJHVLFDQWLS\UHWLFDQWLLQIODPPDWRU\
&RPSDULVRQEHWZHHQDVSLULQDQGVHOHFW16AIDs:
8OFHUVJDVWULWLVDVSLULQ!DOORWKHU16AIDs
Uncoupling: only aspirin
Allergy: common to all
Analgesia:
— Ketorolac is best
— OTC ibuprofen and naproxen are better than aspirin
6XOLQGDFLVVDIHUIRUUHQDOIXQFWLRQ OLYer clearance)
Anti-inflammatory effect: indomethacin is most potent
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 43–5
&KDSWHU‡(LFRVDQRLGV16$,'VDQG$FHWDPLQRSKHQ
4
Pharmacology
Selective COX-2 Inhibitors
Less GI toxicity
Less antiplatelet action
p PGI2 production results in n risk of MI and strokes
1REHWWHUDQWLLQIODPPDWRU\DFWLRQWKDQFRQvHQWLRQDO16AIDs
Celecoxib is the only COX-2 inhibitor available in the U6.:
6XOIRQDPLGHVWUXFWXUH n risk of allergy)
5
Acetaminophen
%ORFNV&16F\FORR[\JHQDVHV
EquivDOHQWDQDOJHVLFWR16AIDs
EquivDOHQWDQWLS\UHWLFWR16AIDs
1RWanti-inflammatory
1RSHULSKHUDO&2;LQKLELWLRQ
1RDQWLSODWHOHWDFWLRQ
1REURQFKRVSDVPVDIHLQDVWKPD
Minimal GI distress
1RHIIHFWRQXULFDFLGVDIHLQJRXW
1RXQFRXSOLQJVDIHLQSHGLDWULFV QR5eye syndrome)
Hepatotoxicity:
Requires more than 10–15 g in adults or a P450 inducer such
as chronic alcohol or phenobarbital.
Acetaminophen is primarily conjugated to inactive metabolites
(glucuronides and sulfates).
)ollowing ovHUGRVHFRQMXJDWLRQSDWKZays become saturated
and glutathione stores depleted.
A toxic P450 intermediate is produced and accumulates:
— 3A4 > 2E1 > 1A2 > 2D6
— 1DFHW\OSEHQ]RTXLQRQHLPLQH 1$34,
Causes free radical damage to liver
Antidote:
—1DFHW\OF\VWHLQH(IV or oral)
— Must be given within the first 10 hours
Chapter 43–6
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡(LFRVDQRLGV16$,'VDQG$FHWDPLQRSKHQ
Pharmacology
dTable 43–5.0 Eicosanoids and NSAIDs Summary
Type
Drug
Lipooxygenase inhibitor
Zileuton
LTD4 antagonists
Zafirlukast
Montelukast
Prostaglandin analogs
PGE1
Misoprostol
Alprostadil
PGI2
Epoprostenol
Iloprost
Treprostinil
3*)D
Latanoprost
Tafluprost
Bimatoprost
Carboprost
Travoprost
PGE2
Dinoprostone
16AIDs
Acetylsalicylic acid
6XOLQGDF
Indomethacin
1DSURxen
Ketorolac
Ibuprofen
COX-2 inhibitors
Celecoxib
Central COX inhibition
Acetaminophen
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 43–7
CHAPTER 44
1
Histamines and H1 Antagonists
Overview
Histamine: Autacoid present in lungs, skin, and GI tract.
Released by mast cells, basophils, and platelets
Triggers:
Type I hypersensitivity (IgE)
Drugs, venoms
Trauma
2
USMLE® Key Concepts
Histamine Pharmacology
Histidine
Histidine
Decarboxylase
For Step 1, you must be able to:
X Describe the pharmacology
of histamine and its
receptors.
Histamine
MAOB
Inactive metabolite
X Explain the indications
and side effects of H1
antagonists.
cFigure 44–2.0 Histamine Synthesis
dTable 44–2.0 Four G-Protein Coupled Receptors
Type
G-protein
Location
Gq
‡ 6PRRWKmuscle
‡ (QGRWKHOLXP
‡ &16
H2
Gs
‡ Gastric parietal cells
‡ Cardiac and smooth muscle
‡ 0DVWcell
‡ &16
H3
Gi
‡ &16(presynaptic)
‡ 0\enteric plexus
H4
Gi
Hematopoietic cells
H1
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 44–1
&KDSWHU‡+LVWDPLQHVDQG+1 Antagonists
Pharmacology
2.1 H1 Stimulation
Endothelium:
†12V\QWKDVH
— Dilation of vessel
n Ca2+:
—Pericyte contraction
—n Capillary permeability
—Edema
Bronchiolar smooth muscle:
n Ca2+
Contraction
Gut smooth muscle:
n Ca2+
Contraction
Peripheral nerve endings
Pain
Itch
AV node: p conduction
H1 stimulation explains anaphylaxis and shock
2.2 H2 Stimulation
†Parietal cells:
n H+ secretion
H2 stimulation has a role in peptic ulcer disease
6A node: n firing rate (automaticity)
Atria and ventricles: n contractility
2.3 Histamine Effects in CNS
H3 receptors modulate neuronal release of neurotransmitters:
Presynaptic inhibition
p Release of 5-HT1($&K'$*$%$DQGKLVWDPLQH
H1 and H2UHFHSWRUVDUHDOVRIRXQGLQ&16
Postsynaptic
H1 is in hypothalamic tuberomammillary neurons:
— Controls circadian rhythm
— †in wakefulness
— ٚ in sleep
— Explains in part sedative effects of antihistamine H1
H1 in cortex is excitatory:
—([SODLQVLQSDUW&16GHSUHVVLRQHIIHFWVRIDQWLKLVWDPLQH+1
Chapter 44–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡+LVWDPLQHVDQG+1 Antagonists
3
Pharmacology
H1 Receptor Blockers
Commonly referred to as "antihistamines."
Competitive blockers of H1 receptors: Ineffective at high levels
of histamine.
0RVWDUHDOVRDQWLPXVFDULQLF and have atropine-like side effects
and indications:
0RWLRQsickness
Parkinson disease
$FXWH(36RIDQWLSV\chotics
Cold medication to dry secretions
Legitimate anti-H1 use:
6HDVRQDOallergy:
— Hay fever
— Rhinitis
Urticaria
6OHHSaids
Adverse effects are extension of pharmacology:
Including 3 Cs of antimuscarinics
AdditivH&16GHSUHVVLRQZLWKEHQ]RGLD]epines, alcohol, etc.
dTable 44–3.0 Selected H1 Antagonists
Drug
M blockade
Comments
First Generation
Diphenhydramine
+++
Anti-motion sickness: marked
sedation
Dimenhydrinate
+++
Anti-motion sickness: marked
sedation
Chlorpheniramine
+
Cold medication component
Hydro[\]LQH
Ø
Also 5-HT2A blocker: anxiolytic;
marked sedation
3URPHWKD]LQH
+++
Weak neuroleptic: antiemetic
Cyproheptadine
+
Blocks 5-HT receptors: used in
serotonin syndrome
Second Generation
Fexofenadine
Ø
Loratadine
Ø
&HWLUL]LQH
Ø
1RQVHGDWLYe antihistamines
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 44–3
CHAPTER 45
1
Therapies for Gastroesophageal Reflux
and Peptic Ulcer Disease
Overview
Reduce stomach acid production or neutralize gastric pH
Prevent long-term complications:
Barrett esophagitis
Esophageal adenocarcinoma
Major treatments for gastroesophageal reflux disease (GERD) and
peptic ulcer disease (PUD):
Histamine H2 receptor antagonists
Proton pump inhibitors (PPIs)
Antacids
Physical protectors of gastric mucosa
Prostaglandin analogs
USMLE® Key Concepts
For Step 1, you must be able to:
X Explain the mechanism
of action of acid-reducing
therapies.
X List the common
therapeutic uses of acidreducing therapies.
David M. Martin, MD/Science Source
X Describe the adverse
effects of acid-reducing
therapies.
cFigure 45–1.0 Barrett Esophagitis
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 45–1
&KDSWHU‡7KHUapies for Gastroesophageal Reflux and Peptic Ulcer Disease
2
Pharmacology
H2 Receptor Antagonists
Cimetidine
Ranitidine
Famotidine
Nizatidine
2.1 Mechanism of Action
Competitive antagonists of H2 receptors
Histamine is released from enterochromaffin-like (ECL) cells after
vagal or gastrin stimulation
Histamine acts as a paracrine regulator of parietal cells
2.2 Therapeutic Uses
Overall, less effective than PPIs but have an immediate effect
PUD
GERD
2.3 Adverse Effects
Cimetidine is a general inhibitor of CYP450:
Drug interactions
p Androgen:
— Gynecomastia
— p Libido
Ranitidine, famotidine, and nizatidine are not P450 inhibitors
All four drugs n stomach pH:
n Absorption of weak bases
p Absorption of weak acids
Chapter 45–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡7KHUapies for Gastroesophageal Reflux and Peptic Ulcer Disease
3
Proton Pump Inhibitors
Most effective blockers of gastric acid secretion:
Omeprazole
Lansoprazole
Pantoprazole
Pharmacology
!
Important Concept
Proton pump inhibitors, as the
most effective acid reducers,
are the drugs of choice for
severe GERD.
Mechanism of action:
Irreversible inhibitors of H+/K+$73DVH
7akes 2–5 days to reduce gastric acid secretion by up to 70%
7KHUapeutic uses (first-line therapy for):
PUD
GERD
Zollinger-Ellison syndrome
Adverse effects:
PPIs are metabolized by CYP450 and can compete with drug
metabolism (e.g., warfarin).
Omeprazole is an inhibitor of 2C19 but an inducer of 1A2:
—ٚ2C19: n Phenytoin
—ْ1A2: p Imipramine, p antipsychotics, p theophylline
All cause hypergastrinemia:
— Risk of acid rebound on discontinuation
Chronic use may result in iron and B12 malabsorption and
greater risk of respiratory and enteric infections.
4
Antacids
Neutralize protons in the gut lumen
Short-term relief of reflux-related symptoms
Aluminum hydroxide: may cause constipation
Magnesium hydroxide: may cause diarrhea
Calcium carbonate and sodium bicarbonate: may cause alkalosis
All antacids n gastric pH and alter absorption of other drugs:
n Weak base absorption (e.g., quinidine toxicity)
p Weak acid absorption (e.g., azoles)
Chelate tetracyclines
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 45–3
&KDSWHU‡7KHUapies for Gastroesophageal Reflux and Peptic Ulcer Disease
5
Pharmacology
Cytoprotectants
5.1 Sucralfate
Sucralfate is a prodrug:
Requires acid pH to polymerize and form a sticky gel
Coats ulcer crater
Prevents further erosion
Antacids block its effect
5.2 Bismuth Subsalicylate
Like sucralfate but not a prodrug
See Helicobacter pylori eradication regimens in topic 6
5.3 Misoprostol
PGE1 analog:
n HCO3í and mucus secretion
p HCl production
Used for NSAIDs-induced ulcer
Contraindicated in pregnancy: causes abortion
Adverse effect: diarrhea
6
+HOLFREDFWHU3\ORULEradication
H. pylori is associated with recurrence of gastritis, PUD
Carcinogenic:
n Gastric adenocarcinoma
n MAL7oma
Combination therapies:
Omeprazole + clarithromycin + amoxicillin
Bismuth + metronidazole + tetracyFOLQH %07
14-day course
dTable 45–6.0 GERD and PUD Drug Summary
Type
Drugs
H2 blockers
Cimetidine
Ranitidine
Famotidine
Nizatidine
PPIs
Omeprazole
Lansoprazole
Pantoprazole
Dexlansoprazole
Esomeprazole
Rabeprazole
Antacids
Al(OH)3
Mg(OH)2
CaCO3
NaHCO3
Cytoprotectants
Sucralfate
Bismuth subsalicylate
Misoprostol
Chapter 45–4
© DeVry/Becker Educational Development Corp. All rights reserved.
Serotonin Pharmacology
CHAPTER 46
1
Overview
Serotonin (5-hydroxytryptamine, 5-HT):
Neurotransmitter synthesized and stored in gastrointestinal cells,
neurons, and platelets
Metabolized by MAOA
Reuptake from synapses by serotonin transporter (SERT)
Tryptophan
Tryptophan hydroxylase
5-hydroxytryptophan
Aromatic
amino acid
decarboxylase
5-hydroxytryptamine
(serotonin)
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe serotonin
pharmacology.
X Identify serotonergic drugs
and the receptor subtype to
which they bind.
X Explain the variety of
indications for serotonergic
drugs.
MAOA
5-hydroxyindoleacetic acid
(5-HIAA)
cFigure 46–1.0 Serotonin Synthesis
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 46–1
&KDSWHU‡6HURWRQLQ3KDUPDFRORJ\
2
Pharmacology
Serotonin Receptors
Largest known neurotransmitter receptor family:
Seven subtypes 5-HT1o7
Each subtype is subdivided
Four of these subtypes have well-defined function: 5-HT1o4
All are G-protein coupled except 5-HT3, which is a cationic channel
dTable 46–2.0 Serotonin Receptors
Subtype
Important Subdivisions
Mechanism
5-HT1
A, B, D, E, F
Gi
5-HT2
A, B, C
Gq
5-HT3
Na+/K+ channel
5-HT4
Gs
5-HT5
5-HT6
5-HT7
A, B
Gi
Gs
Gs
Drugs previously reviewed:
SSRIs: SERT inhibitors used for depression and chronic
management of anxiety disorders
Buspirone:
— 3artial agonist at 5-HT1A
— General anxiety disorder treatment
Atypical antipsychotics:
— 5-HT2A antagonists
— Clozapine, olanzapine, risperidone, quetiapine, etc.
Hydroxyzine and cyproheptadine:
— Antihistamines
— Hydroxyzine is also a 5-HT2A blocker: anxiolytic
— Cyproheptadine blocks all subtypes: used in serotonin
syndrome and also in carcinoid disease
5-HT3 antagonists: antiemetics used in chemotherapy or
radiotherapy (ondansetron family)
Chapter 46–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡6HURWRQLQ3KDUPDFRORJ\
3
Pharmacology
Carcinoid Syndrome
Carcinoids are GI or bronchial tumors producing 5-HT
Carcinoid syndrome occurs when there is systemic circulation
of 5-HT:
Diarrhea, cramping
Flushing, hypotension
Carcinoid heart disease
Bronchospasm, wheezing
Urine marker: 5-HIAA
Treatment:
Somatostatin analog, octreotide
Cyproheptadine: 5-HT receptor blocker
4
Migraine Headaches
4.1 The Triptans
Specific neurologic syndrome with a variety of manifestations:
With or without an aura
May last hours or days
Frequency is variable
10% to 20% of population
5-HT plays a key role in migraine:
3ODVPDDQGXULQDU\FRQFHQWUations of 5-HT and 5-HIAA vary
with the different phases of migraines
Drugs that n 5-HT can precipitate migraines
Triptans are 5-HT1B/1D agonists:
Vasoconstrict cerebral vasculature
p Release of proinflammatory neuropeptides (autoreceptors):
VXEVWDQFH3QHXURNLQLQ$FDOFLWRQLQJHQHUHODWHGSHSWLGH &*53
Adverse effects:
Coronary vasospasm, ischemia, infarction in patients with
coronary artery disease (CAD)
Contraindications:
— Cardio or cerebrovascular disease
— Uncontrolled hypertension
— 3atients on MAO inhibitors
Triptans are not intended for prophylaxis
Include:
Sumatriptan
Rizatriptan
Zolmitriptan
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 46–3
&KDSWHU‡6HURWRQLQ3KDUPDFRORJ\
Pharmacology
4.2 Other Drugs Used in Migraine
Ergotamine:
Ergot alkaloid
3artial agonist at D1 and 5-HT2 receptors
Vasoconstrictive action in CNS
Acute attack management
Adverse effects: ischemia, abortion
Analgesics: aspirin, NSAIDs, opiates
Prophylaxis:
First line:
— Beta-blockers: propranolol
— TCAs: amitriptyline
— Anti-seizure drugs: valproate, topiramate
— Ca2+ channel blockers: verapamil
Second line: methysergide (5-HT2 blocker, ergot alkaloid)
dTable 46–4.2 Summary of Drugs Acting on 5-HT Receptors
5-HT1A
Buspirone
Chapter 46–4
5-HT1B/1D
Sumatriptan
Rizatriptan
Zolmitriptan
Frovatriptan
Eletriptan
Almotriptan
Naratriptan
5-HT2A
Atypical antipsychotics
Methysergide
Cyproheptadine
5-HT3
Ondansetron
© DeVry/Becker Educational Development Corp. All rights reserved.
CHAPTER 47
1
Asthma and COPD Treatments
Overview
Asthma is an inflammatory disease, with symptoms such as
bronchoconstriction (wheezing, difficulty breathing) and increased
airway mucus.
Two types of asthma:
Extrinsic:
— Due to atopy (hypersensitivity to environmental antigens)
— IgE-mediated
— Begins in childhood
Intrinsic:
— Nonimmune
— Triggers include stress, cold, exercise, upper respiratory
infections, aspirin
Antigen
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe the major classes
of drugs used for asthma
and their mechanisms of
action and adverse effects.
X Explain the therapeutic
approaches for
acute versus chronic
management of asthma.
Mediator
release
I
IgE-antigen
iinteraction
IgE
PGD2
LTC4, D4
Sensitize
Sensitized
Se
it zed
mast cell
ECF-A
Histamine,
tryptase
cFigure 47–1.0 Pathogenesis of Extrinsic Asthma
Episodic or chronic symptoms of airway obstruction:
Dyspnea
Wheezing
Prolonged expiration
Reversal of symptoms following E2 agonist administration strongly
suggests a diagnosis of asthma
Status asthmaticus:
Unrelenting bronchospasm
Asphyxia, cyanosis, respiratory acidosis
© DeVry/Becker Educational Development Corp. All rights reserved.
Clinical
Application
‡ Asthma is a chronic
obstructive pulmonary
disease (COPD).
‡ Spirometry: p FEV1/FVC
ratio
‡ Methacholine or
histamine can be used
as a challenge test.
Chapter 47–1
&KDSWHU‡$VWKPDDQG&23'7reatments
2
Pharmacology
Asthma Therapy
Seven main categories of drugs:
1. Corticosteroids
2. E2-adrenergic receptor agonists
3. Muscarinic receptor antagonists
4. Theophylline
5. Cromolyn sodium
6. Leukotriene antagonists
7. Antibodies against IgE (omalizumab)
Management:
Bronchodilators for quick relief
Anti-inflammatory drugs for long-term control
Most asthma medications are inhaled
E2 agonists and low-dose corticosteroids are the most widely used
medications for asthma.
Drugs used in asthma
Bronchodilators
Beta
agonists
Salmeterol
Formoterol
Albuterol
Anti-inflammatory agents
Histaminerelease
inhibitors
Muscarinic
antagonists
Cromolyn
Nedocromil
Tiotropium
Methylxanthines
Steroids
Leukotriene antagonists
Lipoxygenase
inhibitor
Receptor
antagonists
Zileuton
Zafirlukast
Montelukast
Immune
modulators
Fluticasone
Budesonide Omalizumab
Mometasone
Beclomethasone
Theophylline
cFigure 47–2.0 Asthma Drugs
Chapter 47–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$VWKPDDQG&23'7reatments
Pharmacology
2.1 Corticosteroids
Inhaled corticosteroids:
Have minimal systemic side effects.
Target the inflammatory process in the lungs and prevent
desensitization of E2 receptors.
Include budesonide, beclomethasone, fluticasone, and
mometasone.
Fluticasone and mometasone have the fewest systemic effects.
Indicated for chronic treatment of moderate to severe asthma.
Local immunosuppression may result in oropharyngeal
candidiasis.
Systemic corticosteroids:
Severe asthma when inhaled agents are insufficient.
Prednisone (oral) and prednisolone (intravenous) are
commonly used.
Limited to the shortest duration that brings the asthma
symptoms under control.
Adverse effects: see chapter 39.
2.2 E2-Adrenergic Receptor Agonists
Acute bronchoconstriction
Prophylaxis of exercise-induced asthma
E2 stimulation ncAMP in bronchiolar smooth muscle resulting
in relaxation
Two groups:
Short-acting for quick relief:
— Albuterol, terbutaline
— 2QVHWLQPLQXWHV
Long-acting for prophylaxis:
— Salmeterol, formoterol
— Bronchodilation > 12 hours, but slow onset
— Must be used with steroids: monotherapy has slight n risk of
fatal asthma attack
— Combination inhaler: formoterol + budesonide
Low potential of muscle tremors, anxiety, palpitations
2.3 Muscarinic Receptor Antagonists
'2&LQEHWDEORFNer-induced bronchospasm
Second-line therapy for asthma
Ipratropium (short-acting) and tiotropium (long-acting)
Minimal atropine-like effects
© DeVry/Becker Educational Development Corp. All rights reserved.
Memory Aid
You can recognize antimuscarinic
drugs because they often have
"trop" in their names:
‡ Atropine
‡ Ipratropium
‡ Tiotropium
Chapter 47–3
&KDSWHU‡$VWKPDDQG&23'7reatments
Pharmacology
2.4 Theophylline
Methylxanthine chemically related to caffeine
Second-line drug
Theophylline and caffeine are both used to treat apnea associated
with prematurity
Mechanism of action:
Inhibition of phosphodiesterase (n cAMP)
Antagonism of the bronchoconstrictive transmitter adenosine.
Aminophylline is an intravenous form of theophylline used for
severe asthma attacks
Adverse effects:
Narrow therapeutic window
Cardiac arrhythmias
Central nervous system excitation
Therapeutic drug monitoring required
2.5 Cromolyn Sodium and Nedocromil
Seldom-used asthma drugs
Prevent degranulation of mast cells:p Histamine and leukotrienes
AvDLODEOH2TC for seasonal allergies
2.6 Leukotriene Antagonists
Montelukast and zafirlukast:
Block leukotriene receptors
Given orally but produce clinical effect in only about one third
of patients
Association with Churg-Strauss syndrome: autoimmune
vasculitis affecting the lung and other organs
Zileuton:
,QKLELWRURIOLSR[\JHQDVH
Very effective for preventing exacerbation of asthma by aspirin
n Risk of infection
2.7 Omalizumab
Humanized monoclonal antibody to IgE.
Prevents mast cell activation.
Given parenterally.
Reserved for treatment of asthma not responsive to other less
expensive therapies.
Reduces need for corticosteroids.
Chapter 47–4
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡$VWKPDDQG&23'7reatments
Pharmacology
Exposure to antigen
(e.g., dust, pollen)
Avoidance
Antigen and IgE
on mast cells
Cromolyn,
steroids,
zileuton,
omalizumab
Mediators
(e.g., leukotrienes, cytokines,
histamine)
Beta agonists,
theophylline,
muscarinic
antagonists,
leukotriene
antagonists
Steroids,
cromolyn,
leukotriene
antagonists
Early response:
bronchoconstriction
Late response:
inflammation
Acute symptoms
Bronchial
hyperreactivity
cFigure 47–2.7 Asthma Treatment Strategies
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU±
&KDSWHU‡$VWKPDDQG&23'7reatments
Pharmacology
dTable 47–2.7 Asthma Therapy Drug Summary
Type
Corticosteroids
Drug
Inhaled
Budesonide
Fluticasone
Mometasone
Beclomethasone
Flunisolide
Triamcinolone
Systemic
Prednisone
Prednisolone
Methylprednisolone
E2 agonists
Salmeterol
Formoterol
Albuterol
Terbutaline
Bitolterol
Pirbuterol
Muscarinic antagonists
Ipratropium
Tiotropium
Adenosine and PDE antagonist
Theophylline
Leukotriene antagonists
Zileuton
Zafirlukast
Montelukast
p Mast cell degranulation
Cromolyn sodium
Nedocromil
IgE antibody
2PDOL]XPDE
Chapter 47–6
© DeVry/Becker Educational Development Corp. All rights reserved.
Therapies for Gout
CHAPTER 48
1
Overview
Gout results from the crystallization of uric acid in joints (tophi)
with a subsequent acute inflammatory reaction.
Gout therapies either relieve acute symptoms or reduce the risk of
gouty attacks by lowering the uric acid pool.
Uric acid is an end product of purine metabolism.
2
Therapies for Acute Gout Attacks
USMLE® Key Concepts
For Step 1, you must be able to:
Indomethacin:
X Describe the pathology of
gout.
First-line therapy for acute gout attacks
Other NSAIDs include naproxen and sulindac
X Differentiate the drugs
used for acute attack
management.
Colchicine:
Inhibits neutrophil mobility and activity
Binds to tubulin and p microtubule polymerization
X Name the drugs used for
prophylaxis of gout.
Narrow therapeutic index:
Gastrointestinal upset
Neutropenia
Peripheral neuropathy
Mediscan/Visuals Unlimited, Inc.
Steroids: DOC in patients who are allergic to NSAIDs
cFigure 48–1.0 Gouty Joints
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 48–1
&KDSWHU‡7KHUapies for Gout
3
Pharmacology
!
Prophylaxis of Gout
Diet modifications
Drug strategy:
Important Concept
Be careful not to confuse
therapies for acute and chronic
gout. For example, colchicine
is not an appropriate therapy
for the management of chronic
gout. Likewise, allopurinol is
an ineffective treatment for an
acute gout attack.
p Uric acid synthesis
n Uric acid excretion
3.1 Dietary Modifications
Gout-promoting foods and drinks:
Red meats
Beer and other alcoholic beverages
Seafood
Fructose-containing beverages
Gout-reducing foods and drinks:
Cherries
Whole grains (with complex carbohydrates)
Coffee
3.2 Decreased Uric Acid Production: Xanthine
Oxidase Inhibitors
Xanthine oxidase catalyzes the last step in the conversion of
purines to uric acid.
Allopurinol and febuxostat inhibit xanthine oxidase.
Both can initially precipitate an acute gout attack.
Allopurinol causes hypersensitivity: rashes including StevensJohnson syndrome.
Febuxostat does not cause hypersensitivity reactions.
Drug interactions:
Inhibition of the metabolism of 6-mercaptopurine and its
prodrug azathioprine.
Xanthine oxidase is one of the enzymes involved in the
clearance of 6-mercaptopurine.
Allopurinol
Xanthine
oxidase
Purines
Hypoxanthine
Xanthine
oxidase
Alloxanthine
Xanthine
Febuxostat
Xanthine
oxidase
Uric acid
cFigure 48–3.2 Action of Xanthine Oxidase Inhibitors
Chapter 48–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡7KHUapies for Gout
Pharmacology
3.3 Uricosuric Drugs
Increase rate of excretion of uric acid
Reduce risk of gout attacks
Probenecid ٚ tubular reabsorption of filtered urate
Should not be used if creatinine clearance is < 50 mL/min
Contraindicated with history of urate renal stones
3.4 Uricases
Enzymes that break down uric acid into allantoin, which is more
water-soluble than uric acid.
Originally used to reduce uric acid in the tumor lysis syndrome:
n Cell turnover in cancers and cell death in chemo/radiotherapy
are associated with hyperuricemia.
Uricase is used to treat gout refractory to other therapies.
Rasburicase: Recombinant uricase approved for the treatment and
prevention of hyperuricemia associated with tumor lysis syndrome.
Pegloticase:
Polyethylene glycol (PEG)-modified uricase has longer elimination
half-life and lower immunogenicity than rasburicase.
Used for longer-term management of chronic gout refractory to
other therapies.
Hypersensitivity (FDA black box warning) may require
prophylactic steroids.
dTable 48–3.4 Gout Drug Summary
Acute Attacks
Prophylaxis
NSAIDs
Indomethacin
Naproxen
Sulindac
Xanthine oxidase inhibitors
Allopurinol
Febuxostat
Colchicine
Uricosuric
Probenecid
Steroids
Uricase
Pegloticase
Rasburicase
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 48–3
CHAPTER 49
1
Disease-Modifying Antirheumatic Drugs
Overview
Rheumatoid arthritis is an autoimmune chronic inflammatory disorder.
Classically affects the small joints in the hands and feet.
More common in women than in men.
Occurs most frequently from ages 40 to 60.
Therapies for rheumatoid arthritis are aimed at managing the
acute symptoms but also at preventing permanent bone erosion
and joint damage.
Often initially managed by NSAIDs:
p Pain and swelling
No effect on disease course
Disease-modifying antirheumatic drugs (DMARDs) aim at slowing
the disease progression—to protect joints from permanent
damage and deformity.
2
USMLE® Key Concepts
For Step 1, you must be able to:
X Explain the mechanism of
action of disease-modifying
antirheumatic drugs.
X Describe the adverse
effects of disease-modifying
antirheumatic drugs.
Drugs
DMARDs are started with NSAIDs: Take weeks to months to
be effective.
Two primary drugs:
Hydroxychloroquine for mild arthritis
Methotrexate for moderate to severe arthritis
2.1 Methotrexate
Cytotoxic effect on lymphocytes.
Suppressive action on bone marrow.
Increases risk of infections.
Inhibits DHF reductase.
2.2 Hydroxychloroquine
Used for malaria treatment and to treat autoimmune disorders
such as lupus and rheumatoid arthritis.
Exact mechanism of action is not known, although the drug
reduces rheumatoid factor and other acute-phase reactants:
May stabilize lysosome and p chemotaxis.
Adverse effects:
Cinchonism
Can trigger hemolytic anemia in patients with G6PD deficiency
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 49–1
&KDSWHU‡'LVHDVH0RGLI\LQJ$QWLUKHXPDWLF'UXJV
Pharmacology
2.3 Sulfasalazine
Prodrug of sulfapyridine and 5-aminosalicylic acid
p B cell functions and inhibits COX
Can cause hemolysis in G6PD-deficiency patients
Neutropenia, thrombocytopenia
2.4 Leflunomide and Teriflunomide
Inhibition of the mitochondrial dihydroorotate dehydrogenase:
p UMP, p ribonucleotide synthesis
Arrest lymphocytes in G1 phase
Teriflunomide is also the active metabolite of leflunomide
Liver toxicity and myelosuppression, either of which can be fatal
2.5 Infliximab
Humanized monoclonal antibody directed against tumor necrosis
factor-D (TNF-D)
Also used for:
Ankylosing spondylitis
Psoriasis
Crohn disease
Ulcerative colitis
Risk of bone marrow suppression, with increased rate of serious
infections: Reactivation of hepatitis B and tuberculosis
2.6 Adalimumab
Fully human monoclonal antibody directed against TNF-D
Adverse effects are similar to those of infliximab
2.7 Etanercept
Recombinant TNF receptor and IgG constant domain chimera
Adverse effects are similar to those of infliximab
2.8 Rituximab
Chimeric monoclonal antibody against CD20
Also used as chemotherapy for B lymphocyte-related leukemias
and lymphomas
Can cause infusion reactions
Immune suppression can cause reactivation of hepatitis B and
other viruses
A rare adverse effect is progressive multifocal leukoencephalopathy
(PML), a fatal disease caused by activation of JC virus
2.9 Penicillamine
Suppresses the function of T lymphocytes: chelator of heavy
metals, interferes with metalloprotease functions
Bone marrow suppression, nephropathy, and a lupus-like syndrome
Penicillamine is also DOC in Wilson disease: chelates copper
Chapter 49–2
© DeVry/Becker Educational Development Corp. All rights reserved.
&KDSWHU‡'LVHDVH0RGLI\LQJ$QWLUKHXPDWLF'UXJV
Pharmacology
2.10 Gold Salts (Auranofin, Aurothioglucose)
Infrequently used group of DMARDs
p Lysosomal and macrophage function
Common adverse effects: skin rash and mouth sores
Nephrotoxicity and hematoxicity are infrequent
2.11 Glucocorticoids
Chronic doses of glucocorticoids cause too many side effects:
ACTH suppression
Cushingoid states
Osteoporosis
dTable 49–2.11 DMARDs Summary
Drugs
Methotrexate
Hydroxychloroquine
Sulfasalazine
Leflunomide
Teriflunomide
Infliximab
Adalimumab
Etanercept
Rituximab
Penicillamine
Auranofin
Aurothioglucose
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 49–3
CHAPTER 50
1
Immunosuppressants (Anti-rejection Drugs)
Overview
Immunosuppressants are used to prevent the rejection of
transplanted organs as well as for the treatment of autoimmune
diseases such as rheumatoid arthritis and psoriasis.
The prototype anti-rejection drugs are cyclosporine and tacrolimus.
Other agents include sirolimus and mycophenolic acid.
2
Cyclosporine
First widely used drug to prevent organ transplant rejection.
Also used to treat autoimmune diseases.
As an ophthalmic solution, used to treat dry eyes.
2.1 Mechanism of Action
pActivity and growth of T lymphocytes.
Binds to cyclophilins, which p calcineurin.
Results in p expression of IL-2 and J-IFN.
2.2 Pharmacokinetics
Predominantly metabolized by cytochrome CYP3A4.
Drug interactions with CYP inhibitors or inducers.
2.3 Adverse Effects
Dose-limiting nephrotoxicity.
When cyclosporine is used in a renal transplant recipient, it can be
difficult to determine whether an increasing creatinine value is due
to drug toxicity or allograft rejection.
Neuropathy.
Gingival hyperplasia.
3
USMLE® Key Concepts
For Step 1, you must be able to:
X Describe the mechanism
of action and common
therapeutic uses of antirejection drugs.
X Identify the adverse effects
associated with antirejection drugs.
!
Important Concept
For exam questions involving
cyclosporine therapies, remember
that inhibitors of CYP3A4 prevent
the metabolism of cyclosporine,
and that inducers of the same
enzyme reduce its level.
Tacrolimus
Similar to cyclosporine but binds to FK binding proteins to inhibit
calcineurin.
Nephrotoxicity is dose-limiting.
Tacrolimus is also used for the treatment of autoimmune diseases,
such as ulcerative colitis and vitiligo.
© DeVry/Becker Educational Development Corp. All rights reserved.
Chapter 50–1
&KDSWHU‡,PPXQRVXSSUHVVDQWV $QWLUHMHFWLRQ'UXJV 4
Pharmacology
Sirolimus (Rapamycin)
Anti-rejection drug that is used most commonly in kidney
transplant recipients.
Main advantage of sirolimus, compared with cyclosporine and
tacrolimus, is low renal toxicity.
Also used as a coating on cardiac stents to prevent restenosis
following balloon angioplasty.
Inhibits the mTOR complex involved in the cellular response to
interleukin-2.
Can cause interstitial pneumonitis.
5
Mycophenolate Mofetil
Immunosuppressant used for the prevention of allograft rejection
and for the treatment of autoimmune diseases.
Mycophenolate may be used in conjunction with other
anti-rejection drugs.
Inhibits inosine 5'-monophosphate dehydrogenase, an enzyme in
the synthesis pathway for purines, especially guanine.
B and T lymphocytes, unable to use a separate scavenger pathway
for purine synthesis.
Opportunistic infections and cytopenias are the most common
serious adverse effects.
dTable 50–5.0 Immunosuppressant Drug Summary
Drugs
Cyclosporine
Tacrolimus
Sirolimus
Mycophenolate mofetil
Chapter 50–2
© DeVry/Becker Educational Development Corp. All rights reserved.
Appendix 1
Pharmacology
Toxicology
dTable 51–1.0 Main Antidotes
Drug
Antidote
Acetaminophen
N-acetylcysteine
Antimuscarinics
Physostigmine
E agonists
Esmolol
Beta-blockers
Glucagon
Benzodiazepines/zolpidem/zaleplon/eszopiclone
Flumazenil
Carbon monoxide
Hyperbaric O2 + ventilation
Copper
Penicillamine
Cyanide
Soduim nitrite and sodium thiosulfate or hydroxocobalamin
Digoxin
Digoxin antibodies
Ethylene glycol/methanol
Fomepizole, IV ethanol
Heavy metals
Chelators (see Table 51–4.0)
Heparins
Protamine sulfate
Iron salts
Deferoxamine (IM, IV), deferasirox (PO)
Isoniazid
Vitamin B6 (pyridoxine)
Opioid analgesics/heroin
Naloxone
Oral sulfonylureas
Glucose, octreotide
Organophosphates/carbamates/
acetylcholinesterase inhibitors
Atropine + pralidoxime (2-PAM)
TCAs/quinidine
Sodium bicarbonate (do not use physostigmine if there is
conduction block)
Theophylline
Esmolol
Warfarin
Fresh frozen plasma, vitamin K
© DeVry/Becker Educational Development Corp. All rights reserved.
Appendix 1–1
Appendix 1
Pharmacology
dTable 51–2.0 Main Toxic Syndromes
Drug
Toxic Syndrome
Acetaminophen
‡ >
7 g in an adult is considered toxic
‡ >150–200 mg/L after 4 hours: patient at risk of
liver injury
‡ Initially asymptomatic
‡ 24–36 hours signs of hepatitis (n LFTs, p factor II)
‡ Liver failure, hepatic encephalopathy, death within days
Acetylcholinesterase inhibitors (organophosphates)
n All secretions, miosis, bradycardia, bronchospasm,
diarrhea, incontinence, muscle and respiratory paralysis
Anticholinergics (muscarinic blockers)
‡ p All secretions: dry mouth; dry, hot, red skin
‡ Mydriasis, cycloplegia, urinary retention, constipation
‡ Confusion, delirium
‡ 3 Cs: cardiotoxicity (torsade), convulsions, coma
Aspirin
‡ Hyperventilation, respiratory alkalosis
‡ Followed by metabolic acidosis (n anion gap)
‡ Hyperthermia
‡ Severe poisoning: combined acidosis, seizures, death
Carbon monoxide
‡ Headache, dizziness, nausea
‡ Vomiting, seizures
‡ Coma, death
Cocaine/amphetamine/methamphetamine (CNS stimulants)
‡ Euphoria, wakefulness
‡ Restlessness, agitation, acute psychosis, diaphoresis
‡ Hypertension, tachycardia, mydriasis
‡ Hyperthermia seizures, rhabdomyolysis, renal failure
‡ Fatal arrhythmia, strokes, MI
Cyanide
‡ Shortness of breath, agitation, tachycardia, severe
metabolic acidosis
‡ "Almond" scented breath
‡ Followed by seizures, coma, cardiovascular collapse
‡ Death
MAO inhibitors
Hypertensive crisis with tyramine-containing foods
Opioid analgesics
‡ Miosis
‡ Respiratory depression
‡ Coma
Sedative hypnotics/alcohols
‡ Initial disinhibition
‡ Lethargy, ataxia, nystagmus, slurred speech
‡ Coma, respiratory depression, death
SSRIs
‡ Hyperthermia, sweating, myoclonus
‡ Muscle rigidity, n BP, n heart rate
‡ Seizures
TCAs
‡ Anticholinergics, 3 Cs
‡ Alpha-blockers, hypotension
‡ Ventricular conduction block and ventricular tachycardia
© DeVry/Becker Educational Development Corp. All rights reserved.
Appendix 1–2
Appendix 1
Pharmacology
dTable 51–3.0 Heavy Metals: Presentation and Chelator Treatment
Heavy Metal
Mode of Exposure
Symptoms
Chelator Treatment
Lead
‡ O
ld plumbing
‡ O
ld, flaking paint
‡ H
erbal remedies
‡ Lead encephalopathy
‡ Lead colic
‡ Lead nephropathy
‡ Anemia
‡ p Fertility, n stillbirths
‡ IV EDTA +/– IM dimercaprol
‡ PO succimer (children)
Iron
Iron supplements for anemia
‡ Gastroenteritis with
hematemesis and bloody
diarrhea
‡ Shock, coma
‡ IV deferoxamine
‡ PO deferasirox is for iron
overload from transfusions
Arsenic
‡ I nsecticides
‡ W
ood preservatives
‡ A
nt/roach baits
‡ Binds to –SH groups
‡ Acute gastroenteritis
‡ Hypotension
‡ Metabolic acidosis
‡ Followed by cardiac failure,
pancytopenia, and ascending
neuropathy
‡ Chronic exposure is
carcinogenic (lung, skin,
bladder)
‡ Chronic exposure: dermatitis
in "rain drop pattern" and
hyperkeratosis
‡ IM dimercaprol
‡ PO succimer
Mercury
‡ O
ccupational or
environmental exposure
‡ B
atteries
‡ P
roduction of chlorine and
caustic soda
‡ F
luorescent lamps/bulbs
‡ Acute:
—Inhalation of vapor causes
pneumonitis, edema
—Ingestion causes severe
gastroenteritis and acute
tubular necrosis
‡ Chronic (classic triad):
—Intention tremor
—Neuropsychiatric problems
(amnesia, erethism)
—Gingivostomatitis
‡ PO or IV unithiol
‡ IM dimercaprol
‡ PO succimer
© DeVry/Becker Educational Development Corp. All rights reserved.
Appendix 1–3
Appendix 1
Pharmacology
dTable 51–4.0 Chelators
Chelator
Indications and Comments
EDTA (ethylenediaminetetraacetic acid)
‡ Divalent and trivalent cations
‡ Always administered as a calcium disodium salt to
prevent severe hypocalcemia
‡ IV:
—Lead toxicity
—Zinc, manganese
Dimercaprol (British anti-Lewisite, BAL)
‡ Colorless oil with strong mercaptan odor
‡ World War II: against arsenic-containing chemical
weapons
‡ IM:
—Arsenic poisoning
—Inorganic mercury
—Severe lead intoxication (in conjunction with EDTA)
Succimer (dimercaptosuccinic acid, DMSA)
‡ Water-soluble analog of dimercaprol
‡ PO:
—Childhood lead poisoning
—Arsenic and mercury poisoning
Penicillamine (dimethylcysteine)
‡ Water-soluble derivative of penicillin
‡ PO:
—Copper poisoning or Wilson disease
—DMARD
Deferoxamine
IM, IV: Iron poisoning
Prussian blue (ferric hexacyanoferrate)
PO: Exposure to dirty bomb radionuclides (137Cs, various
thallium isotopes)
© DeVry/Becker Educational Development Corp. All rights reserved.
Appendix 1–4
Appendix 1
Pharmacology
dTable 51–5.0 Select Herbal Preparations and Toxicities
Herbal
Indications
Toxicities
Ginkgo biloba
Intermittent claudication
Cerebral insufficiency and dementia
‡ Antiplatelet properties
‡ Interaction with blood drugs
St. John's wort (Hypericum
perforatum)
Antidepressant
‡ P
hotosensitivity
‡ Serotonin syndrome with SSRIs, TCAs,
MAOIs
Saw palmetto (Serenoa repens
or Sabal serrulata)
BPH
‡ p Libido, impotence, back pain, headache
‡ No drug interaction
Red yeast rice (Monascus
purpureus mold)
Hypercholesterolemia
‡ Monacolin K is lovastatin
‡ Rhabdomyolysis
‡ Liver damage
© DeVry/Becker Educational Development Corp. All rights reserved.
Appendix 1–5