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Potential Interactions between Physical Agents and Therapeutic Drugs

Listed here are some potential interactions between physical agents used in rehabilitation and various pharma-
cologic agents. It is impossible to list all the possible relationships between the vast array of therapeutic drugs
and the interventions used in physical therapy and occupational therapy. However, some of the more common
interactions are identified here.

Desired Drugs with Drugs with Other Drug-

Therapeutic Complementary/ Antagonistic Modality
Modality Effect Synergistic Effects Effects Interactions
Cryotherapy Decreased pain, edema, Anti-inflammatory steroids Peripheral vasodilators Some forms of cryotherapy
Cold/ice packs and inflammation (glucocorticoids); non- may exacerbate acute may produce local vaso-
Ice massage steroidal anti-inflamma- local edema constriction that temporarily
Cold bath tory analgesics (aspirin impedes diffusion of drugs
Vapocoolant sprays and similar NSAIDs) to the site of inflammation
Muscle relaxation and Skeletal muscle relaxants Nonselective cholinergic ago- —
decreased spasticity nists may stimulate the
neuromuscular junction

Superficial and Decreased muscle/joint NSAIDs; opioid analgesics; — —

deep heat pain and stiffness local anesthetics
Local application Decreased muscle spasms Skeletal muscle relaxants Nonselective cholinergic ago- —
Hot packs nists may stimulate the
Paraffin neuromuscular junction
Infrared Increased blood flow Peripheral vasodilators Systemic vasoconstrictors —
Fluidotherapy to improve tissue (e.g., alpha-1 agonists)
Diathermy healing may decrease perfusion
Ultrasound of peripheral tissues

Systemic heat Decreased muscle/joint Opioid and nonopioid anal- — Severe hypotension may occur
Large whirlpool stiffness in large areas gesics; skeletal muscle if systemic hot whirlpool is
Hubbard tank of the body relaxants administered to patients
taking peripheral vasodila-
tors and some antihyper-
tensive drugs (e.g., alpha-1
antagonists, nitrates, direct-
acting vasodilators, calcium
channel blockers)

Ultraviolet radiation Increased wound healing Various systemic and — Antibacterial drugs generally
topical antibiotics increase cutaneous sensi-
tivity to ultraviolet light (i.e.,
Management of skin disor- Systemic and topical Many drugs may cause Photosensitivity with antibac-
ders (acne, rashes) antibiotics and anti- hypersensitivity reactions terial drugs
inflammatory steroids that result in skin rashes,
(glucocorticoids) itching

Transcutaneous electrical Decreased pain Opioid and nonopioid Opioid antagonists —

nerve stimulation (TENS) analgesics (naloxone)

Functional neuromuscular Increased skeletal muscle — Skeletal muscle relaxants —

electrical stimulation strength and endurance
Decreased spasticity and Skeletal muscle relaxants Nonselective cholinergic ago- —
muscle spasms nists may stimulate the
neuromuscular junction
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Common Drug Suffixes

Medications that are chemically and functionally similar often have generic names that share a common ending
or suffix. Listed here are some drug classes that contain groups of drugs that share a common suffix. Please note
that some members of a drug class may have a suffix that is different from the one indicated; for instance, not all
benzodiazepines end with “-epam” or “-olam.”

Primary Indication or
Desired Effect (Chapter
Drug Class Suffix Common Examples in Parentheses)
Angiotensin-converting -pril Captopril, enalapril Antihypertensive (21), congestive
enzyme (ACE) inhibitors heart failure (24)

Azole antifungals -azole Fluconazole, miconazole Fungal infections (35)

Barbiturates -barbital Phenobarbital, secobarbital Sedative-hypnotic (6), antiseizure (9),

anesthetic (11)

Benzodiazepines -epam or -olam Diazepam, temazepam, alprazolam, Sedative-hypnotic (6), antianxiety (6),
triazolam antiseizure (9), anesthetic (11)

Beta blockers -olol Metoprolol, propranolol Antihypertensive (21), antianginal

(22), antiarrhythmic (23), conges-
tive heart failure (24)

Bisphosphonates -dronate Alendronate, pamidronate Osteoporosis (31)

Bronchodilators (adrenergic) -erol Albuterol, pirbuterol Bronchodilation (26)

Bronchodilators (xanthine derivatives) -phylline Theophylline, aminophylline Bronchodilation (26)

Calcium channel blockers -ipine Nifedipine, nicardipine Antihypertensive (21),

(dihydropyridine group) antianginal (22)

Cyclooxygenase type 2 -coxib Celecoxib Pain, inflammation (15)

(COX-2) inhibitors

Glucocorticoids -sone or -olone* Cortisone, dexamethasone, prednis- Anti-inflammatory (16, 29), immuno-
one, prednisolone, triamcinolone suppressants (37)

Histamine H2-receptor blockers -idine Cimetidine, ranitidine Gastric ulcers (27)

HIV protease inhibitors -avir Ritonavir, saquinavir HIV infection (34)

HMG-CoA reductase inhibitors (statins) -statin Pravastatin, simvastatin Hyperlipidemia (25)

Local anesthetics -caine Lidocaine, bupivicaine Local anesthetic (12),

antiarrhythmics (23)

Low molecular-weight heparins -parin Dalteparin, enoxaparin Anticoagulants (25)

Oral antidiabetics -amide Chlorpropamide, tolbutamide Antidiabetic (type II diabetes melli-

(sulfonylurea group) tus) (32)

Penicillin antibiotics -cillin Penicillin, ampicillin, amoxicillin Bacterial infections (33)

Proton pump inhibitors -prazole Omeprazole, lansoprazole Gastric ulcers (27)

Tetracycline antibiotics -cycline Tetracycline, doxycycline Bacterial infections (33)

Various other antibacterials -micin or -mycin† Streptomycin, gentamicin, Bacterial infections (33)

*Some anabolic steroids also end with -olone, e.g., nandrolone, oxymetholone (Chapter 30).
†Some antibiotics ending with “-mycin” or “rubicin” are used as antineoplastics (Chapter 36).
00Ciccone(p)-FM 2/6/07 4:25 PM Page i

Pharmacology in
4th Edition
00Ciccone(p)-FM 2/2/07 6:59 PM Page ii

Contemporary Perspectives in Rehabilitation

Steven L. Wolf, PT, PhD, FAPTA, Editor-in-Chief

Pharmacology in Rehabilitation, 4th Edition

Charles D. Ciccone, PT, PhD

Vestibular Rehabilitation, 3rd Edition

Susan J. Herdman, PT, PhD, FAPTA

Modalities for Therapeutic Intervention, 4th Edition

Susan L. Michlovitz, PT, PhD, CHT and Thomas P. Nolan, Jr., PT, MS, OCS

Fundamentals of Musculoskeletal Imaging, 2nd Edition

Lynn N. McKinnis, PT, OCS

Wound Healing: Alternatives in Management, 3rd Edition

Luther C. Kloth, PT, MS, CWS, FAPTA, and
Joseph M. McCulloch, PT, PhD, CWS, FAPTA

Evaluation and Treatment of the Shoulder:

An Integration of the Guide to Physical Therapist Practice
Brian J. Tovin, PT, MMSc, SCS, ATC, FAAOMPT and
Bruce H. Greenfield, PT, MMSc, OCS

Cardiopulmonary Rehabilitation: Basic Theory and Application, 3rd Edition

Frances J. Brannon, PhD, Margaret W. Foley, RN, MN,
Julie Ann Starr, PT, MS, CCS, and Lauren M. Saul, MSN, CCRN

For more information on each title in the Contemporary Perspectives in Rehabilitation

series, go to
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Pharmacology in
4th Edition

Charles D. Ciccone, PT, PhD

Department of Physical Therapy
School of Health Sciences
and Human Performance
Ithaca College
Ithaca, New York
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F. A. Davis Company
1915 Arch Street
Philadelphia, PA 19103

Copyright © 2007 by F. A. Davis Company

Copyright © 1990 and 1996 by F. A. Davis Company. All rights reserved. This book is protected by
copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any from or by
any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission
from the publisher.

Printed in the United States of America

Last digit indicates print number: 10 9 8 7 6 5 4 3 2 1

Publisher: Margaret Biblis

Acquisitions Editor/Developmental Editor: Melissa Duffield
Manager Art and Design: Carolyn O’Brien

As new scientific information becomes available through basic and clinical research, recommended
treatments and drug threrapies undergo changes. The author and publisher have done everything
possible to make this book accurate, up to date, and in accord with accepted standards at the time of
publication. The author, editors, and publisher are not responsible for errors or omissions or for
consequences from application of the book, and make no warranty, expressed or implied, in regard to the
contents of the book. Any practice described in this book should be applied by the reader in accordance
with professional standards of care used in regard to the unique circumstances that may apply in each
situation. The reader is advised always to check product information (package inserts) for changes and
new information regarding dose and contraindications before administering any drug. Caution is
especially urged when using new or infrequently ordered drugs.

Library of Congress Cataloging-in-Publication Data

Ciccone, Charles D., 1953–

Pharmacology in rehabilitation / Charles D. Ciccone. — 4th ed.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-0-8036-1377-5
ISBN-10: 0-8036-1377-6
1. Pharmacology. 2. Medical rehabilitation. I. Title.
[DNLM: 1. Drug Therapy. 2. Pharmacokinetics. 3. Pharmacology. 4. Rehabilitation.
WB 330 C568p 2007]
RM301.C515 2007

Authorization to photocopy items for internal or personal use, or the internal or personal use of specific
clients, is granted by F. A. Davis Company for users registered with the Copyright Clearance Center
(CCC) Transactional Reporting Service, provided that the fee of $.10 per copy is paid directly to CCC,
222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy
license by CCC, a separate system of payment has been arranged. The fee code for users of the
Transactional Reporting Service is: 8036–1377/07 0 ⫹ $.10
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Dedicated to Penny, Kate, and Alex for providing con-

stant faith, support, and inspiration.

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There are very peculiar ways in which one can mark patient responses to pharmacy. As one physical thera-
time. We often do so by observing the rate at which pist so astutely told me, her recognition that a patient
our siblings, children, or grandchildren grow, espe- was not responding to pain medication taken well
cially when we are not in daily contact, or by how we above the specified dosage, in the absence of any evi-
inevitably underestimate the length of time transpired dence for malingering behavior, resulted in the subse-
since we last encountered an old friend. In this con- quent detection and successful removal of a renal
text, it seems remarkable that over 13 years have tran- tumor. Third, as practitioners, the DPT or DOT now
spired since I first discussed with Chuck Ciccone the assumes a greater responsibility for keeping a contem-
prospects for a text on pharmacology for our Contem- porary knowledge base about the interface between
porary Perspectives in Rehabilitation. The realization treatment plan and concurrent synergies or exacerba-
that the first edition of Pharmacology in Rehabilitation tions that might result from single or multiple med-
appeared more than a decade ago is even more ications taken by the patient.
astounding. The basis for the genesis of such a book This collection of attributes can be best appreci-
was founded on the belief that rehabilitation spe- ated if the student is first informed and the clinician is
cialists received little formal training about drug educated about the most recent medications, their
interactions and how any single pharmacological pharmokinetics, and the interactions they have with
agent could impact either treatment plans or out- patients with specific diagnoses. Since the drug indus-
comes. Chuck took it upon himself to generate a text try is arguably one of the most dynamic corporate
that would address this educational and clinical short- structures in the world, changes in pharmacy occur at
coming. The result is very clear. Pharmacology in Reha- an alarmingly fast rate, one that will increase even
bilitation is the “gold standard” among all texts more dramatically as transplants and the sequelae
addressing this content for nonphysician rehabilita- resulting from genetic engineering (as two examples)
tion specialists. take on greater roles in medicine. Such rapid changes,
So why is it important to create a fourth edition then, call for contemporary and comprehensive
within one decade? Why is a more superficial com- updates in available information. Such updates must
pendium of information about drugs and their actions be presented in a manner that is compelling, yet easy
inadequate? The answer to these questions is directly to understand.
related to the rapidly emerging responsibilities incum- Inclusive in this perception is the absolute
bent upon rehabilitation specialists. During the past 5 requirement that the student or clinician be able
years, the advent of clinical doctoral programs in to relate to the text meaningfully. Toward this impor-
physical and occupational therapy has heralded a rapid tant goal, the 4th edition of Pharmacology in Rehabilita-
transformation in these educational arenas. Several tion is designed to address rehabilitation relevance
attributes now take on a meaning that previously in every clinical chapter as well as to present impor-
might have been underappreciated. First, the label of tant case histories to reinforce this relevance. New
“doctor” implies an expectation on the part of the con- materials on agents used in or even as complemen-
sumer that the practitioner is the penultimate expert tary and alternative medicines have been added.
on providing an analysis and treatment plan for Moreover, we have made efforts to add to the appeal
improving upon the pathology of any system’s move- of the book through the addition of colorization,
ment, whether muscle, joint, pulmonary, etc. Second, use of double columns, and encasing the text within
given the status associated with the professional label, a newly designed hard cover. These changes are in
there is an associated obligation on the part of the contradistinction to one standard that remains
practitioner to address all aspects of the patients’ signs immutable—Dr. Ciccone’s remarkable gift for tak-
and symptoms. This obligation requires that the clini- ing complex material and making it easy to under-
cian differentiate patient responses to treatment from stand.

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viii Foreword

For those clinicians who have in their possession The thought of having a reference text for reha-
early editions of this book, I invite you to compare bilitation specialists was considered by us to be a
your copy to the 4th edition as validation for the asser- unique concept 13 years ago. Today, many doctoral
tions made in this Foreword. We have not compro- programs include pharmacology as a separate course or
mised the comprehensive nature of this volume in as an important component in teaching the rationale
favor of a “simpler” approach to understanding for treatment approaches and their assessment. There
pharmacology. We believe that the topic, by its very is much gratification to be gained from recognizing
nature and from the implications inherent in its this transformation and in knowing that the content of
knowledge base, requires a comprehensive, yet user- this book contributes to the evolving maturation of our
friendly, delivery. This belief system remains unhin- educational programs and our clinical services.
dered in this latest edition; yet the problem-solving
and evidence-based nature of the content is preserved Steven L. Wolf, PT, PhD, FAPTA
and enhanced. Series Editor
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In one sense, pharmacology can be considered a “good drug applications in specific diseases and pathological
news, bad news” scenario. The good news is that conditions. Chapters that deal with specific diseases
exciting and innovative changes in drug therapy con- begin with background information on each system or
tinue to occur at lightning speed. The bad news is that disorder, followed by detailed descriptions of the
it is often difficult for health care practitioners to stay physiologic and pharmacologic actions of these drugs,
abreast of this rapidly changing field. Oftentimes, their primary beneficial and adverse effect, and how
drug therapies that were considered state-of-the-art drug therapy can impact physical rehabilitation. A new
only a few years ago are now outdated and replaced by chapter on complementary and alternative medica-
more contemporary treatments. tions (Chapter 38) has been added to this edition. This
Hence, the fourth edition of this text has been chapter complements the other chapters that deal with
revised extensively to reflect the science and practice more traditional and conventional medications. This
of pharmacology, with particular emphasis on how edition also has a new “look,” with many features
drug therapy impacts patients receiving physical reha- added to help students and clinicians access this infor-
bilitation. Efforts were made to use the peer-reviewed mation more easily.
literature to obtain the most recent information on Once again, I am pleased to present students and
pharmacotherapeutics. This information has become clinicians with a resource that might ultimately
incredibly accessible because of computerized data- improve their ability to provide therapeutic interven-
bases such as PubMed and resources such as the FDA tions. Pharmacology continues to expand both in
website. The volume of this information, however, is terms of the number of medications available to our
so extensive that I was often astounded by the number patients, and in our understanding of how drugs can
of articles on a given topic. It was certainly a challenge be used most effectively as part of a comprehensive
to condense this information into a meaningful format health care regimen. It is essential that we understand
for busy students and clinicians. Nonetheless, I believe the beneficial and adverse affects of medications com-
this edition is successful in presenting the most recent monly taken by our patients, and consider how we can
and pertinent details of pharmacotherapeutics and capitalize on the beneficial effects while dealing with
that it underscores the relevance of this topic to phys- drug side effects. I hope this book will continue to
ical therapy and occupational therapy. serve as a primary resource on this topic, and that
As in previous editions, basic pharmacology con- readers find this fourth edition interesting and useful.
cepts are addressed in the first section (Chapters 1
through 4), with subsequent chapters dealing with Charles D. Ciccone

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This edition is the culmination of the invaluable assis- Finally, Steve Wolf, editor of the CPR series, has
tance and input from some very talented people. In been a strong and consistent advocate for this book,
particular, I want to thank Barbara MacDermott and I thank him for his steadfast support and encour-
Costa, Linda D. Crane, John F. Decker, Mark Greve, agement over the years. I also want to thank the staff at
Sandra B. Levine, Donald L. Merrill, Grace Minerbo, F. A. Davis Company for their help and proficiency in
Peter Panus, and Jeffrey Rothman. I am deeply developing this text. In particular, Margaret Biblis and
indebted to these individuals for their suggestions on Melissa Duffield were instrumental in developing the
previous editions. Without their help, it is unlikely fourth edition of this text, and for implementing most
that the fourth edition of this text would have ever of the obvious changes in the design and presentation
become a reality. of this material. I cannot thank them enough for all
I would also like to thank Bonnie DeSombre, their insight and expertise, and I am sure their efforts
Fred Estabrook, and Cheryl Tarbell for their help in will be appreciated by everyone who uses this text.
preparing various tables and figures appearing in this

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Reviewer List

Susan Sullivan Glenney, PT, MS Ellen Wruble Hakim, PT, DScPT, MS, CWS
Former Assistant Professor Assistant Professor
Department of Physical Therapy Department of Physical Therapy and Rehabilitation
University of Hartford Science
West Hartford, Connecticut University of Maryland School of Medicine
Baltimore, Maryland
Gary Gorniak, PT, PhD
Director and Associate Professor Steven Raymond Tippett, PT, PhD, SCS, ATC
Physical Therapy Program Associate Professor
University of St. Augustine for Health Sciences Department of Physical Therapy and Health Science
St. Augustine, Florida Bradley University
Peoria, Illinois

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Drug Storage, 22
Section 1. General Principles of Storage Sites, 22
Pharmacology, 1 Adverse Consequences of Drug Storage, 23

Chapter 1. Basic Principles of Newer Techniques for Drug Delivery, 23

Controlled-Release Preparations, 23
Pharmacology, 3 Implanted Drug Delivery Systems, 23
Drug Nomenclature, 4 Targeting Drug Delivery to Specific Cells and
Tissues, 24
Substitution of Generic Drugs for Brand-Name
Products, 5
Chapter 3. Pharmacokinetics II: Drug
What Constitutes a Drug: Development and Elimination, 29
Approval of Therapeutic Agents, 5
Drug Approval Process, 5 Biotransformation, 29
Prescription Versus Over-the-Counter Cellular Mechanisms of Drug Biotransformation, 29
Medication, 7 Organs Responsible for Drug Biotransformation, 31
Controlled Substances, 8 Enzyme Induction, 31

Basic Concepts in Drug Therapy, 8 Drug Excretion, 31

Dose-Response Curves and Maximal Efficacy, 8 Drug Elimination Rates, 32
Potency, 9 Clearance, 33
Elements of Drug Safety, 10 Half-Life, 33
Quantal Dose-Response Curves and the Median Dosing Schedules and Plasma Concentration, 34
Effective Dose, 10
Median Toxic Dose, 10 Variations in Drug Response and Metabolism, 34
Therapeutic Index, 11
Chapter 4. Drug Receptors, 41
Chapter 2. Pharmacokinetics I: Receptors Located on the Cell’s Surface, 41
Drug Administration, Absorption, Surface Receptors Linked Directly to Ion Channels, 41
and Distribution, 13 Surface Receptors Linked Directly to Enzymes, 42
Surface Receptors Linked to Regulatory (G) Proteins:
Routes of Administration, 13
Role of the Second Messenger, 42
Enteral, 13
Parenteral, 15 Intracellular Receptors, 44
Transdermal, 17
Drug-Receptor Interactions, 44
Drug Absorption and Distribution:
Functional Aspects of Drug-Receptor
Bioavailability, 17
Interactions, 45
Membrane Structure and Function, 17
Drug Selectivity and Receptor Subtypes, 45
Movement Across Membrane Barriers, 18
Dose-Response, 46
Active Transport, 20
Classification of Drugs: Agonist Versus Antagonist, 46
Distribution of Drugs Within the Body, 21 Competitive Versus Noncompetitive Antagonists, 46
Factors Affecting Distribution, 21 Partial Agonists, 47
Volume of Distribution, 21 Mixed Agonist–Antagonists and Inverse Agonists, 48

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xvi Contents

Receptor Regulation, 48 Special Consideration of Sedative-Hypnotic and

Receptor Desensitization and Down-Regulation, 48 Antianxiety Agents in Rehabilitation, 73
Receptor Supersensitivity, 49
Case Study
Nonreceptor Drug Mechanisms, 50 Sedative-Hypnotic Drugs, 74

Chapter 7: Drugs Used to Treat

Section 2. Pharmacology of the Affective Disorders: Depression and
Central Nervous System, 53 Bipolar Syndrome, 77
Chapter 5. General Principles of Depression, 77
Central Nervous System Clinical Picture, 77
Pharmacology, 55 Pathophysiology of Depression, 78
Antidepressant Drugs, 79
CNS Organization, 55
Use of Antidepressants in Chronic Pain, 86
Cerebrum, 55
Basal Ganglia, 55 Treatment of Bipolar Disorder: Antimanic
Diencephalon, 56 Drugs, 86
Mesencephalon and Brainstem, 56 Bipolar Disorder, 86
Cerebellum, 56 Lithium, 86
Limbic System, 57 Other Drugs Used in Bipolar Disorder, 87
Spinal Cord, 57
Special Concerns in Rehabilitation
The Blood-Brain Barrier, 57 Patients, 88

CNS Neurotransmitters, 57 Case Study

Acetylcholine, 58 Antidepressant Drugs, 89
Monoamines, 59
Amino Acids, 59 Chapter 8. Antipsychotic Drugs, 93
Peptides, 59
Other Transmitters, 59 Schizophrenia, 93
CNS Drugs: General Mechanisms, 60 Neurotransmitter Changes in Schizophrenia, 94
Antipsychotic Mechanism of Action, 94
Chapter 6. Sedative-Hypnotic and
Antianxiety Agents, 65 Antipsychotic Medications, 95
Traditional Antipsychotics, 95
Sedative-Hypnotic Agents, 65 Atypical Antipsychotics, 95
Benzodiazepines, 65
Pharmacokinetics, 96
Nonbenzodiazepines, 68
Other Uses of Antipsychotics, 98
Pharmacokinetics, 69
Problems and Adverse Effects, 98
Problems and Adverse Effects, 69 Extrapyramidal Symptoms, 98
Residual Effects, 69
Tolerance and Physical Dependence, 69 Nonmotor Effects, 100
Other Side Effects, 70 Sedation, 100
Anticholinergic Effects, 100
Antianxiety Drugs, 70 Other Side Effects, 100
Benzodiazepines, 70
Special Concerns in Rehabilitation
Buspirone, 71
Patients, 101
Use of Antidepressants in Anxiety, 72
Other Antianxiety Drugs, 72 Case Study
Problems and Adverse Effects, 72 Antipsychotic Drugs, 101
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Contents xvii

Chapter 9. Antiepileptic Drugs, 105 Chapter 11. General Anesthetics, 135

General Anesthesia: Requirements, 135
Classification of Epileptic Seizures, 105
Stages of General Anesthesia, 135
Rationale for Drug Treatment, 107
General Anesthetics: Classification and Use
Drugs Used to Treat Epilepsy, 107
According to Route of Administration, 136
Barbiturates, 107
Benzodiazepines, 107 General Anesthetics: Specific Agents, 136
Hydantoins, 108 Inhalation Anesthetics, 136
Iminostilbenes, 109 Intravenous Anesthetics, 136
Succinimides, 109
Pharmacokinetics, 139
Valproic Acid, 109
Newer “Second-Generation” Agents, 110 Mechanisms of Action, 139
Selection of a Specific Antiepileptic Adjuvants in General Anesthesia, 141
Agent, 111 Preoperative Medications, 141
Single-Drug Therapy Versus Drug Neuromuscular Blockers, 141
Combinations in Epilepsy, 113 Special Concerns in Rehabilitation, 145
Pharmacokinetics, 113 Case Study
Special Precautions During Pregnancy, 113 General Anesthetics, 145

Treatment of Status Epilepticus, 113 Chapter 12. Local Anesthetics, 149

Withdrawal of Antiseizure Medications, 114 Types of Local Anesthetics, 149
Special Concerns in Rehabilitation Pharmacokinetics, 150
Patients, 114
Clinical Use of Local Anesthetics, 150
Case Study
Antiepileptic Drugs, 115 Mechanism of Action, 154
Differential Nerve Block, 155
Chapter 10. Pharmacological Systemic Effects of Local Anesthetics, 156
Management of Parkinson
Disease, 119 Significance in Rehabilitation, 157

Pathophysiology of Parkinson Disease, 119 Case Study

Local Anesthetics, 157
Etiology of Parkinson Disease: Genetic and
Environmental Factors, 120
Therapeutic Agents in Parkinsonism, 121
Section 3. Drugs Affecting Skeletal
Levodopa, 122 Muscle, 161
Other Drugs Used to Treat Parkinson Chapter 13. Skeletal Muscle
Disease, 126
Relaxants, 163
Clinical Course of Parkinson Disease: When to
Use Specific Drugs, 129 Increased Muscle Tone: Spasticity Versus Muscle
Spasms, 163
Neurosurgical Interventions in Parkinson
Specific Agents Used to Produce Skeletal
Disease, 129
Muscle Relaxation, 164
Special Considerations for Rehabilitation, 130
Agents Used to Treat Muscle Spasms, 164
Case Study Diazepam, 164
Anti-Parkinson Drugs, 131 Polysynaptic Inhibitors, 165
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xviii Contents

Agents Used to Treat Spasticity, 166 Chapter 15. Nonsteroidal

Baclofen, 167 Anti-Inflammatory Drugs, 199
Intrathecal Baclofen, 168
Dantrolene Sodium, 169 Aspirin and Other NSAIDs: General Aspects, 199
Diazepam, 170 Prostaglandins, Thromboxanes, and
Gabapentin, 170 Leukotrienes, 200
Tizanidine, 171 Eicosanoid Biosynthesis, 200
Use of Botulinum Toxin as a Muscle Relaxant, 171 Role of Eicosanoids in Health and Disease, 201

Pharmacokinetics, 174 Mechanism of NSAID Action: Inhibition

of Prostaglandin and Thromboxane
Special Concerns in Rehabilitation Patients, 174 Synthesis, 202
Case Study Aspirin: Prototypical NSAID, 203
Muscle Relaxants, 175
Clinical Applications of Aspirinlike Drugs, 203
Treatment of Pain and Inflammation, 203
Section 4. Drugs Used to Treat Treatment of Fever, 204
Pain and Inflammation, 181 Treatment of Vascular Disorders, 204
Prevention of Cancer, 204
Chapter 14. Opioid Analgesics, 183
Problems and Adverse Effects of Aspirinlike
Source of Opioid Analgesics, 183 Drugs, 204
Endogenous Opioid Peptides and Opioid Gastrointestinal Problems, 204
Receptors, 184 Other Side Effects, 205
Endogenous Opioids, 184 Comparison of Aspirin with Other NSAIDs, 206
Opioid Receptors, 184
COX-2 Selective Drugs, 209
Classification of Specific Agents, 185 COX-2 Drugs and the Risk of Heart Attack and
Pharmacokinetics, 187 Stroke, 210

Mechanism of Action, 188 Acetaminophen, 210

Effect of Opioids on the CNS, 188 Pharmacokinetics of NSAIDs and
Effect of Opioids on CNS Synapses, 188 Acetaminophen, 211
Peripheral Effects of Opioids, 190
Clinical Applications, 190 Special Concerns in Rehabilitation Patients, 212
Treatment of Pain, 190 Case Study
Use of Opioids in Patient-Controlled Analgesia, 191 Nonsteroidal Anti-Inflammatory Drugs, 212
Other Opioid Uses, 191
Problems and Adverse Effects, 192 Chapter 16. Pharmacologic
Management of Rheumatoid Arthritis
Concepts of Addiction, Tolerance, and Physical
Dependence, 192
and Osteoarthritis, 217
Tolerance, 192 Rheumatoid Arthritis, 217
Physical Dependence, 193 Immune Basis for Rheumatoid Arthritis, 218
Tolerance and Dependence During Therapeutic Opioid Overview of Drug Therapy in Rheumatoid
Use, 193 Arthritis, 219
Pharmacological Treatment of Opioid Addiction, 193 Nonsteroidal Anti-Inflammatory Drugs, 219
Glucocorticoids, 221
Special Concerns in Rehabilitation
Disease-Modifying Antirheumatic Drugs, 222
Patients, 194
DMARD Combinations Used in Rheumatoid
Case Study Arthritis, 228
Opioid Analgesics, 195 Dietary Implications for Rheumatoid Arthritis, 229
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Contents xix

Osteoarthritis, 229 Functional Aspects of the Sympathetic and Parasympa-

Acetaminophen and NSAIDs, 230 thetic Divisions, 254
Viscosupplementation, 230
Function of the Adrenal Medulla, 255
Glucosamine and Chondroitin Sulfate, 230
Special Concerns for Antiarthritic Drug Therapy Autonomic Integration and Control, 256
in Rehabilitation Patients, 231 Autonomic Neurotransmitters, 257
Case Study Acetylcholine and Norepinephrine, 257
Rheumatoid Arthritis, 232 Other Autonomic Neurotransmitters, 257

Chapter 17. Patient-Controlled Autonomic Receptors, 258

Analgesia, 237 Cholinergic Receptors, 258
Adrenergic Receptors, 259
Pharmacokinetic Basis for PCA, 237
Pharmacologic Significance of Autonomic
PCA Dosing Strategies and Parameters, 238
Receptors, 261
Loading Dose, 238
Demand Dose, 238
Lockout Interval, 238
Chapter 19. Cholinergic Drugs, 263
1- and 4-Hour Limits, 238 Cholinergic Receptors, 263
Background Infusion Rate, 239
Successful Versus Total Demands, 239 Cholinergic Stimulants, 264
Direct-Acting Cholinergic Stimulants, 264
Types of Analgesics Used for PCA, 239 Indirect-Acting Cholinergic Stimulants, 264
Administration Routes During PCA, 240 Clinical Applications of Cholinergic Stimulants, 266
Intravenous PCA, 240 Adverse Effects of Cholinergic Stimulants, 267
Epidural PCA, 241
Transdermal PCA, 241
Anticholinergic Drugs, 268
Source and Mechanism of Action of Antimuscarinic
Regional PCA, 242
Anticholinergic Drugs, 268
PCA Pumps, 242 Clinical Applications of Antimuscarinic Drugs, 268
Comparison of PCA to Traditional Methods of Side Effects of Anticholinergic Drugs, 271
Analgesic Administration, 243
Problems and Side Effects of PCA, 245
Chapter 20. Adrenergic Drugs, 273
Pharmacologic Side Effects, 245 Adrenergic Receptor Subclassifications, 273
Problems with PCA Delivery, 245
Adrenergic Agonists, 274
Special Concerns for PCA in Rehabilitation Alpha Agonists, 275
Patients, 246 Beta Agonists, 276
Case Study Drugs with Mixed Alpha- and Beta-Agonist
Patient-Controlled Analgesia, 247 Activity, 278
Adrenergic Antagonists, 279
Alpha Antagonists, 279
Section 5. Autonomic and Beta Antagonists, 281
Cardiovascular Pharmacology, 251 Other Drugs That Inhibit Adrenergic Neurons, 284
Chapter 18. Introduction to Chapter 21. Antihypertensive
Autonomic Pharmacology, 253 Drugs, 287
Anatomy of the Autonomic Nervous System:
Normal Control of Blood Pressure, 288
Sympathetic and Parasympathetic Divisions, 253
Preganglionic and Postganglionic Neurons, 253 Pathogenesis of Hypertension, 288
Sympathetic Organization, 254 Essential Versus Secondary Hypertension, 288
Parasympathetic Organization, 254 Possible Mechanisms in Essential Hypertension, 288
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Drug Therapy, 289 Specific Agents, 311

Adverse Side Effects, 312
Diuretics, 290
Mechanism of Action and Rationale for Use, 290 Use of Anticoagulants in Angina Pectoris, 312
Classification of Diuretics, 291 Treatment of Specific Types of Angina
Adverse Effects of Diuretics, 292 Pectoris, 313
Sympatholytic Drugs, 292 Stable Angina, 314
Beta Blockers, 292 Variant Angina (Prinzmetal Ischemia), 314
Alpha Blockers, 293 Unstable Angina, 315
Presynaptic Adrenergic Inhibitors, 294 Nonpharmacologic Management of Angina
Centrally Acting Agents, 295 Pectoris, 315
Ganglionic Blockers, 295
Special Concerns in Rehabilitation Patients, 316
Vasodilators, 296
Mechanism of Action and Rationale for Use, 296 Case Study
Specific Agents, 296 Antianginal Drugs, 316
Adverse Effects, 297
Inhibition of the Renin-Angiotensin Chapter 23. Treatment of Cardiac
System, 297 Arrhythmias, 321
Mechanism of Action and Rationale for Cardiac Electrophysiology, 321
Use, 297 Cardiac Action Potentials, 321
Specific Agents, 298 Normal Cardiac Rhythm, 322
Adverse Effects, 298 Normal Conduction of the Cardiac Action
Calcium Channel Blockers, 299 Potential, 322
Specific Agents, 299 Mechanisms of Cardiac Arrhythmias, 323
Adverse Effects, 299
Types of Arrhythmias, 324
Stepped-Care Approach to Hypertension, 300
Classification of Antiarrhythmic Drugs, 324
Nonpharmacologic Treatment of Class I: Sodium Channel Blockers, 324
Hypertension, 300 Class II: Beta Blockers, 326
Special Concerns in Rehabilitation Class III. Drugs That Prolong Repolarization, 326
Patients, 301 Class IV: Calcium Channel Blockers, 327

Case Study Other Drugs Used to Treat Arrhythmias, 327

Hypertension, 301 Nonpharmacologic Treatment of
Arrhythmias, 327
Chapter 22. Treatment of Angina
Special Concerns in Rehabilitation Patients, 328
Pectoris, 307
Case Study
Drugs Used to Treat Angina Pectoris, 308 Antiarrhythmic Drugs, 328
Organic Nitrates, 308
Mechanism of Action and Rationale for Use, 308 Chapter 24. Treatment of Congestive
Specific Agents, 309
Adverse Side Effects of Nitrates, 310
Heart Failure, 331
Pathophysiology of Congestive Heart Failure, 331
Beta-Adrenergic Blockers, 310
Vicious Cycle of Heart Failure, 331
Mechanism of Action and Rationale for Use, 310
Congestion in Left and Right Heart Failure, 333
Specific Agents, 310
Adverse Side Effects, 311 Pharmacotherapy, 334
Calcium Channel Blockers, 311 Drugs That Increase Myocardial Contraction
Mechanism of Action and Rationale for Use, 311 Force (Positive Inotropic Agents), 334
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Digitalis, 334 Antihistamines, 370

Other Positive Inotropic Agents, 338 Mucolytics and Expectorants, 373
Agents That Decrease Cardiac Workload, 339 Drugs Used to Maintain Airway Patency in
Drugs Affecting the Renin-Angiotensin System, 339 Obstructive Pulmonary Disease, 373
Beta Blockers, 340 Beta-Adrenergic Agonists, 373
Diuretics, 341 Xanthine Derivatives, 376
Vasodilators, 342 Anticholinergic Drugs, 377
Glucocorticoids, 378
Summary of Drug Therapy, 342
Cromones, 379
Special Concerns in Rehabilitation Patients, 343 Leukotriene Inhibitors, 380
Case Study Treatment of Bronchial Asthma, 380
Congestive Heart Failure, 343 Pathophysiology of Bronchial Asthma, 380
Long-Term Management of Asthma, 381
Chapter 25. Treatment of Coagulation
Treatment of Reversible Bronchospasm in
Disorders and Hyperlipidemia, 347 COPD, 382
Normal Mechanism of Blood Coagulation, 347 Treatment of Respiratory Problems in Cystic
Clot Formation, 348
Fibrosis, 382
Clot Breakdown, 349
Special Concerns in Rehabilitation Patients, 383
Drugs Used to Treat Overactive Clotting, 349
Anticoagulants, 349 Case Study
Antithrombotic Drugs, 352 Respiratory Drugs, 384
Thrombolytic Drugs, 354
Treatment of Clotting Deficiencies, 356 Chapter 27. Gastrointestinal
Hemophilia, 356 Drugs, 389
Deficiencies of Vitamin K-Dependent Clotting
Factors, 357 Drugs Used to Control Gastric Acidity and
Antifibrinolytics, 357 Secretion, 389
Antacids, 389
Agents Used to Treat Hyperlipidemia, 357 H2 Receptor Blockers, 390
HMG-CoA Reductase Inhibitors (Statins), 358 Proton Pump Inhibitors, 391
Fibric Acids, 359 Treatment of H. Pylori Infection in Gastric Ulcer
Other Lipid-Lowering Agents, 360 Disease, 392
Adverse Effects of Antihyperlipidemia Agents, 360 Other Agents Used to Control and Treat Gastric
Special Concerns in Rehabilitation Ulcers, 393
Patients, 361 Antidiarrheal Agents, 393
Opioid Derivatives, 394
Case Study
Adsorbents, 395
Clotting Disorders, 362
Bismuth Salicylate, 395
Miscellaneous Agents Used to Treat Diarrhea, 395
Section 6. Respiratory and Laxatives and Cathartics, 395
Gastrointestinal Pharmacology, Rationale for Use, 395
367 Specific Agents and Mechanism of Action, 396
Adverse Effects, 397
Chapter 26. Respiratory Drugs, 369 Miscellaneous Gastrointestinal Drugs 397
Drugs Used to Treat Respiratory Tract Irritation Digestants, 397
and Control Respiratory Secretions, 369 Emetics, 397
Antitussives, 369 Antiemetics, 397
Decongestants, 370 Cholelitholytic Agents, 397
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Special Concerns in Rehabilitation Patients, 398 Mineralocorticoids, 426

Regulation of Mineralocorticoid Secretion, 426
Case Study
Mechanism of Action and Physiologic Effects of
Gastrointestinal Drugs, 398
Mineralocorticoids, 426
Therapeutic Use of Mineralocorticoid Drugs, 428
Adverse Effects of Mineralocorticoid Agonists, 428
Section 7. Endocrine Mineralocorticoid Antagonists, 428
Pharmacology, 401
Special Concerns of Adrenal Steroid Use in
Chapter 28. Introduction to Endocrine Rehabilitation Patients, 429
Pharmacology, 403 Case Study
Primary Endocrine Glands and Their Hormones, Adrenocorticosteroids, 430
Hypothalamus and Pituitary Gland, 403 Chapter 30. Male and Female
Thyroid Gland, 405 Hormones, 435
Parathyroid Gland, 406
Androgens, 435
Pancreas, 406
Source and Regulation of Androgen Synthesis, 435
Adrenal Gland, 406
Physiologic Effects of Androgens, 437
Gonads, 407
Pharmacologic Use of Androgens, 437
Endocrine Physiology and Pharmacology, 407 Clinical Use of Androgens, 437
Hormone Chemistry, 407 Specific Agents, 438
Synthesis and Release of Hormones, 407 Adverse Effects of Clinical Androgen Use, 439
Feedback Control Mechanisms in Endocrine Antiandrogens, 440
Function, 408
Hormone Transport, 408 Androgen Abuse, 440
Hormone Effects on the Target Cell, 409 Nature of Androgen Abuse, 440
Effects of Androgens on Athletic Performance, 442
Clinical Use of Endocrine Drugs, 411 Adverse Effects of Androgen Abuse, 442
Chapter 29. Adrenocorticosteroids, Estrogen and Progesterone, 443
415 Effects of Estrogen and Progesterone on Sexual
Maturation, 443
Steroid Synthesis, 415 Regulation and Effects of Hormonal Synthesis During
the Menstrual Cycle, 443
Glucocorticoids, 417
Role of Glucocorticoids in Normal Function, 417 Female Hormones in Pregnancy and Parturition, 445
Mechanism of Action of Glucocorticoids, 417 Pharmacologic Use of Estrogen and
Physiologic Effects of Glucocorticoids, 418 Progesterone, 445
Therapeutic Glucocorticoid Agents, 421 Conditions Treated with Estrogen and Progesterone, 445
Specific Agents, 446
Clinical Uses of Glucocorticoids, 421 Adverse Effects of Estrogen and Progesterone, 447
Glucocorticoid Use in Endocrine Conditions, 421 Selective Estrogen Receptor Modulators, 448
Use in Nonendocrine Conditions, 421 Antiestrogens, 449
Adverse Effects of Glucocorticoids, 423 Antiprogestins, 449
Adrenocortical Suppression, 423 Hormonal Contraceptives, 450
Drug-Induced Cushing Syndrome, 423 Types of Contraceptive Preparations, 450
Breakdown of Supporting Tissues, 425 Mechanism of Contraceptive Action, 452
Other Adverse Effects, 425 Adverse Effects of Hormonal Contraceptives, 452
Drugs That Inhibit Adrenocortical Hormone Case Study
Biosynthesis, 426 Male and Female Hormones, 453
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Special Concerns of Sex Hormone Pharmacology Use of Insulin in Diabetes Mellitus, 483
in Rehabilitation Patients 454 Therapeutic Effects and Rationale for Use, 483
Insulin Preparations, 483
Chapter 31. Thyroid and Parathyroid Administration of Insulin, 485
Drugs: Agents Affecting Bone Intensive Insulin Therapy, 485
Mineralization, 459 Adverse Effects of Insulin Therapy, 486

Function of the Thyroid Gland, 459 Oral Antidiabetic Drugs, 486

Synthesis of Thyroid Hormones, 459 Sulfonylureas, 487
Regulation of Thyroid Hormone Release, 461 Other Orally Active Drugs, 488
Physiologic Effects of Thyroid Hormones, 461 Other Drugs Used in the Management of
Mechanism of Action of Thyroid Hormones, 461 Diabetes Mellitus, 488
Treatment of Thyroid Disorders 462 Glucagon, 488
Hyperthyroidism, 462 Glucagon-like Peptide 1, 488
Hypothyroidism, 463 Immunosuppressants, 489
Aldose Reductase Inhibitors, 489
Function of the Parathyroid Glands, 464
Parathyroid Hormone, 465 Nonpharmacologic Intervention in Diabetes
Mellitus, 489
Regulation of Bone Mineral Homeostasis, 465 Dietary Management and Weight Reduction, 489
Pharmacologic Control of Bone Mineral Exercise, 490
Homeostasis, 466 Tissue Transplants and Gene Therapy, 490
Calcium Supplements, 467
Significance of Diabetes Mellitus in
Vitamin D, 469
Rehabilitation, 490
Bisphosphonates, 469
Calcitonin, 469 Case Study
Estrogen Therapy, 470 Diabetes Mellitus, 491
Other Agents That Promote Bone Mineral
Content, 470
Special Concerns in Rehabilitation Section 8. Chemotherapy of
Patients, 471 Infectious and Neoplastic
Case Study Diseases, 497
Agents Affecting Bone Mineral Metabolism, 471
Chapter 33. Treatment of Infections I:
Antibacterial Drugs, 499
Chapter 32. Pancreatic Hormones
and the Treatment of Diabetes Bacteria: Basic Concepts, 499
Bacterial Structure and Function, 499
Mellitus, 477
Pathogenic Effects of Bacteria, 500
Structure and Function of the Endocrine Bacterial Nomenclature and Classification, 500
Pancreas, 477
Treatment of Bacterial Infections: Basic
Insulin, 477 Principles, 500
Cellular Mechanism of Insulin Action, 478 Spectrum of Antibacterial Activity, 500
Bactericidal Versus Bacteriostatic Activity, 500
Glucagon, 479
Basic Mechanisms of Antibacterial Drugs, 501
Control of Insulin and Glucagon Release, 480
Inhibition of Bacterial Cell Wall Synthesis and
Diabetes Mellitus, 480 Function, 501
Type 1 Diabetes, 481 Inhibition of Bacterial Protein Synthesis, 502
Type 2 Diabetes, 481 Inhibition of Bacterial DNA/RNA Synthesis and
Effects and Complications of Diabetes Mellitus, 482 Function, 502
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xxiv Contents

Specific Antibacterial Agents 503 Specific Antiviral Drugs, 525

Acyclovir and Valacyclovir, 527
Antibacterial Drugs That Inhibit Bacterial Cell
Amantadine and Rimantadine, 527
Wall Synthesis and Function 503
Cidofovir, 528
Penicillins, 503
Docosanol, 528
Cephalosporins, 505
Enfuvirtide, 528
Other Agents That Inhibit Bacterial Cell Wall
Famciclovir and Penciclovir, 528
Synthesis, 505
Fomivirsen, 529
Use of Beta-Lactamase Inhibitors, 506
Foscarnet, 529
Drugs That Inhibit Bacterial Protein Synthesis Ganciclovir and Valganciclovir, 529
507 Imiquimod, 529
Aminoglycosides, 507 Trifluridine, 530
Erythromycin and Other Macrolides, 508 Oseltamivir and Zanamivir, 530
Tetracyclines, 508 Protease Inhibitors, 530
Other Agents That Inhibit Bacterial Protein Reverse Transcriptase Inhibitors, 531
Synthesis, 509 Ribavirin, 532
Vidarabine, 533
Drugs That Inhibit Bacterial DNA/RNA Synthesis
and Function, 510 Viral Resistance, 533
Aminosalicylic Acid, 510 Interferons, 533
Clofazimine, 510 Synthesis and Cellular Effects of Interferons, 534
Dapsone, 511 Pharmacologic Applications of Interferons, 535
Ethambutol, 511 Adverse Effects of Interferons, 535
Fluoroquinolones, 511
Metronidazole, 511 Control of Viral Infection with Vaccines, 535
Mupirocin, 512 HIV and the Treatment of AIDS, 536
Rifampin, 512 Inhibition of HIV Proliferation in Infected
Sulfonamides, 512 Individuals, 537
Trimethoprim, 513 Anti-HIV Drug Combinations: Use of Highly Active
Other Antibacterial Drugs, 513 Antiretroviral Therapy, 537
Capreomycin, 513 HIV Vaccines, 538
Daptomycin, 513 Management of Opportunistic Infections, 539
Isoniazid, 513 Relevance of Antiviral Chemotherapy in
Methenamine, 513 Rehabilitation Patients, 540
Nitrofurantoin, 513
Pyrazinamide, 514 Case Study
Antiviral Drugs, 541
Clinical Use of Antibacterial Drugs: Relationship
to Specific Bacterial Infections, 514 Chapter 35. Treatment of Infections
Resistance to Antibacterial Drugs, 514 III: Antifungal and Antiparasitic
Special Concerns in Rehabilitation Patients, 518 Drugs, 545
Case Study Antifungal Agents, 545
Antibacterial Drugs, 519 Systemic Antifungal Agents, 546
Topical Antifungal Agents, 550
Chapter 34. Treatment of Infections Antiprotozoal Agents, 551
II: Antiviral Drugs, 523 Antimalarial Agents, 551
Drugs Used to Treat Protozoal Infections in the
Viral Structure and Function, 523
Intestines and Other Tissues, 555
Classification of Viruses, 523
Other Antiprotozoal Drugs, 557
Characteristics of Viruses, 523
Viral Replication, 524 Anthelmintics, 557
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Contents xxv

Albendazole, 557 Chapter 37. Immunomodulating

Diethylcarbamazine, 558 Agents, 591
Ivermectin, 558
Mebendazole, 559 Overview of the Immune Response, 591
Niclosamide, 559 Pharmacologic Suppression of the Immune
Oxamniquine, 559 Response, 593
Piperazine Citrate, 559
Praziquantel, 559 Specific Immunosuppresive Agents, 593
Pyrantel Pamoate, 559 Azathioprine, 593
Thiabendazole, 559 Cyclophosphamide, 595
Cyclosporine, 595
Significance of Antifungal and Antiparasitic Glucocorticoids, 596
Drugs in Rehabilitation, 560 Methotrexate, 596
Case Study Mycophenolate Mofetil, 597
Antifungal Drugs, 560 Sulfasalazine, 597
Sirolimus, 597
Tacrolimus, 598
Chapter 36. Cancer Other Methods of Immunosuppression, 598
Chemotherapy, 565
Immunostimulants, 599
General Principles, 565 Bacille Calmette-Guérin, 600
Cytotoxic Strategy, 565 Immune Globulin, 600
Cell-Cycle–Specific Versus Cell-Cycle–Nonspecific Levamisole, 600
Drugs, 566
Concepts of Growth Fraction and Total Cell Other Immunomodulators, 600
Kill, 566 Significance of Immunomodulating Agents in
Prevalence and Management of Adverse Effects, 566 Rehabilitation, 601
Specific Drugs, 568 Case Study
Alkylating Agents, 568 Immunomodulating Agents, 601
Antimetabolites, 569
Antibiotics, 569
Plant Alkaloids, 569 Chapter 38. Complementary and
Hormones, 573 Alternative Medications, 605
Biologic Response Modifiers, 577 Unique Aspects of CAMs, 605
Heavy Metal Compounds, 579 Misconceptions about CAM Safety, 605
Aspirin and Other NSAIDs, 580 Failure to Report CAM Use, 606
Tyrosine Kinase Inhibitors, 580 Lack of Standards for Quality and Purity of CAMs, 606
Miscellaneous Agents, 580 Delayed Use of Conventional Medications, 606
Combination Chemotherapy, 582 Potential Adverse Effects of CAMs, 606
Use of Anticancer Drugs with Other Specific CAMs, 607
Treatments, 582 Bee Venom, 607
Success of Anticancer Drugs, 583 Echinacea, 607
Garlic, 607
Resistance to Cancer Chemotherapy Ginger, 609
Drugs, 584 Ginkgo biloba, 609
Future Perspectives, 585 Ginseng, 609
Glucosamine and Chondroitin, 609
Implications of Cancer Chemotherapy in
Kava, 609
Rehabilitation Patients, 586
Melatonin, 610
Case Study Saw Palmetto, 610
Cancer Chemotherapy, 586 St. John’s Wort, 610
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Valerian, 610 Appendix A: Drugs Administered by

Iontophoresis and Phonophoresis, 619
Vitamins and Minerals, 611
Vitamins, 611 Appendix B: Use of the Physicians’ Desk
Minerals, 614 Reference, 621
Special Concerns in Rehabilitation Patients, 614 Appendix C: Drugs of Abuse, 623
Case Study Glossary, 625
Complementary and Alternative Medications, 615 Index, 633
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General Principles
of Pharmacology
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Chapter 1
Basic Principles
of Pharmacology

Pharmacology is the study of drugs. In its broadest def- may improve the therapy session dramatically. This
inition, a drug can be described as “any substance that, may be true for drugs that decrease pain (analgesics) or
when taken into a living organism, may modify one or improve the patient’s motor skills (anti-Parkinson
more of its functions.”28 In this sense, a drug includes drugs). Conversely, some therapy sessions that require
any substance that alters physiologic function in the the patient’s active participation may be rendered use-
organism, regardless of whether the effect is beneficial less if scheduled when medications such as sedatives
or harmful. In terms of clinical pharmacology, it has reach their peak effect. Also, any adverse responses
traditionally been the beneficial or therapeutic effects occurring due to direct interaction between the thera-
that have been of special interest. Throughout history, py treatment and certain medications may be avoided
certain naturally occurring chemicals have been used or controlled by understanding a drug’s pharmacolog-
to relieve pain or treat disease in humans. Within the ic aspects. For example, a patient who is taking a peri-
past century, the use of natural, semisynthetic, and syn- pheral vasodilator may experience a profound decrease
thetic chemical agents has expanded to the point where in blood pressure when he or she is placed in a hot
many diseases can be prevented or cured, and the gen- whirlpool. By understanding the implications of such
eral health and well-being of many individuals has dra- an interaction, the therapist can be especially alert for
matically improved through therapeutic drug use. any detrimental effects on the patient, or they may
Because of the extensive clinical use of therapeu- institute a different therapy treatment for them.
tic medications, members of the medical community In order to help the reader have a more focused
must have some knowledge of the basic types of drugs approach to the study of drugs, pharmacology is often
and the mechanisms of their actions. Although this has divided into several areas of interest (Fig. 1–1). Phar-
always been true for individuals who prescribe and macotherapeutics is the area of pharmacology that
administer drugs (i.e., physicians and nurses), it is now refers to the use of specific drugs to prevent, treat, or
recognized that members of other health-related pro- diagnose a disease. For the purposes of this text, the
fessions must have a fundamental knowledge of phar- effects of drugs on humans will be of primary concern,
macology. with animal pharmacology mentioned only in refer-
An understanding of basic drug mechanisms can ence to drug testing and research in animals.
help practitioners such as physical therapists, occupa- When drugs are used therapeutically in humans,
tional therapists, and other rehabilitation specialists the way that the body interacts with the drug and what
better understand a patient’s response to the drug. In specific effect it has on an individual must be known.
addition, the knowledge of how certain rehabilitative Consequently, pharmacotherapeutics is divided into
procedures may interact with medications is helpful in two functional areas: pharmacokinetics and pharma-
getting an optimal response in the patient’s drug and codynamics (see Fig. 1–1). Pharmacokinetics is the
therapy treatment. For instance, scheduling the patient study of how the body deals with the drug in terms of
for therapy when certain drugs reach their peak effect the way it is absorbed, distributed, and eliminated.

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4 SECTION 1 General Principles of Pharmacology


Pharmacotherapeutics Toxicology

Pharmacokinetics Pharmacodynamics

Absorption Distribution Elimination Systemic Effects Cellular Effects

FIGURE 1–1 ▼ Areas of study within pharmacology.

Pharmacodynamics is the analysis of what the drug Pharmacy deals with the preparation and dis-
does to the body, including the mechanism by which pensing of medications. Although pharmacy is also
the drug exerts its effect. In this text, the basic princi- frequently considered a subdivision of pharmacology,
ples of pharmacokinetics will be outlined in Chapters this area has evolved into a distinct professional disci-
2 and 3, and the pharmacodynamics and pharmacoki- pline. Care must be taken not to use the terms “phar-
netics of specific drugs will be discussed in their macy” and “pharmacology” interchangeably, because
respective chapters. these are quite different areas of study.
Toxicology is the study of the harmful effects of
chemicals. Although it can be viewed as a subdivision
of pharmacology, toxicology has evolved into a sepa-
rate area of study because of the scope of all the thera-
Drug Nomenclature
peutic agents’ adverse effects as well as environmental One of the most potentially confusing aspects of phar-
toxins and poisons. However, because virtually every macology is the variety of names given to different
medication can produce adverse effects, a discussion of drugs or even to the same compound. Students of
toxicology must be included in pharmacotherapeutics. pharmacology, as well as clinicians, are often faced with
For the purposes of this text, discussions of drug toxi- myriad terms representing the same drug.14,17 Many
city are limited to the unwanted effects that occur problems in drug terminology arise from the fact that
when therapeutic drugs reach excessively high (toxic) each drug can be identified according to its chemical,
levels. The toxic side effects of individual drugs are generic, or trade name12 (Table 1–1). Chemical names
covered in the chapters describing the therapeutic refer to the specific compound’s structure and are usu-
effects of that drug. ally fairly long and cumbersome. The generic name


Chemical Generic (Nonproprietary) (Proprietary)
N-Acetyl-p-aminophenol Acetaminophen Tylenol, Panadol, many others

3,4-Dihydroxyphenyl-L-alanine Levodopa Larodopa

5,5-Phenylethylbarbituric acid Phenobarbital Luminal, Eskabarb

7-Chloro-1,3-dihydro-1-methyl- Diazepam Valium

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Chapter 1 Basic Principles of Pharmacology 5

(also known as the “official” or “nonproprietary” profile (drug absorption, plasma levels, and so forth),
name) tends to be somewhat shorter and is often and the same therapeutic effects as the brand-name
derived from the chemical name. A trade name (also drug.3 If such testing is done, the two drugs are said to
known as the brand name) is assigned to the compound be “bioequivalent.”7
by the pharmaceutical company and may or may not Unless bioequivalence is established, however, it
bear any reference at all to the chemical and generic can only be assumed that substituting a generic drug
terminology. An additional problem with trade names will produce therapeutic effects that are similar to the
is that several manufacturers may be marketing the brand-name drug. Likewise, establishing bioequiva-
same compound under different names, thus adding to lence of a generic form does not guarantee that a given
the confusion. If there is no existing patent for that patient will not experience different effects from the
compound or if the patent has expired, the same drug generic form compared to the brand-name product.
may be marketed by separate drug companies.24 For That is, certain patients might simply respond differ-
practical purposes, the generic name is often the easi- ently to a the generic form of a drug because of indi-
est and most effective way to refer to a drug, and this vidual differences in their ability to absorb and
terminology will be used frequently in this text. metabolize certain generic products, even if these pro-
Drug nomenclature is also a source of confusion ducts have been shown to be similar to their brand-
and potential errors in medication use, especially name counterpart during bioequivalence testing. This
when different drugs have names that look or sound fact seems especially true for drugs that tend to pro-
alike.14 It has been estimated, for example, that up to duce a wider range of therapeutic and adverse effects
25 percent of all medication errors are caused by name when tested in a specific patient, or within a group of
confusion.2,13 This fact seems especially true for drugs patients (i.e., drugs with more intrasubject and inter-
with similar brand names.14 Consider, for example, the subject variability).20 Hence, there are a number of
confusion that could occur when trying to differenti- issues that should be considered before a generic drug
ate between the following three brand-name products: is substituted, and practitioners may want to prescribe
Celebrex, Cerebryx, and Celexa.14 These three brand a specific brand-name drug based on the pharmacolog-
names correspond with an analgesic (see Chapter 15), ic profile of that drug and the specific way that the
an antiseizure drug (see Chapter 9) and an antidepres- drug may affect a given patient.
sant (see Chapter 7), respectively. Despite their simi-
lar brand names, these three products represent three
distinct pharmacologic classes that are used in very What Constitutes a Drug:
different clinical situations. Hence, practitioners need
to be especially careful when documenting the use of
Development and Approval
specific medications, and make sure that the correct of Therapeutic Agents
drug name is used to identify each product. In the United States, the Food and Drug Adminis-
tration (FDA) is responsible for monitoring the use of
existing drugs as well as developing and approving of
Substitution of Generic new ones.9,19,21 The analogous body in Canada is the
Health Products and Food Branch of the Department
Drugs for Brand-Name Products of National Health and Welfare. The two primary
A common question among practitioners and patients concerns of these agencies are (1) whether or not the
is whether the generic form of a drug can be substi- drug is effective in treating a certain condition and (2)
tuted for the brand-name product. Generic forms are whether the drug is reasonably safe for human use.
typically less expensive than their brand-name coun-
terparts, and substitution of a generic drug can help
reduce health care costs.16 The generic form of the
Drug Approval Process
drug should be as safe and effective as the original The development of a new drug involves extensive
brand-name product, provided that the generic form preclinical (animal) and clinical (human) studies.19,21
satisfies certain criteria.10,29 Specifically, the generic The basic procedure for testing a new drug is outlined
form should undergo testing to establish that it has the here and is summarized in Table 1–2. Details about
same type and amount of the active ingredient(s), the the phases of drug testing can also be found on the
same administration route, the same pharmacokinetic FDA website (
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6 SECTION 1 General Principles of Pharmacology


Testing Phase Purpose Subjects Usual Time Period

Preclinical testing Initial laboratory tests to deter- Laboratory animals 1–2 yrs
mine drug effects and safety

Investigational New Drug (IND) Application

Human (clinical) testing:
Phase I Determine effects, safe Small number (⬍ 100) of ⬍1 yr
dosage, pharmacokinetics healthy volunteers

Phase II Assess drug’s effectiveness in Limited number (200–300) 2 yrs

treating a specific patients with target disorder

Phase III Assess safety and effective- Large number (1000–3000) 3 yrs
ness in a larger patient pop- patients targeted

New Drug Application (NDA) Approval

Phase IV (postmarketing Monitor any problems that General patient population Indefinite
surveillance) occur after NDA approval

Animal (Preclinical) Studies ease or pathologic condition. The primary goal

of phase 2 is to evaluate the effectiveness of the
Drugs are typically tested in animals initially, often
drug, and to assess the side effects and other
using several different species. Initial information on
the basic pharmacokinetic and pharmacodynamic
Phase III. Clinical evaluation is expanded to include
properties of the compound is obtained. Information
more patients (several hundred to several thou-
on dosage and toxicity is also obtained from these ani-
sand) as well as more evaluators. Additional
mal trials.
information is obtained regarding the drug’s
safety and effectiveness in a large patient popu-
Human (Clinical) Studies lation.
If the results from animal trials are favorable, the drug
At the end of phase III, the drug sponsor applies
sponsor files an investigational new drug (IND) appli-
for a new drug application (NDA). Results from clini-
cation with the FDA. If approved as an IND, the spon-
cal testing are reviewed extensively by the FDA, and if
sor may begin testing the drug in humans. Human, or
found favorable, the NDA is approved. At this point,
“clinical’ testing, is divided into three primary phases.
the drug can be marketed and prescribed for use in the
Phase I. The drug is usually tested in a relatively general population.
small number of healthy volunteers. The pur- A fourth phase known as “postmarketing surveil-
pose of this phase is to obtain some initial infor- lance” should be instituted after the NDA is approved.
mation about the pharmacologic actions, and Postmarketing surveillance refers to all of the methods
the drug’s possible toxic effects in humans. In used to continue monitoring drug safety and effective-
general, between 20 to 80 subjects are studied ness after approval for public use.19,21 These methods
in phase 1, but the actual number of subjects often consist of reports from health care providers that
will vary according to the drug, describe specific rare adverse effects that were not dis-
Phase II. The drug is tested in a relatively small covered during clinical testing.24 A certain drug, for
sample (200 to 300 people) with a specific dis- example, could cause a specific adverse effect in only 1
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Chapter 1 Basic Principles of Pharmacology 7

in 10,000 patients taking the drug.1 It is very likely that chased directly by the consumer, whereas prescription
such an adverse effect could be missed during phase medications may be ordered or dispensed only by an
I through phase III of the clinical trials because the authorized practitioner (i.e., physician, dentist, or
drug is typically tested only in a few thousand subjects other appropriate health care provider). Prescription
(e.g., 1000 to 3000 people). In addition to monitoring or nonprescription drug classification falls under the
adverse effects, postmarketing surveillance can use jurisdiction of the FDA.8 In general, OTC medica-
more formal research methods to obtain information tions are used to treat relatively minor problems and
about how a specific drug is used in clinical practice to make the consumer more comfortable until the
and how that drug compares to similar drugs on the condition is resolved. These medications have been
market.24 Hence, postmarketing surveillance has been judged to be safe for use by the consumer without
advocated as being critical in ensuring that the safety direct medical supervision, and the chances of toxic
and efficacy of the drug continues to be monitored effects are usually small when the medications are
when it is used by the general patient population.18,24 taken in the recommended amounts.8 Of course, the
The development of a new drug in the United patient may ingest more than the recommended
States is an extremely expensive and time-consuming amount, and in the case of an overdose, the danger
process.11 The time course for the entire testing always exists for potentially harmful effects, even if the
process from the beginning of animal trials to the end drug is nonprescription in nature.6,15,22
of phase III human testing may be as long as 7 to 9 The role of OTC products in the health care
years. The FDA has made provisions, however, to market has expanded dramatically in recent years.4,23
shorten the development and review process for drugs Many drugs that were formerly available only by pre-
designed to treat serious and life-threatening condi- scription are now available in a nonprescription form.
tions, especially if the drug shows substantial benefits Transition of a prescription drug to an OTC product
over existing treatments, or no drugs are currently usually occurs when the drug’s marketing company
available for these conditions.25 This type of accelerat- applies to the FDA and receives approval to develop
ed development/review (also known as “fast track” and market it in a nonprescription form. FDA
drug development) is typically used for drugs that show approval is based on the drug having an adequate safe-
promise in treating conditions such as cancer or ty profile, and the FDA may require other stipulations
acquired immunodeficiency syndrome (AIDS). Hence, such as lowering the drug dosage in the OTC product.
these fast tract drugs may be made available for patient The fact that more and more prescription drugs
use even before formal clinical testing is completed.27 are now available in a nonprescription form offers
The FDA will, however, require that drug testing be some obvious benefits. Increased availability of OTC
continued even after the drug is approved, and efforts products can make it easier for consumers to gain
must be made to ensure that it actually provides the access to these medications.4,5 In addition, OTC prod-
therapeutic benefits that were initially promised.27 The ucts are typically less expensive than prescription
approval process can also be expedited if a drug has drugs, and the purported savings might help contain
already received approval for treating one condition, overall medication costs. The actual cost to the patient,
but is now being considered for use in other “supple- however, might be greater for an OTC product be-
mental” conditions.24 cause the patient must pay directly “out of pocket.”4
The process of drug testing and approval does That is, health care programs with prescription drug
seem to be fairly rigorous in its ability to screen out plans may cover the majority of a prescription drug’s
ineffective or potentially harmful drugs. Out of thou- cost, whereas the patient often must pay directly for
sands of newly synthesized compounds, only one will the entire cost of an OTC product. The actual money
ever be released as a prescription drug.1 spent by patients (i.e., the out-of-pocket cost) might
therefore be greater for OTC products compared to
Prescription Versus Over- prescription drugs. Hence the overall benefits of OTC
products on health care costs remains complex.4
the-Counter Medication Despite the potential benefits of OTC products,
In the United States, pharmacotherapeutic agents are there are some obvious concerns about their increased
divided into drugs requiring a prescription for use and use and emphasis on self-care that permeates today’s
drugs available as nonprescription, or over-the- health care market. Consumers must realize that these
counter (OTC).8 Nonprescription drugs can be pur- products are important therapeutic medications and
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8 SECTION 1 General Principles of Pharmacology

must be used appropriately.23,26 There is also the psychologic dependence, or both. Drugs in
chance that inappropriate OTC use can cause serious schedule III include certain opioids (e.g.,
interactions with a patient’s prescription medications, codeine) that are combined in a limited
or that OTC products can delay the use of more effec- dosage with other nonopioid drugs. Other
tive medications.4 The impact of such OTC com- drugs in this category are anabolic steroids,
pounds is discussed in this text in the appropriate certain barbiturates, and amphetamines that
chapters. are not included in schedule II.
It is therefore clear that consumers need to be Schedule IV. These drugs supposedly have a lower
educated about the use of such medications and potential for abuse than schedule III drugs,
reminded that OTC products can produce substantial with only a limited possibility of physical
benefits and adverse effects. All health care providers, dependence, psychologic dependence, or
including physical therapists and occupational thera- both. Examples include certain antianxiety
pists, need to be in a position to help educate and drugs (meprobamate), certain barbiturates
counsel their patients about the benefits and draw- (barbital, phenobarbital), and a variety of
backs of such medications. While therapists should other depressants and stimulants.
not directly prescribe or administer OTC products, Schedule V. These drugs have the lowest relative
therapists can provide information about the proper abuse potential. Drugs in this category con-
use and potential benefits of these medications. sist primarily of low doses of opioids that are
used in cough medications and antidiarrheal
Controlled Substances
Several other criteria relate to the different con-
In 1970, federal legislation was enacted to help control trolled substance schedules, such as restrictions on
the abuse of legal and illegal drugs. The Comprehen- prescription renewal and penalties for illegal posses-
sive Drug Abuse Prevention and Control Act (or Con- sion of drugs in different schedules. For a further dis-
trolled Substances Act) placed drugs into specific cussion of controlled substances, the reader is referred
categories, or “schedules,” according to their potential to another source.12
for abuse.12 Descriptions of the schedules for con-
trolled drugs can be found on the FDA website
(http://www.fda.goc/opacom/laws/cntrlsbb.htm), and
these schedules are described briefly below.
Basic Concepts
in Drug Therapy
Schedule I. These drugs are regarded as having the
highest potential for abuse, and are not typically All drugs exert their beneficial effects by reaching
used as an acceptable medical treatment in the some specific target cell or tissue. On the cellular
United States. Legal use of agents in this cate- level, the drug in some way changes the function of
gory is restricted to approved research studies the cell either to help restore normal physiologic
or therapeutic use in a very limited number of function or to prevent a disease process from occur-
patients (e.g., use of marijuana as an antiemetic). ring. In general, the dose of a drug must be large
Examples of schedule I drugs include heroin, enough to allow an adequate concentration to reach
lysergic acid diethylamide (LSD), psilocybin, the target site, thus producing a beneficial response.
mescaline, peyote, marijuana, tetrahydro- However, the administered dosage must not be so
cannabinols, and several other hallucinogens. excessive that toxicologic effects are produced. Some
Schedule II. Drugs in this category are approved aspects of the relationship between dose and response
for specific therapeutic purposes but still have a are discussed here.
high potential for abuse and possible addiction.
Examples include opioids such as morphine and Dose-Response Curves
fentanyl, and drugs containing methampheta-
and Maximal Efficacy
Schedule III. Although these drugs have a lower The relationship between the dose of a drug and a spe-
abuse potential than those in schedules I and cific response to the drug is illustrated in Figure 1–2.
II, there is still the possibility of developing Typically, very low doses do not produce any ob-
mild to moderate physical dependence, strong servable effect. At some threshold dose, the response
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Chapter 1 Basic Principles of Pharmacology 9

ence of the plateau associated with maximal efficacy

Ceiling can be used to indicate specific information about the
binding of the drug to cellular receptors. The rele-
vance of dose-response curves to drug-receptor inter-

actions is discussed further in Chapter 4.

One criterion used frequently when comparing drugs
Threshold is the concept of potency. Potency is related to the
dose that produces a given response in a specific
amplitude.24 When two drugs are compared, the more
potent drug requires a lower dose to produce the same
Dose (log scale) effect as a higher dose of the second drug. For
FIGURE 1–2 ▼ Dose-response curve. instance, in Figure 1–3, a dose of 10 mg of drug A
would lower blood pressure by 25 percent, whereas
80 mg of drug B would be required to produce the
begins to occur and continues to increase in magnitude same response. Consequently, drug A would be
before reaching a plateau. The plateau in the response described as being more potent. It should be noted
indicates that there will be no further increment in the that potency is not synonymous with maximal efficacy.
response even if the dosage continues to be increased. Drug B is clearly able to exert a greater maximal effect
The point at which there is no further increase in the than drug A. Consequently, the term “potency” is
response is known as ceiling effect, or maximal effi- often taken to be much more significant than it really
cacy, of the drug.24 is.24 The potency of a drug is often misinterpreted by
Dose-response curves are used to provide the layperson as an indication of the drug’s overall
information about the dosage range over which the therapeutic benefits, whereas potency really just refers
drug is effective, as well as the peak response that can to the fact that less of the compound is required to
be expected from the drug. In addition, the character- produce a given response. In fact, neither potency nor
istic shape of the dose-response curve and the pres- maximal efficacy fully indicates a drug’s therapeutic

Drug "B"
Decrease in Mean Arterial Pressure


Drug "A"


5 10 20 40 80 160
Dose (mg)
FIGURE 1–3 ▼ Relative potency and maximal efficacy of two drugs. Drug A is more potent, and
drug B has a greater maximal efficacy.
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10 SECTION 1 General Principles of Pharmacology

potential. Other factors such as the therapeutic index exhibit a specific response as the dosage is increased.
(described further on) and drug selectivity (see Chap- The response is not graded; it is either present or it is
ter 4) are also important in comparing and ultimately absent in each member of the population. For example,
choosing the best medication for a given problem. a headache medication is administered in an increasing
dosage to 1000 people. At some dose, some of the indi-
viduals will begin to respond to the drug by reporting
the absence of their headache. As the dosage is
Elements of Drug Safety increased, more and more individuals will experience
Quantal Dose-Response Curves pain relief because of the medication, until finally 100
and the Median Effective Dose percent of the population report that their headaches
are gone. Again, it is the percentage of the population
The dose-response curves shown in Figures 1–2 and who respond in a specific way (e.g., reporting loss of
1–3 represent the graded response to a drug as it would their headaches) that is measured relative to the dose of
occur in a single individual or in a homogeneous pop- the drug. An important reference point in this type of
ulation. In reality, variations in drug responses that are cumulative dose-response curve is the median effec-
caused by individual differences in the clinical popula- tive dose (ED50).24 This is the dose at which 50 per-
tion need to be considered when trying to assess cent of the population respond to the drug in a
whether a drug is safe as well as effective. Consequent- specified manner.
ly, the relationship between the dose of the drug and
the occurrence of a certain response is measured in a
large group of people (or animals if the drug is being
Median Toxic Dose
tested preclinically). When plotted, this relationship In the aforementioned example, relief from pain was
yields a cumulative, or quantal, dose-response curve the desired response, which is often termed the “bene-
(Fig. 1–4).24 This curve differs from the dose-response ficial” effect. As dosages of the drug continue to be
curve discussed previously in that it is not the magni- increased, however, adverse or toxic effects may
tude of the response that increases with increasing the become apparent. To continue the earlier example,
dosage, but the percentage of the population who higher doses of the same medication may be associated

"Beneficial" Effect Toxic Effect

Percent of Individuals Responding



5 10 20 40 80 160 320 640 1280

Dose (mg)
ED50 TD50
FIGURE 1–4 ▼ Cumulative dose-response curve. The median effective dose (ED50) is 10 mg,
and the median toxic dose (TD50) is 320 mg. The therapeutic index (TI) for this drug is 32.
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Chapter 1 Basic Principles of Pharmacology 11

with the appearance of a specific toxic effect such as has a TI of 8, and the sedative-hypnotic diazepam
acute gastric hemorrhage. As the dosage is increased, (Valium) has a TI equal to 3. Other prescription agents
more and more individuals will then begin to exhibit such as cancer chemotherapeutics (methotrexate, vin-
that particular adverse effect. The dose at which 50 cristine, and so on) may have very low TIs, some close
percent of the group exhibits the adverse effect is to 1. However, a low TI is often acceptable in these
termed the median toxic dose (TD50). In animal stud- agents, considering the critical nature of cancer and
ies, the toxic effect studied is often the death of the ani- similar serious conditions. The consequences of not
mal. In these cases, high doses of the drug are used to using the drug outweighs the risks of some of the toxic
determine the median lethal dose (LD50)—the dose effects.
that causes death in 50 percent of the animals stud- To help keep the risk of toxicity to a minimum
ied.24 Of course, the LD50 is not a relevant term in with low-TI drugs, it is generally advisable to period-
clinical use of the drug in humans, but it does serve to ically monitor blood levels. This helps prevent con-
provide some indication of the drug’s safety in preclin- centrations from quickly reaching toxic levels. This
ical animal trials. precaution is usually not necessary with high-TI
drugs, because there is a greater margin of error (i.e.,
Therapeutic Index blood levels can rise quite a lot above the therapeutic
concentration before becoming dangerous).
The median effective and toxic doses are used to
determine the therapeutic index (TI).24 The TI is
calculated as the ratio of the TD50 to the ED50: SUMMARY
TD50 In its broadest sense, pharmacology is the study of the
TI ⫽ effects of chemicals on living organisms. Most discus-
sions of clinical pharmacology deal primarily with the
In animal studies in which the median lethal dose beneficial effects of specific drugs on humans, and the
is known, the TI is often calculated using the LD50 in manner in which these drugs exert their therapeutic
place of the TD50. In either human or animal studies, effects. Since all drugs have the potential to produce
the TI is used as an indicator of the drug’s safety.24 unwanted or toxic responses, some discussion of a
The greater the value of the TI, the safer the drug is drug’s adverse effects is also essential in pharmacology.
considered to be. In essence, a large TI indicates that Drugs used therapeutically are subjected to extensive
it takes a much larger dose to evoke a toxic response testing prior to approval for use in humans and are
than it does to cause a beneficial effect. classified as either prescription or over-the-counter,
It should be noted, however, that the TI is a depending on their dosage, effectiveness, and safety
relative term. Acetaminophen, a nonprescription anal- profile. Finally, certain characteristic relationships
gesic, has a TI of approximately 27 (i.e., the ratio of the exist between the dose of a drug and the response or
median toxic dose to the median effective dose equals effect it produces. Such relationships can provide use-
27). Prescription agents tend to have lower TIs. For ful information about drug efficacy and potency and
instance, the narcotic analgesic meperidine (Demerol) about the relative safety of different compounds.

References 5. Brass EP. Implications of a switch from prescription to

over-the-counter status for allergy drugs. Curr Allergy
1. Berkowitz BA. Basic and clinical evaluation of new Asthma Rep. 2004;4:245–250.
drugs. In: Katzung BG, ed. Basic and Clinical Pharmacol- 6. Bromer MQ, Black M. Acetaminophen hepatotoxicity.
ogy. 9th ed. New York: Lange Medical Books/McGraw Clin Liver Dis. 2003;7:351–367.
Hill; 2004. 7. Chen ML, Shah V, Patnaik R, et al. Bioavailability and
2. Berman A. Reducing medication errors through bioequivalence: an FDA regulatory overview. Pharm Res.
naming, labeling, and packaging. J Med Syst. 2004; 2001;18:1645–1650.
28:9–29. 8. Corelli RL. Therapeutic and toxic potential of over-
3. Borgheini G. The bioequivalence and therapeutic effi- the-counter agents. In: Katzung BG, ed. Basic and Clini-
cacy of generic versus brand-name psychoactive drugs. cal Pharmacology. 9th ed. New York: Lange Medical
Clin Ther. 2003;25:1578–1592. Books/McGraw Hill; 2004.
4. Brass EP. Changing the status of drugs from prescrip- 9. Cowan CC. The process of evaluating and regulating a
tion to over-the-counter availability. N Engl J Med. new drug: phases of a drug study. AANA J. 2002;70:
2001;345:810–816. 385–390.
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12 SECTION 1 General Principles of Pharmacology

10. Dighe SV. A review of the safety of generic drugs. 20. Meredith P. Bioequivalence and other unresolved
Transplant Proc. 1999;31(suppl 3A):23S–24S. issues in generic drug substitution. Clin Ther. 2003;
11. DiMasi JA, Hansen RW, Grabowski HG. The price 25:2875–2890.
of innovation: new estimates of drug development 21. Moore SW. An overview of drug development in the
costs. J Health Econ. 2003;22:151–185. United States and current challenges. South Med J.
12. Edwards L. Appendix I. Principles of prescrip- 2003;96:1244–1256.
tion order writing and patient compliance. In: 22. Motola G, Mazzeo F, Rinaldi B, et al. Self-prescribed
Hardman JG, et al, eds. The Pharmacological Basis laxative use: a drug-utilization review. Adv Ther. 2002;
of Therapeutics. 10th ed. New York: McGraw Hill; 19:203–238.
2001. 23. Newton GD, Pray WS, Popovich NG. New OTC
13. Gremillion L, Hogan DJ. Dermatologic look- or drugs and devices 2003: a selective review. J Am Pharm
sound-alike medications. J Drugs Dermatol. 2004;3: Assoc (Wash DC). 2004;44:211–225.
61–64. 24. Nies AS. Principles of therapeutics. In: Hardman JG,
14. Hoffman JM, Proulx SM. Medication errors caused et al, eds. The Pharmacological Basis of Therapeutics. 10th
by confusion of drug names. Drug Saf. 2003;26: ed. New York: McGraw Hill; 2001.
445–452. 25. Reichert JM. Trends in development and approval
15. Jones A. Over-the-counter analgesics: a toxicology times for new therapeutics in the United States. Nat
perspective. Am J Ther. 2002;9:245–257. Rev Drug Discov. 2003;2:695–702.
16. Kirking DM, Ascione FJ, Gaither CA, Welage LS. 26. Roumie CL, Griffin MR0. Over-the-counter anal-
Economics and structure of the generic pharma- gesics in older adults: a call for improved labelling and
ceutical industry. J Am Pharm Assoc. 2001;41: consumer education. Drugs Aging. 2004;21:485–498.
578–584. 27. Shih WJ, Ouyang P, Quan H, Lin Y, Michiels B,
17. Lambert BL, Chang KY, Lin SJ. Immediate free recall Bijnens L. Controlling type I error rate for fast track
of drug names: effects of similarity and availability. Am drug development programmes. Stat Med. 2003;22:
J Health Syst Pharm. 2003;60:156–168. 665–675.
18. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing 28. Venes D, Thomas CL (eds). Taber’s Cyclopedic Medical
of new black box warnings and withdrawals for pre- Dictionary. 19th ed. Philadelphia: FA Davis;2004.
scription medications. JAMA. 2002;287:2215–2120. 29. Welage LS, Kirking DM, Ascione FJ, Gaither CA.
19. Lipsky MS, Sharp LK. From idea to market: the drug Understanding the scientific issues embedded in the
approval process. J Am Board Fam Pract. 2001;14: generic drug approval process. J Am Pharm Assoc (Wash
362–367. DC). 2001;41:856–867.
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Chapter 2
Pharmacokinetics I: Drug
Administration, Absorption,
and Distribution

Pharmacokinetics is the study of the way that the body system in a fairly controlled manner. This avoids the
deals with pharmacologic compounds. In other words, large, sudden increase in plasma drug levels, which can
what does the body do to the drug? This includes the occur when the drug is administered by other methods
manner in which the drug is administered, absorbed, such as through intravenous injection. Most medica-
distributed, and eventually eliminated from the body. tions that are administered orally are absorbed from
These topics are discussed in this chapter and the next. the small intestine, thus utilizing the large surface area
of the intestinal microvilli to enhance its entry into the
Routes of Administration Several disadvantages may preclude drugs from
being given orally. Drugs that are administered by
In general, drugs can be administered via two primary mouth must have a relatively high degree of lipid sol-
routes: through the alimentary canal (enteral admin- ubility in order to pass through the gastrointestinal
istration) or through nonalimentary routes (par- mucosa and into the bloodstream. Large, nonlipid-
enteral administration). Each major route has several soluble compounds are absorbed very poorly from the
variations, and each offers distinct advantages and dis- alimentary canal and will eventually be lost from the
advantages. The primary features of some of the major body in the feces. Absorption of some nonlipid-soluble
routes are discussed here. For a more detailed descrip- substances (peptides, small proteins) can be enhanced
tion of the specific methodology involved in drug to some extent by encapsulating these agents in lipid
administration, the reader is referred to several excel- vesicles (liposomes); this technique was recently devel-
lent discussions of this topic.10,34,86 oped to enable the oral administration of drugs that
were formerly administered only through injection or
Enteral some other parenteral route.82 Other drawbacks to the
oral route include the fact that certain medications
Oral may irritate the stomach and cause discomfort, vomit-
The primary way that drugs are given enterally is ing, or even damage to the gastric mucosa. The acidic
through the oral route. This is the most common environment and presence of digestive proteases in the
method of administering medications and offers sev- stomach may also cause various compounds to be
eral distinct advantages. Oral administration is the degraded and destroyed prior to absorption from the
easiest method of taking medications, especially when gastrointestinal tract.49
self-administration is necessary or desired. The oral Drugs that are given orally are subject to a phe-
route is also relatively safe because drugs enter the nomenon known as the first-pass effect.10,86 After

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14 SECTION 1 General Principles of Pharmacology


Route Advantages Disadvantages Examples

Oral Easy, safe, convenient Limited or erratic absorption of Analgesics; sedative-
some drugs; chance of first- hypnotics; many others
pass inactivation in liver

Sublingual Rapid onset; not subject to first- Drug must be easily absorbed Nitroglycerin
pass inactivation from oral mucosa

Rectal Alternative to oral route; local Poor or incomplete absorption; Laxatives; suppository forms
effect on rectal tissues chance of rectal irritation of other drugs

Inhalation Rapid onset; direct application Chance of tissue irritation; General anesthetics; anti-
for respiratory disorders; large patient compliance some- asthmatic agents
surface area for systemic times a problem

Injection Provides more direct administra- Chance of infection if sterility is Insulin; antibiotics; anti-
tion to target tissues; rapid not maintained cancer drugs; narcotic
onset analgesics

Topical Local effects on surface of skin Only effective in treating outer Antibiotic ointments; creams
layers of skin used to treat minor skin
irritation and injury

Transdermal Introduces drug into body with- Drug must be able to pass Nitroglycerin; motion sick-
out breaking the skin; can through dermal layers intact ness medications; drugs
provide steady, prolonged used with phonophoresis
delivery via medicated patch and iontophoresis

absorption from the alimentary canal, the drug is trans- rate of gastric emptying, amount of visceral blood flow,
ported directly into the liver via the portal vein, where and so on) can alter the usual manner in which a drug
a significant amount of the drug may be metabolized is absorbed into the body from the gastrointestinal
and destroyed prior to reaching its site of action. The tract.6,21,39,86
dosage of the orally administered drug must be suffi-
cient enough to allow an adequate amount of the com-
Sublingual and Buccal
pound to survive hepatic degradation and to eventually
reach the target tissue.10 Some drugs—such as nitro- Drugs are administered sublingually by placing the
glycerin—undergo such extensive inactivation from drug under the tongue. Buccal administration occurs
the first-pass effect that it is usually preferable to when the drug is placed between the cheek and gums.
administer them through nonoral routes.86 A drug that is administered sublingually or buccally
A final limitation of the oral route is that the is then absorbed through the oral mucosa into the
amount and rate at which the drug eventually reaches venous system that is draining the mouth region.
the bloodstream tends to be somewhat less predictable These veins eventually carry blood to the superior vena
with oral administration compared with more direct cava, which in turn carries blood to the heart. Conse-
routes, such as injection. Factors that affect intes- quently, a drug administered sublingually or buccally
tinal absorption (intestinal infection, presence of food, can reach the systemic circulation without being sub-
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Chapter 2 Pharmacokinetics I 15

jected to first-pass inactivation in the liver.70,90 This to the bronchial and alveolar tissues for the treatment
provides an obvious advantage for drugs such as nitro- of specific pulmonary pathologies.42 The pulmonary
glycerin that would be destroyed in the liver when route may also be a potential way to administer larger
absorbed from the stomach or intestines. These routes nonlipid-soluble agents such as peptides, small pro-
also offer a means of enteral administration to people teins (including insulin), and DNA.3,30,69
who have difficulty swallowing or to patients who One limitation of the inhalation route is that the
cannot be given drugs rectally.54 The restrictions of drug must not irritate the alveoli or other areas of the
the sublingual and buccal routes are that the amount respiratory tract. Also, some patients have trouble
of drug that can be administered is somewhat limited, administering drugs by this route, and drug particles
and the drug must be able to pass easily through the tend to be trapped by cilia and mucus in the respirato-
oral mucosa in order to reach the venous drainage of ry tract. Both of these factors tend to limit the ability
the mouth. to predict exactly how much of the drug eventually
reaches the lungs. Efforts continue to advance the use
of inhaled drugs by improving the physicochemical
Rectal properties of these drugs, and also by improving the
A final method of enteral administration is via the rec- devices used to deliver these drugs (i.e., inhalers).20
tum. Many drugs are available as rectal suppositories to Technological advancements in inhaled drugs will be
allow administration through this route. This method addressed in more detail when respiratory medications
is less favorable because many drugs are absorbed are addressed later in this text (see Chapter 26).
poorly or incompletely, and irritation of the rectal
mucosa may occur.86 Rectal administration does offer
the advantage of allowing drugs to be given to a patient
who is unconscious, or when vomiting prevents drugs Various types of injection can be used to introduce the
from being taken orally. However, the rectal route is drug either systemically or locally. If sterility is not
used most often for treating local conditions such as maintained, all types of injection have the disadvan-
hemorrhoids. tage of possible infection, and certain types of injec-
tion are more difficult, if not impossible, for the
patient to self-administer. Specific types of injection
Parenteral include the following routes.
All methods of drug administration that do not use the Intravenous. The bolus injection of a medication
gastrointestinal tract are termed parenteral. Parenteral into a peripheral vein allows an accurate, known quan-
administration generally allows the drug to be deliv- tity of the drug to be introduced into the bloodstream
ered to the target site more directly, and the quantity over a short period of time, frequently resulting in
of the drug that actually reaches the target site is often peak levels of the drug appearing almost instanta-
more predictable.86 Also, drugs given parenterally are neously in the peripheral circulation and thus reaching
not usually subject to first-pass inactivation in the liver. the target site rapidly. This occurrence is advantageous
Other advantages and disadvantages of various par- in emergency situations when it is necessary for the
enteral routes are discussed further on in this section. medication to exert an immediate effect. Of course,
adverse reactions may also occur because of the sudden
appearance of large titers of the drug in the plasma.
Inhalation Any unexpected side effects or miscalculations in the
Drugs that exist in a gaseous or volatile state, or that amount of the administered drug are often difficult to
can be suspended as tiny droplets in an aerosol form, deal with after the full dose has been injected. In cer-
may be given via inhalation. Pulmonary administra- tain situations, an indwelling intravenous cannula (IV
tion is advantageous because of the large (alveolar) “line”) can be used to allow the prolonged, steady infu-
surface area for diffusion of the drug into the pul- sion of a drug into the venous system. This method
monary circulation and it is generally associated with prevents large fluctuations in the plasma concentration
rapid entry of the drug into the bloodstream.43 This of the drug and allows the dosage of drug to be main-
method is used extensively in administering the tained at a specific level for as long as desired.
volatile general anesthetics (e.g., halothane) and it is Intra-arterial. The injection of a drug directly into
also advantageous when applying medications directly an artery is understandably a difficult and dangerous
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16 SECTION 1 General Principles of Pharmacology

procedure. This method permits a large dose of the major problem with intramuscular administration is
medication to reach a given site, such as a specific that many drugs injected directly into a muscle cause
organ, and may be used to focus the administration of significant amounts of local pain and prolonged sore-
drugs into certain tissues. Intra-arterial injections are ness, tending to limit the use of this route for repeated
used occasionally in cancer chemotherapy to adminis- injections.
ter the anticancer drug directly to the tumor site with Intrathecal. Intrathecal injections are given by
minimal exposure of the drug to other healthy tissues. injecting the medication within a sheath, and fre-
This route may also be used to focus the administra- quently refer to injections within the spinal subarach-
tion of other substances such as radiopaque dyes for noid space (i.e., the space between the arachnoid
various diagnostic procedures. membrane and the pia mater that help form the
Subcutaneous. Injecting medications directly meninges surrounding the spinal cord). This particu-
beneath the skin is used when a local response is lar type of intrathecal route allows drugs such as nar-
desired, such as in certain situations requiring local cotic analgesics, local anesthetics, and antispasticity
anesthesia. Also, a slower, more prolonged release of drugs to be applied directly to an area adjacent to the
the medication into the systemic circulation can be spinal cord, thereby allowing these drugs to gain bet-
achieved in situations where this is the desired effect. ter access to the cord.55,60,79 Also, intrathecal injections
A primary example is insulin injection in a patient with allow certain drugs—such as antibiotics and anti-
diabetes mellitus. Subcutaneous administration pro- cancer drugs—to bypass the blood-brain barrier and
vides a relatively easy route of parenteral injection that reach the central nervous system (see Chapter 5).86
can be performed by patients themselves, providing Other intrathecal injections include administration of
they are properly trained. the drug within a tendon sheath or bursa, which may
Some limitations are that the amount of drug that be used to treat a local condition such as an inflamma-
can be injected in this fashion is fairly small and that tion within those structures.
the injected drug must not irritate or inflame the sub-
cutaneous tissues. The subcutaneous route can also be
used when certain types of drug preparations are
implanted surgically beneath the skin, so that the drug Drugs given topically are applied to the surface of the
is slowly dispersed from the implanted preparation and skin or mucous membranes. Most medications applied
then absorbed into the bloodstream for prolonged directly to the skin are absorbed fairly poorly through
periods of time.62,86 A common example of this form of the epidermis and into the systemic circulation and are
subcutaneous administration is the use of implanted used primarily to treat problems that exist on the skin
hormonal contraceptive products (e.g., Norplant).9,53 itself. Common examples of topical administration
The use of these implantable contraceptives is dis- include the use of antibiotics to treat cutaneous infec-
cussed in more detail in Chapter 30. tions, application of anti-inflammatory steroids to
Intramuscular. The large quantity of skeletal mus- reduce skin inflammation, and the use of various top-
cle in the body allows this route to be an easily acces- ical products to promote wound healing.11,59,74,85 Top-
sible site for parenteral administration. Intramuscular ical application to mucous membranes is also used
injections can be used to treat a problem located frequently to treat problems on the membrane itself.86
directly in the injected muscle. For example, botu- Significant amounts of the drug, however, can be
linum toxin and other substances can be injected readily absorbed through the mucous membrane and
directly into hyperexcitable muscles to control certain into the bloodstream. Topical application of drugs to
types of muscle spasms or spasticity (see Chapter mucous membranes can therefore provide a fairly easy
13).7,78 Alternatively, intramuscular injection can be and convenient way to administer drugs systemically.
used as a method for a relatively steady, prolonged Certain medications, for example, can be administered
release of the drug into the systemic circulation to to the nasal mucosa (via nasal spray),22,36 to the occu-
control conditions such as psychosis,2 or to administer lar membranes (via eye drops),87 or to other mucous
certain vaccines. membranes to facilitate systemic absorption and treat
Intramuscular injection offers the advantage of disorders throughout the body.86 Nonetheless, the
providing a relatively rapid effect (i.e., within a few potential for adverse systemic effects must also be con-
minutes), while avoiding the sudden, large increase in sidered if large amounts of topically administered
plasma levels seen with intravenous injection. The drugs are absorbed inadvertently into the body.86
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Chapter 2 Pharmacokinetics I 17

Transdermal these transdermal routes are employed, the reader is

referred to several additional sources.12,18,19
Unlike topical administration, transdermal application
consists of applying drugs directly to the surface of the
skin with the intent that they will be absorbed through Drug Absorption and
the dermal layers and into either the subcutaneous
tissues or the peripheral circulation. A transdermally
Distribution: Bioavailability
administered drug must possess two basic properties: Although several routes exist for the administration of
(1) it must be able to penetrate the skin, and (2) it must drugs, merely introducing the drug into the body does
not be degraded to any major extent by drug-metabo- not ensure that the compound will reach all tissues uni-
lizing enzymes located in the dermis.44 Absorption formly or that the drug will even reach the appropriate
may be enhanced by mixing the drug in an oily base or target site. For instance, oral administration of a drug
in some other chemical enhancer, thus increasing sol- that affects the myocardium will not have any pharma-
ubility and permeability through the dermis.4,80 cologic effect unless the drug is absorbed from the gas-
Transdermal administration provides a slow, con- trointestinal tract into the bloodstream. The extent to
trolled release of the drug into the body that is effec- which the drug reaches the systemic circulation is
tive in maintaining plasma levels of the drug at a referred to as bioavailability, which is a parameter ex-
relatively constant level for prolonged periods of pressed as the percentage of the drug administered that
time.65 Drugs that can be administered transdermally reaches the bloodstream.17,86 For instance, if 100 g of a
are often delivered through medicated “patches” that drug is given orally, and 50 g eventually make it into
can be adhered to the skin much like a small adhesive the systemic circulation, the drug is said to be 50 per-
bandage. This method has been used for some time to cent bioavailable. If 100 g of the same compound were
allow the prolonged administration of drugs such as injected intravenously, the drug would be 100 percent
nitroglycerin and some antimotion sickness medica- bioavailable by that route.
tions such as scopolamine. The use of transdermal Consequently, bioavailability depends on the
patches has been expanded recently to include other route of administration as well as the drug’s ability to
medications such as hormonal agents (estrogen, cross membrane barriers. Once in the systemic circula-
testosterone) and opioid analgesics (fentanyl).58 Like- tion, further distribution into peripheral tissues may
wise, transdermal nicotine patches have received a also be important in allowing the drug to reach the tar-
great deal of attention for their use in helping people get site. Many drugs must eventually leave the systemic
to quit smoking cigarettes.58 Researchers continue to capillaries and enter other cells. Thus, drugs have to
explore the use of the transdermal route, and the use move across cell membranes and tissue barriers to get
of transdermal patches continues to gain acceptance as into the body and be distributed within the body. In
a safe and effective method of administering many this section, the ability of these membranes to affect
medications. absorption and distribution of drugs is discussed.
The transdermal route also includes the use of
iontophoresis and phonophoresis to administer the
drug. In iontophoresis, electric current is used to
Membrane Structure and Function
“drive” the ionized form of the medication through Throughout the body, biologic membranes act as bar-
the skin.4,18,19,56 Phonophoresis uses ultrasound waves riers that permit some substances to pass freely, while
to enhance transmission of the medication through others pass through with difficulty or not at all. This
the dermis.4,12,56 Both phonophoresis and iontophore- differential separation serves an obvious protective
sis are often used to treat pain and inflammation by effect by not allowing certain substances to enter the
transmitting specific medications to a subcutaneous body or by limiting the distribution of the substance
tissue such as a muscle, tendon, or bursa. These forms within the body. In effect, the body is separated into
of transdermal administration are important in a reha- various “compartments” by these membranes. In the
bilitation setting since they are often administered by case of pharmacotherapeutics, there is often the need
a physical therapist following a prescription written by for the drug to cross one or more of these membrane
a physician. Specific medications that can be adminis- barriers to reach the target site.
tered via iontophoresis or phonophoresis are listed in The ability of the membrane to act as a selective
Appendix A. For a more detailed description of how barrier is related to the membrane’s normal structure
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18 SECTION 1 General Principles of Pharmacology

and physiologic function. The cell membrane is com- bilayer. Nonlipid-soluble substances, including water,
posed primarily of lipids and proteins. Membrane may be able to pass through the membrane because of
lipids are actually phospholipids, which are composed of the presence of membrane pores.5 Small holes or
a polar, hydrophilic “head” (which contains a phos- channels appear to exist in the membrane, thereby
phate group) and a lipid, hydrophobic “tail” (Fig. 2–1). allowing certain substances to pass from one side of
The phospholipids appear to be arranged in a bilayer, the membrane to the other. These channels are
with the hydrophobic tails of the molecule oriented believed to be formed by some of the membrane pro-
toward the membrane’s center and the hydrophilic teins that span the width of the membrane.41 The abil-
heads facing away from the center of the membrane. ity a substance has to pass through a specific pore
Interspersed throughout the lipid bilayer are mem- depends primarily on the size, shape, and electrical
brane proteins, which can exist primarily in the outer charge of the molecule. Also, in excitable membranes
or inner portion of the membrane or can span the (nerve, muscle) some of these pores are dynamic in
entire width of the cell membrane (see Fig. 2–1). nature and appear to have the ability to “open” and
Recent evidence also suggests that the distribu- “close,” thus regulating the flow of certain ions in and
tion of phospholipids and proteins within the cell out of the cell.73,91 These dynamic ion channels are
membrane is not random, but that certain areas of the especially important in pharmacology because many
cell membrane are organized into special regions or drugs can affect their ability to open and close, thus
“domains.”35,52,63 In particular, certain domains appear altering cell excitability by regulating the movement
to consist primarily of lipids such as cholesterol and of ions across the cell membrane.45,81,84
sphingolipids.27,50 These lipid domains are often
described as lipid “rafts” that move freely about the
cell membrane and these lipid rafts appear to be
Movement Across Membrane Barriers
important in controlling various cell functions includ- Drugs and other substances that pass through biologic
ing cell signaling, endocytosis, and ion channel func- membranes usually do so via passive diffusion, active
tion.27,50 Future research will help further define the transport, facilitated diffusion, or some “special”
role of the lipid rafts and other specific domains with- process such as endocytosis (Fig. 2–2). Each of these
in the cell membrane. mechanisms is discussed here.
The lipid bilayer that composes the basic struc-
ture of the cell membrane acts as a water barrier. The
Passive Diffusion
lipid portion of the membrane is essentially imperme-
able to water and other nonlipid-soluble substances Drugs and other substances will pass through a mem-
(electrolytes, glucose). Lipid-soluble compounds (in- brane by way of diffusion providing two essential cri-
cluding most drugs) are able to pass directly through teria are met. First, there must be some type of
the membrane by becoming dissolved in the lipid difference or “gradient” on one side of the membrane
(Singer SJ, Nicolson GJ. The fluid mosaic model of the structure of cell membranes.

lipid bilayer

membrane phospholipids:
hydrophilic "heads"
Science. 1972;175:720–731.)

hydrophobic "tails"

FIGURE 2–1 ▼ Schematic diagram of the cell membrane.
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Chapter 2 Pharmacokinetics I 19

Passive Diffusion Active Transport Facilitated Endocytosis


FIGURE 2–2 ▼ Schematic diagram summarizing the ways in which substances may cross the
cell membrane. Energy is expended during active transport by hydrolyzing adenosine triphosphate
(ATP) into adenosine diphosphate (ADP) and inorganic phosphate (Pi). The three other mechanisms
do not require any net energy expenditure. See text for further discussion of how and when each
mechanism is utilized.

compared to the other. A concentration gradient, for neutral, nonionized form. Most drugs are weak acids
example, occurs when the concentration of the sub- or weak bases,86 meaning that they have the potential
stance differs on one side of the membrane compared to become positively charged or negatively charged,
to that on the other side. When this gradient occurs, depending on the pH of certain body fluids. In the
the diffusing substance can move “downhill” from the plasma and in most other fluids, most drugs remain
area of high concentration to that of low concentra- in their neutral, nonionized form because of the rela-
tion. In addition to a concentration difference, diffu- tively neutral pH of these fluids. In specific fluids,
sion can also occur because of the presence of a however, a drug may exist in an ionized state, and the
pressure gradient or, in the case of charged particles, absorption of the drug will be affected because of the
an electrical potential gradient. The rate of the diffu- decreased lipid solubility associated with ionization.
sion is dependent on several factors, including the For instance, when a weak acid is in an acidic environ-
magnitude of the gradient, the size of the diffusing ment (e.g., gastric secretions of the stomach), it tends
substance, the distance over which diffusion occurs, to be in its neutral, nonionized form. The same drug
and the temperature at which diffusion occurs.41 The will become positively charged if the pH of the solu-
term passive diffusion is often used to emphasize the tion increases and becomes more basic (e.g., the diges-
fact that this movement occurs without expending any tive fluids in the duodenum). A weak acid such as
energy. The driving forces in passive diffusion are the aspirin will be nonionized and will therefore be
electrical, chemical, and pressure differences on the absorbed fairly easily from the stomach because of its
two sides of the membrane. lipid solubility (Fig. 2–3). This same drug will be
For passive diffusion through a membrane to poorly absorbed if it reaches the basic pH of the duo-
occur, the second essential factor is that the membrane denum and becomes ionized. Conversely, a drug that
must be permeable to the diffusing substance. As men- is a weak base will be ionized and poorly absorbed
tioned earlier, nonlipid-soluble compounds can diffuse from the acidic environment of the stomach. The
through the membrane via specific pores. Some non- same drug will be nonionized and will therefore be
lipid-soluble drugs such as lithium are small enough to lipid soluble when it reaches the duodenum, allowing
diffuse through these pores. Many drugs, however, are it to be absorbed from the proximal small intestine.
able to diffuse directly through the lipid bilayer; hence, Diffusion Trapping. Changes in lipid solubility
they must be fairly lipid soluble. Passive lipid diffusion caused by ionization can also be important when the
is nonselective, and a drug with a high degree of lipid body attempts to excrete a drug in the urine. Here
solubility can gain access to many tissues because of its the situation becomes slightly more complex because
ability to pass directly through the lipid portion of the the urine can sometimes be acidic and at other times
cell membrane. As indicated earlier, certain nonlipid- basic in nature. In either situation, it is often desirable
soluble substances—including some proteins—can be for the drug to remain ionized while in the urine so
encapsulated in lipid vesicles, thereby enhancing their that the drug will be excreted from the body. If the
lipid solubility and increasing their ability to cross lipid drug becomes nonionized while in the nephron, it
membranes by passive diffusion. may be reabsorbed back into the body because of its
Effect of Ionization on Lipid Diffusion. Passive lipid increased lipid solubility. An ionized form of the drug
diffusion of certain drugs is also dependent on will remain “trapped” in the nephron and will eventu-
whether or not the drug is ionized. Drugs will diffuse ally be excreted in the urine.66 Thus, if the urine is
more readily through the lipid layer if they are in their basic, weak acids will become trapped in the nephron
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20 SECTION 1 General Principles of Pharmacology

Osmosis. Osmosis refers to the special case of dif-

(From Clark JB, Queener SF, and Karb VB. Pharmacological Basis of Nursing Practice 4th ed. St. Louis, MO: CV Mosby; 1993:p. 8, with

fusion where the diffusing substance is water. In this

pH 1 to 3
situation, water moves from an area where it is highly
concentrated to an area of low concentration. Of
STOMACH course, permeability is still a factor when osmosis
Weak acids occurs across a membrane or tissue barrier. During os-
mosis, certain drugs may simply travel with the diffus-
ing water, thus crossing the membrane by the process
Weak bases of “bulk flow.” This is usually limited to osmosis
through the gaps between adjacent cells because mem-
DUODENUM brane pores are often too small to allow the passage of
the drug molecule along with the diffusing water.
Weak bases
pH 5 to 7
Active Transport
Active or carrier-mediated transport involves using
membrane proteins to transport substances across the
pH 7 to 8
cell membrane (see Fig. 2–2). Membrane proteins that
span the entire membrane may serve as some sort of
ILEUM carrier that shuttles substances from one side of the
membrane to the other.41 Characteristics of active

transport include the following:

Carrier specificity. The protein carrier exhibits some
FIGURE 2–3 ▼ Effect of pH and ionization on absorption of drugs degree of specificity for certain substances, usu-
from the gastrointestinal tract. Weak acids and bases are absorbed from ally discriminating among different compounds
the stomach and duodenum, respectively, when they are in their neutral, according to their shape and electrical charge.
nonionized form.
This specificity is not absolute, and some com-
pounds that resemble one another will be trans-
ported by the same group of carriers.
and will be excreted more readily. Weak bases will be
Expenditure of energy. The term active transport
excreted better if the urine is acidic. The importance
implies that some energy must be used to fuel
of the kidneys in excreting drugs from the body is dis-
the carrier system. This energy is usually in
cussed further in Chapter 3.
the form of adenosine triphosphate (ATP)
Diffusion Between Cell Junctions. So far, the diffu-
sion of drugs and other substances through individual
Ability to transport substances against a concentration
cell membranes has been discussed. Often, groups of
gradient. Carrier-mediated active transport may
cells will join together to form a barrier that separates
be able to carry substances “uphill”—that is,
one body compartment from another. In some loca-
from areas of low concentration to areas of high
tions, cells form “tight junctions” with each other and
do not allow any appreciable space to exist between
adjacent cells. In these cases, the primary way that The role of active transport in moving drugs
a drug may diffuse across the barrier is by diffusing across cell membranes has some important implica-
first into and then out of the other side of the cells tions. Essentially, the drug can use one of the body’s
comprising the barrier. Such locations include the active transport systems if the drug resembles some
epithelial lining of the gastrointestinal tract and the endogenous substance that is routinely carried by the
capillary endothelium of the brain (one of the reasons transport system. Thus, drugs that resemble amino
for the blood-brain barrier). In other tissues such as acids and small peptides can be absorbed from the gas-
peripheral capillaries, there may be relatively large trointestinal (GI) tract via active transport proteins
gaps between adjacent cells. Here, relatively large sub- that normally absorb these substances into the body.
stances with molecular weights as high as 30,000 may Active transport systems in the kidneys, liver, brain,
be able to diffuse across the barrier by diffusing intestines, and placenta are likewise responsible for
between adjacent cells. the movement of organic ions, peptides, and other
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Chapter 2 Pharmacokinetics I 21

substances across cell membranes, and these transport 1. Tissue permeability. As discussed earlier, the abil-
systems play an important role in the disposition of ity to pass through membranes radically affects
certain drugs within these tissues.23,40,83,89 Conversely, the extent to which a drug moves around within
some drugs may exert their effect by either facilitating the body. A highly lipid-soluble drug can poten-
or inhibiting endogenous transport systems that affect tially reach all of the different body compart-
cellular homeostasis. For example, some of the drugs ments and enter virtually every cell it reaches.88
used to treat excess gastric acid secretion (e.g., famoti- A large nonlipid-soluble compound will remain
dine, ranitidine; see Chapter 27) inhibit the active primarily in the compartment or tissue to which
transport of hydrogen ions into the stomach, thus it is administered. Also, certain tissues such as
reducing the formation of hydrochloric acid within the brain capillary endothelium have special
the stomach.67 Hence, medications can interact with characteristics that limit the passage of drugs.
the body’s active transport systems in several ways and This so-called blood-brain barrier limits the
researchers continue to develop new methods to movement of drugs out of the bloodstream and
enhance a drug’s effects by using or modifying active into the central nervous system tissue.
transport pathways. 2. Blood flow. If a drug is circulating in the blood-
stream, it will gain greater access to tissues that
are highly perfused. More of the drug will reach
Facilitated Diffusion organs that receive a great deal of blood flow—
Facilitated diffusion, as the name implies, bears some such as the brain, kidneys, and exercising skele-
features of both active transport and passive diffusion. tal muscle—than will other, less active tissues
A protein carrier is present in facilitated diffusion, but such as adipose stores.86 Similarly, diseases that
no net energy is expended in transporting the sub- reduce blood flow to specific tissues and organs
stance across the cell membrane.41 As a result, in most will result in less drug being delivered to those
cases of facilitated diffusion there is an inability to tissues.25
transport substances uphill against a concentration 3. Binding to plasma proteins. Certain drugs will
gradient. The entry of glucose into skeletal muscle form reversible bonds to circulating proteins in
cells via facilitated diffusion is probably the best exam- the bloodstream such as albumin.86 This fact is
ple of this type of transport in the body.61 As in active significant because only the unbound or “free”
transport, the movement of drugs across membranes drug is able to reach the target tissue and exert
through facilitated diffusion is fairly infrequent, but a pharmacologic effect. Basically, the fraction of
certain medications may affect the rate at which the drug that remains bound to the circulating
endogenous facilitated diffusion occurs. proteins is sequestered within the vascular sys-
tem and not available for therapeutic purposes
in other tissues and organs.
Special Processes 4. Binding to subcellular components. In a situation
Certain cells have the ability to transport substances similar to plasma protein binding, drugs that
across their membranes through processes such as are bound within specific cells are unable to
endocytosis. Here the drug is engulfed by the cell leave the cell and be distributed throughout
via an invagination of the cell membrane. Although other fluid compartments. Several drugs, for
limited in scope, this method does allow certain large, example, bind to subcellular organelles such as
nonlipid-soluble drugs to enter the cell. the lysosome, thus trapping the drug within the
cell. Examples of this type of subcellular bind-
ing include certain antidepressants, antipsy-
chotics, and other drugs with a relatively high
Distribution of Drugs pH that are attracted by the acidic environment
Within the Body found inside the lysosome.24,88
Factors Affecting Distribution
Following administration, the extent to which a drug
Volume of Distribution
is uniformly distributed throughout the body or The distribution of a given drug within the body is
sequestered in a specific body compartment depends often described by calculating the volume of distri-
on several factors: bution (Vd) for that drug.8,86 Vd is the ratio of the
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22 SECTION 1 General Principles of Pharmacology

amount of drug administered to the concentration of tively inert tissue that may be different from the
drug in the plasma: target site of the drug. Some storage sites include the
Vd ⫽ amount of drug administered ÷
concentration of drug in plasma. 1. Adipose. The primary site for drug storage in the
body is adipose tissue. Because many drugs are
Vd is used to estimate a drug’s distribution by
lipid soluble, fat deposits throughout the body
comparing the calculated Vd with the total amount of
can serve as a considerable reservoir for these
body water in a normal person. A normal 70 kg man
compounds. In some individuals, the amount of
has a total body fluid content of approximately 42 L
fat in the body can reach as high as 40 to 50
(5.5 L blood, 12.0 L extracellular fluid, 24.5 L intra-
percent of body weight, thus creating an exten-
cellular fluid). If the calculated Vd of a drug is approx-
sive storage compartment. Once drugs have
imately equal to the total amount of body water, then
been stored in adipose tissue, they tend to
the drug is distributed uniformly throughout all of the
remain there for long periods of time because
body’s fluids. If the Vd of the drug is far less than 42 L,
of the low metabolic rate and poor blood perfu-
then the drug is being retained in the bloodstream due
sion of these tissues. Examples of drugs that
to factors such as plasma protein binding. A Vd much
tend to be stored in fat include highly lipid-
greater than 42 L indicates that the drug is being con-
soluble anesthetics such as the barbiturates
centrated in the tissues. It should be noted that Vd is
(thiopental) and inhalation anesthetics
not a “real” value; that is, it does not indicate the
actual amount of fluid in the body, but is merely an
2. Bone. Bone acts as a storage site for several toxic
arbitrary figure that reflects the apparent distribution
agents, especially heavy metals like lead. Also,
of a drug using total body water as a reference point.
drugs such as the tetracyclines, which bind to
Table 2–2 gives some examples of the calculation of
and form molecular complexes with the crystal
the Vd for three different types of drugs.
components within the skeletal matrix, are
stored within bone.
3. Muscle. Binding of drugs to components within
Drug Storage the muscle may create the long-term storage
of these compounds. Various agents may be
Storage Sites actively transported into the muscle cell and
Following administration and absorption, many drugs may form reversible bonds to intracellular
are “stored” to some extent at certain locations in structures such as proteins, nucleoproteins, or
the body86; that is, prior to drug elimination, the phospholipids. An example is the antimalarial
drug may be sequestered in its active form in a rela- drug quinacrine.


Amount Plasma Volume of

Drug Administered Concentration Distribution Indication Examples
A 420 mg 0.01 mg/mL 420 mg ÷ 0.01 Uniform distribution Erythromycin; lithium
mg/mL ⫽ 42,000
mL ⫽ 42 L

B 420 mg 0.05 mg/mL 420 mg ÷ 0.05 Retained in plasma Aspirin; valproic acid
mg/mL ⫽ 8400 mL
⫽ 8.4 L

C 420 mg 0.001 mg/mL 420 mg ÷ 0.001 Sequestered in Morphine; quinidine

mg/mL ⫽ 420,000 tissues
mL ⫽ 420 L
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Chapter 2 Pharmacokinetics I 23

4. Organs. Drugs are often stored within certain redistribution may explain why certain individuals
organs such as the liver and kidneys. As in mus- experience prolonged effects of the drug or extended
cle cells, the drug may enter the cell passively adverse side effects.
or by active transport and then form bonds to
subcellular components. Examples include
antimicrobial aminoglycoside agents (such as Newer Techniques
gentamicin and streptomycin), which accumu-
late in renal proximal tubular cells. for Drug Delivery
Controlled-Release Preparations
Adverse Consequences Controlled-release preparations, also known as
of Drug Storage timed-release, sustained-release, extended-release, or
High concentrations of drugs, drug metabolites, and prolonged-action preparations, are generally designed to
toxic compounds within tissues can cause local dam- permit a slower and more prolonged absorption of the
age to the tissues in which they are stored. This event drug from the gastrointestinal tract and other routes
is particularly true for toxic compounds that are incor- of administration.86 This technique may offer several
porated and stored in the matrix of bone or that are advantages such as decreasing the number of doses
highly concentrated within specific organs. Lead poi- needed each day, preventing large fluctuations in the
soning, for example, causes several well-known and amount of drug appearing in the plasma, and sustain-
potentially devastating effects when this metal accu- ing plasma levels throughout the night.13,37 This type
mulates, in the CNS, bone, GI tract, and several other of preparation has been used successfully with several
tissues. types of drugs, including cardiovascular medications
Exposing various organs to high concentrations (beta blockers, calcium channel blockers),26,77 narcotic
of therapeutic drugs can also result in myriad prob- analgesics such as morphine,13,28 and anti-Parkinson
lems. Actaminophen, for example, is normally metab- medications that contain L-dopa.46,75 Controlled-
olized in the liver to form several highly reactive release preparations will probably continue to gain
by-products or metabolites (see Chapter 15). When popularity as a means for administering these and
normal doses of acetaminophen are metabolized in a other medications in the future.86
reasonably healthy liver, these metabolites are rapidly
inactivated in the liver and subsequently excreted by
the kidneys. Very high doses of acetaminophen, how-
Implanted Drug Delivery Systems
ever, result in the formation of excessive amounts of a Several techniques have been developed whereby a
toxic metabolite that can react with hepatic proteins type of drug “reservoir” is implanted surgically within
and cause severe liver damage.64 Hence, organs such the body and is then released in a controlled fashion
as the liver and the kidneys are often subjected to local from the implanted reservoir.38,76 These drug reser-
damage when these organs must deal with high con- voirs typically consist of a small container placed
centrations of therapeutic and toxic agents. under the skin in the abdomen. The containers
Another problem with drug storage occurs when are often programmed to allow a small, measured
the storage site acts as a reservoir that “soaks up” the dose of the drug to be released periodically from
drug and prevents it from reaching the target site. For the reservoir. Alternatively, the reservoir can be con-
instance, a highly lipid-soluble drug such as a general trolled electronically from outside of the body
anesthetic must be administered at a sufficient dose to through the use of small, remote-controlled devices,
ensure that there will be enough drug available to thus allowing the patient to regulate release of the
reach the CNS, despite the tendency for much of the drug as needed. In some cases, the drug reservoir may
drug to be sequestered in the body’s fat stores. Storage be connected by a small cannula to a specific body
sites may also be responsible for the redistribution of compartment—such as the subarachnoid space or
drugs. This occurrence is seen when the drug begins epidural space—so that the drug can be delivered
to leak out of the storage reservoir after plasma levels directly into that space. This type of system appears to
of the drug have begun to diminish. In this way, the be very helpful in applying certain drugs such as anal-
drug may be reintroduced to the target site long after gesics, anesthetics, and muscle relaxants into the
the original dose should have been eliminated. This spinal cord.29,38,76
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24 SECTION 1 General Principles of Pharmacology

Another type of implantable system has been niques have been particularly important in helping
developed recently that incorporates the drug into deliver DNA to specific cells in order to modify
some type of biodegradable or nonbiodegradable sub- the genetic regulation of those cells (gene-based
stance such as a polymer matrix or gel.53,57,71 The therapy).47,48,51
drug-polymer complex is then implanted in the body Drugs can also be targeted to specific sites by cap-
and the drug is slowly released into surrounding tis- italizing on unique physiologic properties of various
sues (nonbiodegradable), or is released as the matrix tissues and organs. Certain drugs, for example, might
gradually dissolves (biodegradable). This type of sys- be activated by enzymes that are found only in the kid-
tem is probably best known for administering contra- neys, thereby targeting these drugs specifically to the
ceptive hormones such as progesterone (Norplant; see kidneys.31 Abnormal tissues, including some tumors,
Chapter 30); these implants have also shown promise might also have specialized enzymes that could be used
in delivering other medications such as local anesthet- to activate certain drugs only after the drugs reach
ics, insulin, and vaccines.71 these tissues.68 Various techniques can also be used to
Hence, implantable drug delivery systems are modify a drug so that it is activated only after reaching
being considered as a potential means of administer- the colon.15,16 This action will allow the drug to be
ing several drugs including analgesics, muscle relax- administered orally, but remain inactive as a “prodrug”
ants, and hormones. Improvements in the technology until it reaches the colon, where it will then become
of this type of drug delivery will hopefully permit activated to treat local problems or be absorbed into
increased clinical applications of these systems in the the systemic circulation.33,72
near future. The use of implantable drug delivery sys- The idea of targeting drugs to specific tissues
tems with specific types of medications will be dis- through various cellular and chemical mechanisms is
cussed in more detail when these medications are still relatively new. These techniques have shown con-
addressed in subsequent chapters in this book. siderable promise, however, and may ultimately be
extremely useful in increasing the effectiveness of cer-
tain drugs while decreasing side effects.
Targeting Drug Delivery
to Specific Cells and Tissues
Some very innovative approaches have been attempted
on a molecular level to try to target the drug specifi- In order for any drug to be effective, it must be able to
cally to the cells that require treatment. For instance, reach specific target tissues. The goal of drug admin-
specific types of antibodies (monoclonal antibodies) istration is to deliver the drug in the least complicated
can be synthesized and attached to certain drugs manner while still allowing sufficient concentrations
such as the cytotoxic agents often used in cancer of the active form of the drug to arrive at the desired
chemotherapy.1,32 The antibodies are then attracted to site. Each route of administration has certain advan-
antigens located on the surface of the tumor cells. This tages and disadvantages that will determine how much
offers the distinct advantage of focusing the drug more and how fast the drug is delivered to specific tissues. In
directly on the cancerous cells rather than on healthy addition to the route of administration, the distribu-
human tissues. Other cellular techniques have been tion of the drug within the body must be taken into
investigated that could also help direct the drug to the account. Simply introducing the drug into certain
affected tissues. It may be possible, for example, to link body fluids such as the bloodstream does not ensure
a drug to a modified virus so that the virus transports its entry into the desired tissues. Factors such as tissue
and helps insert the drug directly into specific cells;47,51 permeability and protein binding may influence how
the virus, of course, must be modified so that it will the drug is dispersed within the various fluid compart-
not cause viral infection. Other nonviral techniques ments within the body. Finally, some drugs have a ten-
include encapsulating the drug in a certain type of dency to be stored in certain tissues for prolonged
fat particle (liposome) or attaching the drug to certain periods of time. This storage may produce serious
proteins that will be attracted to the surface receptors toxic effects if high concentrations of the compound
of specific cells.14,48 These viral and nonviral tech- damage the cells in which it is stored.
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Chapter 2 Pharmacokinetics I 25

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Chapter 3
Pharmacokinetics II:
Drug Elimination

All drugs must be eliminated from the body eventually must eventually wear off, allowing the patient to
to terminate their effect and to prevent excessive accu- resume normal functioning. Although termination of
mulation of the drug. Drugs are usually eliminated by drug activity can occur when the active form of the
chemically altering the original compound while it is drug is excreted from the body via organs such as the
still in the body so that it is no longer active (biotrans- kidneys, excretory mechanisms are often too slow to
formation), by excreting the active form of the drug effectively terminate any activity within a reasonable
from the body (excretion), or by a combination of bio- time period. If excretion were the only way to termi-
transformation and excretion. These methods of drug nate drug activity, some compounds would continue
elimination will be discussed here. to exert their effects for several days or even weeks.
Drug biotransformation into an inactive form usually
occurs within a matter of minutes or hours, thus
Biotransformation reducing the chance for toxic effects caused by drug
accumulation or prolonged drug activity.
Drug metabolism, or biotransformation, refers to
chemical changes that take place in the drug following
administration. Enzymes that are located within spe- Cellular Mechanisms
cific tissues are responsible for catalyzing changes in of Drug Biotransformation
the drug’s structure and subsequently altering the
The chemical changes that occur during drug metab-
pharmacologic properties of the drug. The location of
olism are usually caused by oxidation, reduction,
these enzymes and the reactions involved in biotrans-
hydrolysis, or conjugation of the original com-
formation are discussed later in this chapter.
pound.28,52,60 Examples of each type of reaction are
Biotransformation usually results in an altered
listed in Table 3–1. Each type of reaction and the loca-
version of the original compound known as a metabo-
tion of the enzymes catalyzing the reaction are also dis-
lite, which is usually inactive or has a greatly reduced
cussed here.
level of pharmacologic activity. Occasionally, the
metabolite has a higher level of activity than the orig- 1. Oxidation. Oxidation occurs when either oxygen
inal compound. In these cases, the drug may be given is added or hydrogen is removed from the origi-
in an inactive, or “prodrug,” form that will activate nal compound. Oxidation reactions comprise the
via biotransformation following administration. How- predominant method of drug biotransformation
ever, after it has exerted its pharmacologic effect, in the body, and the primary enzymes that cat-
drug termination is the primary function of biotrans- alyze these reactions are known collectively as
formation.53 the cytochrome P450 monooxygenases.27,28,52
Inactivating a drug and terminating its effects These enzymes are primarily located on the
after it is no longer needed are often essential. For smooth endoplasmic reticulum of specific cells
instance, the effects of general and local anesthetics and are sometimes referred to as the drug
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30 SECTION 1 General Principles of Pharmacology


I. Oxidation Examples
A. Side chain (aliphatic) hydroxylation
RCH2CH3→RCHCH3 Ibuprofen
B. N-oxidation
(R)2NH→(R)2NOH Acetaminophen
C. Deamination
RCH2NH2→RCHO ⫹ NH3 Diazepam

II. Reduction
A. Nitro reductions
RNO2→RNH2 Dantrolene
B. Carbonyl reductions
RCR′ → RCHR′ Methadone

III. Hydrolysis
A. Esters
RCOR′→RCOOH ⫹ R′OH Aspirin
B. Amides
RCNR′→RCOOH ⫹ R′NH2 Lidocaine

IV. Conjugation
A. Acetylation
RNH2 ⫹ AcetylCoA →RNHCCH3 ⫹ CoA-SH Clonazepam
B. Glycine conjugation
RCNHCH2COOH ⫹ CoA-SH Benzoic acid

Parent drug compounds are represented by the letter “R.” Examples are types of drugs that undergo biotrans-
formation via the respective type of chemical reaction.

microsomal metabolizing system (DMMS). compound. Enzymes that are located in the cell
The general scheme of drug oxidation as cat- cytoplasm are usually responsible for drug
alyzed by the DMMS is shown in Figure 3–1. reduction.
2. Reduction. Reduction reactions consist of remov- 3. Hydrolysis. The original compound is broken
ing oxygen or adding hydrogen to the original into separate parts. The enzymes responsible
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Chapter 3 Pharmacokinetics II: Drug Elimination 31

H OH neys, gastrointestinal epithelium, and skin. Drug meta-

bolism can be radically altered in conditions where
Parent DMMS Enzymes Oxidized + H2O these tissues are damaged. For instance, inactivation of
Drug Metabolite
+ certain drugs may be significantly delayed in the
O2 2H patient with hepatitis or cirrhosis of the liver.47,61 As
FIGURE 3–1 ▼ Drug oxidation catalyzed by drug microsomal expected, dosages in these patients must be adjusted
metabolizing system (DMMS) enzymes. accordingly to prevent drug accumulation and toxicity.

for the hydrolysis of the drug are located at sev- Enzyme Induction
eral sites within the cell (i.e., the endoplasmic
A frequent problem in drug metabolism is the phe-
reticulum and cytoplasm) as well as extracellu-
nomenon of enzyme induction.9,13,62 Prolonged use
larly (e.g., circulating in the plasma).
of certain drugs “induces” the body to be able to enzy-
4. Conjugation. In conjugation reactions, the intact
matically destroy the drug more rapidly, usually
drug or the metabolite of one of the reactions
because either more metabolizing enzymes are being
described earlier, is coupled to an endogenous
manufactured or less are being degraded. Enzyme
substance such as acetyl coenzyme A (acetyl
induction may cause drugs to be metabolized more
CoA), glucuronic acid, or an amino acid.
rapidly than expected, thus decreasing their therapeu-
Enzymes catalyzing drug conjugations are
tic effect. This may be one reason why tolerance to
found in the cytoplasm and on the endo-
some drugs occurs when it is used for extended peri-
plasmic reticulum.
ods (tolerance is the need for increased drug dosages
The chemical reactions involved in drug bio- to produce the same effect). Long-term ingestion or
transformation are also classified as either phase I or inhalation of other exogenous compounds such as
phase II reactions.27,28,52,60 Phase I reactions consist of alcohol, cigarette smoke, or environmental toxins may
those using oxidation, reduction, or hydrolysis. Phase also cause enzyme induction.9,39,49 When this occurs,
II reactions involve conjugation of the parent drug or medicinal drugs may be more rapidly metabolized
the metabolite of a drug that was already metabolized even when they are first administered because of the
using a phase I reaction. preexisting enzyme induction.
Regardless of the type of chemical reaction used,
biotransformation also helps in metabolite excretion
from the body by creating a more polar com- Drug Excretion
pound.18,53,60 After one or more of the reactions just
described occurs, the remaining drug metabolite usu- The kidneys are the primary sites for drug excre-
ally has a greater tendency to be ionized in the body’s tion.33,56 The functional unit of the kidney is the
fluids. The ionized metabolite is more water soluble, nephron (Fig. 3–2), and each kidney is composed of
thus becoming transported more easily in the blood- approximately 1 million nephrons. Usually, the
stream to the kidneys. Upon reaching the kidneys, the metabolized or conjugated version of the original drug
polar metabolite can be excreted from the body in the reaches the nephron and is then filtered at the
urine. The contribution of biotransformation toward glomerulus. Following filtration, the compound trav-
renal excretion is discussed in a later section. erses the proximal convoluted tubule, loop of Henle,
and distal convoluted tubule before reaching the col-
Organs Responsible lecting ducts. If a compound is not reabsorbed while
moving through the nephron, it will ultimately leave
for Drug Biotransformation the body in the urine. As discussed earlier, biotrans-
The primary location for drug metabolism is the formation plays a significant role in creating a polar,
liver.5,60 Enzymes responsible for drug metabolism, water-soluble metabolite that is able to reach the kid-
such as the cytochrome P450 enzymes, are abundant neys through the bloodstream. Only relatively polar
on hepatic smooth endoplasmic reticulum; liver cells drugs or their metabolites will be excreted in signifi-
also contain other cytoplasmic enzymes responsible for cant amounts by the kidneys because the ionized
drug reduction and hydrolysis. Other organs that con- metabolite has a greater tendency to remain in the
tain metabolizing enzymes and exhibit considerable nephron and not be reabsorbed into the body.60 Non-
drug transformation abilities include the lungs, kid- polar compounds that are filtered by the kidneys are
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32 SECTION 1 General Principles of Pharmacology

glomerulus proximal tubule loop of Henle distal tubule collecting duct



Polar metabolite
Nonpolar compound

FIGURE 3–2 ▼ Drug excretion at the nephron. Compounds reach the nephron by filtration
and/or secretion. Polar metabolites remain trapped in the nephron and are eventually excreted. Non-
polar compounds are able to diffuse back into the body (reabsorption).

relatively lipophilic and can easily be reabsorbed back excretion for drugs such as gaseous anesthetics. The
into the body passively by diffusing through the wall gastrointestinal tract usually plays only a minor role in
of the nephron. However, the polar metabolite is rel- drug excretion. Certain drugs can be excreted by the
atively impermeable to the epithelium lining, and the liver into the bile and subsequently reach the duode-
metabolite tends to remain “trapped” in the nephron num via the bile duct. If the drug remains in the gas-
following filtration, where it will eventually be excret- trointestinal tract, it will eventually be excreted in the
ed in the urine (see Fig. 3–2). feces. However, most of the secreted bile is reab-
In addition to filtration, some drugs may be sorbed, and drugs contained in it are often reabsorbed
secreted into the nephron by active transport mecha- simultaneously.
nisms located in the proximal convoluted tubule. Sev- Other minor routes for drug excretion include
eral distinct types of transport proteins have been the sweat, saliva, and breast milk of lactating mothers.
identified that secrete substances such as organic Although drugs excreted via lactation are considered a
cations (e.g., uric acid), organic anions (e.g., choline, relatively minor route with regard to loss from the
histamine), prostaglandins, conjugated drug metabo- mother, the possibility that the infant may imbibe sub-
lites, and a variety of other compounds.25,42,33 Certain stantial concentrations of the drug does exist. Careful
drugs can also be transported by one of these carrier consideration for the welfare of the nursing infant
systems so that they are actively secreted into the must always be a factor when administering medica-
nephron. For example, penicillin G is actively secreted tions to the lactating mother.10,21
via the transport system for organic acids, and mor-
phine is secreted by the organic base transport system.
In these cases, elimination of the drug is enhanced by
the combined effects of tubular secretion and filtration
Drug Elimination Rates
in delivering the drug to the urine. The rate at which a drug is eliminated is significant in
Other routes for drug excretion include the lungs determining the amount and frequency of the dosage
and gastrointestinal tract. The lungs play a significant of the drug. If a drug is administered much faster than
role in excreting volatile drugs, that is, drugs that are it is eliminated, the drug will accumulate excessively in
usually administered by inhalation. Consequently, the the body and reach toxic levels. Conversely, if elimi-
lungs serve as the route of both administration and nation greatly exceeds the rate of delivery, the concen-
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Chapter 3 Pharmacokinetics II: Drug Elimination 33

tration in the body may never reach therapeutic levels. amount of blood reaches the organ. Conversely, high-
Several parameters are used to indicate the rate at ly perfused organs may be ineffective in removing the
which a drug is usually eliminated so that dosages may drug, thus prolonging its activity.
be adjusted accordingly. Two of the primary measure- In terms of drug elimination from the entire
ments are clearance and half-life.58,60 body, systemic clearance is calculated as the sum of all
individual clearances from all organs and tissues (i.e.,
systemic CL ⫽ hepatic CL ⫹ renal CL ⫹ lung CL,
Clearance and so on). Note that the elimination of the drug
Clearance of a drug (CL) can be described either in includes the combined processes of drug loss from the
terms of all organ’s and tissue’s ability to eliminate the body (excretion) as well as inactivation of the drug
drug (systemic clearance) or in terms of a single organ through biotransformation.7,58,60
or tissue’s ability to eliminate the drug.7,38,60 To calcu-
late clearance from a specific organ, two primary fac- Half-Life
tors must be considered. First, the blood flow to the In addition to clearance, the half-life of the drug is
organ (Q) determines how much drug will be deliv- important in describing the duration of activity of the
ered to the organ for elimination. Second, the fraction compound. Half-life is defined as the amount of time
of drug removed from the plasma as it passes through required for 50 percent of the drug remaining in the
the organ must be known. This fraction, termed the body to be eliminated.59,60 Most drugs are eliminated
extraction ratio, is equal to the difference in the con- in a manner such that a fixed portion of the drug is
centration of drug entering (Ci) and exiting (Co) the eliminated in a given time period. For example, a drug
organ, divided by the entering concentration (Ci). such as acetaminophen with a half-life of 2 hours indi-
Clearance by an individual organ is summarized by the cates that in each 2-hour period, 50 percent of the
following equation: acetaminophen still in the body will be eliminated
CL ⫽ Q ⫻ [(Ci ⫺ Co) ÷ Ci]. (Fig. 3–3).
Half-life is a function of both clearance and vol-
The calculation of clearance using this equation is ume of distribution (Vd);38 that is, the time it takes to
illustrated by the following example. Aspirin is metab- eliminate 50 percent of the drug depends not only on
olized primarily in the liver. Normal hepatic blood the ability of the organ(s) to remove the drug from
flow (Q) equals 1500 mL/min. If the blood entering the plasma, but also on the distribution or presence
the liver contains 200 ␮g/mL of aspirin (Ci) and the
blood leaving the liver contains 134 ␮g/mL (Co),
hepatic clearance of aspirin is calculated as follows:
CLhepatic ⫽ Q ⫻ [(Ci ⫺ Co) ÷ Ci]
Plasma Concentration of Drug (%)

⫽ 1500 mL/min ⫻ [(200 ␮g/mL ⫺ 134
␮g/mL) ÷ 200 ␮g/mL]
⫽ 495 mL/min.
This example illustrates that clearance is actually
the amount of plasma that the drug can be totally 50
removed from per unit time. As calculated here, the
liver would be able to completely remove aspirin from
495 mL of blood each minute. Tetracycline, a com-
mon antibacterial drug, has a clearance equal to 130 25
mL/min, indicating that this drug would be complete-
ly removed from approximately 130 mL of plasma
each minute. 0
Clearance is dependent on the organ or tissue’s 1 2 3 4 5 6
ability to extract the drug from the plasma as well as Time (hours)
the perfusion of the organ. Some tissues may have an FIGURE 3–3 ▼ Elimination of a drug with a half-life of 2 hours. Fifty
excellent ability to remove the drug from the blood- percent of the drug remaining in the bloodstream is eliminated in each
stream, but clearance is limited because only a small 2-hour period.
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34 SECTION 1 General Principles of Pharmacology

of the drug in the plasma (see Chapter 2 for a descrip- more frequently provides an equivalent average con-
tion of Vd). A drug that undergoes extensive inactiva- centration without the extreme peaks and valleys asso-
tion in the liver may have a long half-life if it is ciated with longer intervals.
sequestered intracellularly in skeletal muscle. Also,
disease states that affect either clearance or Vd will
affect the half-life of the drug, so dosages must be
altered accordingly.
Variations in Drug
Response and Metabolism
The fact that different people react differently to the
Dosing Schedules and same relative drug dosage is an important and often
Plasma Concentration critical aspect of pharmacology. Two patients who are
given the same drug may exhibit different magnitudes
With most medications, it is desirable to bring plasma of a beneficial response as well as different adverse
concentrations of the drug up to a certain level effects. Several primary factors that are responsible for
and maintain it at that level. If the drug is adminis- variations in the response to drugs are discussed below.
tered by continuous intravenous administration, this
can be done fairly easily by matching the rate of 1. Genetic factors. Genetic variability can result in
administration with the rate of drug elimination altered drug pharmacokinetics in certain indi-
(clearance) once the desired plasma concentration is viduals. In extreme cases, genetic variations may
achieved (Fig. 3–4). In situations where the drug is result in abnormal or absent drug-metabolizing
given at specific intervals, the dosage must be adjusted enzymes.60 This deficiency can be harmful or
to provide an average plasma concentration over the even fatal if the drug is not metabolized and
dosing period. Figure 3–4 illustrates that if the dosing begins exerting toxic effects due to accumula-
interval is relatively long (e.g., 12 hours), the dose tion or prolonged pharmacologic activity. For
must be considerably large to provide the same rela- example, some individuals lack the appropriate
tive plasma concentration that would exist in a short- plasma cholinesterase to break down circulating
er dosing interval (e.g., 8 hours). Note also that larger acetylcholine and acetylcholine-like com-
doses given further apart result in greater plasma fluc- pounds.55 Succinylcholine is a neuromuscular
tuations; that is, greater maximum and minimum plas- blocking agent that is usually administered dur-
ma levels over the dosing period. Giving smaller doses ing general anesthesia to ensure muscular relax-

(From Katzung BG. Basic and Clinical Pharmacology. 9th ed. New York: Lange

Plasma concentration (mg/L)


Medical Books/McGraw-Hill; 2004, with permission.)


8 16 24 32 40 48 56 64 72 80 88 96
Time (hours)
FIGURE 3–4 ▼ Relationship between dosing interval and plasma concentrations of the antiasth-
matic drug theophylline. A constant intravenous infusion (shown by the smoothly rising line) yields a
desired plasma level of 10 mg/L. The same average plasma concentration is achieved when a dose of
224 mg is taken every 8 hours, or a dose of 672 mg every 24 hours. However, note the fluctuations
in plasma concentration seen when doses are taken at specific hourly intervals.
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Chapter 3 Pharmacokinetics II: Drug Elimination 35

ation during surgery. Normally, the succinyl- eases may also impair the absorption and distri-
choline is quickly degraded by plasma bution of the drug, further complicating the
cholinesterase; however, individuals lacking the problem of individualized response. The sig-
appropriate form of cholinesterase may suffer nificance of disease in affecting the patient’s
respiratory paralysis because the succinylcholine response is crucial since response to a medica-
exerts its effect much longer than the expected tion may be affected by the very same pathol-
period of time. ogy that the drug is being used to treat. For
In addition to the extreme case described instance, renal excretion of antibiotics, such as
above, we now realize that many people have the aminoglycosides, is altered radically in many
subtle but important differences in the genes types of bacterial infection, but these drugs are
controlling the synthesis of many drug-related typically administered to treat the same infec-
proteins. These differences—know as genetic tions altering their own excretion.60 Conse-
polymorphisms—will result in the production of quently, great care must be taken to adjust the
proteins that are somewhat different in structure dosage accordingly when administering medica-
and function.32,40,45 From this, various aspects of tions in conditions where drug disposition
drug disposition and response will be affect- might be altered by various diseases.24,47,60
ed.3,23,29 For example, differences in proteins 3. Drug interactions. When two or more drugs are
that transport drugs across membranes will present in the body at the same time, the
result in altered absorption, distribution, and chance exists that they may interact and alter
excretion of drugs using these transport systems. each other’s effects and metabolism.2,19 The
Differences in the genetic control of drug majority of drug-drug interactions are insignifi-
metabolizing proteins (enzymes) will likewise cant and do not result in any clinically mean-
result in altered metabolism and biotransforma- ingful adverse effects.11,46 Likewise, certain drug
tion of specific drugs. Finally, differences in the combinations and interactions can be beneficial
proteins that function as drug receptors on because two or more compounds might act syn-
specific cells and target tissues (see Chapter 4) ergistically to produce a cumulative effect that
might cause variability in the tissues’ responses. is greater than each drug would produce alone.
The potential influence of genetic variability Several drugs, for example, are often adminis-
on drug responses and metabolism has actually tered simultaneously so that they augment each
evolved into a branch of genetics known as other when treating conditions such as hyper-
pharmacogenetics, or pharmacogenomics.15 tension, cancer, and human immunodeficiency
Research in pharmacogenetics will continue to virus infection. However, certain combinations
expand as more details emerge about human can lead to serious adverse effects and interac-
genetic make-up (i.e., the human genome proj- tions. For example, two or more drugs can have
ect). We can tailor drug therapy more specifical- additive effects that cause an adverse response,
ly for patients by realizing how specific genetic even if each drug is given in a nontoxic dose.
differences might influence drug respons- For instance, taking two central nervous system
es.15,20,29,40 That is, doses can be adjusted to (CNS) depressants simultaneously (e.g., barbi-
account for genetic differences in drug disposi- turates and alcohol) may cause such severe CNS
tion, and certain drugs can be avoided altogeth- inhibition that the additive effects are lethal.
er in people who lack the appropriate enzymes In contrast to an additive effect, drugs with
for these drugs. Drug regimens that take into opposite actions may essentially cancel each
account genetic variability will ultimately result other out, thus negating or reducing the benefi-
in better drug effects with fewer side effects. cial effects of one or both medications. A drug
2. Disease. Structural or functional damage to an that causes bronchodilation (i.e., for the treat-
organ or tissue responsible for drug metabolism ment of asthma) will be negated by an agent
or excretion presents an obvious problem in that constricts the bronchioles.
pharmacology. Diseases initiating change in tis- Some of the most serious problems occur
sue function or blood flow to specific organs like during drug interactions because one drug
the liver and kidneys can dramatically affect the delays the biotransformation of the other. If
elimination of various drugs.44,47,60 Certain dis- a second compound inhibits the enzymes that
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36 SECTION 1 General Principles of Pharmacology

normally metabolize a drug, the original drug and kidney function is immature, newborns may
will exert its effect for prolonged periods, possi- be deficient in specific drug-metabolizing
bly leading to toxic effects.60 For instance, the enzymes, thus prolonging the effects of
antiulcer drug cimetidine (Tagamet) inhibits the drugs.1,16,22 Infants also differ from adults in
hepatic metabolism of oral anticoagulants such several other key factors affecting drug disposi-
as warfarin (Coumadin). Taking these two drugs tion including differences in membrane func-
together tends to cause elevated plasma levels tion, plasma proteins, regional blood flow, and
of the anticoagulant, which may prolong blood body composition (i.e., percentage of body fat
clotting and lead to a possible hemorrhage. and total body water).54 Hence, drug absorp-
Another type of interaction occurs when two tion, distribution, and elimination will be
or more drugs alter each other’s absorption and altered in infants, and these alterations will be
distribution, and can occur when they compete especially problematic in infants who are born
for the same active transport carrier or bind to prematurely.
the same plasma proteins. An example is the 5. Diet. Diet is shown to affect the absorption,
interaction between aspirin and methotrexate, metabolism, and response to many drugs.12,30
a drug used to treat cancer and rheumatoid Animal and human studies indicated that the
arthritis. Aspirin can displace methotrexate total caloric input as well as the percentage of
from its binding site on plasma proteins, thus calories obtained from different sources (carbo-
allowing relatively high amounts of unbound or hydrates, proteins, and fats) influence drug
“free” methotrexate to exist in the bloodstream. pharmacokinetics.17,26 Specific dietary con-
The increased levels of free methotrexate may stituents such as cruciferous vegetables and
lead to toxic effects. charcoal-broiled beef can also alter drug
Considering the large number of drugs on metabolism.17
the market, it is well beyond the scope of this Fortunately, most food-drug interactions are
text to discuss all of the clinically relevant drug not serious and will not alter the clinical effects
interactions. The prescribing physician and of the drug. There are, however, a few well-
pharmacist, however, must carefully evaluate known food-drug combinations that should
the potential for drug interactions. Likewise, be avoided because of their potentially serious
physical therapists, occupational therapists, and interaction. For example, it was recently discov-
other individuals dealing with patients taking ered that grapefruit juice inhibits the enzymes
medications must be alert for any abnormal that metabolize certain drugs as they are ab-
symptoms or untoward effects because they sorbed from the gastrointestinal (GI) tract. As
may indicate a possible drug interaction. a result, taking these drugs orally with grape-
4. Age. In general, older patients are more sensitive fruit juice will result in increased drug bioavail-
to drugs.8,37 Drugs are usually not metabolized ability because more of the drug’s active form
as quickly in the elderly, primarily because of will reach the bloodstream.12,19 This increased
decreases in liver and kidney function that typi- bioavailability will result in plasma levels that
cally accompany the aging process.31,48,57 are higher than expected, thereby increasing
Decreased drug elimination therefore results in the risk of side effects and adverse reactions.
higher plasma levels in older adults than those Another important food-drug interaction
occurring in younger adults given equivalent involves certain foods such as fermented cheese
doses.31,63 Older adults also suffer more illnesses, and wine. These foods contain high amounts of
and consequently receive more drugs than tyramine, which stimulates the release of cate-
younger adults; this fact further increases their cholamines (norepinephrine, epinephrine) with-
vulnerability to altered drug responses.4 Various in the body. Hence, these foods should not be
other age-related changes in physiology ingested with drugs that inhibit the monoamine
(increased body fat, decreased cardiovascular oxidase enzyme (MAO inhibitors). MAO-
function, and so forth) can affect pharmacoki- inhibiting drugs work by suppressing the
netics and pharmacodynamics in older adults.8,57 destruction of catecholamines, thus allowing
Children are also subject to problems and higher levels of norepinephrine and epineph-
variability in drug metabolism.54 Because liver rine to occur. (MAO inhibitors are frequently
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Chapter 3 Pharmacokinetics II: Drug Elimination 37

used in the treatment of depression; see Chap- tain drugs from their gastrointestinal tract,
ter 7.) Consequently, when MAO inhibitors are presumably because of a general decrease in gas-
taken with tyramine-containing foods, excessive trointestinal motility.51 Conversely, patients with
levels of catecholamines may develop, leading extensive burn injuries may have increased gas-
to a dangerous increase in blood pressure trointestinal absorption and therefore increased
(hypertensive crisis). bioavailability of certain drugs, although the rea-
A number of other potential food-drug inter- son for this effect is not clear.36,41
actions occur, but it is beyond the scope of this
text to discuss all of them. These interactions There are many factors that influence the way
are addressed in more detail elsewhere.19,30,34 each individual responds to a medication, and these
Clinicians should therefore be aware of these factors must be taken into account whenever possible.
well-known interactions and be on the alert for Clinicians should also realize that these factors are not
others as new drugs arrive on the market. mutually exclusive. For example, a premature infant
6. Sex Men and women may have distinct differ- with genetic polymorphisms might present an ex-
ences in the way that certain drugs are tremely complex pharmacologic dilemma because of
absorbed, distributed, and metabolized.14,35,50 the combination of very young age and genetic vari-
This idea makes sense when one considers that ability.23 In older adults, the combined effects of old
sex-related differences in body composition, age and disease can likewise increase the complexity of
gastrointestinal function, enzyme activity, and pharmacokinetic variability. Hence, special care must
various other systems can potentially affect be taken in prescribing appropriate dosages in any sit-
pharmacokinetic variables.14,35,50 Drug disposi- uation where the predicted responses to drug therapy
tion may also be influenced in women by the might be altered by one or more of the factors
cyclic hormonal variations occurring during the described.
menstrual cycle, whereas men do not typically
undergo such routine hormonal fluctuations.14
Pharmacokinetics can clearly differ between
men and women, and future research is needed Drug elimination occurs because of the combined
to determine how sex-related differences affect effects of drug metabolism and excretion. Elimination
the therapeutic outcomes of specific drugs.14,50 is essential in terminating drug activity within a rea-
7. Other factors. A number of additional factors may sonable and predictable time frame. Various tissues
alter the predicted response of the patient to a and organs (especially the liver and kidneys) are
drug. As discussed earlier, environmental and involved in drug elimination, and injury or disease of
occupational hazards may produce certain toxins these tissues can markedly alter the response to certain
that alter drug absorption and metabolism .9,62 drugs. In cases of disease or injury, dosages must fre-
Factors such as cigarette smoking and alcohol quently be adjusted to prevent adverse side effects
consumption have been shown to influence the from altered elimination rates. Many other environ-
metabolism of specific compounds.39,49 Drug mental, behavioral, and genetic factors may also alter
distribution and metabolism may be altered in drug metabolism and disposition, and possible vari-
the obese patient,6 or in response to chronic and ability in the patient’s response should always be a
acute exercise.7,43 Individuals with spinal cord matter of concern when selecting the type and amount
injuries have a decreased ability to absorb cer- of the drug.

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53. Srivastava P. Drug metabolism and individualized med- Gastroenterol. 2003;9:359–363.
icine. Curr Drug Metab. 2003;4:33–44. 62. You L. Steroid hormone biotransformation and xeno-
54. Strolin Benedetti M, Baltes EL. Drug metabolism and biotic induction of hepatic steroid metabolizing
disposition in children. Fundam Clin Pharmacol. enzymes. Chem Biol Interact. 2004;147:233–246.
2003;17:281–299. 63. Zeeh J, Platt D. The aging liver: structural and func-
55. Taylor P. Agents acting at the neuromuscular junction tional changes and their consequences for drug treat-
and autonomic ganglia. In: Hardman JG, et al, eds. ment in old age. Gerontology. 2002;48:121–127.
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Chapter 4
Drug Receptors

A receptor is a component of the cell where a drug Perhaps the most well-known example is the acetyl-
binds and initiates a chain of biochemical events.2 choline receptor located on the postsynaptic mem-
Most drugs exert their effect by binding to and activat- brane of the neuromuscular junction49,56 (Fig. 4–1).
ing such a receptor, which brings about some change When bound by acetylcholine molecules, the receptor
in the physiologic function of the cell. These receptors activates and opens a pore through the cell membrane,
can be any cellular macromolecule, but many receptors thereby increasing the permeability of the muscle cell
have been identified as proteins or protein complexes to sodium.38,56 This action results in depolarization
that are located on or within the cell.45,57 The general and excitation of the cell because of sodium influx.
mechanisms of receptor function, in conjunction with Another important example of a receptor–ion channel
their cellular location, are discussed here. system is the gamma-aminobutyric acid (GABA)-
benzodiazepine–chloride ion channel complex found
on neuronal membranes in the central nervous sys-
Receptors Located
on the Cell’s Surface

(From Bourne, HR and von Zastrow, M. Drug receptors and pharmacodynamics. In: Katzung, BG ed. Basic and Clini-
The principle site for receptors that recognize endoge-
nous and exogenous compounds is the outer surface of ␦

cal Pharmacology. 9th ed. New York: Lange Medical Books/McGraw-Hill; 2004:21, with permission.)
the cell membrane.2 By placing receptors on its outer ␣ ␥ ␣
surface, the cell is able to differentiate and respond to
specific substances that approach the cell, without Outside
actually allowing these substances to enter. These sur-

face receptors are primarily responsive to specific
amino acid, peptide, or amine compounds. Surface
receptors can affect cell function (1) by acting as an ion
channel and directly altering membrane permeability,
(2) by acting enzymatically to directly influence func-
tion within the cell, or (3) by being linked to regulato-
ry proteins that control other chemical and enzymatic
processes within the cell. Each of the three basic ways
that surface receptors can affect cell function is Inside
addressed here.

Surface Receptors Linked Na+

Directly to Ion Channels FIGURE 4–1 ▼ Schematic model of the acetylcholine receptor, an
example of a surface receptor that is linked directly to an ion channel.
Membrane receptors may be involved directly in Binding of two acetylcholine (ACh) molecules to the outer surface of
the cellular response to the drug by acting as an ion the receptor protein induces the opening of a central ion channel, thus
pore and thus changing the membrane permeability.61 allowing sodium to enter the cell.
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42 SECTION 1 General Principles of Pharmacology

tem.46,51 In this situation, the membrane’s permeabili- increases the enzyme activity of the intracellular com-
ty to chloride is increased by the binding of both the ponent (see Fig. 4–2).22,43 The activated enzymatic
neurotransmitter GABA and benzodiazepine drugs component of the receptor then catalyzes the activa-
such as diazepam (Valium) and chlordiazepoxide (Lib- tion of other substrates within the cell.
rium). The function of this chloride ion channel com- It appears that insulin and certain growth factors
plex is discussed in more detail in Chapter 6. Surface may exert their effects by acting through this type of
receptors for other substances—such as ions (sodium, tyrosine kinase receptor-enzyme system.21,44 Insulin,
potassium, calcium) and amino acids (glutamate)— for example, binds to the extracellular component
have been identified, and are likewise linked directly of a protein located on skeletal muscle cells, thereby
to ion channels that control permeability of the cell initiating activation of this protein’s enzymatic activity
membrane.37,61 on the inner surface of the cell membrane. This
change in enzyme function causes further changes in
cell activity, which ultimately result in increased glu-
Surface Receptors Linked cose uptake in the muscle cell. The function of insulin
Directly to Enzymes receptors and their role in the cause and treatment
of diabetes mellitus are discussed in more detail in
Some proteins that span the entire width of the cell Chapter 32.
membrane may have an extracellular receptor site
(binding domain) as well as an intracellular enzymatic
component (catalytic domain)21,44 (Fig. 4–2). Drugs Surface Receptors Linked to
and endogenous chemicals that bind to the receptor Regulatory (G) Proteins: Role
site can change the enzyme activity of the intracellular
of the Second Messenger
catalytic component, thus altering the biochemical
function within the cell.43Receptor-enzyme systems in Rather than directly affecting membrane permeability
this category are often referred to as protein tyrosine or directly influencing enzyme activity, other mem-
kinases because binding of an appropriate substance to brane receptors affect cell function by linking to an
the outer (receptor) component initiates the phospho- intermediate regulatory protein that is located on the
rylation of certain tyrosine amino acids on the inner inner surface of the cell’s membrane.2,23,45 These regu-
(catalytic) component of the protein, which in turn latory proteins are activated by binding guanine

A. B. Agonist Molecules



CD Substrate Substrate
(inactive) (active)

FIGURE 4–2 ▼ Example of a surface receptor that is linked directly to intracellular enzyme activi-
ty. (A) The receptor exists in an inactive state as two subunits: each subunit has a binding domain
(BD) on the outer surface and a catalytic domain (CD) on the inner surface. (B) Binding of agonist
molecules to the BDs causes the subunits to join together and induces phosphorylation (P) of tyro-
sine receptors on the CD. Tyrosine phosphorylation initiates enzymatic activity of the catalytic units,
which then causes substrate activation within the cell.
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Chapter 4 Drug Receptors 43

nucleotides; hence they are often termed G proteins.2 affected through the action of G proteins even after
When an appropriate substance binds to the surface the drug has left the binding site on the cell’s surface2;
receptor, the receptor moves laterally in the cell mem- that is, the drug may bind to the cell for only a short
brane, and attaches to the regulatory G protein.24 This period, but this binding is sufficient to initiate the
attachment activates the G protein, which in turn interaction of the G protein with the intracellular
alters the activity of a type of intracellular effector effector system. Sustained influence of the G protein
(such as an enzyme or ion channel), ultimately leading on the effector system helps explain why the cell may
to a change in cell function.27,59 continue to exhibit a response even after the drug has
Receptors that are linked to G proteins (also dissociated from it, or even after the drug has been
called G protein–coupled receptors) represent the pri- eliminated from the body completely.
mary way that signals from the surface receptor are As indicated earlier, many G protein–coupled
transduced into the appropriate response within the receptors are linked directly to an intracellular
cell.2,23 There appear to be two types of regulatory G enzyme. Drugs and other substances that exert their
proteins: a stimulatory protein (Gs), which increases effects through receptor–G protein–enzyme systems
the cellular response, and an inhibitory protein (Gi), often form (or inhibit the formation of) an intracellu-
which decreases that response (Fig. 4–3). The two lar compound known as a second messenger. In
types of G proteins are linked to two different recep- effect, the drug acts as the first messenger, which trig-
tors that are responsive to different drugs. gers a biochemical change in the cell, but the drug
Certain drugs affect the cell by binding to a recep- itself does not enter. The second messenger, which is
tor that is linked to a Gs protein. The activated recep- the substance produced inside the cell, actually medi-
tor activates the Gs protein, which in turn activates the ates the change in function.
effector system that opens an ion channel or activates The primary example of this type of second mes-
a specific enzyme. Conversely, a drug that binds to a senger strategy is the adenylate cyclase–cyclic
receptor that is linked to a Gi protein, inhibits channel adenosine monophosphate (cAMP) system present
opening or intracellular enzyme activity. in many cells (see Fig. 4–3).50,53 Adenylate cyclase, an
Hence, regulatory G proteins help account for enzyme that is located on the inner surface of the cell
how drugs can bind to one type of receptor and stim- membrane, is responsible for hydrolyzing adenosine
ulate cell function, whereas drugs that bind to a dif- triphosphate (ATP) into cAMP. Cyclic AMP acts as
ferent receptor on the same cell can inhibit cell the second messenger in this system by activating
activity. G proteins also seem to be important in medi- other enzymes (i.e., protein kinases) throughout the
ating the other cell responses to stimulation or inhibi- cell. Thus, drugs that bind to a surface receptor that is
tion. For instance, cell function may continue to be linked to a Gs protein will increase adenylate cyclase
activity, resulting in increased production of cAMP
within the cell. Other drugs bound to a different
receptor that is linked to a Gi protein will inhibit
R1 R2
adenylate cyclase activity, resulting in decreased pro-
G Adenylate G duction of cAMP.
s i
Cyclase The adenylate cyclase–cAMP system is associated
with specific membrane receptors such as the beta-
adrenergic receptors.20 Other surface receptors may
also be linked to this particular effector–second mes-
cyclic AMP
senger system, or they may be linked to other intra-
protein kinase protein kinase cellular processes that use different second messengers
(inactive) (active) including: cyclic guanine monophosphate (cGMP),
cyclic adenosine diphosphoribose (cADPR), diacyl-
glycerol, phosphoinositides, nicotinic acid adenine
FIGURE 4–3 ▼ Schematic diagram of a surface receptor–second dinucleotide phosphate (NAADP), and calcium
messenger system. In this example, the second messenger is cAMP, ions.11,17,28,34,39,42,47,48
which is synthesized from ATP by the adenylate cyclase enzyme. The
Finally, alterations in the synthesis, function, and
enzyme is linked to surface receptors (R1 and R2) by regulatory G pro-
teins. GS stimulates the enzyme and Gi inhibits enzyme activity. Thus, a regulation of G proteins have been identified in certain
drug binding to R1 will increase production of cAMP, while a different pathologic conditions, including alcoholism, diabetes
drug binding to R2 will inhibit cAMP production. mellitus, heart failure, and certain tumors.20.26,35,41,52,60
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44 SECTION 1 General Principles of Pharmacology

This illustrates the fact that G proteins seem to play an and the receptor may also be important in determining
integral role in mediating the cell’s response to various the extent to which the drug binds to the receptor.
substances in both normal and disease states. The im- This drug-receptor interaction is somewhat analogous
portance of these regulatory proteins will almost cer- to a key fitting into a lock. The drug acts as a “key”
tainly continue to emerge as additional information that will only fit into certain receptors. Once inserted
about their structure and function becomes available. into a suitable receptor, the drug activates the receptor,
much like a key turning and “activating” the appropri-
ate lock. To carry this analogy one step further, unlock-
ing a door to a room would increase the “permeability”
Intracellular Receptors of the room in a manner similar to the direct effect of
Receptors have been identified at intracellular loca- certain activated membrane receptors (e.g., the acetyl-
tions such as the cytoplasm and the nucleus.1,4,10 These choline receptor on the neuromuscular junction).
intracellular receptors are specific for certain endoge- Other types of key-lock interactions would be “linked”
nous hormones, and the drugs that affect them. For to some other event, such as using a key to start an
instance, steroid and steroidlike compounds exert automobile engine. This situation is analogous to link-
some of their effects by initially interacting with a ing a surface receptor to some intracellular enzymatic
receptor that is located in the cytoplasm.4,6,31 Specifi- process that would affect the internal “machinery” of
cally, these hormones form a complex with the recep- the cell.
tor in the cytoplasm, and the hormone-receptor Although key-lock analogy serves as a crude
complex then moves to the cell’s nucleus, where it example of drug-receptor interactions, the attraction
affects the function of specific genes. Thyroid hor- between a drug and any receptor is much more com-
mones (thyroxin, triiodothyronine) appear to bind plex. Binding a drug to a receptor is not an all-or-none
directly to a receptor located on the chromatin in the phenomenon, but is graded depending on the drug in
cell’s nucleus.18 In either case, cell function is altered question. Some drugs will bind readily to the receptor,
because the hormone-receptor complex affects specific some moderately, some very little, or some not at all.
genes in the DNA and causes changes in gene expres- The term affinity is used to describe the amount of
sion and messenger RNA transcription. Altered tran- attraction between a drug and a receptor.45 Affinity is
scription of specific genes results in altered cellular actually related to the drug amount that is required to
protein synthesis, which ultimately results in altered bind to the unoccupied receptors.25 A drug with a high
cell function.1 affinity binds readily to the open receptors, even if the
Hence, certain endogenous hormones and hor- concentration of the drug is relatively low. Drugs with
mone-like drugs exert some of their effects by acting moderate or low affinity require a higher concentra-
on receptors located within the cell. It has become tion in the body before the receptors become occupied.
clear, however, that these substances might also exert In addition to the relative degree of affinity of dif-
some of their effects by binding to a second set of ferent drugs for a receptor, apparently the status of the
receptors located on the cell surface.10,18 That is, sur- receptor may also vary under specific conditions.
face receptors have been identified for steroid and thy- Receptors may exist in variable affinity states (super-
roid hormones, and stimulation of these surface high, high, low) depending on the influence of local
receptors might compliment or exaggerate the effects regulators such as guanine nucleotides, ammonium
of the intracellular receptors.1,31 The role of intracel- ions, and divalent cations.45 These local regulators are
lular receptors, and their analogous surface receptors, also known as allosteric modulators, which can bind
is discussed further in this text in the chapters that to specific sites on the receptor that are distinct from
deal with specific drugs that bind to these cellular the primary (drug) binding site, and thereby increase
components. or decrease the affinity for the drug.23,36 Membrane
receptors may also be influenced by the local environ-
ment of the lipid bilayer. The amount of flexibility or
“fluidity” of the cell membrane is recognized as being
Drug-Receptor Interactions critical in providing a suitable environment in which
The ability a drug has to bind to any receptor is dic- membrane constituents such as receptors can optimal-
tated by factors such as the drug’s size and shape rela- ly function. Physical and chemical factors (including
tive to the configuration of the binding site on the other drugs) may change the fluidity and organization
receptor. The electrostatic attraction between the drug of the membrane, thereby disrupting the normal ori-
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Chapter 4 Drug Receptors 45

entation of the receptor and subsequently altering its Drug Selectivity and
affinity state and ability to interact with a drug.9,29 Receptor Subtypes
The exact way in which a drug activates a recep-
tor has been the subject of considerable debate. Bind- A drug is said to be selective if it affects only one type
ing a drug to the receptor is hypothesized to cause the of cell or tissue and produces a specific physiologic
receptor to undergo some sort of temporary change in response. For instance, a drug that is cardioselec-
its shape or conformation. The change in structure of tive will affect heart function without affecting other
the activated receptor then mediates a change in cell tissues such as the gastrointestinal tract or respira-
function, either directly or by linking to some effector tory system. The selectivity of a particular drug is a
system. Studies have suggested that certain receptor function of the drug’s ability to interact with specific
proteins, such as the acetylcholine receptor, undergo a receptors on the target tissue, and not with other
specific change in structure after binding with specific receptors on the target tissue or on other tissues
chemicals.38, 55, 56 This event certainly seems plausible (Fig. 4–4). In reality, drug selectivity is a relative term
because most receptors have been identified as protein because no drug produces only one effect. Drugs can
molecules, and proteins are known to be able to be compared with one another, however, with the
reversibly change their shape and conformation as more selective drug being able to affect one type of tis-
part of normal physiologic function.45 This fact should sue or organ with only a minimum of other responses.
not, however, rule out other possible ways in which an The issue of drug selectivity is related closely to
activated receptor may mediate changes in cell func- the fact that many receptor populations can be divid-
tion. Future research will continue to clarify the role ed into various subtypes according to specific struc-
of conformational changes as well as other possible tural and functional differences between subgroups of
mechanisms of receptor activation. the receptor. A primary example is the cholinergic
(acetylcholine) receptor found on various tissues
throughout the body. These receptors can be classified
Functional Aspects into two primary subtypes: muscarinic and nicotinic.
Acetylcholine will bind to either subtype, but drugs
of Drug-Receptor Interactions such as nicotine will bind preferentially to the nico-
The interaction between the drug and the receptor tinic subtype, and muscarine (a toxin found in certain
dictates several important aspects of pharmacology, mushrooms) will bind preferentially to the muscarinic
including those discussed here. subtype.

Selective Nonselective
Drug Drug

Primary (beneficial) Side Effect



FIGURE 4–4 ▼ Drug selectivity. The diagram represents an ideal situation where the selective
drug produces only beneficial effects and the nonselective drug exerts both beneficial and non-
beneficial effects. Drug selectivity is actually a relative term, because all drugs produce some side
effects; however, a selective drug produces fewer side effects than a nonselective agent.
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46 SECTION 1 General Principles of Pharmacology

Other types of receptors can be divided and sub- occupies half the available receptors, for example, may
divided in a similar manner. For example, the adrener- produce a response that is greater than 50 percent of
gic receptor (i.e., the receptor for epinephrine or the maximal response.25 Clearly, other factors influ-
“adrenaline”) is divided into two primary subtypes ence the absolute magnitude of the response, including
(alpha and beta), with each subtype having two primary factors that influence the relative affinity for the drug,
divisions (alpha-1 and alpha-2; beta-1 and beta-2). Epi- and how well the occupied receptor can transmit the
nephrine will stimulate all adrenergic receptor sub- signal to the cell’s effector mechanisms. It is, nonethe-
types, but certain drugs will only affect one of the less, essentially true that increasing or decreasing the
primary divisions (e.g., a beta-selective drug), or even amount of drug available to the appropriate receptors
one subtype within each division (e.g., a beta-1 selec- will bring about a concomitant increase or decrease in
tive drug). The functional significance of adrenergic the response to that drug.45
and cholinergic receptors is discussed in more detail in
Chapter 18. Receptor subtypes also exist for other sub-
stances (opioids, dopamine, GABA, hormones, and so Classification of Drugs:
forth); the significance of these will be addressed in Agonist Versus Antagonist
their respective chapters in this text.
So far, drug-receptor interactions have been used to
The fact that many receptors can be classified
describe the process by which a drug occupies a recep-
into subtypes presents the opportunity to develop
tor and in some way activates it. The activated recep-
drugs that will produce fairly selective effects because
tor then brings about a change in cell function. A drug
they affect only one receptor subtype.5,16 A beta-1
that can bind to a receptor and initiate a change in the
selective drug, for example, will primarily affect the
function of the cell is referred to as an agonist. An
heart because the heart basically contains the beta-1
agonist is identified as having affinity and efficacy.2,45
subtype of adrenergic receptor, while other tissues
As discussed earlier, affinity refers to the fact that there
(lungs, arterioles) contain other subtypes of adrenergic
is an attraction, or desire, for the drug to bind to a
receptors. Research is ongoing to learn more about
given receptor. The second characteristic, efficacy,
the structure and function of receptor populations and
indicates that the drug will activate the receptor and
their subtypes. By knowing the characteristics of a
will subsequently lead to a change in the function of
specific receptor subtype, drugs can be designed to
the cell. Whereas an agonist has both affinity and effi-
affect only that subtype and therefore will produce
cacy, an antagonist has only affinity. This means that
more selective effects with fewer side effects.5,13
the drug will bind to the receptor, but it will not cause
any direct change in the function of the receptor or
Dose-Response cell (Fig. 4–5). Antagonists are significant because, by
occupying the receptor, they prevent the agonistic
The shape of the typical dose-response curve discussed
compound from having any effect on the cell. Antag-
in Chapter 1 is related to the number of receptors that
onists are often referred to as blockers because of their
are bound by the drug (see Fig. 1–2), because within
ability to block the effect of another chemical. The
certain limits of the drug concentration, the response
primary pharmacologic significance of these antago-
is essentially proportional to the number of receptors
nists has been their use in blocking the effects of cer-
occupied by the drug.2,25 At low dosages, for example,
tain endogenous compounds. A classic example of this
only a few receptors are bound by the drug; hence, the
is the use of the so-called beta blockers, which occupy
effect is relatively small. As the dosage (and drug con-
specific receptors on the myocardium, thus prevent-
centration) increases, more receptors become occupied
ing circulating catecholamines from increasing heart
and the response increases. Finally, at a certain dosage,
rate and contractility. Other examples of antagonistic
all available receptors will be occupied, and the
drugs are discussed in their appropriate chapters.
response will be maximal. Increasing the dosage
beyond the point at which the maximal effect is
reached will not produce any further increase in Competitive Versus
response because all the receptors are bound by the
drug. It should be noted, however, that the relationship
Noncompetitive Antagonists
between drug receptors and drug response is not a sim- Pharmacologic antagonists are generally divided into
ple linear relationship for many drugs. A drug that two categories depending on whether they are com-
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Chapter 4 Drug Receptors 47



Physiologic Effect
FIGURE 4–5 ▼ Drug classification: agonist versus antagonist. The antagonist (blocker) pre-
vents the agonist from binding to the receptor and exerting a physiologic effect.

peting with the agonist for the receptor.2,45 Competitive petitive antagonist cannot be displaced by the agonist,
antagonists are so classified because they seem to be regardless of how much agonist is present. Thus the
vying for the same receptor as the agonist. In other term noncompetitive refers to the inability of the agonist
words, both the agonist and antagonist have an equal to compete with the antagonist for the receptor site.
opportunity to occupy the receptor. For practical pur- The obvious disadvantage to this type of receptor
poses, whichever drug concentration is greater tends blocker is that the inhibition cannot be overcome in
to have the predominant effect. If the number of com- cases of an overdose of the antagonist. Also, noncom-
petitive antagonist molecules far exceeds the number petitive antagonists often remain bound for the recep-
of agonist molecules, the antagonists will occupy most tor’s lifespan, and their effect is terminated only after
of the receptors and the overall effect will be inhibi- the receptor has been replaced as part of the normal
tion of the particular response. Conversely, a high protein turnover within the cell. Consequently, the
concentration of an agonist relative to an antagonist inhibition produced by a noncompetitive blocker tends
will produce a pharmacologic effect, because the ago- to remain in effect for long periods (i.e., several days).
nist will occupy most of the receptors. In fact, raising
the concentration of the agonist with a competitive
antagonist present can actually overcome the original
Partial Agonists
inhibition, because the competitive antagonists form Drugs are classified as partial agonists when they do not
rather weak bonds with the receptor and can be dis- evoke a maximal response compared to a strong ago-
placed from it by a sufficient concentration of agonist nist. This classification is used even though the partial
molecules.2,45 This is an important advantage of com- agonist occupies all available receptors.3,32 In fact, par-
petitive antagonists because, if necessary, the inhibi- tial agonists can be thought of as having an efficacy
tion caused by the antagonist can be overcome simply that lies somewhere between that of a full agonist and
by administering high concentrations of the agonist. a full noncompetitive antagonist. The lack of a maxi-
In contrast to competitive antagonists, noncompet- mal response is not caused by decreased drug-receptor
itive antagonists form strong, essentially permanent, affinity. On the contrary, partial agonists often have a
bonds to the receptor. Noncompetitive antagonists high affinity for the receptor. The decreased efficacy
either have an extremely high affinity for the receptor may be caused by the fact that the partial agonist does
or actually form irreversible covalent bonds to the not completely activate the receptor after it binds, and
receptor.2,45 Once bound to the receptor, the noncom- that binding results in a lower level of any postrecep-
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48 SECTION 1 General Principles of Pharmacology

tor events (e.g., less activation of G proteins, smaller ity in situations where the receptor is too active or
changes in enzyme function). overstimulated.25 Future studies will be needed to
Hence, the realization that certain drugs act as determine to what extent inverse agonists might be
partial agonists has led to the idea that a range of effi- useful as therapeutic agents.
cacy can exist, depending on how specific drugs inter-
act with their respective receptors.3 At one end of this
range are the drugs that bind strongly and produce a Receptor Regulation
high degree of efficacy (strong agonists), while the
other end of the spectrum contains drugs that bind Receptor responses are not static but are regulated by
strongly and produce no effect (strong antagonists). endogenous and exogenous factors. In general, a pro-
Agents that fall between these two extremes (partial longed increase in the stimulation of various receptors
agonists) can have varying degrees of agonistic activi- will lead to a decrease in receptor function, and de-
ty. These partial agonists can also have certain clinical creased stimulation will lead to an increase in receptor
advantages. For instance, certain antipsychotic drugs numbers or sensitivity (Fig. 4–6). The mechanisms
that function as partial agonists may reduce psychotic and significance of these receptor changes are
episodes without excessive side effects.15,32 Other described here.
examples of how partial agonists can be used clinically
are discussed elsewhere in this text. Receptor Desensitization
and Down-Regulation
Mixed Agonist–Antagonists
As presented in Figure 4–6, overstimulation of postsy-
and Inverse Agonists naptic receptors by endogenous substances (neuro-
Some agents will stimulate certain receptor subtypes, transmitters, hormones) or by exogenous agonists
while simultaneously blocking the effects of endoge- (drugs) may lead to a functional decrease in the appro-
nous substances on other receptor subtypes (the priate receptor population.54,58 In effect, the cell
concept of receptor subtypes was addressed earlier in becomes less responsive to the prolonged stimulation
this chapter). These agents are known as mixed ago- by decreasing the number of active receptors. The
nist–antagonists, and they are especially useful in cer- term desensitization is used to describe a fairly brief
tain clinical situations.2 In some women, for example, and transient decrease in responsiveness.2,8 Desensiti-
it is often beneficial to stimulate estrogen receptors on zation is believed to occur because of the addition of
bone to prevent osteoporosis, while simultaneously phosphate residues (phosphorylation) or some other
blocking the effects of estrogen on breast tissues to chemical modification to the receptor protein.25,33
prevent cancer. Hence, certain drugs known as selec- Adding a phosphate molecule seems to cause some
tive estrogen receptor modulators (SERMs; see Chap- membrane receptors to be uncoupled from their inter-
ters 30, 31, and 36) can differentiate between the mediate regulatory proteins and consequently from
subtypes of estrogen receptors on these two tissues, the rest of the cell’s biochemical machinery.40 Recep-
and act as an agonist on bone and an antagonist on tor desensitization helps account for the decrease in
breast tissues.19 These agents are a good example of response that may be seen even though the agonist
drugs with mixed agonist–antagonist activity, and other remains present in high concentration in the body.
drugs with this type of mixed activity will be discussed The decrease in responsiveness caused by desensitiza-
in their respective chapters throughout this text. tion is fairly brief, however, and a return to normal
Finally, it has been proposed that some drugs response may occur within a few minutes after the
could function as inverse agonists.3,25 As this classifica- agonist is removed.
tion implies, these drugs would bind to the same Receptor down-regulation describes a slower,
receptor as the agonist, but have the opposite effect on more prolonged process in which the actual number
cellular function compared to the agonist. This effect of available receptors is diminished.30,33 Although the
is different from a traditional, or neutral, antagonist exact mechanisms responsible for down-regulation are
that binds to the tissue and simply prevents an increase not fully understood, it appears that prolonged expo-
in the agonist’s effect. By creating the opposite effect, sure of the agonist causes increased receptor removal,
inverse agonists could bring about a decrease in activ- decreased receptor synthesis, or a combination of
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Chapter 4 Drug Receptors 49


Terminal Normal Synapse

Increased Stimulation Decreased Stimulation

Receptor Receptor
Desensitization/ Supersensitivity

FIGURE 4–6 ▼ Receptor regulation. Functionally active receptor sites are represented by an “X.”
Increased stimulation results in a decrease in receptor numbers (desensitization/down-regulation),
while decreased stimulation causes increased receptor numbers (supersensitivity).

increased removal and decreased synthesis.40 In any clinical depression. These drugs are discussed in detail
event, the cell undergoes a decrease in responsiveness in Chapter 7.
that remains in effect long after the agonist is removed
(i.e., several days). Normal sensitivity to the agonist
will be reestablished only when the cell has had the
Receptor Supersensitivity
chance to replace and restore the receptors that were A prolonged decrease in the stimulation of the postsy-
eliminated during downregulation. naptic receptors can result in a functional increase in
Receptor desensitization and down-regulation receptor sensitivity. The best example of this is the den-
appear to be examples of a negative feedback system ervation supersensitivity seen when a peripheral nerve
used by the cell to prevent overstimulation by an ago- is severed.7 In this situation, the lack of presynaptic
nist. The cell appears to selectively decrease its respon- neurotransmitter release results in a compensatory
siveness to a particular stimulus in order to protect increase in postsynaptic receptor numbers on the mus-
itself from excessive perturbation. Receptor down-reg- cle cell. Similarly, the loss of the endogenous neuro-
ulation is important pharmacologically because it may transmitter dopamine in neurodegenerative conditions
be one of the primary reasons that a decrease in drug such as Parkinson disease can result in supersensitivity
responsiveness occurs when certain drugs are used for of receptors for that neurotransmitter.14 This increased
prolonged periods.33 Likewise, receptor desensitiza- receptor sensitivity becomes problematic because
tion and downregulation have been linked to several administration of dopaminelike drugs can cause exces-
pathological situations, and drugs that prevent these sive or untoward responses (see Chapter 10).14
decreases in receptor function could prove useful in A somewhat different type of denervation super-
conditions such as acute CNS injury, cardiac disease, sensitivity can also occur when receptor antagonist
or HIV infection.8,12,30 Conversely, some drugs, such as drugs are used for prolonged periods. Here the post-
the antidepressants, may exert their beneficial effects synaptic receptors are blocked by the antagonistic
by intentionally causing receptor down-regulation and drug, and are unavailable for stimulation by the appro-
desensitization in certain neural pathways that cause priate agonist. The postsynaptic neuron interprets this
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50 SECTION 1 General Principles of Pharmacology

as if the synapse were denervated and responds by SUMMARY

manufacturing more receptors, resulting in a compen-
satory increase in function at the synapse that was sup- Many drugs and endogenous chemicals exert their
posed to be blocked by the antagonist. Again, drug effects by first binding to and activating a cellular
therapy could be affected in this situation because the receptor. Cellular receptors seem to be proteins locat-
dose of the blocker will need to be altered to cope with ed on the cell surface or at specific locations within the
the new, larger population of receptors. cell. The primary role of the receptor is to recognize
specific chemicals from the vast number of com-
pounds that are introduced to the cell and to initiate a
Nonreceptor Drug change in cell function by interacting with a spe-
cific agent. Activated receptors mediate a change in
Mechanisms function by altering cell permeability or modifying
Certain drugs do not appear to exert their effects by the biochemical function within the cell, or both.
binding to a specific cellular component.45 For exam- The exact mechanism by which a receptor affects cell
ple, certain cancer chemotherapeutic agents act as function depends on the type and location of the
“antimetabolites” by becoming incorporated into the receptor.
manufacture of specific cellular components. The drug Drug-receptor interactions are significant phar-
acts as an improper ingredient in the biosynthesis of macologically because they account for some of the
the component, so that the cell does not manufacture basic pharmacodynamic principles such as drug selec-
harmful or unwanted materials. In addition, many tivity and the relationship between drug dose and
common antacids work by directly neutralizing stom- response. Also, the development of chemical agents
ach acid; that is, these drugs act via a chemical reaction that block specific receptors (antagonists) has been
rather than through a specific receptor molecule. useful in moderating the effects of endogenous com-
Other drugs may affect cell function without first bind- pounds on specific physiologic processes. Finally,
ing to a receptor by directly altering enzyme function changes in receptor number and sensitivity have been
or by acting as “chelating agents,” which bind to harm- implicated as being important in the altered response
ful compounds such as heavy metals and prevent them seen in certain drugs with prolonged use. Information
from exerting toxic effects. Additional nonreceptor- about the relationship between drugs and cellular
mediated mechanisms of specific compounds are dis- receptors has been, and will continue to be, critical to
cussed when those drugs are examined in their our understanding of how drugs work, as well as to
respective chapters. helping researchers develop new compounds.

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of the Central
Nervous System
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Chapter 5
General Principles of Central
Nervous System Pharmacology

The central nervous system (CNS) is responsible for and occipital). The outer cerebrum, or cerebral cortex,
controlling bodily functions as well as being the cen- is the highest order of conscious function and integra-
ter for behavioral and intellectual abilities. Neurons tion in the CNS. Specific cortical areas are responsible
within the CNS are organized into highly complex for sensory and motor functions as well as intellectual
patterns that mediate information through synaptic and cognitive abilities. Other cortical areas are
interactions. CNS drugs often attempt to modify the involved in short-term memory and speech. The cor-
activity of these neurons in order to treat specific dis- tex also operates in a somewhat supervisory capacity
orders or to alter the general level of arousal of the regarding lower brain functioning and may influence
CNS. This chapter presents a simplified introduction the control of other activities such as the autonomic
to the organization of the CNS and the general strate- nervous system. With regard to CNS drugs, most ther-
gies that can be used with drugs to alter activity with- apeutic medications tend to affect cortical function
in the brain and spinal cord. indirectly by first altering the function of lower brain
and spinal cord structures. An exception is the group of
drugs used to treat epilepsy; these drugs are often tar-
CNS Organization geted directly for hyperexcitable neurons in the cere-
bral cortex. In addition, drugs that attempt to enhance
The CNS can be grossly divided into the brain and cognitive function in conditions such as Alzheimer dis-
spinal cord (Fig. 5–1). The brain is subdivided accord- ease (cholinergic stimulants; see Chapter 19) might
ing to anatomic or functional criteria. The following is also exert their primary effects in the cerebrum.
a brief overview of the general organization of the
brain and spinal cord, with some indication of where
particular CNS drugs tend to exert their effects. This
Basal Ganglia
chapter is not intended to be an extensive review of A group of specific areas located deep within the cere-
neuroanatomy—a more elaborate discussion of CNS bral hemispheres is collectively termed the basal gan-
structure and function can be found in several excel- glia. Components of the basal ganglia include the
lent sources.25,28,40,41 caudate nucleus, putamen, globus pallidus, lentiform
nucleus, and substantia nigra. The basal ganglia are
primarily involved in the control of motor activities;
Cerebrum deficits in this area are significant in movement disor-
The largest and most rostral aspect of the brain is the ders such as Parkinson disease and Huntington
cerebrum (see Fig. 5–1). The cerebrum consists of bilat- chorea. Certain medications used to treat these move-
eral hemispheres, with each hemisphere anatomically ment disorders exert their effects by interacting with
divided into several lobes (frontal, temporal, parietal, basal ganglia structures.

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56 SECTION 2 Pharmacology of the Central Nervous System

Corpus Skull significant in its control over the function of hormon-

callosum Meninges al release from the pituitary gland. Several CNS drugs
Cerebrum affecting sensation and control of the body functions
listed, manifest their effects by interacting with the
thalamus and hypothalamus.

Mesencephalon and Brainstem

The mesencephalon, or midbrain, serves as a bridge
between the higher areas of the brain (cerebrum and
diencephalon) and the brainstem. The brainstem con-
Pons sists of the pons and the medulla oblongata. In addi-
tion to serving as a pathway between the higher brain
and spinal cord, the midbrain and brainstem are the
locations of centers responsible for controlling respi-
Cervical ration and cardiovascular function (vasomotor center).
The reticular formation is also located in the
midbrain and brainstem. The reticular formation is
comprised of a collection of neurons that extend from
Thoracic the reticular substance of the upper spinal cord
through the midbrain and the thalamus. The reticular
formation monitors and controls consciousness and is
Spinal also important in regulating the amount of arousal or
alertness in the cerebral cortex. Consequently, CNS
drugs that affect the arousal state of the individual
tend to exert their effects on the reticular formation.
Sedative-hypnotics and general anesthetics tend to
Lumbar decrease activity in the reticular formation, whereas
certain CNS stimulants (caffeine, amphetamines) may
increase arousal through a stimulatory effect on retic-
ular formation neurons.

Sacral Cerebellum
The cerebellum lies posterior to the brainstem and is
separated from it by the fourth ventricle. Anatomical-
ly it is divided into two hemispheres, each consisting
FIGURE 5–1 ▼ General organization of the CNS.
of three lobes (anterior, posterior, and flocculonodu-
lar). The function of the cerebellum is to help plan
and coordinate motor activity and to assume responsi-
Diencephalon bility for comparing the actual movement with the
The area of the brain enclosing the third ventricle is intended motor pattern. The cerebellum interprets
the diencephalon. This area consists of several impor- various sensory input and helps modulate motor out-
tant structures, including the thalamus and hypothala- put so that the actual movement closely resembles the
mus. The thalamus contains distinct nuclei that are intended motor program. The cerebellum is also con-
crucial in the integration of certain types of sensations cerned with the vestibular mechanisms responsible for
and their relay to other areas of the brain (such as the maintaining balance and posture. Therapeutic med-
somatosensory cortex). The hypothalamus is involved ications are not usually targeted directly for the cere-
in the control of diverse body functions including bellum, but incoordination and other movement
temperature control, appetite, water balance, and cer- disorders may result if a drug exerts a toxic side effect
tain emotional reactions. The hypothalamus is also on the cerebellum.
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Chapter 5 General Principles of Central Nervous System Pharmacology 57

Limbic System peripheral tissues. This fact suggests the existence of

some sort of unique structure and function of the
So far, all of the structures described have been CNS capillaries that prevents many substances from
grouped primarily by their anatomic relationships entering the brain and spinal cord—hence, the term
with the brain. The limbic system is comprised of sev- blood-brain barrier. This barrier effect is caused pri-
eral structures that are dispersed throughout the brain marily by the tight junctions that occur between cap-
but are often considered as a functional unit or system illary endothelial cells; in fact, CNS capillaries lack the
within the CNS. Major components of the limbic sys- gaps and fenestrations that are seen in peripheral cap-
tem include cortical structures (such as the amygdala, illaries. Also, nonneuronal cells in the CNS (e.g.,
hippocampus, and cingulate gyrus), the hypothalamus, astrocytes) and the capillary basement membrane
certain thalamic nuclei, mamillary bodies, septum pel- seem to contribute to the relative impermeability of
lucidum, and several other structures and tracts. this barrier. Functionally, the blood-brain barrier acts
These structures are involved in the control of emo- as a selective filter and seems to protect the CNS by
tional and behavioral activity. Certain aspects of moti- limiting the harmful substances that enter into the
vation, aggression, sexual activity, and instinctive brain and spinal cord.
responses may be influenced by activity within the The blood-brain barrier obviously plays an
limbic system. CNS drugs affecting these aspects of important role in clinical pharmacotherapeutics. To
behavior, including some antianxiety and antipsychot- exert their effects, drugs targeted for the CNS must be
ic medications, are believed to exert their beneficial able to pass from the bloodstream into the brain and
effects primarily by altering activity in the limbic spinal cord. In general, nonpolar, lipid-soluble drugs
structures. are able to cross the blood-brain barrier by passive dif-
fusion.6,13 Polar and lipophobic compounds are usual-
Spinal Cord ly unable to enter the brain. Some exceptions occur
because of the presence of carrier-mediated transport
At the caudal end of the brainstem, the CNS continues systems in the blood-brain barrier.23 Some substances
distally as the spinal cord. The spinal cord is cylindrical- (such as glucose) are transported via facilitated diffu-
ly shaped and consists of centrally located gray matter sion, while other compounds (including some drugs)
that is surrounded by white matter. The gray matter may be able to enter the brain by active transport.
serves as an area for synaptic connections between var- However, the transport processes that carry drugs into
ious neurons. The white matter consists of the myeli- the brain are limited to certain specific compounds,
nated axons of neurons, which are grouped into tracts and the typical manner by which most drugs enter the
ascending or descending between the brain and specif- brain is by passive lipid diffusion.20
ic levels of the cord. Certain CNS drugs exert some or Several active transport systems also exist on the
all of their effects by modifying synaptic transmission blood-brain barrier that are responsible for removing
in specific areas of gray matter, while other CNS drugs and toxins from the brain.6,11 That is, certain
drugs, such as narcotic analgesics, may exert an effect drugs can enter the brain easily via diffusion or anoth-
on synaptic transmission in the gray matter of the cord er process, but these drugs are then rapidly and effi-
as well as on synapses in other areas of the brain. Some ciently transported out of the brain and back into the
drugs may be specifically directed toward the white systemic circulation.6,13 This effect creates an obvious
matter of the cord. Drugs such as local anesthetics can problem because these drugs will not reach therapeu-
be used to block action potential propagation in the tic levels within the CNS, and won’t be beneficial.
white matter so that ascending or descending informa- Hence, the blood-brain barrier has many structural
tion is interrupted (i.e., a spinal block). and functional characteristics that influence CNS
drugs, and researchers continue to explore ways that
these characteristics can be modified to ensure ade-
The Blood-Brain Barrier quate drug delivery to the brain and spinal cord.15,23

The blood-brain barrier refers to the unique structure

and function of CNS capillaries.15,43 Certain sub-
stances are not able to pass from the bloodstream into
CNS Neurotransmitters
the CNS, despite the fact that these substances are The majority of neural connections in the human
able to pass from the systemic circulation into other brain and spinal cord are characterized as chemical
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58 SECTION 2 Pharmacology of the Central Nervous System


Transmitter Primary CNS Location General Effect

Acetylcholine Cerebral cortex (many areas); basal ganglia; lim- Excitation
bic and thalamic regions; spinal interneurons

Norepinephrine Neurons originating in brainstem and hypothala- Inhibition

mus that project throughout other areas of

Dopamine Basal ganglia; limbic system Inhibition

Serotonin Neurons originating in brainstem that project Inhibition

upward (to hypothalamus) and downward (to
spinal cord)

GABA (gamma-aminobutyric acid) Interneurons throughout the spinal cord, cerebel- Inhibition
lum, basal ganglia, cerebral cortex

Glycine Interneurons in spinal cord and brainstem Inhibition

Glutamate, aspartate Interneurons throughout brain and spinal cord Excitation

Substance P Pathways in spinal cord and brain that mediate Excitation

painful stimuli

Enkephalins Pain suppression pathways in spinal cord Excitation

and brain

synapses. The term chemical synapse indicates that a rather specific effect on the CNS, so many disorders
chemical neurotransmitter is used to propagate the may be rectified without radically altering other CNS
nervous impulse across the gap that exists between two functions. Other drugs may have a much more gener-
neurons. Several distinct chemicals have been identi- al effect and may alter transmission in many CNS
fied as neurotransmitters within the brain and spinal regions. To provide an indication of neurotransmitter
cord (Table 5–1). Groups of neurons within the CNS function, the major categories of CNS neurotransmit-
tend to use one of these neurotransmitters to produce ters and their general locations and effects are dis-
either excitation or inhibition of the other neurons. cussed subsequently.
Although each neurotransmitter can be generally
described as either excitatory or inhibitory within the
CNS, some transmitters may have different effects
depending on the nature of the postsynaptic receptor Acetylcholine is the neurotransmitter found in many
involved. As discussed in Chapter 4, the interaction of areas of the brain as well as in the periphery (skeletal
the transmitter and the receptor dictates the effect on neuromuscular junction, some autonomic synapses).
the postsynaptic neuron. In the brain, acetylcholine is abundant in the cere-
The fact that several distinct neurotransmitters bral cortex, and seems to play a critical role in
exist and that neurons using specific transmitters are cognition and memory.22,32 Neurons originating in
organized functionally within the CNS has important the large pyramidal cells of the motor cortex and
pharmacologic implications. Certain drugs may alter many neurons originating in the basal ganglia also
the transmission in pathways using a specific neuro- secrete acetylcholine from their terminal axons. In
transmitter while having little or no effect on other general, acetylcholine synapses in the CNS are excita-
transmitter pathways. This allows the drug to exert a tory in nature.
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Chapter 5 General Principles of Central Nervous System Pharmacology 59

Monoamines of the brain.4,8 Likewise, GABA is found throughout

the CNS, and is believed to be the primary neuro-
Monoamines are a group of structurally similar CNS
transmitter used to cause inhibition at presynaptic and
neurotransmitters that include the catecholamines
postsynaptic neurons in the brain and spinal
(dopamine, norepinephrine) and 5-hydroxytrypta-
cord.5,10,26,30 Other amino acids such as aspartate and
mine (serotonin).36 Dopamine exerts different effects
glutamate have been found in high concentrations
at various locations within the brain.29,37 Within the
throughout the brain and spinal cord; these substances
basal ganglia, dopamine is secreted by neurons that
cause excitation of CNS neurons.2,3,42 These excitato-
originate in the substantia nigra and project to the
ry amino acids have received a great deal of attention
corpus striatum. As such, it is important in regulating
lately because they may also produce neurotoxic
motor control, and the loss of these dopaminergic
effects when released in large amounts during CNS
neurons results in symptoms commonly associated
injury and certain neurologic disorders (epilepsy, amy-
with Parkinson disease (see Chapter 10). Dopamine
otrophic lateral sclerosis, and so forth).1,2,3,16
also influences mood and emotions, primarily via its
presence in the hypothalamus and other structures
within the limbic system. Although its effects within Peptides
the brain are very complex, dopamine generally
Many peptides have already been established as CNS
inhibits the neurons onto which it is released.
neurotransmitters.25 One peptide that is important
Norepinephrine is secreted by neurons that
from a pharmacologic standpoint is substance P, which
originate in the locus caeruleus of the pons and proj-
is an excitatory transmitter that is involved in spinal
ects throughout the reticular formation. Norepineph-
cord pathways transmitting pain impulses.14,19,38
rine is generally regarded as an inhibitory transmitter
Increased activity at substance P synapses in the cord
within the CNS, but the overall effect following activ-
serves to mediate the transmission of painful sensa-
ity of norepinephrine synapses is often general excita-
tions, and certain drugs such as the opioid analgesics
tion of the brain, probably because norepinephrine
may decrease activity at these synapses. Other pep-
directly inhibits other neurons that produce inhibi-
tides that have important pharmacologic implications
tion. This phenomenon of disinhibition causes excita-
include three families of compounds: the endorphins,
tion by removing the influence of inhibitory neurons.
enkephalins, and dynorphins.21 These peptides, also
Serotonin (also known as 5-hydroxytryptamine)
known as the endogenous opioids, are excitatory
is released by cells originating in the midline of the
transmitters in certain brain synapses that inhibit
pons and brainstem and is projected to many different
painful sensations. Hence, endogenous opioids in the
areas, including the dorsal horns of the spinal cord and
brain are able to decrease the central perception of
the hypothalamus. Serotonin is considered to be a
pain. The interaction of these compounds with exoge-
strong inhibitor in most areas of the CNS and is
nous opioid drugs is discussed in Chapter 14.
believed to be important in mediating the inhibition
Finally, peptides such as galanin, leptin, neu-
of painful stimuli. It is also involved in controlling
ropeptide Y, vasoactive intestinal polypeptide (VIP),
many aspects of mood and behavior, and problems
and pituitary adenylate cyclase–activating polypeptide
with serotonergic activity have been implicated in sev-
(PACAP) have been identified in various areas of the
eral psychiatric disorders, including depression and
CNS. These and other peptides may affect various
anxiety.12,17 The roles of serotonin and the other
CNS functions, either by acting directly as neuro-
monoamines in psychiatric disorders are discussed in
transmitters or by acting as cotransmitters moderating
Chapters 6–8.
the effects of other neurotransmitters.7,24,27,34

Amino Acids Other Transmitters

Several amino acids, such as glycine and gamma- In addition to the well-known substances, other chem-
aminobutyric acid (GABA), are important inhibitory icals are continually being identified as potential CNS
transmitters in the brain and spinal cord. Glycine neurotransmitters. Recent evidence has implicated
seems to be the inhibitory transmitter used by certain substances such as adenosine and adenosine triphos-
interneurons located throughout the spinal cord, and phate (ATP) as transmitters or modulators of neural
this amino acid also causes inhibition in certain areas transmission in specific areas of the brain and in the
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60 SECTION 2 Pharmacology of the Central Nervous System

autonomic nervous system.31,39 Many other chemicals the stimulation of postsynaptic receptors, or both.
that are traditionally associated with functions outside When considering a typical synapse, such as the one
the CNS are being identified as possible CNS trans- shown in Figure 5–2, there are several distinct sites
mitters, including histamine, nitric oxide, and certain at which a drug may alter activity in the synapse. Spe-
hormones (vasopressin, oxytocin).9,33 As the function cific ways a drug may modify synaptic transmission are
of these chemicals and other new transmitters becomes presented here.
clearer, the pharmacologic significance of drugs that
affect these synapses will undoubtedly be considered. 1. Presynaptic action potential. The arrival of an
action potential at the presynaptic terminal ini-
tiates neurotransmitter release. Certain drugs,
CNS Drugs: General such as local anesthetics, block propagation
along neural axons so that the action potential
Mechanisms fails to reach the presynaptic terminal, which
The majority of CNS drugs work by modifying synap- effectively eliminates activity at that particular
tic transmission in some way. Figure 5–2 shows a typ- synapse. Also, the amount of depolarization or
ical chemical synapse that is found in the CNS. Most the height of the action potential arriving at the
drugs that attempt to rectify CNS-related disorders presynaptic terminal is directly related to the
do so by either increasing or decreasing transmission amount of transmitter released. Any drug or
at specific synapses. For instance, psychotic behavior endogenous chemical that limits the amount of
has been associated with overactivity in central depolarization occurring in the presynaptic ter-
synapses that use dopamine as a neurotransmitter (see minal will inhibit the synapse because less neu-
Chapter 8). Drug therapy in this situation consists of rotransmitter is released. In certain situations,
agents that decrease activity at central dopamine this is referred to as presynaptic inhibition,
synapses. Conversely, Parkinson disease results from a because the site of this effect is at the presynap-
decrease in activity at specific dopamine synapses (see tic terminal. The endogenous neurotransmitter
Chapter 10). Antiparkinsonian drugs attempt to GABA is believed to exert some of its inhibitory
increase dopaminergic transmission at these synapses effects via this mechanism.
and bring synaptic activity back to normal levels. 2. Synthesis of neurotransmitter. Drugs that block the
A drug that modifies synaptic transmission must synthesis of neurotransmitter will eventually
somehow alter the quantity of the neurotransmitter deplete the presynaptic terminal and impair
that is released from the presynaptic terminal or affect transmission. For example, metyrosine (Demser)

1. Action 4. Release

3. Storage
7. Post-synaptic
5. Reuptake receptor
2. Synthesis

6. Degradation

8. Pre-synaptic
9. Membrane

FIGURE 5–2 ▼ Sites at which drugs can alter transmission at a CNS synapse.
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Chapter 5 General Principles of Central Nervous System Pharmacology 61

inhibits an enzyme that is essential for cate- enzyme as a method of treating myasthenia
cholamine biosynthesis in the presynaptic gravis. In myasthenia gravis, there is a function-
terminal. Treatment with metyrosine results al decrease in activity at the skeletal neuromus-
in decreased synthesis of transmitters such as cular junction. Anticholinesterase drugs such as
dopamine and norepinephrine. neostigmine (Prostigmin) and pyridostigmine
3. Storage of neurotransmitter. A certain amount (Mestinon) inhibit acetylcholine breakdown,
of chemical transmitter is stored in presynaptic allowing more of the released neurotransmitter
vesicles. Drugs that impair this storage will to continue to exert an effect at the neuromus-
decrease the ability of the synapse to continue cular synapse.
to transmit information for extended periods. 7. Postsynaptic receptor. As discussed in Chapter 4,
An example of this is the antihypertensive drug chemical antagonists can be used to block the
reserpine (Serpalan, Serpasil), which impairs the postsynaptic receptor, thus decreasing synaptic
ability of adrenergic terminals to sequester and transmission. The best-known example of this
store norepinephrine in presynaptic vesicles. is the use of beta blockers. These agents are
4. Release. Certain drugs will increase synaptic antagonists that are specific for the beta-adren-
activity by directly increasing the release of neu- ergic receptors on the myocardium, and they
rotransmitter from the presynaptic terminal. are frequently used to treat hypertension, car-
Amphetamines appear to exert their effects on diac arrhythmias, and angina pectoris. Other
the CNS primarily by increasing the presynaptic drugs may improve synaptic transmission by
release of catecholamine neurotransmitters (e.g., affecting the receptor directly so there is a ten-
norepinephrine). Conversely, other compounds dency for increased neurotransmitter binding or
may inhibit the synapse by directly decreasing improved receptor–effector coupling, or both.
the amount of transmitter released during each For instance, benzodiazepines (e.g., diazepam
action potential. An example is botulinum toxin [Valium], chlordiazepoxide [Librium, others])
(Botox), which can be used as a skeletal muscle appear to enhance the postsynaptic effects of
relaxant because of its ability to impair the the inhibitory neurotransmitter GABA.
release of acetylcholine from the skeletal neuro- 8. Presynaptic autoreceptors. In addition to postsy-
muscular junction (see Chapter 13). naptic receptors, there are also receptors on the
5. Reuptake. After the neurotransmitter is released, presynaptic terminal of some types of chemical
some chemical synapses terminate activity pri- synapses. These presynaptic receptors seem to
marily by transmitter reuptake. Reuptake serve as a method of negative feedback in con-
involves the movement of the transmitter mole- trolling neurotransmitter release. 18,35 During
cule back into the presynaptic terminal. A drug high levels of synaptic activity, the accumulation
that impairs the reuptake of transmitter allows of neurotransmitter in the synaptic cleft may
more of it to remain in the synaptic cleft and allow binding to the presynaptic receptors and
continue to exert an effect. Consequently, limit further release of chemical transmitter.
blocking reuptake actually increases activity at Certain drugs may also be able to attenuate
the synapse. For instance, tricyclic antidepres- synaptic activity through presynaptic autorecep-
sants (see Chapter 7) impair the reuptake mech- tors. For instance, clonidine (Catapres), may
anism that pumps amine neurotransmitters back exert some of its antihypertensive effects by
into the presynaptic terminal, which allows the binding to presynaptic receptors on sympathetic
transmitter to continue to exert its effect and postganglionic neurons and impairing the
prolong activity at the synapse. release of norepinephrine onto the peripheral
6. Degradation. Some synapses rely primarily on vasculature. The use of drugs that alter synaptic
the enzymatic breakdown of the released trans- activity by binding to these autoreceptors is still
mitter to terminate synaptic activity. Inhibition somewhat new, however, and the full potential
of the enzyme responsible for terminating the for this area of pharmacology remains to be
transmitter allows more of the active transmit- determined.
ter to remain in the synaptic cleft, thereby 9. Membrane effects. Drugs may alter synaptic
increasing activity at the synapse. An example is transmission by affecting membrane organiza-
using a drug that inhibits the cholinesterase tion and fluidity. Membrane fluidity is basically
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62 SECTION 2 Pharmacology of the Central Nervous System

the amount of flexibility or mobility of the lipid tion. Some drugs may affect the synapse in two or
bilayer. Drugs that alter the fluidity of the more ways. For example, the antihypertensive agent
presynaptic membrane could affect the way that guanethidine (Ismelin) impairs both presynaptic stor-
presynaptic vesicles fuse with and release their age and release of norepinephrine. Other drugs such
neurotransmitter. Drug-induced changes in the as barbiturates may affect both the presynaptic termi-
postsynaptic membrane would affect the recep- nal and the postsynaptic receptor in CNS synapses.
tor environment and thereby alter receptor
function. Membrane modification will result in
either increased or decreased synaptic transmis- SUMMARY
sion, depending on the drug in question and the Drugs affecting the brain and spinal cord usually exert
type and magnitude of membrane change. Alco- their effects by somehow modifying synaptic transmis-
hol (ethanol) and general anesthetics were orig- sion. In some instances, drugs may be targeted for spe-
inally thought to exert their effects by cific synapses in an attempt to rectify some problem
producing reversible changes in the fluidity and with transmission at that particular synapse. Other
organization of the cell membranes of central drugs may increase or decrease the excitability of CNS
neurons. Although this idea has been chal- neurons in an attempt to have a more general effect on
lenged somewhat, these drugs may still exert the overall level of consciousness of the individual.
some of their effects via neuronal membranes. Specific categories of CNS drugs and their pharmaco-
A CNS drug does not have to adhere specifically dynamic mechanisms are discussed in succeeding
to only one of these methods of synaptic modifica- chapters.

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Chapter 6
Sedative-Hypnotic and
Antianxiety Agents

Drugs that are classified as sedative-hypnotics are used essary, this apprehension can be controlled to some
both to relax the patient and to promote sleep.59 As the extent by using antianxiety drugs during the course
name “sedative” implies, these drugs exert a calming of rehabilitation. Consequently, many patients receiv-
effect and serve to pacify the patient. At higher doses, ing physical therapy and occupational therapy take
the same drug can produce drowsiness and initiate a sedative-hypnotic and antianxiety agents to help pro-
relatively normal state of sleep (hypnosis). At still high- mote sleep and decrease anxiety; rehabilitation spe-
er doses, some sedative-hypnotics (especially barbitu- cialists should understand the basic pharmacology of
rates) will eventually bring on a state of general these agents.
anesthesia. Because of their general central nervous
system (CNS)-depressant effects, some sedative-
hypnotic drugs are also used for other functions such Sedative-Hypnotic Agents
as treating epilepsy or producing muscle relaxation.
However, the sleep-enhancing effects will be of con- Sedative-hypnotics fall into two general categories:
cern in this chapter. benzodiazepines and nonbenzodiazepines (Table 6–1).
By producing sedation, many drugs will also At present, benzodiazepines are typically used to
decrease the level of anxiety in a patient. Of course, promote normal sedation and sleep, especially in rela-
these anxiolytic properties often cause a decrease in tively acute or short-term situations. These agents will
the level of alertness in the individual. However, cer- be addressed first, followed by a description of the
tain agents are available that can reduce anxiety with- nonbenzodiazepine hypnotics.
out an overt sedative effect. Those medications that
selectively produce antianxiety effects are discussed
later in this chapter.
Sedative-hypnotic and antianxiety drugs are Benzodiazepines are a family of compounds that share
among the most commonly used drugs worldwide. the same basic chemical structure and pharmacologi-
For example, it is estimated that insomnia affects cal effects. Although the more famous members of this
between 10 to 15 percent of the general population, family are associated with treating anxiety (e.g.,
and that pharmacological management can be helpful diazepam [Valium]; see later in this chapter), several
in promoting normal sleep.18,42 Moreover, people who benzodiazepines are indicated specifically to promote
are ill, or who have recently been relocated to a new sleep (Table 6–1). These agents exert hypnotic effects
environment (hospital, nursing home), will often have similar to those of nonbenzodiazepines—such as the
difficulty sleeping and might need some form of barbiturates—but benzodiazepines are generally
sedative-hypnotic agent.8,35,41 Likewise, a person who regarded as safer because there is less of a chance
sustains an injury or illness will certainly have some for lethal overdose.22 Benzodiazepines, however, are
apprehension concerning his or her welfare.33 If nec- not without their drawbacks, and they can cause resid-

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66 SECTION 2 Pharmacology of the Central Nervous System


Oral Adult Dose (mg)

Generic Name Trade Name Sedative Hypnotic*
Amobarbital Amytal 25–100 BID or TID 65–200
Aprobarbital Alurate 40 TID 40–160
Butabarbital Busodium, Butisol, others 15–30 TID or QID 50–100
Pentobarbital Nembutal 20 TID or QID 100
Phenobarbital Solfoton 15–40 BID or TID 100–320
Secobarbital Seconal 30–50 TID or QID 100

Estazolam ProSom 1–2
Flurazepam Dalmane 15–30
Quazepam Doral 7.5–15
Temazepam Restoril 7.5–30
Triazolam Halcion 0.125–0.25

Chloral hydrate Noctec 250 TID 500–1000
Ethchlorvynol Placidyl 500–1000
Glutethimide (generic) 250–500
Promethazine Phenergan, others 25–50
Zaleplon Sonata 10
Zolpidem Ambien 10

*Hypnotic doses are typically administered as a single dose at bedtime.

**Benzodiazepines listed here are indicated specifically as hypnotic agents and are not approved for other uses
(antianxiety, anticonvulsant, and so forth). Virtually all benzodiazepines have sedative-hypnotic effects, and other
benzodiazepines may be administered to produce sedation or sleep, depending on the dosage and the patient.

ual effects the day after they are administered; pro- initiating an increase in chloride conductance through
longed use can also cause tolerance and physical the channel. Increased chloride conductance facilitates
dependence (see “Problems and Adverse Effects,” chloride entry into the neuron and results in hyperpo-
later in this chapter).39,60 larization, or a decreased ability to raise the neuron
to its firing threshold. By binding to their own respec-
tive site on the complex, benzodiazepines potentiate
Mechanism of Benzodiazepine Effects the effects of GABA and increase the inhibition at
The benzodiazepines exert their effects by increas- these synapses.
ing the inhibitory effects at CNS synapses that use Consequently, the presence of the GABA-
the neurotransmitter gamma-aminobutyric acid benzodiazepine–chloride ion channel complex
(GABA).48,49 These inhibitory synapses are associated accounts for the specific mechanism of action of this
with a membrane protein complex containing three class of sedative-hypnotics. By increasing the inhibito-
primary components: (1) a binding site for GABA, ry effects at GABAergic synapses located in the retic-
(2) a binding site for benzodiazepines, and (3) an ular formation, benzodiazepines can decrease the level
ion channel that is specific for chloride ions (Fig. of arousal in the individual. In other words, the gener-
6–1).48,55 GABA typically exerts its inhibitory effects al excitation level in the reticular activating system
by binding to its receptor site on this complex and by decreases, and relaxation and sleep are enhanced.
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Chapter 6 Sedative-Hypnotic and Antianxiety Agents 67

Chloride channel

Schwartz JH, and Jessell TM, eds. Principles of Neural Science. 4th ed. New York: McGraw-Hill;
(From Kandel, ER. Disorders of mood: depression, mania, and anxiety disorders. In: Kandel ER,
Barbiturate Benzo GABA

␤ Benzo

2000: 882, with permission.)

FIGURE 6–1 ▼ Putative structure of the GABA-benzodiazepine-chloride ion channel complex.
The centrally located chloride ion channel is modulated by the binding of GABA to the alpha subunit
of the receptor. The binding and effects of GABA are enhanced by the binding of benzodiazepines to
the gamma subunits or barbiturates to the beta subunit.

Research has also indicated that there are at least dem (Ambien) and zaleplon (Sonata) appear to be
three primary types of GABA receptors, and these more specific for the alpha 1 subunit, and might there-
receptors are classified as GABA A, B, and C accord- fore produce sedative effects with fewer side effects.51
ing to their structural and functional characteris- These newer drugs are addressed later in this chapter.
tics.5,28,49 GABA A and GABAC receptors, for example, Because of these new advances, scientists continue
cause inhibition by increasing chloride entry, whereas to study the molecular biology of the GABAA receptor,
GABAB receptors may cause inhibition by increasing and clarify how benzodiazepines affect these receptors.
potassium exit (efflux) from CNS neurons.14 At the Likewise, differences between the principal GABA
present time, it appears that benzodiazepines act pri- receptors (A, B, C) has encouraged the development of
marily on the GABAA subtype and that the therapeu- drugs that are more selective to GABA receptors locat-
tic effects of these drugs (sedation, hypnosis, ed in certain areas of the CNS. The muscle relaxant
decreased anxiety) are mediated through the GABAA baclofen (Lioresal), for example, may be somewhat
receptor, which is found in the brain.3,48,49 Hence, more selective for GABAB receptors in the spinal cord
clinically used benzodiazepines are basically GABAA than for other GABAA or GABAC receptors that are
receptor agonists. found in the brain (see Chapter 13). Future drug devel-
Furthermore, the GABAA receptor is composed of opment will continue to exploit the differences
several subunits (alpha, beta, gamma); it appears that between the GABA receptor subtypes so that drugs are
individual subunits on this receptor mediate specific more selective and can produce more specific benefi-
effects.3,11 Sedation, for example, seems to be mediated cial effects with fewer side effects.
by the alpha 1 subunit, whereas other beneficial effects Finally, the discovery of a CNS receptor that is
such as decreased anxiety might be mediated by the specific for benzodiazepines has led to some interesting
alpha 2 and alpha 3 subunits. Benzodiazepines seem to speculation as to the possible existence of some type of
affect all of these subunits, hence their ability to pro- endogenous sedative-like agent. The presence of a cer-
duce sedative and antianxiety effects.3 tain type of receptor to indicate that the body produces
These drugs, however, might also exert certain an appropriate agonist for that receptor makes sense.
side effects (tolerance, dependence) by affecting other For instance, the discovery of opiate receptors initiat-
subunits on the GABAA receptor. A drug that is selec- ed the search for endogenous opiate-like substances,
tive for only the alpha 1 subunit might exert sedative which culminated in the discovery of the enkephalins.
effects without producing as many side effects. Some It has been surmised that certain endogenous steroids
of the newer nonbenzodiazepine drugs such as zolpi- such as allopregnanolone (a metabolic byproduct of
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68 SECTION 2 Pharmacology of the Central Nervous System

progesterone) can bind to the GABA receptors in the by this more extensive CNS depression is discussed in
CNS and produce sedative-hypnotic effects. Contin- Chapter 11.
ued research in this area may someday reveal the exact
role of steroids and other endogenous substances, and
the focus of pharmacologic treatment can then be Newer, Nonbenzodiazepine Sedative-Hypnotics
directed toward stimulating the release of endogenous Several drugs including zolpidem (Ambien) and zale-
sedative-hypnotic agents plon (Sonata) were developed recently as sedative-
hypnotics.19,25 These drugs are chemically different
Nonbenzodiazepines from the benzodiazepines, but still seem to affect the
GABAA receptors in the brain. That is, these newer
Barbiturates drugs bind to the GABAA receptor, which then causes
The barbiturates are a group of CNS depressants that GABA to bind more effectively, thus increasing chlo-
share a common chemical origin: barbituric acid. The ride conductance and the level of inhibition in the neu-
potent sedative-hypnotic properties of these drugs ron. Increased inhibition in certain areas of the brain
have been recognized for some time, and their status as results in less arousal and the promotion of sleep.
the premier medication used to promote sleep went These newer drugs appear to be as effective as the
unchallenged for many years. However, barbiturates benzodiazepines in promoting sleep. The drugs also
are associated with a relatively small therapeutic index; seem to have a lower risk of producing certain side
approximately 10 times the therapeutic dose can often effects and causing problems when discontinued (see
be fatal. These drugs are also very addictive, and their “Problems and Adverse Effects,” below).20,25,62 This
prolonged use is often a problem in terms of drug difference might be explained by the fact that newer,
abuse. Consequently, the lack of safety of the barbitu- nonbenzodiazepine drugs bind preferentially to the
rates and their strong potential for addiction and abuse alpha 1 subunit of the GABAA receptor.19,51,52 As dis-
necessitated the development of alternative nonbarbi- cussed earlier, stimulation of this particular subunit
turate drugs such as the benzodiazepines. Still, some seems to mediate sedation without producing other
barbiturates are occasionally used for their hypnotic side effects. Hence, drugs like zolpidem and zaleplon
properties; these drugs are listed in Table 6–1. are gaining acceptance for the treatment of sleep dis-
Despite their extensive use in the past, the exact orders, and efforts continue to develop other nonben-
mechanism of the barbiturates remains somewhat zodiazepine drugs that selectively affect this receptor.
unclear. When used in sedative-hypnotic doses, barbi-
turates may function in a similar fashion to the benzo-
Other Nonbenzodiazepines
diazepines in that they also potentiate the inhibitory
effects of GABA.21 This idea suggests that barbiturates Several other nonbenzodiazepine compounds can be
may affect the GABA-benzodiazepine–chloride ion prescribed for their sedative-hypnotic properties (see
channel complex described above.21 Indeed, consider- Table 6–1). These compounds are chemically dissimi-
able evidence exists that barbiturates bind directly to lar from one another, but share the ability to promote
the GABAA receptor at a site that is different from the relaxation and sleep via depressing the CNS. Cyclic
binding site for GABA or benzodiazepines (see Fig. ethers and alcohols (including ethanol) can be includ-
6–1).21 Barbiturates may, however, also exert effects ed in this category, but their use specifically as sedative-
that are not mediated through an effect on the GABA- hypnotics is fairly limited at present. The recreational
benzodiazepine–chloride ion channel. At higher doses, use of ethanol in alcoholic beverages is an impor-
for instance, barbiturates may also directly increase the tant topic in terms of abuse and long-term effects.
release of inhibitory transmitters such as glycine, and However, since this area is much too extensive to be
increase the release of excitatory transmitters such as addressed here, only their effects as sedative-hypnotics
glutamate.21,30 Regardless of their exact mechanism, is considered.
barbiturates are effective sedative-hypnotics because of Alcohol (ethanol) and other sedative-hypnotics—
their specificity for neurons in the midbrain portion of neither benzodiazepine nor barbiturate in nature—
the reticular formation as well as some limbic system work through mechanisms that are poorly understood.
structures. At higher doses, barbiturates also depress In the past, it was thought that alcohols exerted their
neuronal excitability in other areas of the brain and CNS-depressant effects directly on neuronal mem-
spinal cord. Their role in producing general anesthesia brane composition and fluidity. These and other high-
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Chapter 6 Sedative-Hypnotic and Antianxiety Agents 69

ly lipid-soluble substances could simply dissolve in the drowsiness and decreased motor performance the next
lipid bilayer and inhibit neuronal excitability by tem- day.39,60,62 These hangoverlike effects may be caused
porarily disrupting membrane structures in the presy- by the drug being redistributed to the CNS from
naptic and postsynaptic regions of CNS neurons.17 peripheral storage sites or may simply occur because
Recent evidence, however, suggests that alcohol may the drug has not been fully metabolized.
act on protein receptors much in the same way as the Anterograde amnesia is another problem some-
benzodiazepines and barbiturates. That is, alcohol times associated with sedative-hypnotic use.39 The
may exert most of its effects by activating GABAA patient may have trouble recalling details of events
receptors and increasing GABA-mediated inhibition that occurred for a certain period of time before the
in the CNS.17,31 In any event, alcohol and similar drug was taken. Although usually a minor problem,
agents bring about a decrease in neuronal transmis- this can become serious if the drug-induced amnesia
sion, which causes fairly widespread CNS depression exacerbates an already existing memory problem, as
which accounts for the subsequent sedative effects of might occur in some elderly patients.
such compounds. These residual problems can be resolved some-
what by taking a smaller dose or by using a drug with
a shorter half-life (see Table 6–2).60,63 Also, newer
Pharmacokinetics nonbenzodiazepine agents such as zolpidem and zale-
plon appear to have milder effects, perhaps because of
Benzodiazepine and nonbenzodiazepine sedative- their relatively short half-life and the limited duration
hypnotics are usually highly lipid soluble. They are of action.32,58 These newer drugs have therefore been
typically administered orally and are absorbed easily advocated in people who are prone to residual effects
and completely from the gastrointestinal tract. Distri- (e.g., older adults), and people who need to use these
bution is fairly uniform throughout the body, and drugs for an extended period of time.
these drugs reach the CNS readily because of their
high degree of lipid solubility. Sedative-hypnotics are
metabolized primarily by the oxidative enzymes of the Tolerance and Physical Dependence
drug-metabolizing system in liver cells. Termination
Another potential problem with long-term sedative-
of their activity is accomplished either by hepatic
hypnotic drug use is that prolonged administration
enzymes or by storage of these drugs in non-CNS tis-
may cause tolerance and physical dependence. Drug
sues; that is, by sequestering the drugs in adipose and
tolerance is the need to take more of a drug to exert the
other peripheral tissues, their CNS-depressant effects
same effect. Dependence is described as the onset of
are not exhibited. However, when the drugs slowly
withdrawal symptoms if drug administration is ceased.
leak out of their peripheral storage sites, they can be
Although these problems were originally thought to
redistributed to the brain and can cause low levels of
be limited to barbiturates, benzodiazepines and other
sedation. This occurrence may help explain the
sedative-hypnotics are now recognized as also causing
“hangoverlike” feelings that are frequently reported
tolerance and dependence when taken continually for
the day after taking sedative-hypnotic drugs. Finally,
several weeks.36
excretion of these drugs takes place through the kid-
The manner and severity of withdrawal symptoms
ney after their metabolism in the liver. As with most
varies according to the type of drug and the extent of
drug biotransformations, metabolism of sedative-
physical dependence.50 Withdrawal after short-term
hypnotics is essential in creating a polar metabolite
benzodiazepine use may be associated with problems
that is readily excreted by the kidney.
such as sleep disturbances (i.e., so-called rebound
insomnia).34,62 As discussed earlier, withdrawal effects
seem to be milder with the newer nonbenzodiazepine
Problems and Adverse Effects agents (zolpidem and zaleplon).34,62 Newer agents,
however, are not devoid of these problems and care
Residual Effects should be taken with prolonged use, especially in peo-
The primary problem associated with sedative- ple with psychiatric disorders or a history of substance
hypnotic use is the residual effects that can occur the abuse.26
day after administration. Individuals who take a seda- Consequently, the long-term use of these drugs
tive-hypnotic to sleep at night sometimes complain of should be avoided, and other nonpharmacologic meth-
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70 SECTION 2 Pharmacology of the Central Nervous System


Time to Peak Plasma

Drug Concentration (hr)* Relative Half-Life Comments
Estazolam (ProSom) 2.0 Intermediate Rapid oral absorption

Flurazepam (Dalmane) 0.5–1.0 Long Long elimination half-life because

of active metabolites

Quazepam (Doral) 2.0 Long Daytime drowsiness more likely

than with other benzodiazepines

Temazepam (Restoril) 1–2 Short–intermediate Slow oral absorption

Triazolam (Halcion) Within 2 Short Rapid oral absorption

*Adult oral hypnotic dose.

ods of reducing stress and promoting relaxation (e.g., associated with many of these syndromes until the sit-
mental imagery, biofeedback) should be instituted uation is resolved or until the individual is counseled
before tolerance and physical dependence.40,56 If the effectively in other methods of dealing with his or her
sedative-hypnotic drug has been used for an extended anxiety.
period, tapering off the dosage rather than abruptly Many drugs—including sedative-hypnotics—have
stopping it has been recommended as a safer way to the ability to decrease anxiety levels, but this is usually
terminate administration.25 at the expense of an increase in sedation. Frequently,
alleviating anxiety without producing excessive seda-
Other Side Effects tion is desirable so that the individual can function at
home, on the job, and so on. Consequently, certain
Other side effects such as gastrointestinal discomfort drugs are available that have significant anxiolytic
(nausea and vomiting), dry mouth, sore throat, and properties at doses that produce minimal sedation.
muscular incoordination have been reported, but Benzodiazepine drugs and other nonbenzodiazepine
these occur fairly infrequently and vary according to strategies for dealing with anxiety are discussed here.
the exact drug used. Cardiovascular and respiratory
depression may also occur, but these problems are
dose-related and are usually not significant, except in Benzodiazepines
cases of overdose.
As discussed previously, because of their relative safe-
ty, the benzodiazepines are typically the front-line
drugs used to treat many forms of anxiety.13,16 In terms
Antianxiety Drugs of anxiolytic properties, diazepam (Valium) is the pro-
Anxiety can be described as a fear or apprehension totypical antianxiety benzodiazepine (Fig. 6–2). The
over a situation or event that an individual feels is extensive use of this drug in treating nervousness and
threatening. These events can range from a change in apprehension has made the trade name of this com-
employment or family life to somewhat irrational pho- pound virtually synonymous with a decrease in tension
bias concerning everyday occurrences. Anxiety disor- and anxiety. When prescribed in anxiolytic dosages,
ders can also be classified in several clinical categories diazepam and certain other benzodiazepines (Table
including generalized anxiety disorder, social anxiety 6–3) will decrease anxiety without major sedative
disorder, panic disorder, obsessive-compulsive disor- effects. Some sedation, however, may occur even at
der, and posttraumatic stress syndrome.54 Antianxiety anxiolytic dosages; these drugs can be used as sedative-
drugs can help decrease the tension and nervousness hypnotics simply by increasing the dosage.
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Chapter 6 Sedative-Hypnotic and Antianxiety Agents 71

CH3 Buspirone
O Buspirone (BuSpar) is an antianxiety agent that was
approved in 1986 for treating general anxiety disor-
der.2 This agent is not a benzodiazepine. It belongs
N instead to a drug class known as the azapirones.2
CI Therefore, buspirone does not act on the GABA
receptor, but exerts its antianxiety effects by increasing
the effects of 5-hydroxytryptamine (serotonin) in cer-
tain areas of the brain.12 Buspirone is basically a sero-
tonin agonist that stimulates certain serotonin
receptors, especially the 5-HT1A serotonin receptor
Diazepam subtype.6,10 This increase in serotonergic influence is
FIGURE 6–2 ▼ Diazepam (Valium). beneficial in treating general anxiety disorder and pos-
sibly in panic disorder, obsessive-compulsive disorder,
posttraumatic stress syndrome, and various other dis-
The mechanism of action of the benzodiazepines orders that are influenced by CNS serotonin levels.7
was discussed previously in this chapter. The antianx- More importantly, buspirone has a much better
iety properties of these drugs involve a mechanism side-effect profile than traditional antianxiety drugs.
similar or identical to their sedative-hypnotic effects Buspirone seems to produce less sedation and psy-
(i.e., potentiating GABAergic transmission).37 Benzo- chomotor impairment than benzodiazepine agents.2
diazepines also seem to increase inhibition in the There is a much smaller risk of developing tolerance
spinal cord, which produces some degree of skeletal and dependence to buspirone and the potential for
muscle relaxation, which may contribute to their abuse is much lower than with other anxiolytics.57
antianxiety effects by making the individual feel more Buspirone has only moderate efficacy, however, and
relaxed. The use of these drugs as skeletal muscle this drug may not take effect as quickly in patients
relaxants is further discussed in Chapter 13. with severe anxiety.57 Nonetheless, buspirone offers a


Generic Name Trade Name Antianxiety Relative Half-Life

Dose (mg)*
Alprazolam Xanax 0.25–0.5 TID Short–intermediate

Chlordiazepoxide Librium, others 5–25 TID or QID Long

Clonazepam Klonopin 0.25–0.50 BID Intermediate

Clorazepate Tranxene, others 7.5–15 BID to QID Long

Diazepam Valium, others 2–10 BID to QID Long

Halazepam Paxipam 20–40 TID or QID Long

Lorazepam Ativan 1–3 BID or TID Short–intermediate

Oxazepam Serax 10–30 TID or QID Short–intermediate

*Dose refers to initial adult oral dose. Dosage is adjusted depending on the patient’s response. Doses are like-
wise often lower in elderly or debilitated patients.
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72 SECTION 2 Pharmacology of the Central Nervous System

safer alternative to traditional antianxiety drugs such these drugs can decrease situational anxiety without
as benzodiazepines, especially if patients need to producing sedation.27 In particular, beta blockers such
receive treatment for an extended period of time. as propranolol (Inderal) have been used by musicians
Development of additional azapirones and other drugs and other performing artists to decrease cardiac palpi-
that influence serotonin activity may continue to pro- tations, muscle tremors, hyperventilation, and other
vide better and safer antianxiety agents in the future. manifestations of anxiety that tend to occur before an
important performance.43 Beta blockers probably exert
their antianxiety effects through their ability to
Use of Antidepressants in Anxiety decrease activity in the sympathetic nervous system,
Many patients with anxiety also have symptoms of that is, through their sympatholytic effects. These
depression.47 It therefore seems reasonable to include drugs may exert both peripheral sympatholytic effects
antidepressant drugs as part of the pharmacological (e.g., blockade of myocardial beta-1 receptors) as well
regimen in these patients. Hence, patients with a com- as decreasing central sympathetic tone. In any event,
bination of anxiety and depression often take a tradi- beta blockers may offer a suitable alternative to
tional antianxiety agent such as a benzodiazepine along decrease the effects of nervousness without a concomi-
with an antidepressant.44 The pharmacology of the tant decrease in levels of alertness or motivation.43
antidepressants is addressed in Chapter 7. Again, these drugs have gained popularity with per-
Antidepressant drugs, however, might have direct forming artists as a way to blunt the symptoms of per-
anxiolytic effects. That is, certain antidepressants such formance anxiety without actually diminishing the
as paroxetine (Paxil) or venlafaxine (Effexor) can help anticipation and excitement that is requisite for a
reduce anxiety independent of their effects on depres- strong performance.
sion.1,47 These antidepressants have therefore been
advocated as an alternative treatment for anxiety, espe-
cially for people who cannot tolerate the side effects of
Problems and Adverse Effects
traditional anxiolytics, or who might be especially sus- Most of the problems that occur with benzodiazepine
ceptible to the addictive properties of drugs like the anxiolytic drugs are similar to those mentioned regard-
benzodiazepines.1,9,46 Moreover, antidepressants such ing the use of these agents as sedative-hypnotics. Seda-
as paroxetine or venlafaxine are now considered effec- tion is still the most common side effect of anxiolytic
tive as the primary treatment for several forms of anx- benzodiazepines, even though this effect is not as pro-
iety, including generalized anxiety disorder, social nounced as with their sedative-hypnotic counter-
phobia, and panic disorder.4,29,53 Antidepressants, parts.61 Still, even short-term use of these drugs can
either used alone or in combination with antianxiety produce psychomotor impairment, especially during
drugs, have become an important component in the activities that require people to remain especially alert,
treatment of anxiety. such as driving a car.60,61 Addiction and abuse are prob-
lems with chronic benzodiazepine use, and withdrawal
from these drugs can be a serious problem.36 Also, anx-
Other Antianxiety Drugs iety can return to, or exceed, pretreatment levels when
The ideal antianxiety agent is nonaddictive, safe (i.e., benzodiazepines are suddenly discontinued, a problem
relatively free from harmful side effects and potential known as rebound anxiety.1,13 The fact that chronic
for lethal overdose), and not associated with any seda- benzodiazepine use can cause these problems rein-
tive properties. Drugs such as meprobamate (Miltown) forces the idea that these drugs are not curative and
and barbiturates are not currently used to any great should be used only for limited periods of time as an
extent because they do not meet any of these criteria adjunct to other nonpharmacologic procedures such as
and are no more effective in reducing anxiety than psychologic counseling.24,45
benzodiazepines. As indicated earlier, buspirone and Problems and side effects associated with bus-
certain antidepressants currently offer an effective and pirone include dizziness, headache, nausea, and rest-
somewhat safer method of treating anxiety, and the use lessness. Antidepressants such as paroxetine and
of these agents has increased dramatically in recent venlafaxine also produce a number of side effects
years. Another option includes the beta-adrenergic (described in Chapter 7) depending on the specific
antagonists (beta blockers, see Chapter 20) because agent. Nonetheless, these newer, nonbenzodiazepine
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Chapter 6 Sedative-Hypnotic and Antianxiety Agents 73

anxiolytics tend to produce less sedation, and their extremely drowsy. Consequently, scheduling patients
potential for addiction is lower compared to benzodi- for certain types of rehabilitation within several hours
azepines. Hence, nonbenzodiazepine drugs might be after administration of sedative-hypnotics or sedative-
an attractive alternative, especially in patients who like anxiolytics is counterproductive and should be
are prone to sedation (e.g., older adults), patients with avoided.
a history of substance abuse, or people who need Finally, benzodiazepines and other drugs used to
chronic anxiolytic treatment. treat sleep disorders and anxiety are often associated
with falls and subsequent trauma including hip frac-
tures, especially in older adults.15,45,60 The risk of falls
Special Consideration of is greater in people who have a history of doing so or
Sedative-Hypnotic and Antianxiety who have other problems that would predispose them
to falling (vestibular disorders, impaired vision, and so
Agents in Rehabilitation forth). Therapists can identify such people and inter-
Although these drugs are not used to directly influ- vene to help prevent this through balance training,
ence the rehabilitation of musculoskeletal or other environmental modifications (removing cluttered fur-
somatic disorders, the prevalence of their use in niture, throw rugs, and so forth), and similar activities.
patient populations is high. Any time a patient is hos- Therapists can help plan and implement nonpharma-
pitalized for treatment of a disorder, a substantial cological interventions to help decrease anxiety and
amount of apprehension and concern exists. The for- improve sleep. Interventions such as regular physical
eign environment of the institution as well as a change activity, massage, and various relaxation techniques
in the individual’s daily routine can understandably may be very helpful in reducing stress levels and pro-
result in sleep disturbances.23 Likewise, older adults moting normal sleep.38,40,56 Therapists can therefore
often have trouble sleeping, and the use of sedative- help substitute nonpharmacological methods for tra-
hypnotic agents is common, especially in patients liv- ditional sedative-hypnotic and antianxiety drugs, thus
ing in nursing homes or other facilities.8,35,41 improving the patient’s quality of life by avoiding
Individuals who are involved in rehabilitation pro- drug-related side effects.
grams, both as inpatients and as outpatients, may also
have a fairly high level of anxiety because of concern
about their health and ability to resume normal func-
tioning.33 Acute and chronic illnesses can create Sedative-hypnotic and antianxiety drugs play a promi-
uncertainty about a patient’s future family and job nent role in today’s society. The normal pressures of
obligations as well as doubts about his or her self- daily life often result in tension and stress, which
image. The tension and anxiety produced may neces- affects an individual’s ability to relax or cope with
sitate pharmacologic management. stress. These problems are compounded when there is
The administration of sedative-hypnotic and some type of illness or injury present. As would be
antianxiety drugs has several direct implications for expected, a number of patients seen in a rehabilitation
the rehabilitation session. Obviously the patient will setting are taking these drugs. Benzodiazepines have
be much calmer and more relaxed after taking an long been the premier agents used to treat sleep disor-
antianxiety drug, thus offering the potential benefit ders and anxiety; they all share a common mechanism
of gaining the patient’s full cooperation during a phys- of action, and they potentiate the inhibitory effects of
ical or occupational therapy treatment. Anxiolytic GABA in the CNS. With regard to their sedative-hyp-
benzodiazepines, for example, reach peak blood levels notic effects, benzodiazepines such as flurazepam and
2 to 4 hours after oral administration, so scheduling triazolam are commonly used to promote sleep.
the rehabilitation session during that time may Although these drugs are generally safer than their
improve the patient’s participation in treatment. Of forerunners, they are not without their problems.
course, this rationale will backfire if the drug produces Newer nonbenzodiazepine sedative-hypnotics such
significant hypnotic effects. Therapy sessions that as zolpidem and zaleplon may also be effective in treat-
require the patient to actively participate in activities ing sleep disorders, and these newer agents may be
such as gait training or therapeutic exercise will be somewhat safer than their benzodiazepine counter-
essentially useless and even hazardous if the patient is parts. Benzodiazepines such as diazepam (Valium)
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74 SECTION 2 Pharmacology of the Central Nervous System

Sedative-Hypnotic Drugs present to a much greater extent than the normal slow start
that occurs in some patients on wakening in the morning. The
Brief History. R.S. is a 34-year-old construction therapists also found that when ADL or mobility training was
worker who sustained a fracture-dislocation of the vertebral taught during the morning sessions, there was poor carryover
column in an automobile accident. He was admitted to an from day to day regarding these activities.
acute care facility, where a diagnosis of complete paraplegia Decision/Solution. The benzodiazepine drug ap-
was made at the T-12 spinal level. Surgery was performed to peared to be producing a hangoverlike effect, which limited
stabilize the vertebral column. During the next 3 weeks, his the patient’s cognitive skills during the early daily activities. Ini-
medical condition improved. At the end of 1 month, he was tially this problem was dealt with by reserving the early
transferred to a rehabilitation facility to begin an intensive pro- morning session for stretching and ROM activities, and then
gram of physical and occupational therapy. Rehabilitation gradually moving into upper-body strengthening. Activities
included strengthening and range-of-motion (ROM) exercis- that required more patient learning and comprehension were
es, as well as training in wheelchair mobility, transfers, and done later in the morning or in the afternoon. Also, this hang-
activities of daily living (ADLs). However, upon arriving at the overlike problem was brought to the attention of the physician,
new institution, R.S. complained of difficulty sleeping. Flu- and the hypnotic drug was ultimately switched to zolpidem
razepam (Dalmane) was prescribed at a dosage of 20 mg (Ambien) because this is a relatively short-acting nonbenzodi-
administered orally each night at bedtime. azepine with a half-life of 2.6 hours (range 1.4–4.5 hours),
Problem/Influence of Medication. During his daily compared to flurazepam (Dalmane), which is a long-acting
rehabilitation regimen, the therapists noted that R.S.’s per- benzodiazepine that can have a half-life of up to 74 hours
formance and level of attentiveness were markedly poor dur- (range 47–100 hours) because of its active metabolites.
ing the morning sessions. He was excessively lethargic and Switching to zolpidem might also result in fewer problems (i.e.,
drowsy, and his speech was slurred. These symptoms were rebound insomnia) when it is time to discontinue the drug.

leave as are also used frequently to reduce anxiety, but ical and psychologic dependence, sedative-hypnotic
the introduction of newer drugs such as buspirone and and antianxiety drugs should not be used indefinitely.
specific antidepressants (paroxetine, venlafaxine) have These drugs should be prescribed judiciously as an
provided an effective but somewhat safer alternative adjunct to helping patients deal with the source of their
for treating anxiety. Because of the potential for phys- problems.

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Database Syst Rev. 2003;CD003592. Journal. 2001;1:192–193.
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49. Rudolph U, Mohler H. Analysis of GABAA receptor apy for persistent insomnia. Am J Psychiatry. 2002;
function and dissection of the pharmacology of benzo- 159:5–11.
diazepines and general anesthetics through mouse 57. Sramek JJ, Zarotsky V, Cutler NR. Generalised anxiety
genetics. Annu Rev Pharmacol Toxicol. 2004;44: disorder: treatment options. Drugs. 2002;62: 1635–
475–498. 1648.
50. Salzman C. Addiction to benzodiazepines. Psychiatr Q. 58. Terzano MG, Rossi M, Palomba V, Smerieri A, Parri-
1998;69:251–261. no L. New drugs for insomnia: comparative tolerabili-
51. Sanger DJ. The pharmacology and mechanisms of ty of zopiclone, zolpidem and zaleplon. Drug Saf.
action of new generation, non-benzodiazepine hypnotic 2003;26:261–282.
agents. CNS Drugs. 2004; 18(suppl 1):9–15; discussion 59. Trevor AJ, Way WL. Sedative-hypnotic drugs. In:
41, 43–45. Katzung BG, ed. Basic and Clinical Pharmacology.
52. Sanna E, Busonero F, Talani G, et al. Comparison of 9th ed. New York: Lange Medical Books/McGraw
the effects of zaleplon, zolpidem, and triazolam at vari- Hill; 2004.
ous GABA (A) receptor subtypes. Eur J Pharmacol. 60. Vermeeren A. Residual effects of hypnotics: epidemiol-
2002;451:103–110. ogy and clinical implications. CNS Drugs. 2004;18:
53. Sheehan DV, Mao CG. Paroxetine treatment of gener- 297–328.
alized anxiety disorder. Psychopharmacol Bull. 2003;37 61. Verster JC, Volkerts ER. Clinical pharmacology,
(suppl 1):64–75. clinical efficacy, and behavioral toxicity of alprazolam:
54. Shelton CI. Diagnosis and management of anxiety dis- a review of the literature. CNS Drug Rev. 2004;10:
orders. J Am Osteopath Assoc. 2004; 104(suppl 3): 45–76.
S2–S5. 62. Wagner J, Wagner ML. Non-benzodiazepines for the
55. Sigel E. Mapping of the benzodiazepine recognition treatment of insomnia. Sleep Med Rev. 2000;4:
site on GABA (A) receptors. Curr Top Med Chem. 551–581.
2002;2:833–839. 63. Wang JS, DeVane CL. Pharmacokinetics and drug
56. Smith MT, Perlis ML, Park A, et al. Comparative interactions of the sedative hypnotics. Psychopharmacol
meta-analysis of pharmacotherapy and behavior ther- Bull. 2003;37:10–29.
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Chapter 7
Drugs Used to Treat Affective
Disorders: Depression and
Bipolar Syndrome

Affective disorders comprise the group of mental con- ings of sadness and despair. While a certain amount of
ditions that includes depression, bipolar syndrome disappointment and sadness is part of everyday life, a
(manic-depression), and several others that are charac- diagnosis of clinical depression indicates that these
terized by a marked disturbance in a patient’s mood.41 feelings are increased in both intensity and duration to
Patients with an affective disorder typically present an incapacitating extent.
with an inappropriate disposition, feeling unreason- Depressive disorders are characterized by a gen-
ably sad and discouraged (major depressive disorder) eral dysphoric mood (sadness, irritability, feeling
or fluctuating between periods of depression and “down in the dumps”), as well as by a general lack of
excessive excitation and elation (bipolar disorder). interest in previously pleasurable activities. Other
Because these forms of mental illness are relative- symptoms including anorexia, sleep disorders (either
ly common, many rehabilitation specialists will work too much or too little), fatigue, lack of self-esteem,
with patients who are receiving drug therapy for an somatic complaints, and irrational guilt. Recurrent
affective disorder. Also, serious injury or illness may thoughts of death and suicide may also help lead to a
precipitate an episode of depression in the patient diagnosis of depression. To initiate effective treat-
undergoing physical rehabilitation. Consequently, this ment, a proper diagnosis must be made; depression
chapter will discuss the pharmacologic management must not be confused with other mental disorders that
of affective disorders, as well as how antidepressant also may influence mood and behavior (e.g., schizo-
and antimanic drugs may influence the patient phrenia). To standardize the terminology and aid in
involved in physical therapy and occupational therapy. recognizing depression, specific criteria for diagnosis
has been outlined by the American Psychiatric Associ-
ation.2 Depressive disorders can also be subclassified
Depression according to the type, duration, and intensity of the
patient’s symptoms.9,41,71 For the purpose of this chap-
Clinical Picture ter, the term depression will be used to indicate major
Depression is considered to be the most prevalent depressive disorder, but readers should be aware that
mental illness in the United States, with approximate- the exact type of depression may vary somewhat from
ly 15 percent of adults experiencing major depression person to person.
at some point in their life.73 Likewise, as many as 10 The causes of depression seem to be complex and
percent of Americans may experience major depres- unclear. Although a recent stressful incident, misfor-
sion over a 1-year period.43 In this sense, depression is tune, or illness can certainly exacerbate an episode of
a form of mental illness characterized by intense feel- depression, some patients may become depressed for

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78 SECTION 2 Pharmacology of the Central Nervous System

no apparent reason. The role of genetic factors in nephrine, and dopamine. Amine neurotransmitters are
depression has been explored but remains uncertain. found in many areas of the brain, and are important in
Over the past few decades, it has been suggested that controlling many aspects of mood and behavior.
a central nervous system (CNS) neurochemical imbal- However, the exact problem in CNS amine neu-
ance may be the underlying feature in depression, as rotransmission remains a subject of much debate. One
well as in other forms of mental illness. The impor- leading theory is that depression may be caused by an
tance of these findings as related to pharmacologic increased sensitivity of the presynaptic or postsynaptic
treatment will be discussed later. However, factors receptors for these transmitters. That is, the neuro-
responsible for initiating these changes in CNS func- chemistry of the brain has been changed in some way
tion are unclear. Depression is undoubtedly caused by to make the amine receptors more sensitive to their
the complex interaction of a number of genetic, envi- respective amine neurotransmitters (norepinephrine,
ronmental, and biochemical factors.18,38,46,57 serotonin, and to a lesser extent, dopamine).21 This
Treatment of depression is essential in minimiz- theory is based primarily on the finding that antide-
ing the disruptive influence that this disease has on the pressant drugs prolong the activity of amine neuro-
patient’s quality of life, and on his or her relationship transmission in the brain, thereby causing a
with their family and job. Procedures ranging from compensatory decrease in the sensitivity of the amine
psychotherapy to electroconvulsive treatment can be receptors.21,47
prescribed, depending on the severity and type. Drug The idea that depression is associated with
treatment plays a major role in alleviating and pre- changes in amine receptor sensitivity is summarized in
venting the occurrence of major depression, and this Figure 7–1. For reasons that are still unclear, depres-
form of therapy is presented here. sion might occur because of an increase in postsynap-
tic receptor sensitivity to amine neurotransmitters,
particularly norepinephrine and serotonin.4 Anti-
Pathophysiology of Depression depressant drugs increase amine transmission by a
It appears that depression is related to a disturbance in variety of methods, thereby bringing about overstim-
CNS neurotransmission involving certain chemicals ulation of the postsynaptic receptor. (The exact
know as amine neurotransmitters. These transmitters method by which these drugs increase amine stimula-
include 5-hydroxytryptamine (serotonin), norepi- tion is discussed later in this chapter.) Overstimulation

1. Depression: 2. Antidepressants: 3. Down-regulations:

receptor "supersensitivity" enhance stimulation of receptor sensitivity
to amine neurotransmitters postsynaptic and decreases
presynaptic receptors
FIGURE 7–1 ▼ Theoretic basis for the mechanism and treatment of depression. Functionally
active receptor sites are indicated by an “*.” Depression is believed to be initiated by increased post-
synaptic or presynaptic receptor sensitivity. Drugs that enhance stimulation of these receptors ulti-
mately lead to receptor down-regulation, thus resolving the depression (see text for details).
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Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome 79

of the postsynaptic receptor then leads to a compensa- determined.59 Nonetheless, it is apparent that stress
tory down-regulation and decreased sensitivity of the hormones such as cortisol can play a role in the patho-
receptor. As discussed in Chapter 4, this down-regula- genesis of depression, and research is currently under-
tion is a normal response to overstimulation by either way to discover how antidepressant medications can
endogenous or exogenous agonists. As receptor sensi- help normalize glucocorticoid responsiveness in cer-
tivity decreases, the clinical symptoms of depression tain types of the disorder.7
might be resolved. Hence, complex neurochemical changes seem to
On the other hand, it has been suggested that the occur in certain areas of the brain in people with
primary problem in depression is an increased sensi- depression, and these changes may vary depending on
tivity to receptors that are located on the presynaptic each person and the specific type of depression. Like-
terminals of amine synapses.54 These presynaptic wise, changes in other brain chemicals—such as brain-
“autoreceptors” normally regulate and limit the derived tropic factor, gamma-aminobutyric acid
release of amine transmitters, such as norepinephrine (GABA), substance P, glutamate, and cyclic adenosine
or serotonin, from the presynaptic terminal. Increas- monophosphate (cAMP) response element may also
ing their sensitivity could result in a relative lack of play a role in the pathophysiology of depression.1,4,36,56
adequate neurotransmitter release at these synapses. Changes in brain chemistry may be associated with
By causing overstimulation of these presynaptic recep- altered neuronal structure and plasticity, and changes
tors, antidepressant drugs could eventually normalize in cellular growth and hippocampus volume have been
their sensitivity and help reestablish proper control reported in people with depression.42,50,66 Future
and regulation of these amine synapses.54 research will continue to clarify the exact cellular and
It must be emphasized that it is difficult to prove subcellular events that occur during depression, and
the neurochemical changes that underlie depression, how these events can be resolved pharmacologically. It
and the way that antidepressant drugs help resolve is apparent, however, that current drug therapy is
depression remains theoretical at present. Still, certain focused on modifying one or more receptor popula-
aspects of drug therapy tend to support the amine tions at brain synapses that use amine transmitters.
hypothesis and the putative changes in receptor sensi- These drugs are discussed here.
tivity induced by drug therapy. For instance, there is
usually a time lag of approximately 2 to 4 weeks before
antidepressant drugs begin to work.54 This latency
Antidepressant Drugs
period would be necessary for a compensatory change The drugs that are currently used to treat depression
in receptor sensitivity to take place after drug therapy are grouped into several categories, according to
is initiated.54 chemical or functional criteria. These categories con-
Still, the exact neurochemical changes in depres- sist of the tricyclics, monoamine oxidase (MAO) inhi-
sion are difficult to determine, and probably involve bitors, and second-generation drugs (Table 7–1). All
other neurotransmitters and receptors. For example, three groups attempt to increase aminergic transmis-
high levels of glucocorticoids, such as cortisol, are sion, but by different mechanisms (Fig 7–2). Sympath-
found in the bloodstream of certain people with omimetic stimulants such as the amphetamine drugs
depression.15 This makes sense because cortisol is were also used on a limited basis to treat depression,
often released from the adrenal cortex in response to but the powerful CNS excitation produced by amphe-
stress, and prolonged or severe stress can be a precip- taminelike drugs and the potential for addiction and
itating factor in certain forms of depression (see Chap- overdose have essentially eliminated their use as anti-
ter 28 for a description of cortisol production).40,68 depressants. The pharmacologic effects of the primary
Apparently, excess glucocorticoid levels overstimulate antidepressant drug categories are discussed below.
glucocorticoid receptors in the brain, bringing about a Tricyclics. Drugs in this category share a common
compensatory decrease in the sensitivity and respon- three-ring chemical structure (hence the name “tri-
siveness of these receptors.7 The decreased respon- cyclic”). These drugs work by blocking the reuptake of
siveness of these glucocorticoid receptors is somehow amine neurotransmitters into the presynaptic termi-
related to the dysfunction in serotonin neurotransmis- nal.61,67 Actively transporting amine neurotransmitters
sion described above.40 The relationship between glu- back into the presynaptic terminal is the method by
cocorticoid receptor sensitivity and dysfunctional which most (50 to 80 percent) of the released trans-
serotonin activity is not completely understood, and mitter is removed from the synaptic cleft. By blocking
the exact way that these systems interact has not been reuptake, tricyclics allow the released amines to
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80 SECTION 2 Pharmacology of the Central Nervous System


Generic Name Trade Name Initial Adult Dose (mg/day) Limits* (mg/day)
Amitriptyline Elavil, Endep, others 50–100 300

Amoxapine Asendin 100–150 600

Clomipramine Anafranil 75 300

Desipramine Norpramin 100–200 300

Doxepin Sinequan 75 300

Imipramine Norfranil, Tofranil, others 75–200 300

Nortriptyline Aventyl, Pamelor 75–100 150

Protriptyline Vivactil 15–40 60

Trimipramine Surmontil 75 300

Monoamine oxidase (MAO) inhibitors

Isocarboxazid Marplan 20 60

Phenelzine Nardil 45 90

Tranylcypromine Parnate 30 60

Second-generation agents
Bupropion Wellbutrin 150 400

Citalopram Celexa 20 60

Escitalopram Lexapro 10 20

Fluoxetine Prozac 20 80

Fluvoxamine Luvox 50 300

Maprotiline Ludiomil 25–75 225

Mirtazapine Remeron 15 45

Nefazodone Serzone 200 600

Paroxetine Paxil 20 50

Sertraline Zoloft 50 200

Trazodone Desyrel 150 600

Venlafaxine Effexor 75 375

*Upper limits reflect dosages administered to patients with severe depression who are being treated
as inpatients.
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Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome 81


MAO Inhibitors
MAO (inhibit breakdown)

Release Tricyclics &
drugs (inhibit reuptake)


FIGURE 7–2 ▼ Effects of antidepressant drugs on amine synapses. All three types of drugs
tend to increase the presence of amine transmitters (norepinephrine, dopamine, serotonin) in
the synaptic cleft. Increased transmitter stimulation leads to postsynaptic receptor down-regula-

remain in the cleft and continue to exert their effects. the tricyclics, MAO inhibitors directly increase activi-
The prolonged stimulation of these neurotransmitters ty at amine synapses, which can bring about changes in
(especially norepinephrine) leads to the compensatory the activity and sensitivity of receptors at this synapse.
decrease in receptor sensitivity, which ultimately leads MAO inhibitors are not usually the drugs of choice in
to a decrease in depression. depression, but they may be helpful if patients do not
In the past, tricyclic drugs such as amitripty- respond to other agents (tricyclics, second-generation
line and nortriptyline were the most commonly used drugs), or if other antidepressants produce intolerable
antidepressants and were the standard against which side effects.
other antidepressants were measured.30 The use of The MAO enzyme exists in two primary forms or
tricyclic drugs as the initial treatment of depression has subtypes: MAO type A and MAO type B.4 These two
diminished somewhat in favor of some of the newer subtypes are differentiated according to their ability to
second-generation drugs, which may have more favor- degrade specific amines and according to the ability of
able side-effect profiles. Tricyclic agents, nonetheless, various drugs to inhibit one or both subtypes of the
remain an important component in the management MAO enzyme. Preliminary evidence suggests that
of depressive disorders, especially in more severe forms selective inhibition of MAO type A may be desirable
of depression that fail to respond to other antide- in treating depression,4 whereas inhibition of MAO
pressants.6,53 type B may be more important in prolonging the
Monoamine Oxidase Inhibitors. Monoamine oxi- effects of dopamine in Parkinson disease (see Chapter
dase (MAO) is an enzyme that is located at amine 10). Regardless, the MAO inhibitors currently used as
synapses and helps remove released transmitters antidepressants are relatively nonselective, meaning
through enzymatic destruction. Drugs that inhibit this that they inhibit MAO A and MAO B fairly equally.
enzyme allow more of the transmitter to remain in the Development of new MAO inhibitors may produce
synaptic cleft and continue to exert an effect.74 As with agents that are more selective for the MAO A subtype
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82 SECTION 2 Pharmacology of the Central Nervous System

and may therefore produce better antidepressant regular basis.58 SSRIs may also be less toxic during
effects with fewer side effects.4 overdose than more traditional antidepressants such
Second-Generation Antidepressants. Because of as the tricyclics.64,72 These serotonin selective drugs
the limitations of first-generation drugs such as the have therefore become the antidepressant drugs of
tricyclics and MAO inhibitors, a number of diverse choice for many patients, and are often prescribed as
compounds have been developed and continue to be the initial method of treatment in people who are
evaluated for their antidepressant effects. There is depressed.64
some evidence that certain second-generation drugs Other selective drugs. Drugs that are relatively
are more effective in treating specific depressive selective for other types of monoamines are also
symptoms in some patients, but the newer agents have administered as possible antidepressants. Reboxetine,
not been proven to be categorically more effective for example, is a relatively new agent that selectively
than the older drugs.12,48,70 The newer agents, howev- inhibits transmitter reuptake at norepinephrine
er, tend to have a lower incidence of side effects such synapses.34,55 There is likewise an emerging group of
as cardiovascular problems, sedation, and so forth. drugs, such as venlafaxine, that selectively decrease
Hence, these newer drugs may be better-tolerated and serotonin and norepinephrine reuptake without an
provide better long-term management of depression appreciable effect of dopamine synapses.31 These drugs
because of improved patient satisfaction and adher- are known as serotonin/norepinephrine reuptake
ence to drug therapy.58 inhibitors (SNRIs), and they may be more effective
Newer antidepressants are chemically diverse, than other agents in resolving depression, especially in
but most work by mechanisms similar to tricyclic resistant cases or in people with severe depres-
drugs; that is, they block reuptake of norepinephrine sion.19,33,69 There is also some evidence that SNRIs
and other monoamines. Hence, these drugs appear to such as venlafaxine and mirtazapine might take effect
exert their beneficial effects by bringing about a recep- more quickly than traditional drugs such as the tri-
tor sensitivity decrease, which seems to be the com- cyclics and SSRIs.11,19 The development of SNRIs and
mon denominator of antidepressant drugs’ action. various other selective drugs—including SSRIs—has
The second-generation drugs and their proposed opened new opportunities for the optimal manage-
mechanisms of action are summarized in Table 7–2. In ment of depression. Future studies will undoubtedly
addition, certain second-generation drugs are distin- shed light on how these more selective agents can be
guished by their ability to selectively influence specif- best used to treat specific depressive symptoms and
ic monoamines rather than all the amine transmitters types of depression.
simultaneously. Subcategories of these selective drugs
are discussed below. Pharmacokinetics
Selective serotonin reuptake inhibitors. Certain
Antidepressants are usually administered orally.
second-generation drugs have received attention
Dosages vary depending not only on each drug but
because of their ability to selectively block the reup-
also on the individual patient. Initial dosages general-
take of 5-hydroxytryptamine (serotonin). Fluoxetine
ly start out relatively low and are increased slowly
(Prozac) and similar agents (citalopram, escitalopram,
within the therapeutic range until beneficial effects are
fluvoxamine, paroxetine, sertraline, see Table 7–2) are
observed. Distribution within the body also varies
functionally grouped together as selective serotonin
with each type of antidepressant, but all eventually
reuptake inhibitors (SSRIs).54,64 This distinguishes
reach the brain to exert their effects. Metabolism takes
them from the tricyclics, MAO inhibitors, and other
place primarily in the liver, and metabolites of several
second-generation drugs because these other drugs
drugs continue to show significant antidepressant
tend to be nonselective in their effect on amine neu-
activity. This fact may be responsible for prolonging
rotransmitters and block the reuptake of norepineph-
the effects of the drug, even after it has undergone
rine and dopamine, as well as serotonin. The primary
hepatic biotransformation. Elimination takes place by
advantage of the SSRIs is that they produce fewer and
biotransformation and renal excretion.
less bothersome side effects than their nonselective
counterparts. This improved side-effect profile can be
very helpful in the long-term management of depres-
Problems and Adverse Effects
sion because patients may tolerate these drugs better Tricyclics. A major problem with the tricyclic
and be more willing to take their medication on a antidepressants is sedation (Table 7–3). Although a
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Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome 83


Drug (Amine selectivity) Advantages Disadvantages
Selective serotonin reuptake inhibitors
Citalopram Strong, selective inhibition Low incidence of sedation May cause sexual dysfunc-
(Celexa) of serotonin reuptake and anticholinergic effects; tion (decreased libido,
does not cause orthostatic impotence)
hypotension or cardiac

Escitalopram Strong, selective inhibition Similar to citalopram Similar to citalopram

(Lexapro) of serotonin reuptake

Fluoxetine Moderate, selective inhibi- No sedative, anticholinergic, May cause anxiety, nausea,
(Prozac) tion of serotonin reuptake or cardiovascular side insomnia; long half-life
effects; helpful in obses- can lead to accumulation
sive-compulsive disorder

Fluvoxamine Strong, selective inhibition Similar to fluoxetine Similar to fluoxetine

(Luvox) of serotonin reuptake

Paroxetine Strong, selective inhibition Similar to citalopram Similar to citalopram

(Paxil) of serotonin reuptake

Sertraline Strong, selective inhibition Similar to fluoxetine Similar to fluoxetine

(Zoloft) of serotonin reuptake

Other second-generation agents

Bupropion Primarily inhibits dopamine Low sedative, anticholinergic, May cause overstimulation
(Wellbutrin, Zyban) reuptake; little effect on and cardiovascular side (insomnia, tremor) and
norepinephrine or sero- effects; also used as an induce psychotic symp-
tonin intervention to quit ciga- toms
rette smoking

Maprotiline Moderate inhibition of nor- Sedating: useful in agitation Possibility of seizures; over-
(Ludiomil) epinephrine reuptake doses lethal; long half-life

Mirtazapine Exact mechanism unclear; Low incidence of sedative, May cause agitation, anxi-
(Remeron) may increase norepi- anticholinergic, and car- ety, other mood changes
nephrine and serotonin diovascular side effects
activity by blocking
inhibitory presynaptic

Nefazodone Slight inhibition of serotonin Sedating: useful in agitation May cause orthostatic
(Serzone) and norepinephrine reup- hypotension because
take; may also block of antagonistic effect
CNS serotonin receptors on vascular alpha-1

(Continued on following page)

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84 SECTION 2 Pharmacology of the Central Nervous System


Drug (Amineselectivity) Advantages Disadvantages
Trazodone Slight inhibition of serotonin Sedating: useful in agitation; May cause orthostatic
(Desyrel) reuptake lower relative risk of over- hypotension (similar to
dose nefazodone); serious
problems related to pri-
apism may also occur
in men

Venlafaxine Strong inhibition of norepi- Low risk of orthostatic May cause hypertension
(Effexor) nephrine and serotonin hypotension, sedation, and
reuptake anticholinergic side effects

certain degree of sedation may be desirable in some concurrently. Also, there is a distinct interaction be-
patients who are agitated and depressed, feelings of tween the MAO inhibitors and certain foods such as
lethargy and sluggishness may impair patient adher- fermented cheese and wines.76 These fermented foods
ence to drug therapy and result in a failure to take contain tyramine, which stimulates the release of
medication. A second major problem is that these endogenous epinephrine and norepinephrine (the so-
drugs tend to have significant anticholinergic proper- called cheese effect). The additive effect of increased
ties; that is, they act as if they are blocking certain cen- catecholamine release (because of the ingested tyra-
tral and peripheral acetylcholine receptors (see Table mine) and decreased catecholamine breakdown
7–3). Impairment of central acetylcholine transmis- (because of MAO inhibition) can lead to excessive cat-
sion may cause confusion and delirium. The peripher- echolamine levels and a hypertensive crisis.76
al anticholinergic properties produce a variety of Second-Generation Drugs. The type and severity
symptoms including dry mouth, constipation, urinary of side effects associated with newer antidepressants
retention, and tachycardia. Other cardiovascular varies according to the specific drug in use. SSRIs and
problems include arrhythmias and orthostatic SNRIs, for example, generally produce less sedation,
hypotension, with the latter being particularly com- anticholinergic effects, and cardiovascular effects than
mon in elderly patients. Finally, tricyclics have the the tricyclics, MAO inhibitors, and other second-
highest potential for fatal overdose from an antide- generation drugs.17 These newer drugs, however, are
pressant.62,72 This fact leads to a serious problem when not devoid of side effects, and these agents often pro-
one considers the risk of suicide among depressed duce more gastrointestinal problems and insomnia
patients. These drugs should be used cautiously in than other antidepressants. Also, drugs that cause an
patients who have suicidal thoughts or a history of sui- excessive increase of serotonin activity in the brain
cidal behaviors. may cause “serotonin syndrome,” which is character-
MAO Inhibitors. In contrast to the tricyclics, ized by sweating, shivering, movement disorders
MAO inhibitors tend to produce CNS excitation, (severe restlessness, dystonias, dyskinesias), muscle fas-
which can result in restlessness, irritability, agitation, ciculations, and other neuromuscular symptoms.22,25
and sleep loss. These drugs also produce some central These symptoms typically disappear if the drug is dis-
and peripheral anticholinergic effects (e.g., tremor, continued, but they should be identified early or this
confusion, dry mouth, urinary retention), but these syndrome could progress to seizures and coma.25
effects tend to occur in a lesser extent than with the Advantages and disadvantages of common sec-
tricyclics (see Table 7–3). Because of the systemic ond-generation drugs are listed in Table 7–2, and
MAO inhibition, excess activity at peripheral sympa- comparison of these drugs to the tricyclics and MAO
thetic adrenergic terminals may cause a profound inhibitors is summarized in Table 7–3. Various factors,
increase in blood pressure, leading to a hypertensive including potential side effects, are considered when
crisis. This situation is exacerbated if other drugs that selecting one of these drugs, and selection of the best
increase sympathetic nervous activity are being taken drug must be done on a patient-by-patient basis.
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Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome 85


Anticholinergic Orthostatic Cardiac

Drug Sedation Effects Hypotension Arrhythmias Seizures
Tricyclic drugs
Amitriptyline ⫹⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹

Amoxapine ⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹

Clomipramine ⫹⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹⫹⫹

Desipramine ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹

Doxepin ⫹⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹

Imipramine ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹

Nortriptyline ⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹⫹

Protriptyline ⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹

Trimipramine ⫹⫹⫹⫹ ⫹⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹

Monoamine oxidase (MAO) inhibitors

Phenelzine ⫹⫹ ⫹ ⫹⫹ ⫹ ⫹

Tranylcypromine ⫹ ⫹ ⫹⫹ ⫹ ⫹

Second-generation drugs
Bupropion 0 ⫹ 0 ⫹ ⫹⫹⫹⫹

Citalopram ⫹ 0 0 0 ⫹⫹

Fluoxetine 0 0 0 0 ⫹⫹

Fluvoxamine 0 0 0 0 ⫹⫹

Maprotiline ⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹⫹

Mirtazapine ⫹⫹ ⫹ ⫹⫹ ⫹ ⫹

Nefazodone ⫹⫹⫹ 0 ⫹⫹⫹ ⫹ ⫹⫹

Paroxetine ⫹ ⫹ 0 0 ⫹⫹

Sertraline 0 0 0 0 ⫹⫹

Trazodone ⫹⫹⫹⫹ 0 ⫹⫹⫹ ⫹ ⫹⫹

Venlafaxine ⫹ ⫹ 0 ⫹ ⫹⫹

*Zero denotes no side effect, ⫹ a very low incidence, ⫹⫹ a low incidence, ⫹⫹⫹ a moderate incidence, and
⫹⫹⫹⫹ a high incidence.
Adapted from Kando, et al. Depressive disorders. In: DiPiro JT, et al, eds. Pharmacotherapy: A Pathophysiologic
Approach. 5th ed. New York: McGraw-Hill; 2002:1250, with permission.
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86 SECTION 2 Pharmacology of the Central Nervous System

Use of Antidepressants associated with mood swings from one extreme

in Chronic Pain (mania) to the other (depression).10 Manic episodes
are characterized by euphoria, hyperactivity, and talk-
Many chronic pain syndromes (neuropathic pain, ativeness, and depressive episodes are similar to those
fibromyalgia, chronic low back pain, and so forth) can described previously. Approximately 10 percent of all
be treated more effectively if antidepressants are patients with depression are considered to exhibit
included in the treatment regimen.45,52,65 In particular, bipolar syndrome.10
certain tricyclic agents such as amitriptyline, nortripty- As in unipolar depression, the exact causes of
line, doxepin, and desipramine: may help provide bet- bipolar disorder are unknown. One theory is that
ter pain relief when used along with traditional genetic and environmental factors conspire to increase
analgesic medications or, in some cases, when these norepinephrine and possibly serotonin influence in
tricyclic drugs are used alone.45,60 Some studies attrib- the brain.23 This increase in neurotransmitter activity
ute this effect to the fact that clinical depression is appears to be responsible for the manic episodes of
present in many patients with chronic pain; adminis- this disorder. The subsequent depression may simply
tering antidepressants will help provide optimal care be a rebound from the general excitement of the
by resolving the depressive symptoms.3,14 There is manic episode. The exact cause of bipolar disorder is
considerable evidence, however, that antidepressants not clear; however, the manic episode of this condition
will help patients with chronic pain even if no symp- may also be caused by neuroendocrine factors, an
toms of depression are present. That is, improvements imbalance in cations such as sodium and calcium, or
in pain have been noted even when there has been no changes in the cellular and subcellular responses in
observed effect on the patient’s mood. As indicated specific brain neurons.10,23 In any event, the treatment
earlier, these drugs have the ability to modulate the of bipolar disorder focuses on preventing the start of
influence of serotonin and other CNS monoamine these pendulumlike mood swings by preventing the
neurotransmitters, and their effects on chronic pain manic episodes. Hence, drugs used to treat manic-
may be related to the influence on monoamine trans- depression are really “antimanic drugs.” The primary
mission in critical pain pathways in the brain.13,24,45 For form of drug treatment consists of lithium salts (i.e.,
the most part, however, the exact way that antidepres- lithium carbonate, lithium citrate).27,44 In addition,
sants affect pain perception remains unknown. lithium is a useful adjunct to other antidepressant
Hence, there is little doubt that antidepressants drugs in treatment-resistant unipolar depression.16,28
may be useful as an adjunct in the treatment of patients
with chronic pain. Traditional tricyclic medications
such as amitriptyline and nortriptyline are often con- Lithium
sidered the drugs of choice for chronic pain.52 Newer Lithium (Li⫹) is a monovalent cation included in the
drugs such as the SSRIs (e.g., paroxetine) and SNRIs alkali metal group. Because of its small size (molecular
(e.g., venlafaxine) might also be considered for some weight 7) and single positive charge, lithium may influ-
patients with fibromyalgia, neuropathies, and other ence neural excitability by competing with other
forms of chronic pain.29 Future research should help cations including sodium, potassium, and calcium.5
clarify how specific antidepressants can be used most The exact way that lithium helps stabilize mood, how-
effectively as part of a comprehensive regimen for ever, is not known.32 Several theories have been pro-
treating various types of chronic pain. posed, and lithium has been shown to produce several
neurochemical effects that could contribute to its anti-
manic properties. In particular, lithium may stabilize
neuronal excitability by decreasing the sensitivity of
Treatment of Bipolar certain postsynaptic receptors and by uncoupling these
Disorder: Antimanic Drugs receptors from their subcellular second-messenger sys-
tems.5,10 For example, studies have shown that lithium
Bipolar Disorder can diminish the function of cAMP and other second-
The form of depression discussed previously is often messenger systems that are normally stimulated by
referred to as major depressive disorder or unipolar norepinephrine.5,10 Lithium has also been shown to
depression, in contrast to bipolar or “manic-depressive” inhibit certain intracellular enzymes such as protein
disorder. As these terms imply, bipolar syndrome is kinase C, glycogen synthetase kinase3-beta, and inosi-
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Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome 87

tol monophosphatase, which may help account for Side effects are frequent with lithium, and the
decreased neuronal excitation and desensitization.8,10,35 degree and type depends on the amount of lithium in
In addition, lithium has been shown to directly the bloodstream. As Table 7–4 indicates, some side
decrease the release of certain amine neurotransmitters effects are present even when serum levels are within
(norepinephrine and dopamine) and to increase the the therapeutic range.23 However, toxic side effects
effects of other transmitters (serotonin, acetylcholine, become more apparent when serum concentrations
and GABA).23 Obviously, lithium has the potential to reach 1.5 mEq/L, and become severe when serum lev-
influence synaptic function and neural excitability in els exceed 3.0 mEq/L.23 Progressive accumulation of
many ways. Exactly how this drug is able to stabilize lithium can lead to seizures, coma, and even death.
mood and prevent the manic episodes associated with Consequently, clinicians with patients receiving lithi-
bipolar disorder remains to be determined.5,32 um should be aware of any changes in behavior that
might indicate that this drug is reaching toxic levels.
Absorption and Distribution These changes can usually be resolved by adjusting
the dosage or using a sustained-release form of lithi-
Lithium is readily absorbed from the gastrointestinal um.27 Also, serum titers of lithium should be moni-
tract and completely distributed throughout all the tored periodically to ensure that blood levels remain
tissues in the body. During an acute manic episode, within the therapeutic range.27
achieving blood serum concentrations between 1.0
and 1.4 mEq/L is desirable. Maintenance doses are Other Drugs Used in Bipolar Disorder
somewhat lower, and serum concentrations that range
from 0.5 to 1.3 mEq/L are optimal. Although lithium remains the cornerstone of treat-
ment for bipolar disorder, it is now recognized that
other agents may be helpful, especially during manic
Problems and Adverse Effects of Lithium
episodes. In particular, antiseizure medications such as
A major problem with lithium use is the danger of carbamazepine, valproic acid, gabapentin, and lamot-
accumulation within the body.27 Lithium is not rigine may help stabilize mood and limit manic symp-
metabolized, and drug elimination takes place almost toms.20,26,49 Antipsychotic medications, including the
exclusively through excretion in the urine. Conse- newer agents such as clozapine and resperidone (see
quently, lithium has a tendency to accumulate in the Chapter 8), may also be helpful as antimanic drugs.63,75
body, and toxic levels can frequently be reached dur- Antiseizure and antipsychotic drugs are believed to be
ing administration. helpful because they act directly on CNS neurons to


Mild (Below 1.5 mEq/L) Moderate (1.5–3.0 mEq/L) Severe (Above 3.0 mEq/L)
Fine hand tremor (resting) Confusion Choreoathetoid movements

Gastrointestinal upset Lethargy Seizures

Muscle weakness Ataxia Respiratory complications

Fatigue Dysarthria Coma

Problems with memory and Nystagmus Death

concentration Emesis
Increased deep tendon reflexes
Increased tremor
Muscle fasciculations

Adapted from: Fankhauser, pp 1280–1281,23 with permission.

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88 SECTION 2 Pharmacology of the Central Nervous System

help prevent the neuronal excitation that seems to pre- mood at baseline levels and to prevent the mood
cipitate manic symptoms.10 (Details about the pharma- swings that characterize bipolar disorder. These addi-
cology of antipsychotic and antiseizure drugs are tional drugs may be discontinued when the mood is
addressed in Chapters 8 and 9, respectively.) Hence, stabilized, or they may be administered alone or with
these drugs can be used initially, along with lithium, to lithium treatment as maintenance therapy in the long-
decrease manic mood swings, or to simply stabilize term treatment of bipolar disorder.28,39,51

Special Concerns in Rehabilitation Patients

■ ■ ■ Some amount of depression is certain to be present as a result of a catastrophic injury or
illness. Patients receiving physical therapy and occupational therapy for any number of acute or
chronic illnesses may be taking antidepressants in order to improve their mood and general
well-being. Of course, therapists working in a psychiatric facility will deal with many patients
taking antidepressant drugs, and severe depression may be the primary reason the patient is
institutionalized in the first place. However, these drugs are also frequently prescribed to
patients with a spinal cord injury, stroke, severe burn, multiple sclerosis, amputation, and so on.
Therapists must realize that adequate treatment of depression is a very difficult clinical task.
Even with optimal pharmacologic and psychologic intervention, it is estimated that up to one
third of patients with depression may not adequately respond.4 Depression is a very serious and
complex psychological disorder, and the effects of drug treatment vary greatly from individual
to individual. It is therefore imperative that the physician and other health care professionals
work closely with the patient and the patient’s family to find the drug that produces optimal
results with a minimum of side effects. Again, this task is complicated by many issues including
the complex interplay of factors causing depression in each patient and their rather unpre-
dictable response to each type of antidepressant.
With regard to the impact of antidepressant and antimanic agents on the rehabilitation
process, these drugs can be extremely beneficial in helping to improve a patient’s outlook. The
patient may become more optimistic regarding the future and may assume a more active role
and interest in the rehabilitation process. This behavior can be invaluable in increasing patient
cooperation and improving compliance with rehabilitation goals. However, certain side effects
can be somewhat troublesome during rehabilitation treatments. Sedation, lethargy, and muscle
weakness can occur with the tricyclics and lithium, which can present a problem if the patient’s
active cooperation is required. Other unpleasant side effects, such as nausea and vomiting, can
also be disturbing during treatments. A more common and potentially more serious problem is
the orthostatic hypotension that occurs predominantly with the tricyclics. This hypotension can
cause syncope and subsequent injury if patients fall during gait training. Conversely, MAO
inhibitors can increase blood pressure, and care should be taken to avoid a hypertensive crisis,
especially during therapy sessions that tend to increase blood pressure (e.g., certain forms of
exercise). Hence, patients should also be monitored regularly to detect an increase or decrease
in blood pressure depending on the drug and the patient.
Finally, rehabilitation specialists should remember that some improvement in mood may
occur within 2 weeks after beginning antidepressant drug treatment, but that these agents must
often be administered for 1 month or more before an appreciable improvement in symptoms
occurs.4 During this period, drug therapy may actually precipitate an increase in depression,
including increased thoughts of suicide.37 Rehabilitation specialists should keep alert for any
signs that a patient is becoming more depressed and possibly suicidal, especially during the first
few weeks after antidepressant drug therapy is initiated.
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Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome 89

Antidepressant Drugs duce orthostatic hypotension during the initial stages of drug
therapy. Since the patient is expressively aphasic, he will have
Brief History. J.G., a 71-year-old retired pharmacist, trouble telling the therapist that he feels dizzy or faint. Also,
was admitted to the hospital with a chief complaint of an the cardiac beta blockers will blunt any compensatory
inability to move his right arm and leg. He was also unable to increase in cardiac output if blood pressure drops during pos-
speak at the time of admission. The clinical impression was tural changes.
right hemiplegia caused by left-middle cerebral artery throm- Decision/Solution. The therapist decided to place
bosis. The patient also had a history of hypertension and had the patient on the tilt table for the first day after imipramine
been taking cardiac beta blockers for several years. J.G.’s was started and to monitor blood pressure regularly. While
medical condition stabilized, and the third day after admission the patient was on the tilt table, weight shifting and upper-
he was seen for the first time by a physical therapist. Speech extremity facilitation activities were performed. The patient tol-
and occupational therapy were also soon initiated. The erated this well, so the therapist had him resume ambulation
patient’s condition improved rapidly, and motor function activities using the parallel bars on the following day. With the
began to return in the right side. Balance and gross motor patient standing inside the bars, the therapist carefully
skills increased until he could transfer from his wheelchair to watched for any subjective signs of dizziness or syncope in
his bed with minimal assistance, and gait training activities the patient (i.e., facial pallor, inability to follow instructions).
were being initiated. J.G. was able to comprehend verbal Standing bouts were also limited in duration. By the third day,
commands, but his speech remained markedly slurred and ambulation training continued with the patient outside the
difficult to understand. During his first 2 weeks in the hospi- parallel bars, but the therapist made a point of having the
tal, J.G. showed signs of severe depression. Symptoms patient’s wheelchair close at hand in case the patient began
increased until cooperation with the rehabilitation and nursing to appear faint. These precautions of careful observation and
staff was being compromised. Imipramine (Tofranil) was pre- short, controlled bouts of ambulation were continued
scribed at a dosage of 150 mg/day. throughout the remainder of the patient’s hospital stay, and
Problem/Influence of Medication. Imipramine is a no incident of orthostatic hypotension was observed during
tricyclic antidepressant, and these drugs are known to pro- physical therapy.

SUMMARY seem to exert their effects by modifying CNS synaptic

transmission and receptor sensitivity in amine path-
Affective disorders such as depression and manic- ways. The exact manner in which these drugs affect
depression are found frequently in the general popu- synaptic activity has shed some light on the possible
lation as well as in rehabilitation patients. Drugs neuronal changes that underlie these forms of mental
commonly prescribed in the treatment of (unipolar) illness. Antidepressant and antimanic drugs can
depression include the tricyclics and MAO inhibitors improve the patient’s attitude and compliance during
as well as the newer second-generation antidepres- rehabilitation, but therapists should be aware that cer-
sants. Lithium is the drug of choice for treating bipo- tain side effects may alter the patient’s physical and
lar disorder, or manic-depression. All of these drugs mental behavior.

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Chapter 8
Antipsychotic Drugs

Psychosis is the term used to describe the more those of schizophrenia, and this specific condition will
severe forms of mental illness. Psychoses are actually a be used as an example of the broader range of psy-
group of mental disorders characterized by marked chotic conditions.
thought disturbance and an impaired perception of
reality. The most common form of psychosis by far is
schizophrenia; it is estimated that 1 percent of the
world population has the disorder.23,47 Other psychot-
ic disorders include psychotic depression and severe The Diagnostic and Statistical Manual of Mental Disor-
paranoid disorders. In the past, strong, sedativelike ders lists several distinct criteria necessary for a diagno-
drugs were the primary method of treating patients sis of schizophrenia.5 These criteria include a marked
with psychosis. The goal was to pacify these patients disturbance in the thought process, which may include
so that they were no longer combative and abusive to bizarre delusions and auditory hallucinations (i.e.,
themselves and others. These drugs were commonly “hearing voices”). Also, a decreased level of function in
referred to as “major tranquilizers” and had the obvi- work, social relations, and self-care may be present.
ous disadvantage of sedating a patient so that his or Other factors include the duration of these and addi-
her cognitive and motor skills were compromised. tional symptoms (at least 6 months) and a differential
As researchers learned more about the neurolog- diagnosis from other forms of mental illness (such as
ic changes involved in psychosis, drugs were devel- affective disorders and organic brain syndrome).
oped to specifically treat disorders rather than simply The exact cause of schizophrenia has been the
sedate the patient. These antipsychotic drugs, or neu- subject of extensive research. It appears that genetic
roleptics, as some clinicians refer to them, represent factors (i.e., chromosomal abnormalities that cause
a major breakthrough in the treatment of schizophre- deviations in brain structure and function) are the pri-
nia and other psychotic disorders. mary risk factors in the majority of people with schiz-
Physical and occupational therapists frequently ophrenia (70% to 80%).15,23 Environmental factors
encounter patients taking antipsychotics. Therapists (social stresses, prenatal or childhood brain injury, and
employed in a psychiatric facility will routinely treat so forth) seem to be the underlying cause in the
patients taking these medications. Therapists who remaining 20% to 30% of people with schizophre-
practice in nonpsychiatric settings may still encounter nia.23 The precise role of these factors, and the inter-
these patients for various reasons. For instance, a play between genetic and environmental factors,
patient on an antipsychotic medication who sustains a continues to be elucidated.28,50, 61
fractured hip may be seen at an orthopedic facility. The advent of antipsychotic drugs represents one
Consequently, knowledge of antipsychotic pharmacol- of the most significant developments in the treatment
ogy will be useful to all rehabilitation specialists. of schizophrenia and similar disorders. These drugs
Because of the prevalence of schizophrenia, this are believed to be the single most important reason for
chapter concentrates on the treatment of this psychot- the abrupt decrease in the number of mental patients
ic disorder. Also, the pathogenesis and subsequent admitted to public hospitals during the 1950s and
treatment of other forms of psychosis are similar to 1960s.22 This observation does not imply that these

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94 SECTION 2 Pharmacology of the Central Nervous System

drugs cure schizophrenia. Schizophrenia and other impairment might result from diminished cortical
psychoses are believed to be incurable, and psychotic dopamine activity.1
episodes can recur throughout a patient’s lifetime. Hence, it appears that the primary neurochemical
However, these drugs can normalize the patient’s change in schizophrenia is increased dopamine activi-
behavior and thinking during an acute psychotic ty in certain limbic structures, but that this dopamine
episode, and maintenance dosages are believed to help hyperactivity brings about subsequent changes in neu-
prevent the recurrence of psychosis. Consequently, the rotransmitter activity in other areas of the brain as
ability of people with psychosis to take care of them- well. Resolving all these neurochemical changes might
selves and cooperate with others is greatly improved. ultimately provide optimal treatment for people with
schizophrenia and other forms of psychosis. For now,
however, antipsychotic drugs are mainly focused on
Neurotransmitter Changes resolving the increased dopaminergic activity that
seems to initiate psychosis. These drugs are discussed
in Schizophrenia in more detail in the next sections of this chapter.
Schizophrenia appears to be caused by an overactivity
of dopamine pathways in certain parts of the brain
such as the limbic system.2,23 This idea is based prima- Antipsychotic Mechanism
rily on the fact that most antipsychotics block
dopamine receptors, thereby reducing dopaminergic
of Action
hyperactivity in mesolimbic pathways and other lim- Antipsychotic drugs used to successfully treat schizo-
bic structures (see the next section of this chapter). phrenia block central dopamine receptors to some
The increased dopamine influence underlying psy- extent (Fig. 8–1).19,23 These drugs share some struc-
chosis could be caused by excessive dopamine synthe- tural similarity to dopamine, which allows them to
sis and release by the presynaptic neuron, decreased bind to the postsynaptic receptor, but they do not acti-
dopamine breakdown at the synapse, increased postsy- vate it. This action effectively blocks the receptor
naptic dopamine receptor sensitivity, or a combination from the effects of the released endogenous neuro-
of these and other factors. transmitter (see Fig. 8–1). Any increased activity at
Consequently, increased dopamine transmission central dopamine synapses is therefore negated by a
in areas such as the limbic system seems to be the pri- postsynaptic receptor blockade.
mary neurochemical change associated with schizo- It has become evident, however, that there are
phrenia and other psychotic syndromes. However, several subcategories of dopamine receptors, and
given the complexity of central neurotransmitter these receptor subtypes are identified as D1, D2, D3,
interaction, changes in dopamine activity in the limbic
system will almost certainly result in changes in other
Antipsychotic Drug
neurotransmitters in other parts of the brain. Indeed,
there is substantial evidence that individuals with psy-
chosis might also have decreased activity in cortical
pathways that use glutamate as a neurotransmit-
ter,15,37,41 and it seems likely that other transmitters
such as gamma-aminobutyric acid (GABA) and 5-
hydroxytriptamine (serotonin) may also be affected
during the pathogenesis and treatment.16,23 Moreover,
the increased dopamine activity in subcortical struc- Presynaptic
terminal Postsynaptic
tures may result in an decreased activity in cortical neuron
dopamine activity.2 This imbalance in dopamine
activity in different brain regions might explain
the different symptoms associated with psychosis. Dopamine
That is, positive symptoms such as agitation and
hallucinations might be caused by excess dopamine FIGURE 8–1 ▼ Effects of antipsychotic drugs on dopamine synaps-
influence in subcortical regions, whereas negative es. Antipsychotics act as postsynaptic receptor antagonists to block the
symptoms such as withdrawn behavior and cognitive effects of overactive dopamine transmission.
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Chapter 8 Antipsychotic Drugs 95

and so on.18 The clinical effects and side effects of spe- creased incidence of extrapyramidal (motor) side
cific antipsychotic medications are therefore related to effects. This increased risk may be due to the tradi-
their ability to affect certain dopamine receptor popu- tional agents’ tendencies to bind to several types of
lations. The receptor that appears to be most impor- CNS dopamine receptors, including the receptors that
tant in mediating antipsychotic effects is the D2 influence motor function. This fact seems especially
receptor subtype.32,51 Most antipsychotic medications true for high-potency traditional agents such as
therefore have some ability to block the D2 subtype. It haloperidol (Haldol) and fluphenazine (Prolixin).
is also clear, however, that other dopamine receptor These agents have a strong affinity for CNS dopamine
subtypes play a role in the pathogenesis of psychosis, receptors and can exert beneficial effects when used in
and that certain antipsychotic drugs may produce spe- low dosages (see Table 8–1). Other traditional agents
cific effects because of their affinity for specific recep- such as chlorpromazine (Thorazine) and thioridazine
tor subtypes. For example, newer antipsychotics such (Mellaril) have lower potency and must be used in
as clozapine block D4 receptors, and this action may high dosages to exert an antipsychotic effect. These
help explain differences in the effects and side effects low-potency agents tend to cause fewer extrapyrami-
of these drugs.62 dal (motor) side effects but are associated with an
Consequently, antipsychotic drugs all share a increased incidence of other problems, such as seda-
basic mechanism of action that involves dopamine tive and anticholinergic side effects (e.g., dry mouth,
receptor blockade. It is apparent, however, that they constipation, urinary retention). These side effects
are not all equal in their ability to affect specific sub- and their possible long-term implications are dis-
types of dopamine receptors, and that their effective- cussed further in this chapter.
ness and side effects are related to their affinity and Traditional agents are also somewhat less pre-
preference for certain receptors. As indicated earlier, dictable, and there tends to be more patient-to-patient
other neurotransmitters may also be involved in the variability in the beneficial (antipsychotic) effects of
pathogenesis of psychosis, and differences in specific these medications.18 Newer atypical drugs may be
antipsychotic medications may be related to their abil- somewhat safer and more predictable, and these
ity to directly or indirectly affect these other transmit- agents are described next.
ters as well as block dopamine influence. Future studies
will continue to clarify how current antipsychotics
Atypical Antipsychotics
exert their beneficial effects and how new agents can be
developed to be more selective in their effects on Several newer antipsychotic medications have been
dopamine and other neurotransmitter pathways. developed that seem different or “atypical,” compared
with their predecessors. These agents include clozap-
ine (Clozaril), risperidone (Risperdal), and several
Antipsychotic Medications others listed in Tables 8–1 and 8–2. Although there is
some debate about what exactly defines these drugs as
Antipsychotic medications are listed in Tables 8–1 and “atypical,” the most distinguishing feature is that they
8–2. These agents comprise a somewhat diverse group have a much better side-effect profile, including a
in terms of their chemical background and potency— decreased risk of producing extrapyramidal (motor)
that is, the dosage range typically needed to achieve side effects.17,45,57
antipsychotic effects. As indicated earlier, these agents These newer, atypical agents seem to affect cer-
all block dopamine receptors to some extent, despite tain dopamine receptor subtypes differently than the
their chemical diversity. In addition to their chemical older, more conventional drugs. In particular, the
differences, antipsychotics can be classified as either atypicals do not block the D2 receptors in the basal
traditional agents or newer “atypical” antipsychotics ganglia as strongly as conventional antipsychotics,
according to their efficacy and side effects. Differences hence their reduced risk of motor side effects.52 There
between these two classes are described here. is also evidence that these drugs might have beneficial
effects on other neurotransmitters, including gluta-
mate, serotonin, and acetylcholine.6,23,52 These addi-
Traditional Antipsychotics tional effects might add to their antipsychotic benefits
Traditional antipsychotics are associated with more by improving cognition and reducing the incidence of
side effects than newer counterparts, including an in- other problems such as social withdrawal.52
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96 SECTION 2 Pharmacology of the Central Nervous System


Usual Dosage Maximum recommended

Generic Name Trade Name Range (mg/d)* dosage (mg/d)**
Aripiprazole*** Abilify 10–30 30

Chlorpromazine Thorazine 100–800 1000

Clozapine*** Clozaril 50–600 900

Fluphenazine Permitil, Prolixin 2–20 40

Haloperidol Haldol 2–20 100

Loxapine Loxitane 10–80 250

Molindone Moban 10–100 225

Mesoridazine Serentil 50–400 500

Olanzapine*** Zyprexa 10–20 20

Perphenazine Trilafon, Triavil 10–64 64

Prochlorperazine Comazol, Compazine 15–150 150

Quetiapine*** Seroquel 250–600 800

Risperidone*** Risperdal 2–6 16

Thioridazine Mellaril 100–800 800

Thiothixene Navane 4–40 60

Trifluoperazine Stelazine 5–40 80

Triflupromazine Vesprin 6–150 150

Ziprasidone*** Geodon 40–160 200

*Dosage range represents usual adult oral dose. Lower dosages may be indicated for older or debilitated
**Maximum recommended dosage represents the upper limit that can be administered each day to control
severe psychotic symptoms, usually in hospitalized patients.
***Atypical antipsychotics. See text for details.

Regarding efficacy, the newer atypical agents

seem to be at least as effective as the conventional Pharmacokinetics
drugs, but the atypical drugs can reduce the incidence
of relapse compared to conventional agents.23,46 Given Antipsychotics are usually administered orally. During
the therapeutic benefits and reduced risk of side the acute stage of a psychotic episode, the daily dosage
effects, these atypical drugs are usually considered first is often divided into three or four equal amounts.
when treating psychosis.23 If these atypical drugs are Maintenance doses are usually lower and can often
not effective, the more conventional or traditional be administered once each day. Under certain condi-
agents are administered.23,45 tions, antipsychotics can be given intramuscularly.
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Chapter 8 Antipsychotic Drugs 97


Drug Sedation Extrapyramidal Effects Anticholinergic Effects

Traditional antipsychotics
Chlorpromazine ⫹⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹

Fluphenazine ⫹ ⫹⫹⫹⫹ ⫹

Haloperidol ⫹ ⫹⫹⫹⫹ ⫹

Loxapine ⫹⫹⫹ ⫹⫹⫹ ⫹⫹

Mesoridazine ⫹⫹⫹ ⫹ ⫹⫹

Molindone ⫹ ⫹⫹⫹ ⫹⫹

Perphenazine ⫹⫹ ⫹⫹⫹ ⫹⫹

Prochlorperazine ⫹⫹ ⫹⫹⫹⫹ ⫹

Thioridazine ⫹⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹⫹

Thiothixene ⫹ ⫹⫹⫹⫹ ⫹

Trifluoperazine ⫹⫹ ⫹⫹⫹ ⫹⫹

Triflupromazine ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹⫹

Atypical antipsychotics
Aripiprazole ⫹⫹ ⫹ ⫹

Clozapine ⫹⫹⫹⫹ ⫹ ⫹⫹⫹⫹

Olanzapine ⫹⫹ ⫹⫹ ⫹⫹

Quetiapine ⫹⫹ ⫹ ⫹

Risperidone ⫹ ⫹⫹ ⫹

Ziprasidone ⫹⫹ ⫹⫹ ⫹

*Incidenceof side effects are classified as follows: ⫹ a very low incidence, ⫹⫹ a low incidence, ⫹⫹⫹ a
moderate incidence, and ⫹⫹⫹⫹ a high incidence.

During acute episodes, intramuscular injections tend her medication regularly.10,34 For example, depot pre-
to reach the bloodstream faster than an orally admin- parations of conventional antipsychotics such as
istered drug and may be used if the patient is especial- fluphenazine decanoate and haloperidol decanoate,
ly agitated. can be injected every 2 to 4 weeks, respectively, and
Conversely, certain forms of intramuscular serve as a method of slow, continual release during the
antipsychotics that enter the bloodstream slowly have maintenance phase of psychosis.4 More recently, an
been developed. This method of “depot administra- injectable form of risperidone, an atypical antipsychot-
tion” may prove helpful if the patient has poor self- ic, has been developed, and this product might provide
adherence to drug therapy and neglects to take his or beneficial long-term effects with fewer side effects.10,26
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98 SECTION 2 Pharmacology of the Central Nervous System

Metabolism of antipsychotics is through two motor side effects are a potential complication. The
mechanisms: conjugation with glucuronic acid and unintentional antagonism of dopamine receptors in
oxidation by hepatic microsomal enzymes. Both areas of motor integration (as opposed to the benefi-
mechanisms of metabolism and subsequent inactiva- cial blockade of behaviorally related receptors) results
tion take place in the liver. Some degree of enzyme in a neurotransmitter imbalance that creates several
induction may occur because of prolonged use of distinct types of movement problems.
antipsychotics, which may be responsible for increas- Thus, most antipsychotics are associated with
ing the rate of metabolism of these drugs. some type of motor side effect because these drugs are
relatively nonselective in their ability to block CNS
dopamine receptors. As noted earlier, the newer (atyp-
Other Uses of Antipsychotics ical) agents such as clozapine and resperidone are not
associated with as high an incidence of extrapyramidal
Occasionally, antipsychotics are prescribed for condi- side effects. Several hypotheses exist to explain the
tions other than classic psychosis. As discussed in lower incidence, including the idea that the atypical
Chapter 7, an antipsychotic can be used alone or com- antipsychotics block serotonin receptors more than
bined with lithium during an acute manic phase of the dopamine type 2 (D2) receptors associated with
bipolar disorder.9,43 These drugs are also effective in motor side effects.13 Alternatively, it has been pro-
decreasing nausea and vomiting occurring when dopa- posed that atypical agents block dopamine receptors
mine agonists and precursors are administered to treat long enough to cause a therapeutic effect, but not long
Parkinson disease. The antiemetic effect of antipsy- enough to cause receptor supersensitivity and other
chotics is probably caused by their ability to block changes that result in motor side effects.13 The exact
dopamine receptors located on the brainstem that reasons for their lower incidence of extrapyramidal
cause vomiting when stimulated by the exogenous side effects, however, is not known.
dopamine. At present, however, extrapyramidal side effects
Antipsychotics are often used in Alzheimer disease continue to be one of the major drawbacks of antipsy-
and other cases of dementia to help control aggression chotic medications. The primary types of extrapyrami-
and agitation.7,38,58 There is concern, however, that dal side effects, the manifestations of each type, and the
these agents should be used carefully in patients with relative time of their onset are shown in Figure 8–2.
Alzheimer disease, and that these drugs should not be Some factors involved in patient susceptibility and pos-
overused just to sedate these patients. Likewise, side sible treatment of these side effects are discussed here.
effects should be minimized by considering one of the Tardive Dyskinesia. The disorder of tardive dysk-
newer atypical agents, and by using the lowest effective inesia is characterized by a number of involuntary and
dose.33,38,40 Still, additional research is needed to deter- fragmented movements.21 In particular, rhythmic
mine how these drugs can be used most effectively to movements of the mouth, tongue, and jaw are present,
improve quality of life in people with various forms of and the patient often produces involuntary sucking
dementia.27,30,56 and smacking noises. Because this condition often
involves the tongue and orofacial musculature, serious
swallowing disorders (dysphagia) may also occur.55
Problems and Adverse Effects Other symptoms include choreoathetoid movements
of the extremities and dystonias of the neck and trunk.
Extrapyramidal Symptoms As indicated in Table 8–2, certain antipsychotics, such
One of the more serious problems occurring from the as the traditional high-potency drugs, are associated
use of antipsychotics is the production of abnormal with a greater incidence of tardive dyskinesia. Other
movement patterns.36,44 Many of these aberrant move- risk factors include advanced patient age, affective
ments are similar to those seen in patients with lesions mood disorders, diabetes mellitus, history of alcohol
of the extrapyramidal system and are often referred to abuse, and continual use of the drug for 6 months or
as extrapyramidal side effects. The basic reason that longer.18,29,49 On the other hand, use of newer, atypi-
these motor problems occur is because dopamine is an cal antipsychotics is associated with a much lower risk
important neurotransmitter in motor pathways, espe- of tardive dyskinesia, even in high-risk patients.20,31
cially in the integration of motor function that takes Still, tardive dyskinesia is relatively common, with an
place in the basal ganglia. Because antipsychotic drugs estimated prevalence of 24% of people with chronic
block CNS dopamine receptors, it makes sense that psychosis.36
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Chapter 8 Antipsychotic Drugs 99

(From Feigenbaum JC and Schneider F. Antipsychotic medications. In: Mathewson MK, ed. Pharmacotherapeutics: A Nursing
Acute Dystonic Akathisia Tardive Dyskinesia
1. Restlessness 1. Protrusion of Tongue
1. Torticollis 2. Difficulty in Sitting Still 2. Puffing of Cheeks
2. Facial Grimacing 3. Strong Urge to Move About 3. Chewing Movements
3. Abnormal Eye 4. Involuntary
Movements Movements of
4. Involuntary Extremities
Muscle 5. Involuntary
Movements Movement of Trunk


Approach. Philadelphia: FA Davis; 1986: 404, with permission.)

1. Motor Retardation
2. Mask-Like Facies
3. Tremor
4. “Pill-Rolling”
5. Rigidity
6. Salivation
7. Shuffling Gait

0 1 2 3 4 5 6 7 8 90 100 365
FIGURE 8–2 ▼ Extrapyramidal side effects and their relative onset after beginning antipsy-
chotic drug therapy.

Tardive dyskinesia induced by antipsychotic drugs symptoms of tardive dyskinesia.18 The motor symp-
may be caused by “disuse supersensitivity” of the toms of tardive dyskinesia can be dealt with by lower-
dopamine receptor.12,36 Although the presynaptic neu- ing the drug dosage or by substituting an antipsychotic
rons are still intact, drug blockade of the postsynaptic that produces fewer extrapyramidal side effects (see
receptor induces the postsynaptic neuron to respond Table 8–2). Early intervention is generally believed to
by “up-regulating” the number or sensitivity of the be the most effective way of preventing the permanent
receptors. This increase in receptor sensitivity causes a changes associated with antipsychotic-induced tardive
functional increase in dopaminergic influence, leading dyskinesia.21
to a neurotransmitter imbalance between dopamine Other drugs have been used to try to alleviate the
and other central neurotransmitters such as acetyl- symptoms of drug-induced tardive dyskinesia.53,54
choline and GABA. In addition, changes in the struc- Agents such as anticholinergic drugs (e.g., atropinelike
ture of striatonigral neurons and other brain structures drugs), GABA-enhancing drugs (e.g., benzodi-
appear to accompany the functional changes in neuro- azepines), and calcium channel blockers have been
transmitter sensitivity.12,36 These functional and struc- used to attempt to rectify the transmitter imbalance
tural changes result in the symptoms of tardive or the cellular changes created by the increased dopa-
dyskinesia. mine sensitivity. Reserpine has also been used in some
Tardive dyskinesia is the most feared side effect of patients because of its ability to deplete presynap-
antipsychotic drugs.24 In some patients, the symptoms tic stores of dopamine, thus limiting the influence of
will disappear if the drug is stopped or if the dosage is this neurotransmitter. However, these additional
decreased, but this can take from several weeks to sev- agents tend to be only marginally successful
eral years to occur. In other individuals, drug-induced in reducing the dyskinesia symptoms, and their use
tardive dyskinesia appears irreversible.24 To prevent tends to add complexity to the drug management
the occurrence of tardive dyskinesia, the lowest effec- of patients with psychoses. Thus, the best course of
tive dose of the antipsychotic should be used, especial- action continues to be judicious administration of
ly during the maintenance phase of drug therapy.18 these drugs, using the lowest effective dose, and early
Also, patients taking these drugs for three months or recognition and intervention if extrapyramidal symp-
more should undergo periodic reevaluation for any toms appear.18
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100 SECTION 2 Pharmacology of the Central Nervous System

Pseudoparkinsonism. The motor symptoms seen include catatonia, stupor, rigidity, tremors, and fever.14
in Parkinson disease (see Chapter 10) are caused by a These symptoms are rather severe, and can lead to
deficiency in dopamine transmission in the basal gan- death if left untreated.48 Treatment typically consists
glia. Because antipsychotic drugs block dopamine of stopping the antipsychotic drug and providing sup-
receptors, some patients may understandably experi- portive care. The exact causes of NMS are unclear, but
ence symptoms similar to those seen in Parkinson dis- the risk of developing this syndrome is increased in
ease. These symptoms include resting tremor, patients who are mentally retarded, who are agitated,
bradykinesia, and rigidity. Elderly patients are more or when traditional antipsychotics are administered at
susceptible to these drug-induced parkinsonian-like high doses or via intramuscular injection.60
symptoms, probably because dopamine content (and
therefore dopaminergic influence) tends to be lower in
older individuals.22 The outcome of antipsychotic- Nonmotor Effects
induced parkinsonism is usually favorable, and these
symptoms normally disappear when the dosage is Sedation
adjusted or the drug is withdrawn. Drugs used as
Antipsychotics have varying degrees of sedative prop-
adjuncts in treating Parkinson disease (e.g., amanta-
erties. Contrary to previous beliefs, sedative proper-
dine, benztropine mesylate) may also be administered
ties do not enhance the antipsychotic efficacy of these
to deal with parkinsonianlike side effects.11 However,
drugs. Consequently, sedative side effects offer no
primary antiparkinsonian drugs such as levodopa and
benefit and can be detrimental in withdrawn psychot-
dopamine agonists are not typically used to treat these
ic patients.
side effects because they tend to exacerbate the psy-
chotic symptoms.
Akathisia. Patients taking antipsychotics may Anticholinergic Effects
experience sensations of motor restlessness and may
complain of an inability to sit or lie still. This condi- Some antipsychotics also produce significant anti-
tion is known as akathisia.25,35 Patients may also cholinergic effects, manifested by a variety of symp-
appear agitated, may “pace the floor,” and may have toms such as blurred vision, dry mouth, constipation,
problems with insomnia. Akathisia can usually be dealt and urinary retention. Fortunately, these problems are
with by altering the dosage or type of medication. usually self-limiting as many patients become tolerant
If this is unsuccessful, beta-2 adrenergic receptor to the anticholinergic side effects while remaining
blockers (propranolol) may help decrease the restless- responsive to the antipsychotic properties.
ness associated with akathisia by a mechanism involv-
ing central adrenergic receptors.25 Anticholinergic
drugs may also be used to treat akathisia, but it is not
Other Side Effects
clear if these drugs actually reduce symptoms associat- Orthostatic hypotension is a frequent problem during
ed with akathisia.42 the initial stages of antipsychotic therapy. This prob-
Dyskinesia and Dystonias. Patients may exhibit a lem usually disappears after a few days. Certain
broad range of movements in the arms, legs, neck, and antipsychotic drugs such as chlorpromazine are asso-
face including torticollis, oculogyric crisis, and ciated with photosensitivity, and care should be taken
opisthotonos.8 These movements are involuntary and when exposing these patients to ultraviolet irradiation.
uncoordinated, and may begin fairly soon after initiat- The newer, atypical drugs can produce metabolic side
ing antipsychotic therapy (i.e., even after a single effects that result in substantial weight gain, increased
dose).8 If they persist during therapy, other drugs such plasma lipids, and diabetes mellitus.3,39 Thus, these
as antiparkinsonian adjuncts or benzodiazepines (e.g., newer drugs pose less risk of motor symptoms, but can
diazepam) may be used to try to combat the aberrant cause side effects that ultimately produce serious car-
motor symptoms. diovascular and endocrine problems.3,59 Finally,
Neuroleptic Malignant Syndrome. Patients taking abrupt withdrawal of antipsychotic drugs after pro-
relatively high doses of the more potent antipsychotics longed use often results in nausea and vomiting, so it
may experience a serious disorder known as neurolep- is advisable to decrease dosage gradually rather than to
tic malignant syndrome (NMS).48 Symptoms of NMS suddenly stop administration.
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Chapter 8 Antipsychotic Drugs 101

Special Concerns in Rehabilitation Patients

■ ■ ■ Antipsychotic drugs have been a great benefit to patients seen in various rehabilitation
facilities. Regardless of the reason these individuals are referred to physical therapy and occupa-
tional therapy, the improved behavior and reality perception usually provided by drug therapy
will surely enhance the patient’s cooperation during rehabilitation. Because these drugs tend to
normalize patient behavior, the withdrawn patient often becomes more active and amiable,
while the agitated patient becomes calmer and more relaxed. Also, remission of some confusion
and impaired thinking will enable the patient to follow instructions more easily. Patients with
paranoid symptoms may have fewer delusions of persecution and will feel less threatened by the
entire therapy environment.
The benefits of antipsychotic drugs must be weighed against their side effect risks. The less
serious side effects such as sedation and some of the anticholinergic effects (blurred vision, dry
mouth, constipation) can be bothersome during the treatment session. Orthostatic hypotension
should be guarded against, especially during the first few days after drug therapy is initiated.
However, the major problems have to do with the antipsychotic drug’s extrapyramidal motor
effects. Therapists treating patients on antipsychotic medications should remain alert for early
signs of motor involvement. Chances are good that the therapist may be the first person to
notice a change in posture, balance, or involuntary movements. Even subtle problems in motor
function should be brought to the attention of the medical staff immediately. This early inter-
vention may diminish the risk of long-term or even permanent motor dysfunction.

Antipsychotic Drugs and slow, progressive increase in writhing gestures of both
upper extremities. Extraneous movements of her mouth and
Brief History. R.F., a 63-year-old woman, has been face were also observed, including chewinglike jaw move-
receiving treatment for schizophrenia intermittently for many ments and tongue protrusion.
years. She was last hospitalized for an acute episode 7 months Decision/Solution. These initial extrapyramidal symp-
ago and has since been on a maintenance dosage of haloperi- toms suggested the onset of tardive dyskinesia. The therapist
dol (Haldol), 25 mg/d. She is also being seen as an outpatient notified the patient’s physician, and drug therapy was pro-
for treatment of rheumatoid arthritis in both hands. Her current gressively shifted from haloperidol to the atypical agent cloza-
treatment consists of gentle heat and active range-of-motion pine (Clozaril), 450 mg/d. The extrapyramidal symptoms
exercises, three times each week. She is being considered for gradually diminished over the next 8 weeks and ultimately dis-
possible metacarpophalangeal joint replacement. appeared.
Problem/Influence of Medication. During the
course of physical therapy, the therapist noticed the onset

SUMMARY with others and to administer self-care. Despite their

chemical diversity, antipsychotics all seem to exert
Antipsychotic drugs represent one of the major beneficial effects by blocking central dopamine recep-
advances in the management of mental illness. Drugs tors. Therefore, psychoses such as schizophrenia may
are currently available that diminish the symptoms of be caused by an overactivity of CNS dopaminergic
psychosis and improve a patient’s ability to cooperate pathways.
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102 SECTION 2 Pharmacology of the Central Nervous System

Because of the rather nonspecific blockade of ties may become irreversible and persist even
dopaminergic receptors, antipsychotics are associ- after drug therapy is terminated. Rehabilitation spe-
ated with several adverse side effects. The most cialists may play a critical role in recognizing the
serious of these are abnormal movement patterns that early onset of these motor abnormalities. When iden-
resemble tardive dyskinesia, Parkinson disease, and tified early, potentially serious motor problems can be
other lesions associated with the extrapyramidal dealt with by altering the dosage or type of antipsy-
system. In some cases, these aberrant motor activi- chotic agent.

References 16. Conley RR, Kelly DL. Current status of antipsychotic

treatment. Curr Drug Targets CNS Neurol Disord.
1. Abi-Dargham A. Do we still believe in the dopamine 2002;1:123–128.
hypothesis? New data bring new evidence. Int J Neu- 17. Correll CU, Leucht S, Kane JM. Lower risk for tar-
ropsychopharmacol. 2004;7(suppl 1): S1–S5. dive dyskinesia associated with second-generation
2. Abi-Dargham A, Moore H. Prefrontal DA transmis- antipsychotics: a systematic review of 1-year studies.
sion at D1 receptors and the pathology of schizophre- Am J Psychiatry. 2004;161:414–425.
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the new long-acting injectable atypical antipsychotic cologic management of psychosis in the elderly: a
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Chapter 9
Antiepileptic Drugs

Epilepsy is a chronic neurologic disorder character- Although some innovative approaches using sur-
ized by recurrent seizures.33 Seizures are episodes of gery, neural stimulation, and dietary control have been
sudden, transient disturbances in cerebral excitation reported,8,9,32,45 drug therapy remains the primary
that occur when a sufficient number of cerebral neu- method for treating epilepsy. In general, antiepileptic
rons begin to fire rapidly and in synchronized bursts.42 medications are successful in eliminating seizures in 50
Depending on the type of seizure, neuronal activity percent of the patient population, and can reduce
may remain localized in a specific area of the brain, or seizure activity substantially in an additional 25 percent
it may spread to other areas of the brain. In some of patients with epilepsy.20 Some of the newer
seizures, neurons in the motor cortex are activated, antiepileptic medications such as gabapentin (Neuron-
leading to skeletal muscle contraction via descend- tin) have also been used to treat certain types of
ing neuronal pathways. These involuntary, paroxys- pain, including neuropathic pain and migraine
mal skeletal muscle contractions seen during certain headaches.25,37 This chapter, however, will focus on the
seizures are referred to as convulsions. However, con- use of these medications in resolving seizure disorders.
vulsions are not associated with all types of epilepsy, Several types of drugs are currently available, and
and other types of seizures are characterized by a wide certain compounds work best in specific types of
variety of sensory or behavioral symptoms. epilepsy. Consequently, the type of epilepsy must be
Epilepsy is associated with the presence of a group determined by observing the patient and using diag-
or focus of cerebral neurons that are hyperexcitable, or nostic tests such as electroencephalography (EEG).21
“irritable.” The spontaneous discharge of these irrita- The classification system most commonly used in
ble neurons initiates the epileptic seizure. The reason characterizing epilepsy is discussed here.
for the altered excitability of these focal neurons, and
thus the cause of epilepsy, varies depending on the
patient.20,42 In some patients, a specific incident such as Classification of
a stroke, tumor, encephalopathy, head trauma, or other
CNS injury probably caused damage to certain neu-
Epileptic Seizures
rons, resulting in their altered threshold. In other In an attempt to standardize the terminology used in
patients, the reason for seizures may be less distinct or describing various forms of epilepsy, the International
unknown, perhaps relating to a congenital abnormali- League Against Epilepsy10 proposed the classification
ty, birth trauma, or genetic factor. A systemic metabol- scheme outlined in Table 9–1. Seizures are divided
ic disorder such as infection, hypoglycemia, hypoxia, into two major categories: partial and generalized. A
or uremia may precipitate seizure activity. Once the third category of “unclassified” seizures is sometimes
cause of the seizures is identified in this last group of included to encompass additional seizure types not fit-
individuals, the epilepsy can be treated by resolving the ting into the two major groups. Originally devised in
metabolic disorder. Epilepsy resulting from these com- the 1980s, this classification system has been revised
bined causes affects approximately 5 to 10 people per periodically, and it will undoubtedly continue to be
1000 in the general population, making this one of the revised as more is learned about the cause and symp-
most common neurologic disorders.30 toms of specific seizures.29,34

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106 SECTION 2 Pharmacology of the Central Nervous System


Seizure Type Classification

I. Partial seizures
A. Simple partial seizures Limited (focal) motor or sensory signs (e.g., convulsions con-
fined to one limb, specific sensory hallucinations); con-
sciousness remains intact

B. Complex partial seizures (needed to differentiate Consciousness impaired; bizarre behavior; wide variety of
this from absence seizures) other manifestations; specific electroencephalography
(EEG) abnormality

C. Partial becoming generalized Symptoms progressively increase until seizure resembles a

generalized (tonic-clonic) seizure

II. Generalized seizures

A. Absence (petit mal) seizures Sudden, brief loss of consciousness; motor signs may be
absent or may range from rapid eye-blinking to symmetrical
jerking movements of entire body

B. Myoclonic seizures Sudden, brief, “shocklike” contractions of muscles in the face

and trunk, or in one or more extremities; contractions may
be single or multiple; consciousness may be impaired

C. Clonic seizures Rhythmic, synchronized contractions throughout the body;

loss of consciousness

D. Tonic seizures Generalized sustained muscle contractions throughout body;

loss of consciousness
E. Tonic-clonic (grand mal) seizures Major convulsions of entire body; sustained contraction of all
muscles (tonic phase) followed by powerful rhythmic con-
tractions (clonic phase); loss of consciousness
F. Atonic seizures Sudden loss of muscle tone in the head and neck, one limb,
or throughout the entire body; consciousness may be main-
tained or lost briefly
III. Unclassified seizures
All other seizures that do not fit into one of the
aforementioned categories.

Source: Modified from Commission on Classification and Terminology of the International League Against
Epilepsy, pp 493–495,10 with permission.

In partial seizures only part of the brain (i.e., one Partial and generalized seizures are subdivided
cerebral hemisphere) is involved, whereas in general- depending on the specific symptoms that occur during
ized seizures the whole brain is involved. Partial the epileptic seizure (see Table 9–1). As a rule, the out-
seizures that spread throughout the entire brain are ward manifestations of the seizure depend on the area
referred to as “partial becoming generalized” or “sec- of the brain involved. Simple partial seizures that
ondarily generalized” seizures. remain localized within the motor cortex for the right
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Chapter 9 Antiepileptic Drugs 107

hand may cause involuntary, spasm like movements of membrane.20,39,42 In some cases, however, the exact
only the right hand. Other partial seizures produce way that antiepileptic drugs exert their beneficial
motor and sensory symptoms, and affect conscious- effects is obscure or unknown.20 Specific details of each
ness and memory as well. These usually fall into the chemical class of drugs are discussed here. Because
category of complex partial seizures. these drugs tend to have many adverse side effects,
Generalized seizures are subclassified depending only the frequently occurring or more serious prob-
on the type and degree of motor involvement, as well lems are listed for each category.
as other factors such as EEG recordings. The most
well-known and dramatic seizure of the generalized Barbiturates
group is the tonic-clonic, or “grand mal,” seizure.
Phenobarbital (various trade names) and other barbi-
Absence, or “petit mal,” seizures also fall into the gen-
turates such as mephobarbital (Mebaral) are pre-
eralized seizure category. Drug therapy for general-
scribed in virtually all types of adult seizures, but seem
ized and partial seizures is discussed later in “Drugs
to be especially effective in generalized tonic-clonic
Used to Treat Epilepsy.”
and simple and complex partial seizures. These agents
are considered to be very safe and effective in the
treatment of seizures, but their use is often limited
Rationale for Drug Treatment because of their strong tendency to produce sedation.
Even in the absence of drug therapy, individual Primidone (Mysoline) is another barbituratelike drug
seizures are usually self-limiting. Brain neurons are that is recommended in several types of epilepsy but is
unable to sustain a high level of synaptic activity for particularly useful in generalized tonic-clonic seizures
more than a few minutes, and the seizure ends sponta- not responding to other drugs.
neously. However, the uncontrolled recurrence of Mechanism of Action. Barbiturates are known to
seizures is believed to cause further damage to the increase the inhibitory effects of GABA (see Chap-
already injured neurons, and can be potentially harm- ter 6), and this effect is probably the primary way that
ful to healthy cells.15,36 In particular, seizures can cause these drugs decrease seizure activity. Barbiturates may
structural and functional changes in neuronal path- also produce some of their antiseizure effects by
ways, resulting in impaired cerebral activity and inhibiting calcium entry into excitatory presynaptic
increased susceptibility to additional seizures.22,36 nerve terminals and thereby decreasing the release of
Certain types of seizures will also be harmful if excitatory neurotransmitters such as glutamate.20
the patient loses consciousness or goes into convul- Adverse Side Effects. Sedation (primary prob-
sions and injures himself or herself during a fall. Cer- lem), nystagmus, ataxia, folate deficiency, vitamin K
tain types of convulsions are potentially fatal if cardiac deficiency, and skin problems are typical side effects. A
irregularities result and the individual goes into car- paradoxical increase in seizures and an increase in
diac arrest. Even relatively minor seizures may be hyperactivity may occur in some children.
embarrassing to a person, and social interaction may
be compromised if the individual is afraid of having a Benzodiazepines
seizure in public. Consequently, a strong effort is
Several members of the benzodiazepine group are
made to find an effective way to control or eliminate
effective in treating epilepsy, but most are limited
the incidence of seizures.
because of problems with sedation and tolerance. Some
agents such as diazepam (Valium) and lorazepam (Ati-
van) are used in the acute treatment of status epilepti-
Drugs Used to Treat Epilepsy cus (see “Treatment of Status Epilepticus”), but only a
Table 9–2 lists the drugs commonly used to treat few are used in the long-term treatment of epilepsy.
epilepsy according to their chemical classes and mech- Clonazepam (Klonopin) is recommended in specific
anisms of action. These drugs generally try to inhibit forms of absence seizures (e.g., the Lennox-Gastaut
firing of certain cerebral neurons, usually by increasing variant) and may also be useful in minor generalized
the inhibitory effects of gamma-aminobutyric acid seizures such as akinetic spells and myoclonic jerks.
(GABA), by decreasing the effects of excitatory amino Clorazepate (Tranxene) is another benzodiazepine that
acids (glutamate, aspartate), or by altering the move- is occasionally used as an adjunct in certain partial
ment of ions (sodium, calcium) across the neuronal seizures.
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108 SECTION 2 Pharmacology of the Central Nervous System


Chemical Class Possible Mechanism of Action

Barbiturates Potentiate inhibitory effects of GABA**; may also decrease
Amobarbital (Amytal)* excitatory effects of glutamate
Mephobarbital (Mebaral)
Pentobarbital (Nembutal)*
Phenobarbital (Solfoton, others)
Primidone (Mysoline)
Secobarbital (Seconal)*

Benzodiazepines Potentiate inhibitory effects of GABA

Clonazepam (Klonopin)
Clorazepate (Tranxene)
Diazepam (Valium)
Lorazepam (Ativan)

Carboxylic acids Unclear; may hyperpolarize membrane through an effect on

Valproic acid (Depakene, Depakote, others) potassium channels; higher concentrations increase CNS
GABA concentrations

Hydantoins Primary effect is to stabilize membrane by blocking sodium

Ethotoin (Peganone) channels in repetitive-firing neurons; higher concentrations
Fosphenytoin (Cerebyx)* may also influence concentrations of other neurotransmit-
Mephenytoin (Mesantoin) ters (GABA, norepinephrine, others)
Phenytoin (Dilantin)

Iminostilbenes Similar to hydantoins

Carbamazepine (Tegretol)
Oxcarbazepine (Trileptal)

Succinimides Affect calcium channels; appear to inhibit spontaneous firing

Ethosuximide (Zarontin) in thalamic neurons by limiting calcium entry
Methsuximide (Celontin)

*Parental use only (IV injection).

**GABA ⫽ gamma-aminobutyric acid.

Mechanism of Action. These drugs are known to drug considered in treating many types of epilep-
potentiate the inhibitory effects of GABA in the brain sy, and it is especially effective in treating partial
(see Chapter 6), and their antiepileptic properties are seizures and generalized tonic-clonic seizures.
probably exerted through this mechanism. Mephenytoin has similar properties but is some-
Adverse Side Effects. Sedation, ataxia, and behav- what more toxic, and ethotoin has been effective in
ioral changes can be observed. treating absence seizures. The latter two drugs are
usually reserved for use if the patient has not respond-
ed to other, less toxic drugs. Finally, fosphenytoin
Hydantoins can be administered intravenously in emergency
This category includes phenytoin (Dilantin), situations to treat continuous, uncontrolled seizures
mephenytoin (Mesantoin), ethotoin (Peganone), and (status epilepticus, a condition addressed later in
fosphenytoin (Cerebyx). Phenytoin is often the first this chapter).
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Chapter 9 Antiepileptic Drugs 109

Mechanism of Action. Phenytoin stabilizes neural Succinimides

membranes and decreases neuronal excitability by
decreasing sodium entry into rapidly firing neurons. Drugs in this category include ethosuximide (Zaron-
This drug basically inhibits the ability of sodium chan- tin), methsuximide (Celontin), and phensuximide
nels to reset from an inactive to active state after the (Milontin). All three drugs are primary agents in the
neuron has fired an action potential. By inhibiting the treatment of absence (petit mal) seizures, but ethosux-
reactivation of sodium channels, phenytoin prolongs imide is the most commonly prescribed.
the time between action potentials (absolute refractory Mechanism of Action. These drugs are known to
period) so that neurons must slow their firing rate to a increase the seizure threshold and limit the spread of
normal level. At higher doses, phenytoin may also electrical activity in the brain, but their exact cellular
decrease neuronal excitability by increasing the effects mechanism is unknown. They may exert their benefi-
of GABA and by influencing the movement of potassi- cial effects by decreasing calcium influx in certain thal-
um and calcium across the nerve membrane, but these amic neurons. The spontaneous, rhythmic entry of
effects generally occur at higher drug concentrations calcium into thalamic neurons may be responsible for
than those used therapeutically to control seizures. initiating partial seizures, and the succinimides pre-
Less is known about the molecular mechanisms of the vent their onset by blunting calcium influx. Addition-
other drugs in this category, but they probably work by al research is needed to elaborate on this theory.
a similar effect on the sodium channels. Adverse Side Effects. Gastrointestinal distress
Adverse Side Effects. Gastric irritation, confu- (nausea, vomiting), headache, dizziness, fatigue, lethar-
sion, sedation, dizziness, headache, cerebellar signs gy, movement disorders (dyskinesia, bradykinesia), and
(nystagmus, ataxia, dysarthria), gingival hyperplasia, skin rashes and itching are common side effects.
increased body and facial hair (hirsutism), and skin dis-
orders are typical adverse effects.
Valproic Acid
Valproic acid (Depakene, Depakote, other trade
Iminostilbenes names) is classified as a carboxylic acid, and is used pri-
The primary drugs in this category are carbamazepine marily to treat absence seizures or as a secondary
(Tegretol) and oxcarbazepine (Trileptal). Carba- agent in generalized tonic-clonic forms of epilepsy.
mazepine has been shown to be effective in treating all This drug is also used to treat bipolar disorder (manic-
types of epilepsy except absence seizures, and it is depression), especially during the acute manic phase
often considered the primary agent for treating partial (see Chapter 7).
and tonic-clonic seizures. Carbamazepine is regarded Mechanism of Action. High concentrations of val-
as equivalent to phenytoin in efficacy and side effects, proic acid are associated with increased levels of GABA
and may be substituted for that drug, depending on in the brain, and this increase in GABAergic inhibition
patient response. Alternatively, oxcarbazepine can be may be responsible for this drug’s antiepileptic action.
used alone or with other antiepileptics to treat partial However, lower concentrations are still effective in
seizures in adults, and it is a treatment adjunct in par- limiting seizures and do not increase CNS GABA,
tial seizures in children between ages 4 to 16. indicating that some other mechanism must occur.
Mechanism of Action. These drugs are believed This drug may, for example, increase potassium con-
to exert their primary antiepileptic effects in a manner ductance and efflux from certain neurons, thereby
similar to phenytoin—that is, they stabilize the neu- hyperpolarizing the neuron and decreasing its exci-
ronal membrane by slowing the recovery of sodium tability. Valproic acid also exerts some of its effects in a
channels firing too rapidly. Carbamazepine may also manner similar to phenytoin; that is, it limits sodium
inhibit the presynaptic uptake and release of norepi- entry into rapidly firing neurons. Hence, the exact way
nephrine, and this effect may contribute to its anti- in which this drug is effective against partial seizures
seizure activity. remains to be determined, and valproic acid may actu-
Adverse Side Effects. Dizziness, drowsiness, atax- ally work through a combination of several different
ia, blurred vision, anemia, water retention (because of molecular mechanisms.
abnormal antidiuretic hormone [ADH] release), car- Adverse Side Effects. Gastrointestinal distress,
diac arrhythmias, and congestive heart failure can temporary hair loss, weight gain or loss, and impaired
occur with use of these drugs. platelet function are documented adverse reactions.
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110 SECTION 2 Pharmacology of the Central Nervous System

Newer “Second-Generation” Agents to specific receptors in the brain (the N-methyl-D-

aspartate receptor) and block the effects of excitatory
The medications described earlier have been on the amino acids such as glutamate. Reduced influence
market for many years and have been used routinely of these excitatory amino acids results in decreased
for decreasing seizure activity. Beginning with the seizure activity. As indicated, this drug first appeared
introduction of felbamate in 1993, several new or on the market in 1993, and represented the first “new
“second-generation” drugs have also been approved generation” antiseizure agent. It was soon recog-
by the FDA and are currently in use (Table 9–3). In nized, however, that felbamate may cause severe toxic
most cases, these newer drugs are not more effective effects such as aplastic anemia and liver failure.20 Fel-
than their predecessors.24 These newer agents, howev- bamate is therefore not widely prescribed and its use is
er, generally have favorable pharmacokinetic charac- typically limited to patients with severe epilepsy who
teristics (absorption, distribution, metabolism, and so fail to respond to other antiseizure drugs. Other com-
forth) and have relatively mild side effects that allow mon side effects include insomnia, headache, dizzi-
their use along with the more traditional antiseizure ness, and gastrointestinal problems (anorexia, nausea,
medications.5,16 and vomiting).
Hence, these newer drugs are often used as Gabapentin (Neurontin). Gabapentin is used pri-
adjuncts or “add-on” therapy to other drugs.11,13 The marily to treat partial seizures in adults and partial
combinations often allow adequate seizure control in seizures in children that have not responded to
patients who did not respond to a single traditional other treatments. As the name implies, gabapentin
antiseizure agent. Likewise, as more is learned about was designed to act as a GABA agonist. However,
these newer drugs, some are being used alone as the the exact antiseizure mechanism of this drug is
initial treatment, or in certain types of seizures that unclear.20 Gabapentin appears to work by increasing
are resistant to other drugs.11,14,12 Second-generation GABA release or by acting at a receptor that is
antiseizure medications currently available are different from the GABA receptor.3,17 The primary
described here. side effects of this drug are sedation, fatigue, dizziness,
Felbamate (Felbatol). Felbamate is indicated for and ataxia.
treatment of partial seizures in adults and children as Lamotrigine (Lamictal). Lamotrigine is used pri-
well as generalized absence seizures (Lennox-Gastaut marily as an adjunct to other medications in adults
syndrome) in children. Felbamate appears to bind with partial seizures, although it has also been used


Generic Name Trade Name Primary Indication(s)

Felbamate Felbatol Used alone or as an adjunct in partial seizures in adults; treatment
adjunct in partial and generalized seizures associated with Lennox-
Gastaut syndrome in children

Gabapentin Neurontin Treatment adjunct in partial seizures in adults and children over age 3

Lamotrigine Lamictal Use alone or as a treatment adjunct in partial seizures in adults over
age 16; treatment adjunct in generalized seizures associated with
Lennox-Gastaut syndrome in adults and children over age 2

Levetiracetam Keppra Treatment adjunct in partial onset seizures in adults

Tiagabine Gabitril Treatment adjunct in partial seizures in adults and children over age 12

Topiramate Topamax Treatment adjunct in partial onset seizures

Zonisamide Zonegran Treatment adjunct in partial seizures in adults

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Chapter 9 Antiepileptic Drugs 111

alone to treat partial and generalized seizures in adults weakness, and a slight tendency for psychiatric distur-
and children. This drug exerts some of its effects by a bances (anxiety, depression).
stabilizing sodium channels in a manner similar to car- Topiramate (Topamax). Topiramate is used prima-
bamazepine and phenytoin. Lamotrigine may also rily as an adjunct to other medications in adults with
inhibit the release of excitatory amino acids by inhibit- partial seizures. This drug appears to limit seizure
ing sodium entry into the presynaptic terminals of activity through several complimentary mechanisms
neurons firing too rapidly.20 The primary side effects including inhibition of sodium channel opening,
include dizziness, headache, ataxia, vision problems, blockade of excitatory amino acid receptors, and stim-
and skin rash. ulation of GABA receptors.2,41 Primary side effects
Levetiracetam (Keppra). Levetiracetam has been include sedation, dizziness, fatigue, and ataxia.
successful in treating partial seizures in adults when Zonisamide (Zonegran). Zonisamide is used pri-
used in conjunction with traditional antiseizure drugs. marily as an adjunct to other medications in adults
This drug does not appear to decrease seizure activity with partial seizures. This drug stabilizes sodium chan-
via one of the common antiseizure mechanisms (stabi- nels in a manner similar to carbamazepine and pheny-
lize sodium channels, increase GABA inhibition, and toin, and may also exert some of its antiseizure effects
so forth), and the mechanism of this drug is therefore by inhibiting calcium entry into rapidly firing neurons.
unknown. Levetiracetam is usually well tolerated, Zonisamide is fairly well tolerated, although side
although some patients may experience sedation, effects may include sedation, ataxia, loss of appetite,
dizziness, and generalized weakness. and fatigue.
Tiagabine (Gabitril). Tiagabine is used primarily
as an adjunct to other drugs in adults with partial
seizures that are poorly controlled by traditional drug Selection of a Specific
therapy. This drug inhibits the reuptake of GABA
after it is released from presynaptic terminals, thereby
Antiepileptic Agent
inhibiting seizure activity by enabling GABA to It is apparent from the preceding discussion that cer-
remain active in the synaptic cleft for longer periods.2 tain drugs are often preferred when treating certain
The primary side effects of this drug are dizziness, types of seizures. Table 9–4 lists some of the more


Seizure Type First-line Drugs Alternative Agents

Partial seizures Carbamazepine Gabapentin
Phenytoin Topiramate
Lamotrigine Levetiracetam
Valproic acid Zonisamide
Oxcarbazepine Tiagabine
Primidone, phenobarbital

Generalized seizures

Absence Valproic acid, ethosuximide Lamotrigine

Myoclonic Valproic acid, clonazepam Lamotrigine, topiramate, felbamate

Tonic-clonic Phenytoin, carbamazepine, valproic acid Lamotrigine, topiramate, phenobarbital,

primidone, oxcarbazepine

Source: Gidal BE, et al. Epilepsy. In: DiPiro JT, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 5th ed.
New York: McGraw-Hill; 2002:1036.
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112 SECTION 2 Pharmacology of the Central Nervous System

common types of seizures and the primary and alter- Thus, a fairly large number of drugs can be used
native agents used to treat each seizure type. It is to treat epileptic seizures (see Tables 9–2 and 9–3), but
important to note, however, that while Table 9–4 indi- certain agents are usually considered first when
cates general guidelines for drug selection, selection of attempting to treat the most common types. These
the best agent must be done on a patient-by-patient agents comprise a fairly small group that tend to be
basis. Some patients will understandably exhibit a bet- used most often; the drugs and their relevant dosing
ter response to agents that are not typically used as the parameters are listed in Table 9–5. Again, alterna-
first or second choice for a specific type of seizure. tive antiseizure drugs can be used if commonly used
Hence, some trial and error may occur before the best drugs are ineffective or poorly tolerated. As indicated
drug is found, and drug selection may need to be earlier, one of the newer agents can also be added to
altered periodically throughout the patient’s lifetime traditional drugs if patients do not respond to single-
to achieve optimal results.31 drug therapy.


Adult Child
Initial Dose Increment** Maintenance Initial Dose Maintenance
Drug (mg) (mg) (mg/d) (mg/kg/d) (mg/kg/d)
Carbamazepine 200 BID 200 q wk 600–1800 10 qd 10–35 (⬍6 years)

Ethosuximide 250 qd 250 q 3–7d 750 15 15–40

Felbamate 600–1200 qd 600–1200 q 1–2 wk 2400–3600 15 15–45

Gabapentin 300 qd 300 q 3–7 d 1200–3600 10 25–50

Lamotrigine 25 qd 25 q 2 wk 400 0.15–0.5 5

Levetiracetam 500 BID 500 q wk 2000–4000 20 40–100

Oxcarbazepine 300 qd 300 q wk 900–2400 8–10 30–46

Phenobarbital 30–60 qd 30 q 1–2 wk 60–120 3 3–6

Phenytoin 200 qd 100 q 5–7 d 200–300 4 4–8

Primidone 125–250 qd 250 q 1–2 wk 500–750 10 10–25

Tiagabine 4 qd 4–8 q wk 16–32 0.1 0.4

Topiramate 25 qd 25 q 1–2 wk 100–400 3 3–9

Valproic acid 250 qd 250 q 3–7 d 750–3000 15 15–45

Zonisamide 100 qd 100 q 2 wk 200–400 4 4–12

Abbreviations: BID ⫽ twice a day; qd ⫽ every day.

*Dosages reflect monotherapy. Dosages may vary if combining the drug with other antiseizure agents, or other
drugs that affect liver enzyme function.
**Increments reflect the rate that dosage can typically be increased when trying to find the appropriate thera-
peutic dose.
Source: Ranta A, Fountain NB. Seizures and epilepsy in adolescents and adults. In: Rakel RE, Bope ET, eds.
Conn’s Current Therapy 2005. New York: Elsevier/Saunders; 2005: 1026.
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Chapter 9 Antiepileptic Drugs 113

tic.23,26,44 Problems such as stillbirth, microencephaly,

Single-Drug Therapy Versus mental retardation, infant seizures, and congenital
Drug Combinations in Epilepsy malformations (cleft palate, cardiac defects, neural tube
defects) occur more frequently in children of women
In the past, an effort was made to use only one drug with seizure disorders. There is considerable debate as
(primary agent), with an additional drug (secondary to whether this is a side effect of antiepileptic drug
agent) being added only if the epilepsy is especially therapy or a sequela of the epilepsy itself. Because
resistant to management with the primary medica- there is at least some concern that fetal malformations
tion.6 The use of a single drug (monotherapy) offers may be a drug side effect, some mothers may choose to
several advantages, including fewer side effects, a lack discontinue drug therapy during their pregnancies.44
of drug interactions, better ability of the patient to This action obviously places the mother at risk for
adhere to the drug regimen, lower cost, and better uncontrolled seizures, which may be even more harm-
seizure control because the patient was able to tolerate ful to the mother and unborn child.
a higher dose of a single agent.31 Likewise, manage- Hence, women taking antiepileptic drugs should
ment of adverse side effects in single-drug therapy is discuss the potential risks with their family members
easier because there is no question about which drug and physician, and consider whether they will continue
is producing the adverse effect. taking their medication(s).38 If an expectant mother
As indicated earlier, the development of the continues to take her medication(s), using one drug
newer antiseizure medications has advanced the strat- (monotherapy) at the lowest effective dose will help
egy of using two drugs rather than a single agent. reduce the risk of harmful effects on the fetus.1,43 In
Because these newer drugs have relatively predictable addition, mothers should receive optimal prenatal care
pharmacokinetic and side-effect profiles, they can be (folic acid supplementation, proper amounts of exer-
added to traditional medications without excessive cise, rest, and so forth) to help ensure the baby’s
complications and risk to the patient.4,31 Combination health.27,43 After delivery, the baby should be moni-
therapy is therefore a more common approach to tored initially for drug-related effects such as with-
treating seizure disorders than it was in the past. drawal symptoms, and should be subsequently
evaluated for developmental delays that might become
apparent later in childhood.27
When given for the long-term control of epilepsy,
these drugs are normally administered orally. Daily Treatment of Status
oral doses are usually divided into three or four equal Epilepticus
quantities, and the amount of each dose varies widely
depending on the specific drug and the severity of Status epilepticus is a series of seizures occurring with-
patient seizures. Distribution within the body is fairly out any appreciable period of recovery between indi-
extensive, with all antiepileptic drugs eventually vidual seizures.19,28 Essentially the patient experiences
reaching the brain to exert their beneficial effects. one long, extended seizure. This may be brought on
Drug biotransformation usually occurs via liver by a number of factors such as sudden withdrawal
microsomal oxidases, and this is the primary method from antiepileptic drugs, cerebral infarct, systemic or
of drug termination. intracranial infection, or withdrawal from addictive
drugs including alcohol.19,28 If untreated, status
epilepticus will result in permanent damage or death,
Special Precautions especially if the seizures are generalized tonic-clonic
in nature.18 Consequently, this event is regarded as a
During Pregnancy medical emergency that should be resolved as rapidly
Most women with epilepsy continue to take their anti- as possible.
seizure medications when they become pregnant, and Treatment begins with standard emergency pro-
eventually give birth to normal, healthy babies.44 cedures such as maintaining an airway, starting an IV
Nonetheless, the incidence of birth defects is increased line for blood sampling and drug administration, and
somewhat in children of mothers with epilepsy com- so on.28 The first drugs administered are usually ben-
pared with children of mothers who are not epilep- zodiazepines: lorazepam (Ativan) or diazepam (Valium)
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114 SECTION 2 Pharmacology of the Central Nervous System

given intravenously. This approach is followed by their lifetime. There appears, however, to be a certain
phenytoin, which is also administered intravenously. percentage of patients who can discontinue their med-
The phenytoin is given concurrently with or immedi- ications once their seizures are under control. It is esti-
ately after the benzodiazepine so that seizures are mated, for example, that as many as 60 to 70 percent of
controlled when the relatively short-acting benzodi- people who have epilepsy can remain seizure-free after
azepine is metabolized. If seizures continue despite their medication is withdrawn.7 Factors associated with
these drugs, phenobarbital is given intravenously. If all successful medication withdrawal include being free of
other attempts fail, general anesthesia (e.g., halothane) seizures for at least 2 years while on medication(s), hav-
may be used as a last resort. When the status epilepti- ing a normal neurologic examination prior to with-
cus is eventually controlled, an attempt is made to drawal, and being young when the seizures started.35,40
begin or reinstitute chronic antiepileptic therapy. Withdrawal of medications must, of course, be
done under close medical supervision. Likewise, med-
ications are usually tapered-off over an extended peri-
Withdrawal of Antiseizure od of time (6 months) rather than being suddenly
discontinued.7 Nonetheless, it appears that a large
Medications proportion of people with epilepsy may be able to
Many people with seizure disorders will need to adhere maintain seizure-free status once their seizures are
to a regimen of antiseizure medications throughout controlled by the appropriate medications.

Special Concerns in Rehabilitation Patients

■ ■ ■ Rehabilitation specialists must always be cognizant of their patients who have a history
of seizures and who are taking antiepileptic drugs. Patients being treated for conditions unre-
lated to epilepsy (e.g., the outpatient with low back pain) should be identified as potentially at
risk for a seizure during the therapy session. This knowledge will better prepare the therapist to
recognize and deal with such an episode. This approach emphasizes the need for a thorough
medical history of all patients. Also, therapists may help determine the efficacy of antiepileptic
drug therapy. The primary goal in any patient taking antiepileptic drugs is maintaining the drug
dosage within a therapeutic window. Dosage must be high enough to adequately control seizure
activity, but not so high as to invoke serious side effects. By constantly observing and monitor-
ing patient progress, rehabilitation specialists may help determine if this goal is being met. By
noting changes in either seizure frequency or side effects, physical therapists, occupational ther-
apists, and other rehabilitation personnel may help the medical staff arrive at an effective dos-
ing regimen. This information can be invaluable in helping achieve optimal patient care with a
minimum of adverse side effects.
Some of the more frequent side effects may affect physical therapy and other rehabilitation
procedures. Headache, dizziness, sedation, and gastric disturbances (nausea, vomiting) may be
bothersome during the therapy session. Often, these reactions can be addressed by scheduling
therapy at a time of day when these problems are relatively mild. The optimal treatment time
will vary from patient to patient, depending on the particular drug, dosing schedule, and age of
the patient. Cerebellar side effects such as ataxia also occur frequently and may impair the
patient’s ability to participate in various functional activities. If ataxia persists despite efforts to
alter drug dosage or substitute another agent, coordination exercises may be instituted to help
resolve this problem. Skin conditions (dermatitis, rashes, etc.) are another frequent problem in
long-term antiepileptic therapy. Any therapeutic modalities that might exacerbate these condi-
tions should be discontinued.
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Chapter 9 Antiepileptic Drugs 115

Finally, in some patients, seizures tend to be exacerbated by environmental stimuli such as

lights and sound. In such patients, conducting the therapy session in a busy, noisy clinic may be
sufficient to precipitate a seizure, especially if the epilepsy is poorly controlled by drug therapy.
Also, certain patients may have a history of increased seizure activity at certain times of the day,
which may be related to when the antiepileptic drug is administered. Consequently, certain
patients may benefit if the therapy session is held in a relatively quiet setting at a time when the
chance of a seizure is minimal.

Antiepileptic Drugs table, and hot packs were placed over his low back. As the
heat was applied, he began to drift off to sleep. Five minutes
Brief History. F.B. is a 43-year-old man who works in into the treatment, he had a seizure. Because of a thorough
the mail room of a large company. He was diagnosed in child- initial evaluation, the therapist was aware of his epileptic con-
hood as having generalized tonic-clonic epilepsy, and his dition and protected him from injury during the seizure. The
seizures have been managed successfully with various drugs patient regained consciousness and rested quietly until he felt
over the years. Most recently, he has been taking carba- able to go home. No long-term effects were noted from the
mazepine (Tegretol), 800 mg/d (i.e., one 200-mg tablet, QID). seizure.
One month ago, he began complaining of dizziness and Decision/Solution. The seizure may have been pre-
blurred vision, so the dosage was reduced to 600 mg/d (one cipitated by a number of factors, including the recent decrease
200 mg tablet TID). He usually took the medication after in drug dosage and the fact that he was nearing the end of a
meals. Two weeks ago, he injured his back while lifting a large dosing interval. (He had taken his last dose at lunch and would
box at work. He was evaluated in physical therapy as having take his next dose after he went home and had dinner.) The
an acute lumbosacral strain. He began to attend physical fact that he was tired and fell asleep during the treatment
therapy daily as an outpatient. Treatment included heat, ultra- probably played a role. He reported later that when seizures
sound, and manual therapy, and the patient was also being do occur, they tend to be when he is asleep. To prevent the
instructed in proper body mechanics and lifting technique. recurrence of seizures, the therapy session was rescheduled
F.B. continued to work at his normal job, but he avoided heavy to earlier in the day, at 8 AM (his schedule was flexible enough
lifting. He would attend therapy on his way home from work, that he could attend therapy before going to work). Also, he
at about 5 PM. took his first dose of the day approximately 1 hour before arriv-
Problem/Influence of Medication. F.B. arrived at ing at physical therapy. No further seizures occurred during
physical therapy the first afternoon stating that he had had a the course of rehabilitation, and F.B.’s lumbosacral strain was
particularly long day. He was positioned prone on a treatment resolved after 2 weeks of physical therapy.

SUMMARY not cure this disorder, reduction or elimination of

seizures will prevent further CNS damage. Currently,
Epilepsy is a chronic condition characterized by recur- a wide variety of drugs are used, with certain agents
rent seizures. Causes of this disorder range from a being the most successful in specific types of epilepsy.
distinct traumatic episode to obscure or unknown ori- As in any area of pharmacotherapeutics, these drugs
gins. Seizures are categorized according to the clinical are not without adverse side effects. Some of these
and electrophysiologic manifestations that occur side effects may become a problem in rehabilita-
during the seizure. Fortunately, most individuals with tion patients, so therapists should be ready to alter
epilepsy (up to 75 percent) can be treated success- the time and type of treatment as needed to accom-
fully with antiepileptic drugs. Although these drugs do modate these side effects. Physical therapists and
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116 SECTION 2 Pharmacology of the Central Nervous System

other rehabilitation personnel should also be alert increased seizures) or possible drug toxicity (as evi-
for any behavioral or functional changes in the denced by increased side effects) should be brought
patient that might indicate a problem in drug ther- to the physician’s attention so that these problems can
apy. Insufficient drug therapy (as evidenced by be rectified.

References 14. Gil-Nagel A. Review of new antiepileptic drugs as ini-

tial therapy. Epilepsia. 2003;44(suppl 4):3–10.
1. Adab N, Tudur SC, Vinten J, et al. Common 15. Haut SR, Veliskova J, Moshe SL. Susceptibility of
antiepileptic drugs in pregnancy in women with immature and adult brains to seizure effects. Lancet
epilepsy. Cochrane Database Syst Rev. 2004;CD004848. Neurol. 2004;3:608–617.
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son E. Novel mechanisms of action of three antiepilep- drugs: scientific review. JAMA. 2004;291:605–614.
tic drugs, vigabatrin, tiagabine, and topiramate. 17. Maneuf YP, Gonzalez MI, Sutton KS, et al. Cellular
Neurochem Res. 2003;28:333–340. and molecular action of the putative GABA-mimetic,
3. Ashton H, Young AH. GABA-ergic drugs: exit stage gabapentin. Cell Mol Life Sci. 2003;60:742–750.
left, enter stage right. J Psychopharmacol. 2003;17: 18. Manno EM. New management strategies in the treat-
174–178. ment of status epilepticus. Mayo Clin Proc. 2003;78:
4. Baulac M. Rational conversion from antiepileptic poly- 508–518.
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125–132. ticus. Chest. 2004;126:582–591.
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antiepileptic drugs: comparison of two recent guide- epilepsies. In: Hardman JG, et al, eds. The Pharmaco-
lines. Lancet Neurol. 2004;3:618–621. logical Basic of Therapeutics. 10th ed. New York:
6. Ben-Menachem E, Scheepers B, Stodieck S. Epilepsy: McGraw-Hill; 2001.
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Suppl. 2003;180:5–15. Curr Neurol Neurosci Rep. 2003;3:332–340.
7. Britton JW. Antiepileptic drug withdrawal: literature 22. Morimoto K, Fahnestock M, Racine RJ. Kindling and
review. Mayo Clin Proc. 2002;77:1378–1388. status epilepticus models of epilepsy: rewiring the
8. Buchhalter JR, Jarrar RG. Therapeutics in pediatric brain. Prog Neurobiol. 2004;73:1–60.
epilepsy, part 2: epilepsy surgery and vagus nerve stim- 23. Morrow JI, Craig JJ. Anti-epileptic drugs in pregnan-
ulation. Mayo Clin Proc. 2003;78:371–378. cy: current safety and other issues. Expert Opin Phar-
9. Cohen-Gadol AA, Britton JW, Wetjen NM, et al. macother. 2003;4:445–456.
Neurostimulation therapy for epilepsy: current modali- 24. Onat F, Ozkara C. Adverse effects of new antiepileptic
ties and future directions. Mayo Clin Proc. 2003; drugs. Drugs Today (Barc). 2004;40:325–342.
78:238–248. 25. Pappagallo M. Newer antiepileptic drugs: possible uses
10. Commission on Classification and Terminology in the treatment of neuropathic pain and migraine.
of the International League Against Epilepsy. Proposal Clin Ther. 2003;25:2506–2538.
for revised clinical and electroencephalographic classi- 26. Pennell PB. The importance of monotherapy in preg-
fication of epileptic seizures. Epilepsia. 1989;30: nancy. Neurology. 2003;60(suppl 4):S31–S38.
389–399. 27. Penovich PE, Eck KE, Economou VV. Recommenda-
11. Deckers CL, Knoester PD, de Haan GJ, et al. tions for the care of women with epilepsy. Cleve Clin J
Selection criteria for the clinical use of the newer Med. 2004;71(suppl 2):S49–S57.
antiepileptic drugs. CNS Drugs. 2003;17:405–421. 28. Phelps SJ, Hovinga CA, Boucher BA. Status epilepti-
12. French JA, Kanner AM, Bautista J, et al. Efficacy and cus. In: DiPiro JT, et al, eds. Pharmacotherapy: A Patho-
tolerability of the new antiepileptic drugs I: treatment physiologic Approach. 5th ed. New York: McGraw-Hill;
of new onset epilepsy: report of the Therapeutics and 2002.
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34. Sirven JI. Classifying seizures and epilepsy: a synopsis. therapy: a practical approach. Ann Med. 2003;35:
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Chapter 10
Pharmacological Management
of Parkinson Disease
Parkinson disease is a movement disorder character- tion specialists are often involved in treating patients
ized by resting tremor, bradykinesia, rigidity, and pos- with this illness due to its prevalence and its associated
tural instability.3,29,32 In Parkinson disease, there is a motor problems.
slow, progressive degeneration of certain dopamine- Fortunately, the pharmacologic management of
secreting neurons in the basal ganglia.29,59,66 Several Parkinson disease has evolved to where the symptoms
theories have been proposed to explain this sponta- associated with this disorder can be greatly diminished
neous neuronal degeneration, including the possibili- in many patients. The use of levodopa (L-dopa) alone
ty that the disease may be caused by a combination of or in combination with other drugs can improve
genetic and environmental factors (see “Etiology of motor function and general mobility well into the
Parkinson Disease: Potential Role of Toxic Sub- advanced stages of this disease. Drugs used in treating
stances”).22,83 However, the precise initiating factor in Parkinson disease do not cure this condition, and
Parkinson disease is still unknown. motor function often tends to slowly deteriorate
The clinical syndrome of parkinsonism (i.e., regardless of when drug therapy is initiated.51,57,79
rigidity, bradykinesia) may be caused by other factors However, by alleviating the motor symptoms (i.e.,
such as trauma, infectious agents, antipsychotic drugs, bradykinesia and rigidity), drug therapy can allow
cerebrovascular disease, and various forms of cortical patients with Parkinson disease to continue to lead
degeneration (including Alzheimer disease).46,48,54,63 relatively active lifestyles, thus improving their overall
However, the most frequent cause of parkinsonism is physiologic and psychologic well-being.
the spontaneous slow, selective neuronal degeneration
characteristic of Parkinson disease itself.59,66 Also, the
drug management of parkinsonism caused by these Pathophysiology
other factors closely resembles the management of
Parkinson disease.48 Consequently, this chapter will
of Parkinson Disease
address the idiopathic onset and pharmacologic treat- During the past 40 years, the specific neuronal
ment of Parkinson disease per se. changes associated with the onset and progression of
Parkinson disease usually begins in the fifth or Parkinson disease have been established. Specific
sixth decade, and symptoms progressively worsen over alterations in neurotransmitter balance in the basal
a period of 10 to 20 years. It is estimated that more ganglia are responsible for the symptoms associated
than 1 percent of the U.S. population older than 60 with this disorder.59,66 The basal ganglia are groups
years is afflicted with Parkinson disease, making it one of nuclei located in the brain that are involved in
of the most prevalent neurologic disorders affecting the coordination and regulation of motor function.
elderly individuals.59 In addition to the symptoms of One such nucleus, the substantia nigra, contains the
bradykinesia and rigidity, a patient with advanced cell bodies of neurons that project to other areas
Parkinson disease maintains a flexed posture and such as the putamen and caudate nucleus (known col-
speaks in a low, soft voice (microphonia). If left lectively as the “corpus striatum”). The neurotrans-
untreated, the motor problems associated with this ill- mitter used in this nigrostriatal pathway is dopamine.
ness eventually lead to total incapacitation. Rehabilita- The primary neural abnormality in Parkinson disease

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120 SECTION 2 Pharmacology of the Central Nervous System

is that dopamine-producing cells in the substantia inhibitory dopaminergic influence allows excitatory
nigra begin to degenerate, resulting in the eventual acetylcholine pathways to run wild. Thus, the symp-
loss of dopaminergic input into the corpus stria- toms associated with Parkinson disease may be direct-
tum.48,59 ly caused by increased cholinergic influence occurring
Consequently, the decrease in striatal dopamine secondary to dopamine loss. Current research also sug-
seems to be the initiating factor in the symptom onset gests that other imbalances involving transmitters such
associated with Parkinson disease. However, it also as gamma-aminobutyric acid (GABA), 5-hydroxytrypt-
appears that the lack of dopamine results in an activi- amine (serotonin), endogenous opioids, and excitatory
ty increase in basal ganglia cholinergic pathways.3 amino acids (glutamate) may also be present in the
Illustrated in Figure 10–1, there is a balance between basal ganglia subsequent to the loss of dopamine.3,66 In
dopaminergic and cholinergic influence in the basal any event, drug therapy focuses on resolving the
ganglia under normal conditions. However, the loss of dopamine-acetylcholine imbalance to restore normal
dopaminergic influence in Parkinson disease appears motor function in Parkinson disease.
to allow cholinergic influence to dominate.
The relationship between these two neurotrans-
mitters suggests that the role of striatal dopamine may Etiology of Parkinson Disease:
be to modulate acetylcholine release; that is, the lack of
Genetic and Environmental Factors
As stated previously, the exact factors that initiate the
NORMAL loss of striatal dopamine are unknown in most patients
with Parkinson disease. However, recent evidence
Dopamine Acetylcholine suggests that genetic factors may interact with envi-
ronmental factors to make certain individuals suscep-
tible to the destruction of dopaminergic neurons in
the substantia nigra.22,35,83
Regarding the genetic factors, mutations of sev-
eral genes have been identified that might play a
causative role in Parkinson disease.22,35 These genes
are responsible for controlling the production of
Basal alpha-synuclein (a small presynaptic protein) and
Ganglia other neuronal proteins.6,14,45 Defects in the genes
regulating the production of these proteins appear to
lead to the overproduction and abnormal accumula-
PARKINSON DISEASE tion of proteins in neuronal tissues, especially in peo-
Acetylcholine ple with certain forms of Parkinson disease such as
early onset parkinsonism and other familial forms.11,34
As proteins accumulate, they can cause damage to
specific cellular components such as the mitochon-
Dopamine dria and cell membrane.33,42 Indeed, Parkinson disease
and several other neurodegenerative disorders are
associated with the formation of Lewy bodies, which
are clumps of proteins found in the neuronal tis-
Abnormal protein accumulation therefore seems
Basal to play a role in the degenerative changes seen in
Ganglia Parkinson disease. The actual neuronal death, howev-
er, may be caused by the formation of harmful byprod-
ucts of oxygen metabolism, better known as oxygen
FIGURE 10–1 ▼ Schematic representation of the neurotransmitter “free radicals.”38,75 A free radical is a chemical species
imbalance in Parkinson disease. Normally, a balance exists between
dopamine and acetylcholine in the basal ganglia. In Parkinson disease,
that has an unpaired electron in its outer shell.15 In
decreased dopaminergic influence results in increased acetylcholine order to become more stable, the free radical steals an
influence. electron from some other cellular component such as a
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Chapter 10 Pharmacological Management of Parkinson Disease 121

protein, DNA molecule, or membrane phospholipid. The discovery of toxin-induced parkinsonism in

In this process, the free radical damages the cellular drug addicts led to the idea that idiopathic Parkinson
component, subsequently damaging the cell. Free rad- disease may occur when susceptible individuals are
icals, for example, might initiate or accelerate the exposed to some environmental toxin.14 Exposure to
abnormal accumulation and aggregation of alpha- such a toxin through industrial waste or certain herbi-
synuclein and other proteins within the neuron.20 Con- cides may begin the neuronal changes that ultimately
sequently, cells subjected to this free radical-induced result in Parkinson disease. A specific environmental
damage are said to undergo oxidative stress because factor, however, has not been identified yet.
loss of electrons (oxidation) of proteins and other Nonetheless, it seems possible that environmen-
cellular components leads to harmful effects on the tal factors might interact with genetic factors to bring
cell.15,33 about the neuronal destruction associated with
Hence, oxygen free radicals might ultimately be Parkinson disease. Environmental toxins, for example,
responsible for causing the degeneration and death might serve as the trigger for neuronal death in peo-
of substantia nigra neurons. Production of these free ple who have genetic variations that make them vul-
radicals appears to be increased in people with Parkin- nerable to these toxins. The exact cause of Parkinson
son disease, either in response to protein accumula- disease remains unknown, however, and future
tion, or because of a primary defect in mitochondrial research will hopefully clarify the link between genet-
function.8,14,21 Regardless of the initiating factor, ic factors, environmental factors, and the mechanism
excess production of free radicals in the basal ganglia of cell death in the substantia nigra.
could lead to a vicious cycle whereby the free radicals The idea that toxins and free radicals may cause
accelerate protein accumulation and damage the mito- neuronal damage in Parkinson disease has also led to
chondria, which in turn causes more free radical pro- research in ways to delay or prevent the destructive
duction, and so on.30,38 effects of these chemicals.49,60 For example, it has been
It therefore appears that neurons in the substan- suggested that certain medications might have neuro-
tia nigra might ultimately be destroyed because genet- protective effects if they control the production and
ic factors lead to neuronal protein accumulation harmful effects of endogenous toxins such as free radi-
and free radical-induced oxidative stress that causes cals. Such medications are often referred to as “antiox-
the degeneration and death of these neurons. As indi- idants” because they may help control oxidative stress
cated earlier, however, the influence of environmental caused by free radicals. This idea has encouraged the
factors should be considered.49,64 It has been theo- development and use of agents that might delay the
rized, for example, that environmental toxins (e.g., neurodegenerative changes seen in Parkinson disease.
herbicides, insecticides, fungicides) accelerate the In particular, drugs used to decrease the symptoms of
neuronal destruction in people with Parkinson dis- Parkinson disease (dopamine agonists, selegiline, see
ease.14 Much of this evidence is based on the finding later) as well as antioxidants such as vitamin E, have
that a compound known as 1-methyl-4-phenyl- been investigated for any possible neuroprotective
1,2,3,6-tetrahydropyridine (MPTP) appears to be effects.15,30,66 To date, no agent has been identified that
selectively toxic to these neurons and can invoke is overwhelmingly successful in delaying the neuronal
parkinsonism in primates.84 changes occurring in Parkinson disease. Nonetheless,
The theory that a toxin like MPTP might cause future research may continue to clarify the exact rea-
Parkinson disease was formulated in a rather interest- son for the degeneration of substantia nigra neurons,
ing fashion. In 1982, several young adults in their 20s and drugs that help prevent this degeneration could
and 30s developed permanent, severe parkinsonism.5 conceivably be developed to decrease or even eliminate
Since the onset of Parkinson disease before age 40 is the neuronal death that underlies the disease.
extremely rare, these individuals aroused a great deal
of interest. Upon close investigation, all of these indi-
viduals were found to have experimented with syn- Therapeutic Agents
thetic heroin-like drugs. These so-called designer
drugs were manufactured by drug dealers in an
in Parkinsonism
attempt to create an illicit supply of narcotics for sale An overview of the drugs used to treat Parkinson
to heroin addicts. However, the illicit narcotics con- disease is shown in Table 10–1. The primary drug
tained the toxin MPTP, which was discovered to cause used is levodopa. Other agents such as amantadine,
selective destruction of substantia nigra neurons.5 anticholinergic drugs, catechol-O-methyltransferase
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122 SECTION 2 Pharmacology of the Central Nervous System


Drug Mechanism of Action Special Comments

Levodopa Resolves dopamine deficiency by being convert- Still the best drug for resolving parkinsonian
ed to dopamine after crossing blood-brain symptoms; long-term use limited by side
barrier. effects and decreased efficacy.

Dopamine agonists Directly stimulates dopamine receptors in basal May produce fewer side effects (dyskine-
Bromocriptine ganglia. sias, fluctuations in response) than lev-
Cabergoline odopa; preliminary evidence suggests
Pergolide that early use may also delay the progres-
Pramipexole sion of Parkinson disease.

Anticholinergics Inhibit excessive acetylcholine influence caused Use in Parkinson disease limited by frequent
(see Table 10–2) by dopamine deficiency. side effects.

Amantadine Unclear; may inhibit the effects of excitatory May be used alone during early/mild stages
amino acids in the basal ganglia. or added to drug regimen when levodopa
loses effectiveness.

Selegiline Inhibits the enzyme that breaks down dopamine May improve symptoms, especially in early
in the basal ganglia; enables dopamine to stages of Parkinson disease; ability to
remain active for longer periods of time. produce long-term benefits unclear.

COMT* inhibitors Help prevent breakdown of dopamine in periph- Useful as an adjunct to levodopa/carbidopa
Entacapone eral tissues; allows more levodopa to reach administration; may improve and prolong
Tolcapone the brain. effects of levodopa.

*COMT: catechol-O-methyltransferase

inhibitors, and direct-acting dopamine agonists can be an active transport process that is specific for this mol-
used alone or in conjunction with levodopa, depend- ecule and other large amino acids.66,71 Upon entering
ing on the needs of the patient. Each of these agents is the brain, levodopa is then transformed into dopamine
discussed below. by decarboxylation from the enzyme dopa decar-
boxylase (Fig. 10–3).
Administration of levodopa often dramatically
Levodopa improves all symptoms of parkinsonism, especially
Because the underlying problem in Parkinson disease bradykinesia and rigidity. The decrease in symptoms
is a deficiency of dopamine in the basal ganglia, sim- and increase in function are remarkable in patients
ple substitution of this chemical would seem to be a who respond well to the drug. As with any medication,
logical course of action. However, dopamine does not there is a portion of the population who—for unknown
cross the blood-brain barrier. Administration of reasons—do not respond well or simply cannot toler-
dopamine either orally or parenterally will therefore ate the drug. Also, prolonged use of levodopa is associ-
be ineffective because it will be unable to cross from ated with some rather troublesome and frustrating side
the systemic circulation into the brain where it is effects (see “Problems and Adverse Effects of Lev-
needed. Fortunately, the immediate precursor to odopa Therapy”). However, the use of levodopa has
dopamine, dihydroxyphenylalanine (dopa; Fig. 10–2), been the most significant advancement in the manage-
crosses the blood-brain barrier quite readily. Dopa, or ment of Parkinson disease, and it remains the most
more specifically levodopa (the L-isomer of dopa), is effective single drug in the treatment of most patients
able to cross the brain capillary endothelium through with this disorder.32,41,52
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Chapter 10 Pharmacological Management of Parkinson Disease 123

Tyrosine Endothelium
(blood-brain barrier)

Cerebral Capillary Cerebral Tissue


Levodopa Levodopa

decarboxylase FIGURE 10–3 ▼ Selective permeability of the blood-brain barrier to

to dopamine in the periphery is rather extensive—less

HO CH2 CH2 NH2 than 1 percent of the levodopa that is administered
reaches the brain in that form.66 This fact is significant
HO because only levodopa will be able to cross the blood-
brain barrier to be subsequently transformed into
Dopamine dopamine. Any levodopa that is converted premature-
ly to dopamine in the periphery must remain there,
FIGURE 10–2 ▼ Synthesis of dopamine. becoming essentially useless in alleviating parkinson-
ism symptoms.
Consequently, when given alone, rather large
Levodopa Administration and Metabolism:
quantities of levodopa must be administered to ensure
Use of Peripheral Decarboxylase Inhibitors
that enough levodopa reaches the brain in that form.
Levodopa is usually administered orally; the daily dose This is often undesirable because the majority of the
is determined according to each patient’s needs. levodopa ends up as dopamine in the peripheral circu-
Dosages of levodopa are also minimized by adminis- lation, and these high levels of circulating dopamine
tering it with a companion drug that inhibits prema- can cause some unpleasant gastrointestinal and cardio-
ture levodopa breakdown (i.e., a peripheral vascular side effects (see the next section). An alterna-
decarboxylase inhibitor such as carbidopa, discussed tive method is to give levodopa in conjunction with a
later in this section). Levodopa dosages are progres- peripheral decarboxylase inhibitor (Fig. 10–4). The
sively increased until a noticeable reduction in symp- simultaneous use of a drug that selectively inhibits the
toms occurs, or until side effects begin to be a dopa decarboxylase enzyme outside of the CNS
problem. Daily titers are usually divided into two to enables more levodopa to reach the brain before being
three doses per day, and individual doses are often converted to dopamine.
given with meals to decrease gastrointestinal irritation. Carbidopa is a peripheral decarboxylase inhibitor
Following absorption from the gastrointestinal that is given in conjunction with levodopa to prevent
tract, levodopa is rapidly converted to dopamine by peripheral decarboxylation (see Fig. 10–4).48,66 Use of
the enzyme dopa decarboxylase. This enzyme is dis- carbidopa with levodopa dramatically decreases the
tributed extensively throughout the body and can be amount of levodopa needed to achieve a desired
found in locations such as the liver, intestinal mucosa, effect.48 Another decarboxylase inhibitor known as
kidneys, and skeletal muscle. Conversion of levodopa benserazide is available outside of the United States;
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124 SECTION 2 Pharmacology of the Central Nervous System


Without Carbidopa

Levodopa Dopamine

With Carbidopa

Levodopa Levodopa Dopamine

FIGURE 10–4 ▼ Use of a carbidopa, a peripheral decarboxylase inhibitor, on lev-

odopa absorption. Without carbidopa, most of the levodopa is converted to dopamine in
the periphery, rendering it unable to cross the blood-brain barrier. Carbidopa inhibits
the peripheral decarboxylase (D-C ase) enzyme so that levodopa can cross the blood-
brain barrier intact. Carbidopa does not cross the blood-brain barrier so that conversion
of levodopa to dopamine still occurs within the CNS.

this drug can also be used to prevent peripheral con- and fluctuations in response, such as end-of-dose aki-
version of levodopa to dopamine.62 nesia and the on-off phenomenon.48 Problems related
Since levodopa is almost always administered to levodopa therapy are described in the next section
along with a decarboxylase inhibitor such as carbidopa, of this chapter.
these two drugs are often combined in the same pill
and marketed under the trade name Sinemet. (Prepa-
Problems and Adverse Effects
rations of levodopa with benserazide are marketed as
of Levodopa Therapy
Madopar.) When prepared together as Sinemet, lev-
odopa and carbidopa are combined in specific propor- Gastrointestinal Problems. Levodopa administra-
tions, usually a fixed carbidopa-to-levodopa ratio of tion is often associated with nausea and vomiting.
either 1:4 or 1:10.48 The Sinemet preparation that is These symptoms can be quite severe, especially during
typically used to initiate therapy consists of tablets con- the first few days of drug use. However, the incidence
taining 25 mg of carbidopa and 100 mg of levodopa. of this problem is greatly reduced if levodopa is given
This ratio is used to achieve a rapid and effective inhi- in conjunction with a peripheral decarboxylase
bition of the dopa decarboxylase enzyme. A 10:100- or inhibitor such as carbidopa. The reduction in nausea
25:250-mg preparation of carbidopa to levodopa is and vomiting when levodopa peripheral decarboxyla-
usually instituted as the parkinsonism symptoms tion to dopamine is inhibited suggests that these
become more pronounced and there is a need for larg- symptoms may be caused by excessive levels of periph-
er relative amounts of levodopa. When administered erally circulating dopamine.
with carbidopa, levodopa dosages typically begin at Cardiovascular Problems. Some problems with
200–300 mg/d, and are increased periodically accord- cardiac arrhythmias may arise in a patient taking
ing to the needs of the patient. Average maintenance levodopa. However, these problems are usually fairly
dosages of levodopa range between 600–700 mg/d, and minor unless the patient has a history of cardiac
the maximum dosage is often 800 mg/d; however, irregularity. Caution should be used in cardiac patients
these are highly variable from patient to patient. undergoing levodopa therapy, especially during
Levodopa-carbidopa is also available in a con- exercise.
trolled-release preparation (Sinemet CR) that is Postural hypotension can also be an extremely
absorbed more slowly and is intended to provide pro- troublesome problem in a patient taking levodopa.
longed effects.48 The use of this controlled-release Again, this side effect is usually diminished when
preparation may be helpful in patients who respond peripheral decarboxylation is inhibited and periph-
well to levodopa initially but experience dyskinesias eral dopamine levels are not allowed to increase exces-
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Chapter 10 Pharmacological Management of Parkinson Disease 125

sively. Still, patients undergoing physical therapy or controlled-release form of this drug, and incorporating
similar regimens should be carefully observed during other anti-Parkinson medications into the patient’s
changes in posture and should be instructed to drug regimen.7,68 In some patients, dyskinesias may be
avoid sudden postural adjustments. This factor is somewhat difficult to control because the optimal
especially true in patients beginning or resuming lev- dosage of levodopa may fall into a fairly narrow range,
odopa therapy. and some of the parkinsonism symptoms may appear
Dyskinesias. A more persistent and challenging quite similar to the dyskinetic side effects. The physi-
problem is the appearance of various movement disor- cian, physical therapist, patient, and other individuals
ders in patients taking levodopa for prolonged peri- dealing with the patient should make careful observa-
ods. Approximately 80 percent of patients receiving tions to determine if adjustments in levodopa therapy
chronic levodopa therapy begin to exhibit various are resulting in the desired effect.
dyskinesias such as choreoathetoid movements, ballis- Behavioral Changes. A variety of mental side
mus, dystonia, myoclonus, and various tics and effects have been reported in patients taking levodopa.
tremors.3 The specific type of movement disorder can Psychotic symptoms seem especially prevalent,
vary from patient to patient, but tends to remain con- although depression, anxiety, and other changes in
stant within the individual patient. The onset of dysk- behavior have also been noted.29,57 These problems
inetic side effects is particularly frustrating since are especially prevalent in older patients or individuals
levodopa ameliorates one form of the movement dis- who have some preexisting psychologic disturbance.48
order only to institute a different motor problem. Unlike the gastrointestinal and vascular problems
The onset of dyskinesias usually occurs after the described earlier, psychotic symptoms appear to be
patient has been receiving levodopa therapy for peri- exacerbated if levodopa is used in conjunction with
ods ranging from 3 months to several years. In some carbidopa. This event may be caused by greater quan-
patients, these abnormal movements may simply be tities of levodopa crossing the blood-brain barrier
caused by drug-induced overstimulation of dopamin- before being converted to dopamine, thus generating
ergic pathways in the basal ganglia, and decreasing the higher quantities of dopamine within the brain. This
daily dosage of levodopa should help. Because lev- idea seems logical considering that increased activity
odopa has a short half-life and erratic absorption, the in certain dopamine pathways seems to be the under-
drug may also cause dyskinesias due to its intermittent lying cause of psychosis (see Chapter 8). Treatment of
or pulsatile stimulation of dopamine receptors.43,68 these symptoms is often difficult because traditional
That is, the sudden rapid influx of levodopa into the antipsychotic medications tend to increase the symp-
brain may combine with endogenous neuronal toms of Parkinson disease. However, some of the
dopamine release to cause excessive stimulation result- newer “atypical” antipsychotics such as clozapine
ing in various dyskinesias.52 (Chapter 8) may help decrease psychotic symptoms
The reason for dyskinesias in some patients, how- without causing an increase in parkinsonism.48,77
ever, may be far more complex. Certain patients, for Diminished Response to Levodopa. One of the
example, may exhibit dyskinesias when plasma lev- most serious problems in levodopa therapy is that the
odopa levels are rising or falling, or even when plasma drug seems to become less effective in many patients
levels are at a minimum.66 There is evidently an intri- when it is administered for prolonged periods. When
cate relationship between the basal ganglia neurons used continually for periods of 3 to 4 years, the ability
that continue to release or respond to dopamine and of levodopa to relieve parkinsonism symptoms often
the pharmacologic replacement of dopamine through progressively diminishes to the point where the drug
levodopa therapy. Dyskinesias may actually be the is no longer effective.57,79 One explanation for this
result of functional and structural adaptations of these occurrence is that the patient develops a tolerance to
neurons caused by periodic fluctuations in dopamine the drug. A second theory is that the decreased effec-
influence supplied from exogenous sources (lev- tiveness of levodopa may be caused by a progressive
odopa).7,68 increase in the severity of the underlying disease
Regardless of the exact neural mechanism that rather than a decrease in drug’s efficacy. These two
underlies these dyskinesias, the goal of levodopa ther- theories on the decreased effectiveness of levodopa
apy is to find a regimen that diminishes the incapaci- have initiated a controversy as to whether or not lev-
tating parkinsonism symptoms without causing other odopa therapy should be started early or late in the
movement disorders.73 Strategies for minimizing dysk- course of Parkinson disease (see “Clinical Course of
inesias include adjusting the dose of levodopa, using a Parkinson Disease: When to Use Specific Drugs”).
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126 SECTION 2 Pharmacology of the Central Nervous System

Regardless of why this occurs, the loss of levodopa effects.3 During this period, the patient is gradually
efficacy can be a devastating blow to the patient who removed from all anti-Parkinson medication for
had previously experienced excellent therapeutic 3 days to 3 weeks while under close medical supervi-
results from this drug. sion. The purpose of the holiday is to allow the body
Fluctuations in Response to Levodopa. Several to recover from any toxicity or tolerance that may
distinct fluctuations in the response to levodopa are have developed because of prolonged use of levodopa
fairly common in most patients.67,69,80 End-of-dose at relatively high dosages. Drug holidays are done
akinesia describes the phenomenon where the effec- with the hope that levodopa can eventually be
tiveness of the drug simply seems to wear off prior to resumed at a lower dosage and with better results.
the next dose. This condition, known also as “wearing Drug holidays do appear to be successful in some
off,” is usually resolved by adjusting the quantity and patients with Parkinson disease. Beneficial effects may
timing of levodopa administration (i.e., smaller doses be achieved at only half of the preholiday dosage, and
may be given more frequently), or by using a sustained the incidence of side effects (such as dyskinesias, con-
release form of the drug. fusion, and the on-off phenomenon) may be markedly
A more bizarre and less understood fluctuation in reduced.3
response is the on-off phenomenon. Here, the effec- Despite these potential benefits, drug holidays are
tiveness of levodopa may suddenly and spontaneously no longer used routinely because of their potential risk
decrease, resulting in the abrupt worsening of parkin- to the patient. Considering that these patients are in
sonism symptoms (the “off” period). Remission of the advanced stages of Parkinson disease, discontinu-
symptoms may then occur spontaneously or after tak- ing the anti-Parkinson medications even temporarily
ing a dose of levodopa (the “on” period). This on-off results in severe immobility, which can lead to prob-
pattern may repeat itself several times during the day. lems such as venous thrombosis, pulmonary embolism,
Although the exact reasons for this phenomenon are pneumonia, and other impairments that could increase
unclear, the off periods are directly related to dimin- morbidity and mortality.3 Hence, drug holidays may
ishing plasma levels of levodopa.66 These low levels still be used on a limited basis in a few select patients
may occur when the absorption of orally administered with Parkinson disease, but this intervention is not
levodopa is delayed by poor gastrointestinal motility used routinely at the present time.
or if levodopa must compete with large amino acids for
transport across the intestinal mucosa.24 The off peri-
ods can be eliminated by administering levodopa con- Other Drugs Used
tinuously by intravenous infusion, thus preventing the
fall in plasma levels. However, this is not a long-term
to Treat Parkinson Disease
solution, and alterations in the oral dosage schedule Dopamine Agonists
may have to be made in an attempt to maintain plasma
Because the basic problem in Parkinson disease is a
levels at a relatively constant level. Specifically, the
deficiency of striatal dopamine, it would seem logical
drug can be taken with smaller amounts of food and
that drugs similar in function to dopamine would be
meals that are relatively low in protein so that lev-
effective in treating this problem. However, many
odopa absorption is not overwhelmed by dietary
dopamine agonists have serious side effects that pre-
amino acid absorption. As indicated earlier, use of a
vent their clinical use. A few dopamine agonists such
controlled-release formulation such as Sinemet CR
as bromocriptine (Parlodel), pergolide (Permax), and
can also help alleviate various fluctuations by allowing
newer agents such as pramipexole (Mirapex), ropini-
a more steady, controlled release of levodopa into the
role (Requip), and cabergoline (Dostinex) (see Table
bloodstream, thus preventing the fluctuations in plas-
10–1) have been developed to treat Parkinson disease
ma levodopa that seem to be responsible for the on-off
without causing excessive adverse effects.37,61 These
phenomenon and similar problems.
dopamine agonists have traditionally been used in
conjunction with levodopa, especially in patients who
Drug Holidays from Levodopa
have begun to experience a decrease in levodopa
Drug holidays are sometimes used in the patient who effects, or in those who experience problems such as
has become refractory to the beneficial effects of lev- end-of-dose akinesia and the on-off effect.48 Simulta-
odopa or has had a sudden increase in adverse side neous administration of levodopa with a dopamine
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Chapter 10 Pharmacological Management of Parkinson Disease 127

agonist permits optimal results with relatively smaller Dopamine agonists may produce adverse side
doses of each drug. effects such as nausea and vomiting. Postural hypoten-
Dopamine agonists can also be used alone in the sion is also a problem in some patients. With pro-
early stages of mild-to-moderate parkinsonism, thus longed use, these drugs may cause CNS-related side
providing an alternative if other anti-Parkinson drugs effects such as confusion and hallucinations.
(including levodopa) are poorly tolerated.61,76 When
used alone, dopamine agonists do not usually cause
Anticholinergic Drugs
the dyskinesias and fluctuations in motor responses
occurring with levodopa therapy.36,76 Several of these As mentioned previously, the deficiency of striatal
drugs tend to have a longer half-life than levodopa, dopamine results in excessive activity in certain
and therefore produce a steadier and more prolonged cholinergic pathways in the basal ganglia. Conse-
effect on dopamine receptors.9,19 Dopamine agonists quently, drugs that limit acetylcholine transmission
may also be more selective than levodopa in stimulat- are used to help alleviate the symptoms of Parkinson
ing certain dopamine receptor subtypes such as the disease, especially tremors and rigidity. Various anti-
D2 receptor, thus resulting in fewer abnormal motor cholinergic agents are available for this purpose,
responses.37 Hence, these drugs continue to gain (Table 10–2), and these drugs work by blocking acetyl-
acceptance as initial treatment for patients with choline receptors in the basal ganglia.66 These drugs
Parkinson disease. are fairly nonselective, however, and they tend to pro-
There is also evidence that dopamine agonists duce a wide variety of side effects because they block
may help normalize endogenous dopamine activity, acetylcholine receptors in various tissues throughout
thus having a neuroprotective effect on substantia the body (see below). When used alone, anticholiner-
nigra neurons.61 As indicated earlier, certain medica- gics are usually only mildly to moderately successful in
tions are being investigated for their potential to delay reducing symptoms and they are typically used in con-
or prevent the degeneration of dopamine-producing junction with levodopa or other anti-Parkinson drugs
neurons in the basal ganglia. Dopamine agonists could to obtain optimal results.
produce such a neuroprotective effect by providing Anticholinergics are associated with many side
continuous stimulation of dopamine receptors and effects including mood change, confusion, hallucina-
preventing the free radical-induced damage that is tions, drowsiness, and cardiac irregularity.13,39 In addi-
associated with abnormal dopamine synthesis and tion, blurred vision, dryness of the mouth, nausea/
breakdown.12,86 Long-term studies should help clarify vomiting, constipation, and urinary retention are fairly
if early use of dopamine agonists is successful in slow- common. Antihistamine drugs with anticholinergic
ing the progression of Parkinson disease. properties are also used occasionally (Table 10–2).


Generic Name Trade Name Daily Dosage (mg/d) Prescribing Limit (mg/d)
Benztropine mesylate Cogentin 1.0–2.0 6

Biperiden Akineton 6.0–8.0 16

Diphenhydramine* Benadryl 75–200 300

Ethopropazine Parsidol 50–100 600

Procyclidine Kemadrin 7.5–15.0 20

Trihexyphenidyl Artane 6.0–10.0 15

*Antihistamine drug with anticholinergic properties.

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128 SECTION 2 Pharmacology of the Central Nervous System

These drugs tend to be somewhat less effective in to begin taking levodopa until later in the course of this
treating parkinsonism, but appear to have milder side disease.48 Selegiline may also be combined with lev-
effects than their anticholinergic counterparts. odopa therapy because selegiline prolongs the action of
dopamine and allows the reduction of parkinsonism
symptoms using a relatively low dose of levodopa.48
Another MAOB inhibitor, rasagiline (Azilect), has also
Amantadine (Symmetrel) was originally developed as been developed recently, and exerts effects similar to
an antiviral drug, and its ability to reduce parkinson- selegiline.2,85
ian symptoms was discovered by chance.18 Amanta- It has been suggested that selegiline may actually
dine was being used to treat influenza in a patient with slow the progression of Parkinson disease.70 Theoret-
Parkinson disease, and a noticeable improvement in ically, selegiline could have neuroprotective effects
the patient’s tremor and rigidity was also observed. because this drug inhibits dopamine oxidation, thus
Since that time, amantadine has been approved for use preventing excessive production of harmful free radi-
in patients with Parkinson disease and is usually given cals during dopamine breakdown.15,28 Selegiline, how-
along with levodopa. Preliminary evidence suggests ever, may actually have neuroprotective effects that
that this drug may help reduce dyskinesias and other are unrelated to its effects on dopamine metabolism.70
motor complications associated with levodopa therapy It has been suggested, for example, that selegiline may
in people with advanced Parkinson disease.23,55,65,74 decrease the synthesis of proteins that ultimately lead
Additional research, however, is needed to confirm to cell death (apoptosis) in neurons that have under-
this effect.18 gone some sort of injury.27,72 Thus, administration of
Amantadine appears to work by blocking the N- selegiline early in the course of Parkinson disease may
methyl-D-aspartate (NMDA) receptor in the brain, help delay its progression. Nonetheless, the actual
thereby inhibiting the effects of excitatory amino acids effects of this drug on disease progression remain
such as glutamate.18,47 This suggests that excitatory unclear, and future studies will hopefully clarify
neurotransmitters play a role in motor complications whether early use produces long-term benefits in peo-
associated with advanced Parkinson disease.23,65 ple with Parkinson disease.
Future research may discover other ways of control- Selegiline is relatively safe in terms of short-term
ling these excitatory neurotransmitters, thus providing adverse side effects. With some MAO inhibitors, there
additional treatments for people with advanced is frequently a sudden, large increase in blood pressure
Parkinson disease. if the patient ingests foods containing tyramine (see
The primary adverse effects associated with Chapter 7). However, selegiline does not appear to
amantadine are orthostatic hypotension, CNS distur- cause a hypertensive crisis even when such tyramine-
bance (e.g., depression, confusion, hallucinations), and containing foods are eaten.48 Other side effects
patches of skin discoloration on the lower extremities include dizziness, sedation, gastrointestinal distress,
(livedo reticularis). However, these side effects are rel- and headache.
atively mild compared to those of other anti-Parkinson
drugs and are usually reversed by altering the drug
Catechol-O-Methyltransferase Inhibitors
A relatively new group of drugs including entacapone
(Comtan) and tolcapone (Tasmar) were developed to
enhance the effects of levodopa. These drugs inhibit an
Selegiline (Deprenyl, Eldepryl) is a drug that potently enzyme known as catechol-O-methyltransferase
and selectively inhibits the monoamine oxidase type B (COMT). This enzyme converts levodopa to an inac-
(MAOB) enzyme. This enzyme is responsible for tive metabolite known as 3-O-methyldopa; hence,
breaking down dopamine. By inhibiting this enzyme, these drugs are referred to as COMT inhibitors.10 By
selegiline prolongs the local effects of dopamine at preventing levodopa conversion in peripheral tissues,
CNS synapses. Thus, selegiline can be used alone in more levodopa is available to reach the brain and exert
the early stages of Parkinson disease to prolong the beneficial effects. Hence, these drugs are used as
effects of endogenous dopamine produced within the an adjunct to levodopa therapy to provide better
basal ganglia. Early administration of selegiline may therapeutic effects using smaller doses of levodopa.53
alleviate motor symptoms so that patients do not need Evidence suggests that adding a COMT inhibitor to
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Chapter 10 Pharmacological Management of Parkinson Disease 129

levodopa therapy may also reduce fluctuations in the cian should select specific medications based on a
response to levodopa, and prolong the periods of lev- patient’s individual characteristics at each stage of the
odopa effectiveness (“on” time) with shorter periods of disease.48
unresponsiveness (“off” time).53,56
The primary problem associated with COMT
inhibitors is an initial increase in dyskinesias.10 This Neurosurgical Interventions
problem may be due to the fact that the COMT
inhibitor is allowing more levodopa to reach the brain,
in Parkinson Disease
and that the levodopa dosage needs to be lowered Several innovative approaches have been studied to try
accordingly. Other side effects include nausea, diar- to achieve a more permanent resolution to the
rhea, dizziness, and muscle pain/cramps. dopamine imbalance in Parkinson disease. One
approach is to surgically implant dopamine-producing
cells into the substantia nigra to replace the cells that
Clinical Course of have been destroyed by the disease process.26,58 This
Parkinson Disease: When strategy, however, is limited by several issues, includ-
ing how to get a supply of viable cells. A potential
to Use Specific Drugs source of these cells has been from fetal mesenchymal
Controversy exists as to when specific anti-Parkinson tissues. Embryonically derived stem cells have the
drugs should be employed.1,16 Much of the debate potential to differentiate into virtually any type of
focuses on when levodopa therapy should be initiated. human cell, thus providing a source that could be used
Without question, levodopa is the most effective phar- to repair damaged tissues in many degenerative condi-
macological treatment for reducing the motor symp- tions including Parkinson disease.25,40
toms of Parkinson disease. As mentioned previously, This approach, however, has generated consider-
however, long-term use of levodopa poses several risks, able concern about the ethical use of fetal tissues for
and the effectiveness of this drug seems to diminish medical research and treatment. Alternative sources
after several years of use. Consequently, some practi- such as stem cells from adult bone marrow or human
tioners question whether levodopa therapy should be chromaffin cells have also been considered, but these
withheld until the parkinsonian symptoms become sources might not be as effective as cells from embry-
severe enough to truly impair motor function. In the- onic tissues.26 Regardless of their source, there are
ory, this saves the levodopa for more advanced stages some practical limitations associated with implanting a
of this disease, when it would be needed the most.48 sufficient number of these cells into a small area deep
Recently, some sources suggested that dopamine in the brain and then keeping these cells alive and pro-
agonists might be a suitable alternative to levodopa as ducing dopamine. Patients who would benefit from
the initial treatment of Parkinson disease.1,16 such transplants are typically older and somewhat
Dopamine agonists can help resolve parkinsonian debilitated with a possible reduction in blood flow and
symptoms, sparing the use of levodopa until later in oxygenation of tissues deep in the brain. These facts,
the course of the disease. As indicated, dopamine ago- combined with the presence of the original patholog-
nists may also have a reduced incidence of dyskinesias, ic process that caused Parkinson disease, may limit the
and may slow the degeneration of substantia nigra transplanted tissues chances for survival.
neurons (neuroprotective effect). Thus, early use of Hence, tissue transplants have not shown
these medications could potentially slow the progres- overwhelming clinical success, and the future of this
sion of Parkinson disease. Levodopa can also be incor- technique as an effective and widely used method
porated into the drug regimen as disability increases, of treating Parkinson disease remains doubtful at
along with other medications such as amantadine, present.58 It may be possible that new developments,
anticholinergics, COMT inhibitors, and selegiline.48 including the use of cell cultures as a source of
There is no clear consensus of which drugs should dopamine-producing cells and the use of drugs to pro-
be used in the initial and subsequent treatment of long the survival of transplanted tissues, may improve
Parkinson disease. Future research should help clarify the clinical outcome of this technique. Still, it remains
whether it is better to begin treatment with dopamine to be seen whether tissue transplants will ever be a
agonists, and to save levodopa and other medications practical and routine method of treating the rather
until later in the disease course. Ultimately, the physi- large number of patients with the disease.
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130 SECTION 2 Pharmacology of the Central Nervous System

An alternative nonpharmacological treatment of this chapter to review these newer surgical and
involves the use of specific surgeries (pallidotomy, electrical stimulation techniques. Nonetheless, these
thalotomy) to produce lesions in specific neuronal nonpharmacologic interventions continue to be
pathways in patients with advanced Parkinson dis- developed and will hopefully provide an alterna-
ease.82 These surgical lesions, however, are associ- tive treatment for patients who have become refracto-
ated with many risks and side effects.50 An alternative ry to drug therapy during the advanced stages of
strategy consists of surgically implanting electrodes the disease.82
into deep brain structures such as the globus pal-
lidus, thalamus, and subthalamic nucleus.44,82 High-
frequency stimulation of these structures may help
normalize neuronal circuitry within the basal gan- The cause of Parkinson disease remains unknown.
glia, and help resolve the motor symptoms of However, the neuronal changes that produce the
advanced Parkinson disease.4,44 It is beyond the scope symptoms associated with this movement disorder

Special Considerations for Rehabilitation

■ ■ ■ Therapists who are treating patients with Parkinson disease usually wish to coordinate
the therapy session with the peak effects of drug therapy. In patients receiving levodopa, this usu-
ally occurs approximately 1 hour after a dose of the medication has been taken. If possible, sched-
uling the primary therapy session in elderly patients after the breakfast dose of levodopa often
yields optimal effects from the standpoint of both maximal drug efficacy and low fatigue levels.
Therapists working in hospitals and other institutions are sometimes faced with the respon-
sibility of treating patients who are on a drug holiday. As discussed previously, the patient is
placed in the hospital for several days and all anti-Parkinson medication is withdrawn so that the
patient may recover from the adverse effects of prolonged levodopa administration. During the
drug holiday, the goal of physical therapy is to maintain patient mobility as much as possible.
Obviously, without anti-Parkinson drugs, this task is often quite difficult. Many patients are well
into the advanced stages of the disease, and even a few days without medication can produce
profound debilitating effects. Consequently, any efforts to maintain joint range of motion and
cardiovascular fitness during the drug holiday are crucial in helping the patient resume activity
when medications are reinstated.
Therapists should also be aware of the need to monitor blood pressure in patients receiv-
ing anti-Parkinson drugs. Most of these drugs cause orthostatic hypotension, especially during
the first few days treatment. Dizziness and syncope often occur because of a sudden drop in
blood pressure when the patient stands up. Because patients with Parkinson disease are suscep-
tible to falls, this problem is only increased by the chance of orthostatic hypotension. Conse-
quently, therapists must be especially careful to guard against falls by the patient taking
anti-Parkinson drugs.
Finally, rehabilitation specialists should recognize that they can have a direct and positive
influence on the patient’s health and need for drug treatment. There is consensus that an aggres-
sive program of gait training, balance activities, and other appropriate exercises can be extreme-
ly helpful in promoting optimal health and function in patients with Parkinson disease.17,31,81
Using physical therapy and occupational therapy interventions to maintain motor function can
diminish the patient’s need for anti-Parkinson drugs. The synergistic effects of physical reha-
bilitation and the judicious use of drugs will ultimately provide better results than either inter-
vention used alone.
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Chapter 10 Pharmacological Management of Parkinson Disease 131

Anti-Parkinson Drugs cise and gait activities was virtually impossible. There was
no pattern to her good and bad days, and the beneficial
Brief History. M.M. is a 67-year-old woman who was effects of the rehabilitation program seemed limited by the
diagnosed with Parkinson disease 6 years ago, at which time rather random effects of her medication. The patient stated
she was treated with anticholinergic drugs (i.e., benztropine that these akinetic episodes sometimes occurred even on
mesylate, diphenhydramine). After approximately 2 years, nontherapy days.
bradykinesia and the rigidity associated with this disease Decision/Solution. After discussions with the patient
began to be more pronounced, so she was started on a com- and her husband, the therapist realized that the morning dose
bination of levodopa-carbidopa. The initial levodopa dosage of levodopa was sometimes taken with a rather large break-
was 400 mg/d. She was successfully maintained on levodopa fast. On other days, the patient consumed only a light break-
for the next 3 years, with minor adjustments in the dosage. fast. In retrospect, the akinetic episodes usually occurred on
During that time, M.M. had been living at home with her hus- days when a large morning meal was consumed. The thera-
band. During the past 12 months, her husband noted that her pist surmised that this probably occurred because the large
ability to get around seemed to be declining, so the levodopa breakfast was impairing absorption of levodopa from the gas-
dosage was progressively increased to 600 mg/d. The patient trointestinal tract. The patient was probably exhibiting the on-
was also referred to physical therapy on an outpatient basis in off phenomenon sometimes seen in patients receiving
an attempt to maintain mobility and activities of daily living long-term levodopa therapy, which was brought on by the
(ADL). She began attending physical therapy three times per impaired absorption of the drug. This problem was resolved
week, and a regimen designed to maintain musculoskeletal by having the patient consistently take the morning dose with
flexibility, posture, and balance was initiated. a light breakfast. On mornings when the patient was still hun-
Problem/Influence of Medication. The patient was gry, she waited 1 hour before consuming additional food to
seen by the therapist three mornings each week. After a allow complete absorption of the medication. The problem
few sessions, the therapist observed that there were certain was also brought to the physician’s attention, and the physi-
days when the patient was able to actively and vigorously par- cian prescribed a sustained release form of levodopa/car-
ticipate in the therapy program. On other days, the patient bidopa (Sinemet CR) to help provide a more continuous and
was essentially akinetic, and her active participation in exer- prolonged absorption.

have been identified. Degeneration of dopaminergic improvements in motor function. However, levodopa
neurons in the substantia nigra results in a deficiency is associated with several troublesome side effects, and
of dopamine and subsequent overactivity of acetyl- the effectiveness of this drug tends to diminish with
choline in the basal ganglia. Pharmacologic treatment time. Other agents, such as dopamine agonists, aman-
attempts to rectify this dopamine-acetylcholine imbal- tadine, selegiline, anticholinergic drugs, and COMT
ance. Although no cure is currently available, drug inhibitors, can be used alone, in combination with lev-
therapy can dramatically improve the clinical picture odopa, or with each other to prolong the functional
in many patients by reducing the incapacitating symp- status of the patient. Physical therapists and other
toms of parkinsonism. rehabilitation specialists can maximize the effective-
The use of levodopa and several other medica- ness of their treatments by coordinating therapy ses-
tions has allowed many patients with Parkinson disease sions with drug administration. Therapists also play a
to remain active despite the disease’s steadily degener- vital role in maintaining function in the patient with
ative nature. Levodopa, currently the drug of choice in Parkinson disease when the efficacy of these drugs
treating parkinsonism, often produces remarkable begins to diminish.

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