Pharmacology in Rehabilitation 4th Edition docx

General Principles ofWhat Constitutes a Drug: Development and Approval of Therapeutic Agents, 5 Drug Approval Process, 5 Prescription Versus Over-the-Counter Medication, 7 Controlled Sub

Potential Interactions between Physical Agents and Therapeutic Drugs

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

Increased blood flow

to improve tissue healing

Decreased muscle/joint stiffness in large areas

of the body

Increased wound healing

Management of skin ders (acne, rashes)

disor-Decreased pain

Increased skeletal muscle strength and endurance Decreased spasticity and muscle spasms

Anti-inflammatory steroids (glucocorticoids); non- steroidal anti-inflamma- tory analgesics (aspirin and similar NSAIDs) Skeletal muscle relaxants

NSAIDs; opioid analgesics;

local anesthetics Skeletal muscle relaxants

Peripheral vasodilators

Opioid and nonopioid gesics; skeletal muscle relaxants

anal-Various systemic and topical antibiotics

Systemic and topical antibiotics and anti- inflammatory steroids (glucocorticoids) Opioid and nonopioid analgesics

— Skeletal muscle relaxants

Peripheral vasodilators may exacerbate acute local edema

Nonselective cholinergic nists may stimulate the neuromuscular junction

ago-— Nonselective cholinergic ago- nists may stimulate the neuromuscular junction Systemic vasoconstrictors (e.g., alpha-1 agonists) may decrease perfusion

Opioid antagonists (naloxone) Skeletal muscle relaxants Nonselective cholinergic ago- nists may stimulate the neuromuscular junction

Some forms of cryotherapy may produce local vaso- constriction that temporarily impedes diffusion of drugs

to the site of inflammation

—

—

—

—

Severe hypotension may occur

if systemic hot whirlpool is administered to patients taking peripheral vasodila- tors and some antihyper- tensive drugs (e.g., alpha-1 antagonists, nitrates, direct- acting vasodilators, calcium channel blockers) Antibacterial drugs generally increase cutaneous sensi- tivity to ultraviolet light (i.e., photosensitivity) Photosensitivity with antibac- terial drugs

—

—

—

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 notethat some members of a drug class may have a suffix that is different from the one indicated; for instance, not allbenzodiazepines end with “-epam” or “-olam.”

Primary Indication or Desired Effect (Chapter

Bronchodilators (xanthine derivatives)

Calcium channel blockers

(dihydropyridine group) Cyclooxygenase type 2

(COX-2) inhibitors Glucocorticoids

Histamine H2-receptor blockers

HIV protease inhibitors

HMG-CoA reductase inhibitors (statins)

Local anesthetics

Low molecular-weight heparins

Oral antidiabetics

(sulfonylurea group) Penicillin antibiotics

Proton pump inhibitors

Tetracycline antibiotics

Various other antibacterials

*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).

-pril

-azole -barbital

-epam or -olam

-olol

-dronate -erol -phylline -ipine

-coxib

-sone or -olone *

-idine -avir -statin -caine

-parin -amide

-cillin -prazole -cycline -micin or -mycin †

Captopril, enalapril

Fluconazole, miconazole Phenobarbital, secobarbital

Diazepam, temazepam, alprazolam, triazolam

Metoprolol, propranolol

Alendronate, pamidronate Albuterol, pirbuterol Theophylline, aminophylline Nifedipine, nicardipine

Celecoxib

Cortisone, dexamethasone, one, prednisolone, triamcinolone Cimetidine, ranitidine

prednis-Ritonavir, saquinavir Pravastatin, simvastatin Lidocaine, bupivicaine

Dalteparin, enoxaparin Chlorpropamide, tolbutamide

Penicillin, ampicillin, amoxicillin Omeprazole, lansoprazole Tetracycline, doxycycline Streptomycin, gentamicin, erythromycin

Antihypertensive (21), congestive heart failure (24)

Fungal infections (35) Sedative-hypnotic (6), antiseizure (9), anesthetic (11)

Sedative-hypnotic (6), antianxiety (6), antiseizure (9), anesthetic (11) Antihypertensive (21), antianginal (22), antiarrhythmic (23), conges- tive heart failure (24)

Osteoporosis (31) Bronchodilation (26) Bronchodilation (26) Antihypertensive (21), antianginal (22) Pain, inflammation (15)

Anti-inflammatory (16, 29), suppressants (37)

immuno-Gastric ulcers (27) HIV infection (34) Hyperlipidemia (25) Local anesthetic (12), antiarrhythmics (23) Anticoagulants (25) Antidiabetic (type II diabetes melli- tus) (32)

Bacterial infections (33) Gastric ulcers (27) Bacterial infections (33) Bacterial infections (33)

Pharmacology in

Rehabilitation

4th Edition

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 www.fadavis.com

Ithaca College Ithaca, New York

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

1 Pharmacology 2 Medical rehabilitation I Title.

[DNLM: 1 Drug Therapy 2 Pharmacokinetics 3 Pharmacology 4 Rehabilitation.

WB 330 C568p 2007]

RM301.C515 2007

615 ′.1—dc22

2006101581 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,

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Dedicated to Penny, Kate, and Alex for providing stant faith, support, and inspiration.

con-v

This page has been left intentionally blank.

There are very peculiar ways in which one can mark

time We often do so by observing the rate at which

our siblings, children, or grandchildren grow,

espe-cially when we are not in daily contact, or by how we

inevitably underestimate the length of time transpired

since we last encountered an old friend In this

con-text, it seems remarkable that over 13 years have

tran-spired since I first discussed with Chuck Ciccone the

prospects for a text on pharmacology for our

Contem-porary Perspectives in Rehabilitation The realization

that the first edition of Pharmacology in Rehabilitation

appeared more than a decade ago is even more

astounding The basis for the genesis of such a book

was founded on the belief that rehabilitation

spe-cialists received little formal training about drug

interactions and how any single pharmacological

agent could impact either treatment plans or

out-comes Chuck took it upon himself to generate a text

that would address this educational and clinical

short-coming The result is very clear Pharmacology in

Reha-bilitation is the “gold standard” among all texts

addressing this content for nonphysician

rehabilita-tion specialists

So why is it important to create a fourth editionwithin one decade? Why is a more superficial com-

pendium of information about drugs and their actions

inadequate? The answer to these questions is directly

related to the rapidly emerging responsibilities

incum-bent upon rehabilitation specialists During the past 5

years, the advent of clinical doctoral programs in

physical and occupational therapy has heralded a rapid

transformation in these educational arenas Several

attributes now take on a meaning that previously

might have been underappreciated First, the label of

“doctor” implies an expectation on the part of the

con-sumer that the practitioner is the penultimate expert

on providing an analysis and treatment plan for

improving upon the pathology of any system’s

move-ment, whether muscle, joint, pulmonary, etc Second,

given the status associated with the professional label,

there is an associated obligation on the part of the

practitioner to address all aspects of the patients’ signs

and symptoms This obligation requires that the

clini-cian differentiate patient responses to treatment from

patient responses to pharmacy As one physical pist so astutely told me, her recognition that a patientwas not responding to pain medication taken wellabove the specified dosage, in the absence of any evi-dence for malingering behavior, resulted in the subse-quent detection and successful removal of a renaltumor Third, as practitioners, the DPT or DOT now

thera-assumes a greater responsibility for keeping a

contem-porary knowledge base about the interface betweentreatment plan and concurrent synergies or exacerba-tions that might result from single or multiple med-ications taken by the patient

This collection of attributes can be best ated if the student is first informed and the clinician iseducated about the most recent medications, theirpharmokinetics, and the interactions they have withpatients with specific diagnoses Since the drug indus-try is arguably one of the most dynamic corporatestructures in the world, changes in pharmacy occur at

appreci-an alarmingly fast rate, one that will increase evenmore dramatically as transplants and the sequelaeresulting from genetic engineering (as two examples)take on greater roles in medicine Such rapid changes,then, call for contemporary and comprehensiveupdates in available information Such updates must

be presented in a manner that is compelling, yet easy

to understand

Inclusive in this perception is the absoluterequirement that the student or clinician be able

to relate to the text meaningfully Toward this

impor-tant goal, the 4th edition of Pharmacology in tion is designed to address rehabilitation relevance

Rehabilita-in every clRehabilita-inical chapter as well as to present tant case histories to reinforce this relevance Newmaterials on agents used in or even as complemen-tary and alternative medicines have been added.Moreover, we have made efforts to add to the appeal

impor-of the book through the addition impor-of colorization,use of double columns, and encasing the text within

a newly designed hard cover These changes are incontradistinction to one standard that remainsimmutable—Dr Ciccone’s remarkable gift for tak-ing complex material and making it easy to under-stand

vii

Foreword

For those clinicians who have in their possession

early editions of this book, I invite you to compare

your copy to the 4th edition as validation for the

asser-tions made in this Foreword We have not

compro-mised the comprehensive nature of this volume in

favor of a “simpler” approach to understanding

pharmacology We believe that the topic, by its very

nature and from the implications inherent in its

knowledge base, requires a comprehensive, yet

user-friendly, delivery This belief system remains

unhin-dered in this latest edition; yet the problem-solving

and evidence-based nature of the content is preserved

and enhanced

The thought of having a reference text for bilitation specialists was considered by us to be aunique concept 13 years ago Today, many doctoralprograms include pharmacology as a separate course or

reha-as an important component in teaching the rationalefor treatment approaches and their assessment There

is much gratification to be gained from recognizingthis transformation and in knowing that the content ofthis book contributes to the evolving maturation of oureducational programs and our clinical services

Steven L Wolf, PT, PhD, FAPTA

Series Editor

In one sense, pharmacology can be considered a “good

news, bad news” scenario The good news is that

exciting and innovative changes in drug therapy

con-tinue to occur at lightning speed The bad news is that

it is often difficult for health care practitioners to stay

abreast of this rapidly changing field Oftentimes,

drug therapies that were considered state-of-the-art

only a few years ago are now outdated and replaced by

more contemporary treatments

Hence, the fourth edition of this text has beenrevised extensively to reflect the science and practice

of pharmacology, with particular emphasis on how

drug therapy impacts patients receiving physical

reha-bilitation Efforts were made to use the peer-reviewed

literature to obtain the most recent information on

pharmacotherapeutics This information has become

incredibly accessible because of computerized

data-bases such as PubMed and resources such as the FDA

website The volume of this information, however, is

so extensive that I was often astounded by the number

of articles on a given topic It was certainly a challenge

to condense this information into a meaningful format

for busy students and clinicians Nonetheless, I believe

this edition is successful in presenting the most recent

and pertinent details of pharmacotherapeutics and

that it underscores the relevance of this topic to

phys-ical therapy and occupational therapy

As in previous editions, basic pharmacology cepts are addressed in the first section (Chapters 1

con-through 4), with subsequent chapters dealing with

drug applications in specific diseases and pathologicalconditions Chapters that deal with specific diseasesbegin with background information on each system ordisorder, followed by detailed descriptions of thephysiologic and pharmacologic actions of these drugs,their primary beneficial and adverse effect, and howdrug therapy can impact physical rehabilitation A newchapter on complementary and alternative medica-tions (Chapter 38) has been added to this edition Thischapter complements the other chapters that deal withmore traditional and conventional medications Thisedition also has a new “look,” with many featuresadded to help students and clinicians access this infor-mation more easily

Once again, I am pleased to present students andclinicians with a resource that might ultimatelyimprove their ability to provide therapeutic interven-tions Pharmacology continues to expand both interms of the number of medications available to ourpatients, and in our understanding of how drugs can

be used most effectively as part of a comprehensivehealth care regimen It is essential that we understandthe beneficial and adverse affects of medications com-monly taken by our patients, and consider how we cancapitalize on the beneficial effects while dealing withdrug side effects I hope this book will continue toserve as a primary resource on this topic, and thatreaders find this fourth edition interesting and useful

Charles D Ciccone

ix

Preface

This page has been left intentionally blank.

This edition is the culmination of the invaluable

assis-tance and input from some very talented people In

particular, I want to thank Barbara MacDermott

Costa, Linda D Crane, John F Decker, Mark Greve,

Sandra B Levine, Donald L Merrill, Grace Minerbo,

Peter Panus, and Jeffrey Rothman I am deeply

indebted to these individuals for their suggestions on

previous editions Without their help, it is unlikely

that the fourth edition of this text would have ever

F A Davis Company for their help and proficiency indeveloping this text In particular, Margaret Biblis andMelissa Duffield were instrumental in developing thefourth edition of this text, and for implementing most

of the obvious changes in the design and presentation

of this material I cannot thank them enough for alltheir insight and expertise, and I am sure their effortswill be appreciated by everyone who uses this text

xi

Acknowledgments

This page has been left intentionally blank.

Susan Sullivan Glenney, PT, MS

Former Assistant Professor

Department of Physical Therapy

University of Hartford

West Hartford, Connecticut

Gary Gorniak, PT, PhD

Director and Associate Professor

Physical Therapy Program

University of St Augustine for Health Sciences

St Augustine, Florida

Ellen Wruble Hakim, PT, DScPT, MS, CWS

Assistant ProfessorDepartment of Physical Therapy and RehabilitationScience

University of Maryland School of MedicineBaltimore, Maryland

Steven Raymond Tippett, PT, PhD, SCS, ATC

Associate ProfessorDepartment of Physical Therapy and Health ScienceBradley University

Peoria, Illinois

xiii

Reviewer List

This page has been left intentionally blank.

Section 1 General Principles of

What Constitutes a Drug: Development and

Approval of Therapeutic Agents, 5

Drug Approval Process, 5

Prescription Versus Over-the-Counter

Medication, 7 Controlled Substances, 8

Basic Concepts in Drug Therapy, 8

Dose-Response Curves and Maximal Efficacy, 8

Potency, 9

Elements of Drug Safety, 10

Quantal Dose-Response Curves and the Median

Effective Dose, 10 Median Toxic Dose, 10

Membrane Structure and Function, 17

Movement Across Membrane Barriers, 18

Active Transport, 20

Distribution of Drugs Within the Body, 21

Factors Affecting Distribution, 21

Volume of Distribution, 21

Drug Storage, 22

Storage Sites, 22 Adverse Consequences of Drug Storage, 23

Newer Techniques for Drug Delivery, 23

Controlled-Release Preparations, 23 Implanted Drug Delivery Systems, 23 Targeting Drug Delivery to Specific Cells and Tissues, 24

Chapter 3 Pharmacokinetics II: Drug Elimination, 29

Biotransformation, 29

Cellular Mechanisms of Drug Biotransformation, 29 Organs Responsible for Drug Biotransformation, 31 Enzyme Induction, 31

Drug Excretion, 31Drug Elimination Rates, 32

Clearance, 33 Half-Life, 33

Dosing Schedules and Plasma Concentration, 34Variations in Drug Response and Metabolism, 34

Chapter 4 Drug Receptors, 41

Receptors Located on the Cell’s Surface, 41

Surface Receptors Linked Directly to Ion Channels, 41 Surface Receptors Linked Directly to Enzymes, 42 Surface Receptors Linked to Regulatory (G) Proteins: Role of the Second Messenger, 42

Intracellular Receptors, 44Drug-Receptor Interactions, 44Functional Aspects of Drug-ReceptorInteractions, 45

Drug Selectivity and Receptor Subtypes, 45 Dose-Response, 46

Classification of Drugs: Agonist Versus Antagonist, 46 Competitive Versus Noncompetitive Antagonists, 46 Partial Agonists, 47

Mixed Agonist–Antagonists and Inverse Agonists, 48

xv

Contents

Receptor Regulation, 48

Receptor Desensitization and Down-Regulation, 48

Receptor Supersensitivity, 49

Nonreceptor Drug Mechanisms, 50

Section 2 Pharmacology of the

Central Nervous System, 53

Chapter 5 General Principles of

Central Nervous System

CNS Drugs: General Mechanisms, 60

Chapter 6 Sedative-Hypnotic and

Tolerance and Physical Dependence, 69

Other Side Effects, 70

Antianxiety Drugs, 70

Benzodiazepines, 70

Buspirone, 71

Use of Antidepressants in Anxiety, 72

Other Antianxiety Drugs, 72

Problems and Adverse Effects, 72

Special Consideration of Sedative-Hypnotic andAntianxiety Agents in Rehabilitation, 73

Case Study

Sedative-Hypnotic Drugs, 74

Chapter 7: Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome, 77

Depression, 77

Clinical Picture, 77 Pathophysiology of Depression, 78 Antidepressant Drugs, 79

Use of Antidepressants in Chronic Pain, 86

Treatment of Bipolar Disorder: AntimanicDrugs, 86

Bipolar Disorder, 86 Lithium, 86

Other Drugs Used in Bipolar Disorder, 87

Special Concerns in RehabilitationPatients, 88

Case Study

Antidepressant Drugs, 89

Chapter 8 Antipsychotic Drugs, 93

Schizophrenia, 93Neurotransmitter Changes in Schizophrenia, 94Antipsychotic Mechanism of Action, 94

Antipsychotic Medications, 95

Traditional Antipsychotics, 95 Atypical Antipsychotics, 95

Pharmacokinetics, 96Other Uses of Antipsychotics, 98Problems and Adverse Effects, 98

Extrapyramidal Symptoms, 98

Nonmotor Effects, 100

Sedation, 100 Anticholinergic Effects, 100 Other Side Effects, 100

Special Concerns in RehabilitationPatients, 101

Case Study

Antipsychotic Drugs, 101

Chapter 9 Antiepileptic Drugs, 105

Classification of Epileptic Seizures, 105

Rationale for Drug Treatment, 107

Drugs Used to Treat Epilepsy, 107

Newer “Second-Generation” Agents, 110

Selection of a Specific Antiepileptic

Agent, 111

Single-Drug Therapy Versus Drug

Combinations in Epilepsy, 113

Pharmacokinetics, 113

Special Precautions During Pregnancy, 113

Treatment of Status Epilepticus, 113

Withdrawal of Antiseizure Medications, 114

Special Concerns in Rehabilitation

Pathophysiology of Parkinson Disease, 119

Etiology of Parkinson Disease: Genetic and

Clinical Course of Parkinson Disease: When to

Use Specific Drugs, 129

Neurosurgical Interventions in Parkinson

Disease, 129

Special Considerations for Rehabilitation, 130

Case Study

Anti-Parkinson Drugs, 131

Chapter 11 General Anesthetics, 135

General Anesthesia: Requirements, 135Stages of General Anesthesia, 135General Anesthetics: Classification and UseAccording to Route of Administration, 136General Anesthetics: Specific Agents, 136

Inhalation Anesthetics, 136 Intravenous Anesthetics, 136

Pharmacokinetics, 139Mechanisms of Action, 139Adjuvants in General Anesthesia, 141

Preoperative Medications, 141 Neuromuscular Blockers, 141

Special Concerns in Rehabilitation, 145Case Study

General Anesthetics, 145

Chapter 12 Local Anesthetics, 149

Types of Local Anesthetics, 149Pharmacokinetics, 150

Clinical Use of Local Anesthetics, 150Mechanism of Action, 154

Differential Nerve Block, 155Systemic Effects of Local Anesthetics, 156Significance in Rehabilitation, 157

Agents Used to Treat Spasticity, 166

Section 4 Drugs Used to Treat

Pain and Inflammation, 181

Chapter 14 Opioid Analgesics, 183

Source of Opioid Analgesics, 183

Endogenous Opioid Peptides and Opioid

Effect of Opioids on the CNS, 188

Effect of Opioids on CNS Synapses, 188

Peripheral Effects of Opioids, 190

Clinical Applications, 190

Treatment of Pain, 190

Use of Opioids in Patient-Controlled Analgesia, 191

Other Opioid Uses, 191

Problems and Adverse Effects, 192

Concepts of Addiction, Tolerance, and Physical

Special Concerns in Rehabilitation

Patients, 194

Case Study

Opioid Analgesics, 195

Chapter 15 Nonsteroidal Anti-Inflammatory Drugs, 199

Aspirin and Other NSAIDs: General Aspects, 199Prostaglandins, Thromboxanes, and

Leukotrienes, 200

Eicosanoid Biosynthesis, 200 Role of Eicosanoids in Health and Disease, 201

Mechanism of NSAID Action: Inhibition

of Prostaglandin and ThromboxaneSynthesis, 202

Aspirin: Prototypical NSAID, 203Clinical Applications of Aspirinlike Drugs, 203

Treatment of Pain and Inflammation, 203 Treatment of Fever, 204

Treatment of Vascular Disorders, 204 Prevention of Cancer, 204

Problems and Adverse Effects of AspirinlikeDrugs, 204

Gastrointestinal Problems, 204 Other Side Effects, 205

Comparison of Aspirin with Other NSAIDs, 206COX-2 Selective Drugs, 209

COX-2 Drugs and the Risk of Heart Attack and Stroke, 210

Acetaminophen, 210Pharmacokinetics of NSAIDs andAcetaminophen, 211

Special Concerns in Rehabilitation Patients, 212Case Study

Nonsteroidal Anti-Inflammatory Drugs, 212

Chapter 16 Pharmacologic Management of Rheumatoid Arthritis and Osteoarthritis, 217

Rheumatoid Arthritis, 217

Immune Basis for Rheumatoid Arthritis, 218 Overview of Drug Therapy in Rheumatoid Arthritis, 219

Nonsteroidal Anti-Inflammatory Drugs, 219 Glucocorticoids, 221

Disease-Modifying Antirheumatic Drugs, 222 DMARD Combinations Used in Rheumatoid Arthritis, 228

Dietary Implications for Rheumatoid Arthritis, 229

Osteoarthritis, 229

Acetaminophen and NSAIDs, 230

Viscosupplementation, 230

Glucosamine and Chondroitin Sulfate, 230

Special Concerns for Antiarthritic Drug Therapy

Pharmacokinetic Basis for PCA, 237

PCA Dosing Strategies and Parameters, 238

Loading Dose, 238

Demand Dose, 238

Lockout Interval, 238

1- and 4-Hour Limits, 238

Background Infusion Rate, 239

Successful Versus Total Demands, 239

Types of Analgesics Used for PCA, 239

Administration Routes During PCA, 240

Problems and Side Effects of PCA, 245

Pharmacologic Side Effects, 245

Problems with PCA Delivery, 245

Special Concerns for PCA in Rehabilitation

Anatomy of the Autonomic Nervous System:

Sympathetic and Parasympathetic Divisions, 253

Preganglionic and Postganglionic Neurons, 253

Acetylcholine and Norepinephrine, 257 Other Autonomic Neurotransmitters, 257

Autonomic Receptors, 258Cholinergic Receptors, 258

Direct-Acting Cholinergic Stimulants, 264 Indirect-Acting Cholinergic Stimulants, 264 Clinical Applications of Cholinergic Stimulants, 266 Adverse Effects of Cholinergic Stimulants, 267

Chapter 20 Adrenergic Drugs, 273

Adrenergic Receptor Subclassifications, 273Adrenergic Agonists, 274

Alpha Agonists, 275 Beta Agonists, 276 Drugs with Mixed Alpha- and Beta-Agonist Activity, 278

Adrenergic Antagonists, 279

Alpha Antagonists, 279 Beta Antagonists, 281 Other Drugs That Inhibit Adrenergic Neurons, 284

Chapter 21 Antihypertensive Drugs, 287

Normal Control of Blood Pressure, 288Pathogenesis of Hypertension, 288

Essential Versus Secondary Hypertension, 288 Possible Mechanisms in Essential Hypertension, 288

Presynaptic Adrenergic Inhibitors, 294

Centrally Acting Agents, 295

Adverse Side Effects, 311

Calcium Channel Blockers, 311

Mechanism of Action and Rationale for Use, 311

Specific Agents, 311 Adverse Side Effects, 312

Use of Anticoagulants in Angina Pectoris, 312Treatment of Specific Types of Angina

Pectoris, 313

Stable Angina, 314 Variant Angina (Prinzmetal Ischemia), 314 Unstable Angina, 315

Nonpharmacologic Management of AnginaPectoris, 315

Special Concerns in Rehabilitation Patients, 316Case Study

Mechanisms of Cardiac Arrhythmias, 323Types of Arrhythmias, 324

Classification of Antiarrhythmic Drugs, 324

Class I: Sodium Channel Blockers, 324 Class II: Beta Blockers, 326

Class III Drugs That Prolong Repolarization, 326 Class IV: Calcium Channel Blockers, 327

Other Drugs Used to Treat Arrhythmias, 327Nonpharmacologic Treatment of

Arrhythmias, 327Special Concerns in Rehabilitation Patients, 328Case Study

Antiarrhythmic Drugs, 328

Chapter 24 Treatment of Congestive Heart Failure, 331

Pathophysiology of Congestive Heart Failure, 331

Vicious Cycle of Heart Failure, 331 Congestion in Left and Right Heart Failure, 333

Pharmacotherapy, 334Drugs That Increase Myocardial ContractionForce (Positive Inotropic Agents), 334

Digitalis, 334

Other Positive Inotropic Agents, 338

Agents That Decrease Cardiac Workload, 339

Drugs Affecting the Renin-Angiotensin System, 339

Beta Blockers, 340

Diuretics, 341

Vasodilators, 342

Summary of Drug Therapy, 342

Special Concerns in Rehabilitation Patients, 343

Case Study

Congestive Heart Failure, 343

Chapter 25 Treatment of Coagulation

Disorders and Hyperlipidemia, 347

Normal Mechanism of Blood Coagulation, 347

Agents Used to Treat Hyperlipidemia, 357

HMG-CoA Reductase Inhibitors (Statins), 358

Fibric Acids, 359

Other Lipid-Lowering Agents, 360

Adverse Effects of Antihyperlipidemia Agents, 360

Special Concerns in Rehabilitation

Chapter 26 Respiratory Drugs, 369

Drugs Used to Treat Respiratory Tract Irritation

and Control Respiratory Secretions, 369

Antitussives, 369

Decongestants, 370

Antihistamines, 370 Mucolytics and Expectorants, 373

Drugs Used to Maintain Airway Patency inObstructive Pulmonary Disease, 373

Beta-Adrenergic Agonists, 373 Xanthine Derivatives, 376 Anticholinergic Drugs, 377 Glucocorticoids, 378 Cromones, 379 Leukotriene Inhibitors, 380

Treatment of Bronchial Asthma, 380

Pathophysiology of Bronchial Asthma, 380 Long-Term Management of Asthma, 381

Treatment of Reversible Bronchospasm inCOPD, 382

Treatment of Respiratory Problems in CysticFibrosis, 382

Special Concerns in Rehabilitation Patients, 383Case Study

Respiratory Drugs, 384

Chapter 27 Gastrointestinal Drugs, 389

Drugs Used to Control Gastric Acidity andSecretion, 389

Antacids, 389

H 2 Receptor Blockers, 390 Proton Pump Inhibitors, 391 Treatment of H Pylori Infection in Gastric Ulcer Disease, 392

Other Agents Used to Control and Treat Gastric Ulcers, 393

Antidiarrheal Agents, 393

Opioid Derivatives, 394 Adsorbents, 395 Bismuth Salicylate, 395 Miscellaneous Agents Used to Treat Diarrhea, 395

Laxatives and Cathartics, 395

Rationale for Use, 395 Specific Agents and Mechanism of Action, 396 Adverse Effects, 397

Miscellaneous Gastrointestinal Drugs 397

Digestants, 397 Emetics, 397 Antiemetics, 397 Cholelitholytic Agents, 397

Special Concerns in Rehabilitation Patients, 398

Synthesis and Release of Hormones, 407

Feedback Control Mechanisms in Endocrine

Function, 408 Hormone Transport, 408

Hormone Effects on the Target Cell, 409

Clinical Use of Endocrine Drugs, 411

Chapter 29 Adrenocorticosteroids,

415

Steroid Synthesis, 415

Glucocorticoids, 417

Role of Glucocorticoids in Normal Function, 417

Mechanism of Action of Glucocorticoids, 417

Physiologic Effects of Glucocorticoids, 418

Therapeutic Glucocorticoid Agents, 421

Clinical Uses of Glucocorticoids, 421

Glucocorticoid Use in Endocrine Conditions, 421

Use in Nonendocrine Conditions, 421

Adverse Effects of Glucocorticoids, 423

Adrenocortical Suppression, 423

Drug-Induced Cushing Syndrome, 423

Breakdown of Supporting Tissues, 425

Other Adverse Effects, 425

Drugs That Inhibit Adrenocortical Hormone

Biosynthesis, 426

Mineralocorticoids, 426

Regulation of Mineralocorticoid Secretion, 426 Mechanism of Action and Physiologic Effects of Mineralocorticoids, 426

Therapeutic Use of Mineralocorticoid Drugs, 428 Adverse Effects of Mineralocorticoid Agonists, 428 Mineralocorticoid Antagonists, 428

Special Concerns of Adrenal Steroid Use inRehabilitation Patients, 429

Pharmacologic Use of Androgens, 437

Clinical Use of Androgens, 437 Specific Agents, 438

Adverse Effects of Clinical Androgen Use, 439 Antiandrogens, 440

Androgen Abuse, 440

Nature of Androgen Abuse, 440 Effects of Androgens on Athletic Performance, 442 Adverse Effects of Androgen Abuse, 442

Estrogen and Progesterone, 443

Effects of Estrogen and Progesterone on Sexual Maturation, 443

Regulation and Effects of Hormonal Synthesis During the Menstrual Cycle, 443

Female Hormones in Pregnancy and Parturition, 445

Pharmacologic Use of Estrogen andProgesterone, 445

Conditions Treated with Estrogen and Progesterone, 445 Specific Agents, 446

Adverse Effects of Estrogen and Progesterone, 447 Selective Estrogen Receptor Modulators, 448 Antiestrogens, 449

Antiprogestins, 449

Hormonal Contraceptives, 450 Types of Contraceptive Preparations, 450 Mechanism of Contraceptive Action, 452 Adverse Effects of Hormonal Contraceptives, 452

Case Study

Male and Female Hormones, 453

Special Concerns of Sex Hormone Pharmacology

in Rehabilitation Patients 454

Chapter 31 Thyroid and Parathyroid

Drugs: Agents Affecting Bone

Mineralization, 459

Function of the Thyroid Gland, 459

Synthesis of Thyroid Hormones, 459

Regulation of Thyroid Hormone Release, 461

Physiologic Effects of Thyroid Hormones, 461

Mechanism of Action of Thyroid Hormones, 461

Treatment of Thyroid Disorders 462

Hyperthyroidism, 462

Hypothyroidism, 463

Function of the Parathyroid Glands, 464

Parathyroid Hormone, 465

Regulation of Bone Mineral Homeostasis, 465

Pharmacologic Control of Bone Mineral

Agents Affecting Bone Mineral Metabolism, 471

Chapter 32 Pancreatic Hormones

and the Treatment of Diabetes

Effects and Complications of Diabetes Mellitus, 482

Use of Insulin in Diabetes Mellitus, 483

Therapeutic Effects and Rationale for Use, 483 Insulin Preparations, 483

Administration of Insulin, 485 Intensive Insulin Therapy, 485 Adverse Effects of Insulin Therapy, 486

Oral Antidiabetic Drugs, 486

Sulfonylureas, 487 Other Orally Active Drugs, 488

Other Drugs Used in the Management ofDiabetes Mellitus, 488

Glucagon, 488 Glucagon-like Peptide 1, 488 Immunosuppressants, 489 Aldose Reductase Inhibitors, 489

Nonpharmacologic Intervention in DiabetesMellitus, 489

Dietary Management and Weight Reduction, 489 Exercise, 490

Tissue Transplants and Gene Therapy, 490

Significance of Diabetes Mellitus inRehabilitation, 490

Case Study

Diabetes Mellitus, 491

Section 8 Chemotherapy of Infectious and Neoplastic Diseases, 497

Chapter 33 Treatment of Infections I: Antibacterial Drugs, 499

Bacteria: Basic Concepts, 499

Bacterial Structure and Function, 499 Pathogenic Effects of Bacteria, 500 Bacterial Nomenclature and Classification, 500

Treatment of Bacterial Infections: BasicPrinciples, 500

Spectrum of Antibacterial Activity, 500 Bactericidal Versus Bacteriostatic Activity, 500

Basic Mechanisms of Antibacterial Drugs, 501

Inhibition of Bacterial Cell Wall Synthesis and Function, 501

Inhibition of Bacterial Protein Synthesis, 502 Inhibition of Bacterial DNA/RNA Synthesis and Function, 502

Specific Antibacterial Agents 503

Antibacterial Drugs That Inhibit Bacterial Cell

Wall Synthesis and Function 503

Penicillins, 503

Cephalosporins, 505

Other Agents That Inhibit Bacterial Cell Wall

Synthesis, 505 Use of Beta-Lactamase Inhibitors, 506

Drugs That Inhibit Bacterial Protein Synthesis

Clinical Use of Antibacterial Drugs: Relationship

to Specific Bacterial Infections, 514

Resistance to Antibacterial Drugs, 514

Special Concerns in Rehabilitation Patients, 518

Case Study

Antibacterial Drugs, 519

Chapter 34 Treatment of Infections

II: Antiviral Drugs, 523

Viral Structure and Function, 523

Classification of Viruses, 523

Characteristics of Viruses, 523

Viral Replication, 524

Specific Antiviral Drugs, 525

Acyclovir and Valacyclovir, 527 Amantadine and Rimantadine, 527 Cidofovir, 528

Docosanol, 528 Enfuvirtide, 528 Famciclovir and Penciclovir, 528 Fomivirsen, 529

Foscarnet, 529 Ganciclovir and Valganciclovir, 529 Imiquimod, 529

Trifluridine, 530 Oseltamivir and Zanamivir, 530 Protease Inhibitors, 530 Reverse Transcriptase Inhibitors, 531 Ribavirin, 532

Vidarabine, 533

Viral Resistance, 533Interferons, 533

Synthesis and Cellular Effects of Interferons, 534 Pharmacologic Applications of Interferons, 535 Adverse Effects of Interferons, 535

Control of Viral Infection with Vaccines, 535HIV and the Treatment of AIDS, 536

Inhibition of HIV Proliferation in Infected Individuals, 537

Anti-HIV Drug Combinations: Use of Highly Active Antiretroviral Therapy, 537

HIV Vaccines, 538 Management of Opportunistic Infections, 539

Relevance of Antiviral Chemotherapy inRehabilitation Patients, 540

Case Study

Antiviral Drugs, 541

Chapter 35 Treatment of Infections III: Antifungal and Antiparasitic Drugs, 545

Anthelmintics, 557

Kill, 566 Prevalence and Management of Adverse Effects, 566

Biologic Response Modifiers, 577

Heavy Metal Compounds, 579

Aspirin and Other NSAIDs, 580

Tyrosine Kinase Inhibitors, 580

Miscellaneous Agents, 580

Combination Chemotherapy, 582

Use of Anticancer Drugs with Other

Treatments, 582

Success of Anticancer Drugs, 583

Resistance to Cancer Chemotherapy

Overview of the Immune Response, 591Pharmacologic Suppression of the ImmuneResponse, 593

Specific Immunosuppresive Agents, 593

Azathioprine, 593 Cyclophosphamide, 595 Cyclosporine, 595 Glucocorticoids, 596 Methotrexate, 596 Mycophenolate Mofetil, 597 Sulfasalazine, 597

Sirolimus, 597 Tacrolimus, 598 Other Methods of Immunosuppression, 598

Immunostimulants, 599

Bacille Calmette-Guérin, 600 Immune Globulin, 600 Levamisole, 600

Other Immunomodulators, 600Significance of Immunomodulating Agents inRehabilitation, 601

Case Study

Immunomodulating Agents, 601

Chapter 38 Complementary and Alternative Medications, 605

Unique Aspects of CAMs, 605

Misconceptions about CAM Safety, 605 Failure to Report CAM Use, 606 Lack of Standards for Quality and Purity of CAMs, 606 Delayed Use of Conventional Medications, 606

Potential Adverse Effects of CAMs, 606Specific CAMs, 607

Bee Venom, 607 Echinacea, 607 Garlic, 607 Ginger, 609 Ginkgo biloba, 609 Ginseng, 609 Glucosamine and Chondroitin, 609 Kava, 609

Melatonin, 610 Saw Palmetto, 610

St John’s Wort, 610

Complementary and Alternative Medications, 615

Appendix A: Drugs Administered byIontophoresis and Phonophoresis, 619

Appendix B: Use of the Physicians’ Desk

Reference, 621

Appendix C: Drugs of Abuse, 623Glossary, 625

Index, 633

S E C T I O N

1

General Principles

of Pharmacology

Pharmacology is the study of drugs In its broadest

def-inition, a drug can be described as “any substance that,

when taken into a living organism, may modify one or

more of its functions.”28In this sense, a drug includes

any substance that alters physiologic function in the

organism, regardless of whether the effect is beneficial

or harmful In terms of clinical pharmacology, it has

traditionally been the beneficial or therapeutic effects

that have been of special interest Throughout history,

certain naturally occurring chemicals have been used

to relieve pain or treat disease in humans Within the

past century, the use of natural, semisynthetic, and

syn-thetic chemical agents has expanded to the point where

many diseases can be prevented or cured, and the

gen-eral health and well-being of many individuals has

dra-matically improved through therapeutic drug use

Because of the extensive clinical use of tic medications, members of the medical community

therapeu-must have some knowledge of the basic types of drugs

and the mechanisms of their actions Although this has

always been true for individuals who prescribe and

administer drugs (i.e., physicians and nurses), it is now

recognized that members of other health-related

pro-fessions must have a fundamental knowledge of

phar-macology

An understanding of basic drug mechanisms canhelp practitioners such as physical therapists, occupa-

tional therapists, and other rehabilitation specialists

better understand a patient’s response to the drug In

addition, the knowledge of how certain rehabilitative

procedures may interact with medications is helpful in

getting an optimal response in the patient’s drug and

therapy treatment For instance, scheduling the patient

for therapy when certain drugs reach their peak effect

may improve the therapy session dramatically Thismay be true for drugs that decrease pain (analgesics) orimprove the patient’s motor skills (anti-Parkinsondrugs) Conversely, some therapy sessions that requirethe patient’s active participation may be rendered use-less if scheduled when medications such as sedativesreach their peak effect Also, any adverse responsesoccurring due to direct interaction between the thera-

py treatment and certain medications may be avoided

or controlled by understanding a drug’s

pharmacolog-ic aspects For example, a patient who is taking a pheral vasodilator may experience a profound decrease

peri-in blood pressure when he or she is placed peri-in a hotwhirlpool By understanding the implications of such

an interaction, the therapist can be especially alert forany detrimental effects on the patient, or they mayinstitute a different therapy treatment for them

In order to help the reader have a more focusedapproach to the study of drugs, pharmacology is often

divided into several areas of interest (Fig 1–1)

Phar-macotherapeutics is the area of pharmacology that

refers to the use of specific drugs to prevent, treat, ordiagnose a disease For the purposes of this text, theeffects of drugs on humans will be of primary concern,with animal pharmacology mentioned only in refer-ence to drug testing and research in animals

When drugs are used therapeutically in humans,the way that the body interacts with the drug and whatspecific effect it has on an individual must be known.Consequently, pharmacotherapeutics is divided intotwo functional areas: pharmacokinetics and pharma-

codynamics (see Fig 1–1) Pharmacokinetics is the

study of how the body deals with the drug in terms ofthe way it is absorbed, distributed, and eliminated

3

C h a p t e r 1

Basic Principles

of Pharmacology

Pharmacodynamics is the analysis of what the drug

does to the body, including the mechanism by which

the drug exerts its effect In this text, the basic

princi-ples of pharmacokinetics will be outlined in Chapters

2 and 3, and the pharmacodynamics and

pharmacoki-netics of specific drugs will be discussed in their

respective chapters

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-peutic agents’ adverse effects as well as environmental

toxins and poisons However, because virtually every

medication can produce adverse effects, a discussion of

toxicology must be included in pharmacotherapeutics

For the purposes of this text, discussions of drug

toxi-city are limited to the unwanted effects that occur

when therapeutic drugs reach excessively high (toxic)

levels The toxic side effects of individual drugs are

covered in the chapters describing the therapeutic

effects of that drug

Pharmacy deals with the preparation and

dis-pensing of medications Although pharmacy is alsofrequently considered a subdivision of pharmacology,this area has evolved into a distinct professional disci-pline Care must be taken not to use the terms “phar-macy” and “pharmacology” interchangeably, becausethese are quite different areas of study

Drug Nomenclature

One of the most potentially confusing aspects of macology is the variety of names given to differentdrugs or even to the same compound Students ofpharmacology, as well as clinicians, are often faced withmyriad terms representing the same drug.14,17 Manyproblems in drug terminology arise from the fact that

phar-each drug can be identified according to its chemical, generic, or trade name12(Table 1–1) Chemical names

refer to the specific compound’s structure and are

usu-ally fairly long and cumbersome The generic name

Pharmacology

Pharmacotherapeutics

Pharmacokinetics Pharmacodynamics

Cellular Effects Distribution

Absorption

Toxicology

Systemic Effects Elimination

FIGURE 1–1 ▼ Areas of study within pharmacology.

Trade/Brand-Name Chemical Generic (Nonproprietary) (Proprietary)

Tylenol, Panadol, many othersLarodopa

Luminal, EskabarbValium

(also known as the “official” or “nonproprietary”

name) tends to be somewhat shorter and is often

derived from the chemical name A trade name (also

known as the brand name) is assigned to the compound

by the pharmaceutical company and may or may not

bear any reference at all to the chemical and generic

terminology An additional problem with trade names

is that several manufacturers may be marketing the

same compound under different names, thus adding to

the confusion If there is no existing patent for that

compound or if the patent has expired, the same drug

may be marketed by separate drug companies.24 For

practical purposes, the generic name is often the

easi-est and most effective way to refer to a drug, and this

terminology will be used frequently in this text

Drug nomenclature is also a source of confusionand potential errors in medication use, especially

when different drugs have names that look or sound

alike.14It has been estimated, for example, that up to

25 percent of all medication errors are caused by name

confusion.2,13This fact seems especially true for drugs

with similar brand names.14Consider, for example, the

confusion that could occur when trying to

differenti-ate between the following three brand-name products:

Celebrex, Cerebryx, and Celexa.14These three brand

names correspond with an analgesic (see Chapter 15),

an antiseizure drug (see Chapter 9) and an

antidepres-sant (see Chapter 7), respectively Despite their

simi-lar brand names, these three products represent three

distinct pharmacologic classes that are used in very

different clinical situations Hence, practitioners need

to be especially careful when documenting the use of

specific medications, and make sure that the correct

drug name is used to identify each product

Substitution of Generic Drugs for Brand-Name Products

A common question among practitioners and patients

is whether the generic form of a drug can be

substi-tuted for the brand-name product Generic forms are

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 should be as safe and effective as the original

brand-name product, provided that the generic form

satisfies certain criteria.10,29 Specifically, the generic

form should undergo testing to establish that it has the

same type and amount of the active ingredient(s), the

same administration route, the same pharmacokinetic

profile (drug absorption, plasma levels, and so forth),and the same therapeutic effects as the brand-namedrug.3If such testing is done, the two drugs are said to

be “bioequivalent.”7

Unless bioequivalence is established, however, itcan only be assumed that substituting a generic drugwill produce therapeutic effects that are similar to thebrand-name drug Likewise, establishing bioequiva-lence of a generic form does not guarantee that a givenpatient will not experience different effects from thegeneric form compared to the brand-name product.That is, certain patients might simply respond differ-ently to a the generic form of a drug because of indi-vidual differences in their ability to absorb andmetabolize certain generic products, even if these pro-ducts have been shown to be similar to their brand-name counterpart during bioequivalence testing Thisfact seems especially true for drugs that tend to pro-duce a wider range of therapeutic and adverse effectswhen tested in a specific patient, or within a group ofpatients (i.e., drugs with more intrasubject and inter-subject variability).20 Hence, there are a number ofissues that should be considered before a generic drug

is substituted, and practitioners may want to prescribe

a specific brand-name drug based on the

pharmacolog-ic profile of that drug and the specifpharmacolog-ic way that thedrug may affect a given patient

What Constitutes a Drug:

Development and Approval

of Therapeutic Agents

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 ofnew ones.9,19,21The analogous body in Canada is theHealth Products and Food Branch of the Department

of National Health and Welfare The two primaryconcerns of these agencies are (1) whether or not thedrug is effective in treating a certain condition and (2)whether the drug is reasonably safe for human use

Drug Approval Process

The development of a new drug involves extensivepreclinical (animal) and clinical (human) studies.19,21

The basic procedure for testing a new drug is outlinedhere and is summarized in Table 1–2 Details aboutthe phases of drug testing can also be found on theFDA website (http://www.fda.gov/cder/handbook)

Animal (Preclinical) Studies

Drugs are typically tested in animals initially, often

using several different species Initial information on

the basic pharmacokinetic and pharmacodynamic

properties of the compound is obtained Information

on dosage and toxicity is also obtained from these

ani-mal trials

Human (Clinical) Studies

If the results from animal trials are favorable, the drug

sponsor files an investigational new drug (IND)

appli-cation with the FDA If approved as an IND, the

spon-sor may begin testing the drug in humans Human, or

“clinical’ testing, is divided into three primary phases

Phase I The drug is usually tested in a relatively

small number of healthy volunteers The pose of this phase is to obtain some initial infor-mation about the pharmacologic actions, andthe drug’s possible toxic effects in humans Ingeneral, between 20 to 80 subjects are studied

pur-in phase 1, but the actual number of subjectswill vary according to the drug,

Phase II The drug is tested in a relatively small

sample (200 to 300 people) with a specific

dis-ease or pathologic condition The primary goal

of phase 2 is to evaluate the effectiveness of thedrug, and to assess the side effects and otherrisks

Phase III Clinical evaluation is expanded to include

more patients (several hundred to several sand) as well as more evaluators Additionalinformation is obtained regarding the drug’ssafety and effectiveness in a large patient popu-lation

thou-At the end of phase III, the drug sponsor appliesfor a new drug application (NDA) Results from clini-cal testing are reviewed extensively by the FDA, and iffound favorable, the NDA is approved At this point,the drug can be marketed and prescribed for use in thegeneral population

A fourth phase known as “postmarketing lance” should be instituted after the NDA is approved.Postmarketing surveillance refers to all of the methodsused to continue monitoring drug safety and effective-ness after approval for public use.19,21These methodsoften consist of reports from health care providers thatdescribe specific rare adverse effects that were not dis-covered during clinical testing.24 A certain drug, forexample, could cause a specific adverse effect in only 1

Testing Phase Purpose Subjects Usual Time Period

Preclinical testing

Investigational New Drug (IND) Application

Human (clinical) testing:

disease/disorderAssess safety and effective-ness in a larger patient pop-ulation

Monitor any problems thatoccur after NDA approval

Laboratory animals

Small number (⬍ 100) ofhealthy volunteersLimited number (200–300)patients with target disorder

Large number (1000–3000)patients targeted

General patient population

in 10,000 patients taking the drug.1It is very likely that

such an adverse effect could be missed during phase

I through phase III of the clinical trials because the

drug is typically tested only in a few thousand subjects

(e.g., 1000 to 3000 people) In addition to monitoring

adverse effects, postmarketing surveillance can use

more formal research methods to obtain information

about how a specific drug is used in clinical practice

and how that drug compares to similar drugs on the

market.24Hence, postmarketing surveillance has been

advocated as being critical in ensuring that the safety

and efficacy of the drug continues to be monitored

when it is used by the general patient population.18,24

The development of a new drug in the UnitedStates is an extremely expensive and time-consuming

process.11 The time course for the entire testing

process from the beginning of animal trials to the end

of phase III human testing may be as long as 7 to 9

years The FDA has made provisions, however, to

shorten the development and review process for drugs

designed to treat serious and life-threatening

condi-tions, especially if the drug shows substantial benefits

over existing treatments, or no drugs are currently

available for these conditions.25This type of

accelerat-ed development/review (also known as “fast track”

drug development) is typically used for drugs that show

promise in treating conditions such as cancer or

acquired immunodeficiency syndrome (AIDS) Hence,

these fast tract drugs may be made available for patient

use even before formal clinical testing is completed.27

The FDA will, however, require that drug testing be

continued even after the drug is approved, and efforts

must be made to ensure that it actually provides the

therapeutic benefits that were initially promised.27The

approval process can also be expedited if a drug has

already received approval for treating one condition,

but is now being considered for use in other

“supple-mental” conditions.24

The process of drug testing and approval doesseem to be fairly rigorous in its ability to screen out

ineffective or potentially harmful drugs Out of

thou-sands of newly synthesized compounds, only one will

ever be released as a prescription drug.1

Prescription Versus

Over-the-Counter Medication

In the United States, pharmacotherapeutic agents are

divided into drugs requiring a prescription for use and

drugs available as nonprescription, or

over-the-counter (OTC).8Nonprescription drugs can be

pur-chased directly by the consumer, whereas prescriptionmedications may be ordered or dispensed only by anauthorized practitioner (i.e., physician, dentist, orother appropriate health care provider) Prescription

or nonprescription drug classification falls under thejurisdiction of the FDA.8 In general, OTC medica-tions are used to treat relatively minor problems and

to make the consumer more comfortable until thecondition is resolved These medications have beenjudged to be safe for use by the consumer withoutdirect medical supervision, and the chances of toxiceffects are usually small when the medications aretaken in the recommended amounts.8 Of course, thepatient may ingest more than the recommendedamount, and in the case of an overdose, the dangeralways exists for potentially harmful effects, even if thedrug is nonprescription in nature.6,15,22

The role of OTC products in the health caremarket has expanded dramatically in recent years.4,23

Many drugs that were formerly available only by scription are now available in a nonprescription form.Transition of a prescription drug to an OTC productusually occurs when the drug’s marketing companyapplies to the FDA and receives approval to developand market it in a nonprescription form FDAapproval is based on the drug having an adequate safe-

pre-ty profile, and the FDA may require other stipulationssuch as lowering the drug dosage in the OTC product.The fact that more and more prescription drugsare now available in a nonprescription form offerssome obvious benefits Increased availability of OTCproducts can make it easier for consumers to gainaccess to these medications.4,5In addition, OTC prod-ucts are typically less expensive than prescriptiondrugs, and the purported savings might help containoverall medication costs The actual cost to the patient,however, might be greater for an OTC product be-cause the patient must pay directly “out of pocket.”4

That is, health care programs with prescription drugplans may cover the majority of a prescription drug’scost, whereas the patient often must pay directly forthe entire cost of an OTC product The actual moneyspent by patients (i.e., the out-of-pocket cost) mighttherefore be greater for OTC products compared toprescription drugs Hence the overall benefits of OTCproducts on health care costs remains complex.4

Despite the potential benefits of OTC products,there are some obvious concerns about their increaseduse and emphasis on self-care that permeates today’shealth care market Consumers must realize that theseproducts are important therapeutic medications and

must be used appropriately.23,26 There is also the

chance that inappropriate OTC use can cause serious

interactions with a patient’s prescription medications,

or that OTC products can delay the use of more

effec-tive medications.4 The impact of such OTC

com-pounds is discussed in this text in the appropriate

chapters

It is therefore clear that consumers need to be

educated about the use of such medications and

reminded that OTC products can produce substantial

benefits and adverse effects All health care providers,

including physical therapists and occupational

thera-pists, need to be in a position to help educate and

counsel their patients about the benefits and

draw-backs of such medications While therapists should

not directly prescribe or administer OTC products,

therapists can provide information about the proper

use and potential benefits of these medications

Controlled Substances

In 1970, federal legislation was enacted to help control

the abuse of legal and illegal drugs The

Comprehen-sive Drug Abuse Prevention and Control Act (or

Con-trolled Substances Act) placed drugs into specific

categories, or “schedules,” according to their potential

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

Schedule I These drugs are regarded as having the

highest potential for abuse, and are not typicallyused as an acceptable medical treatment in theUnited States Legal use of agents in this cate-gory is restricted to approved research studies

or therapeutic use in a very limited number ofpatients (e.g., use of marijuana as an antiemetic)

Examples of schedule I drugs include heroin,lysergic acid diethylamide (LSD), psilocybin,mescaline, peyote, marijuana, tetrahydro-cannabinols, and several other hallucinogens

Schedule II Drugs in this category are approved

for specific therapeutic purposes but still have ahigh potential for abuse and possible addiction

Examples include opioids such as morphine andfentanyl, and drugs containing methampheta-mine

Schedule III Although these drugs have a lower

abuse potential than those in schedules I and

II, there is still the possibility of developingmild to moderate physical dependence, strong

psychologic dependence, or both Drugs inschedule III include certain opioids (e.g.,codeine) that are combined in a limiteddosage with other nonopioid drugs Otherdrugs in this category are anabolic steroids,certain barbiturates, and amphetamines thatare not included in schedule II

Schedule IV These drugs supposedly have a lower

potential for abuse than schedule III drugs,with only a limited possibility of physicaldependence, psychologic dependence, orboth Examples include certain antianxietydrugs (meprobamate), certain barbiturates(barbital, phenobarbital), and a variety ofother depressants and stimulants

Schedule V These drugs have the lowest relative

abuse potential Drugs in this category sist primarily of low doses of opioids that areused in cough medications and antidiarrhealpreparations

Several other criteria relate to the different trolled substance schedules, such as restrictions onprescription renewal and penalties for illegal posses-sion of drugs in different schedules For a further dis-cussion of controlled substances, the reader is referred

ring In general, the dose of a drug must be large

enough to allow an adequate concentration to reachthe target site, thus producing a beneficial response

However, the administered dosage must not be so

excessive that toxicologic effects are produced Someaspects of the relationship between dose and responseare discussed here

Dose-Response Curves and Maximal Efficacy

The relationship between the dose of a drug and a cific response to the drug is illustrated in Figure 1–2.Typically, very low doses do not produce any ob-servable effect At some threshold dose, the response

spe-begins to occur and continues to increase in magnitude

before reaching a plateau The plateau in the response

indicates that there will be no further increment in the

response even if the dosage continues to be increased

The point at which there is no further increase in the

response is known as ceiling effect, or maximal

effi-cacy, of the drug.24

Dose-response curves are used to provide

information about the dosage range over which the

drug is effective, as well as the peak response that can

be expected from the drug In addition, the

character-istic shape of the dose-response curve and the

pres-ence of the plateau associated with maximal efficacycan be used to indicate specific information about thebinding of the drug to cellular receptors The rele-vance of dose-response curves to drug-receptor inter-actions is discussed further in Chapter 4

Potency

One criterion used frequently when comparing drugs

is the concept of potency Potency is related to the

dose that produces a given response in a specificamplitude.24When two drugs are compared, the morepotent drug requires a lower dose to produce the sameeffect as a higher dose of the second drug Forinstance, in Figure 1–3, a dose of 10 mg of drug Awould lower blood pressure by 25 percent, whereas

80 mg of drug B would be required to produce thesame response Consequently, drug A would bedescribed as being more potent It should be notedthat potency is not synonymous with maximal efficacy.Drug B is clearly able to exert a greater maximal effectthan drug A Consequently, the term “potency” isoften taken to be much more significant than it really

is.24The potency of a drug is often misinterpreted bythe layperson as an indication of the drug’s overalltherapeutic benefits, whereas potency really just refers

to the fact that less of the compound is required toproduce a given response In fact, neither potency normaximal efficacy fully indicates a drug’s therapeutic

Dose (log scale)

Threshold dose

Ceiling effect

potential Other factors such as the therapeutic index

(described further on) and drug selectivity (see

Chap-ter 4) are also important in comparing and ultimately

choosing the best medication for a given problem

Elements of Drug Safety Quantal Dose-Response Curves

and the Median Effective Dose

The dose-response curves shown in Figures 1–2 and

1–3 represent the graded response to a drug as it would

occur in a single individual or in a homogeneous

pop-ulation In reality, variations in drug responses that are

caused by individual differences in the clinical

popula-tion need to be considered when trying to assess

whether a drug is safe as well as effective

Consequent-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

tested preclinically) When plotted, this relationship

yields a cumulative, or quantal, dose-response curve

(Fig 1–4).24This curve differs from the dose-response

curve discussed previously in that it is not the

magni-tude of the response that increases with increasing the

dosage, but the percentage of the population who

exhibit a specific response as the dosage is increased.The response is not graded; it is either present or it isabsent in each member of the population For example,

a headache medication is administered in an increasingdosage to 1000 people At some dose, some of the indi-viduals will begin to respond to the drug by reportingthe absence of their headache As the dosage isincreased, more and more individuals will experiencepain relief because of the medication, until finally 100percent of the population report that their headachesare gone Again, it is the percentage of the populationwho respond in a specific way (e.g., reporting loss oftheir headaches) that is measured relative to the dose ofthe drug An important reference point in this type of

cumulative dose-response curve is the median

effec-tive dose (ED50).24 This is the dose at which 50 cent of the population respond to the drug in aspecified manner

per-Median Toxic Dose

In the aforementioned example, relief from pain wasthe desired response, which is often termed the “bene-ficial” effect As dosages of the drug continue to beincreased, however, adverse or toxic effects maybecome apparent To continue the earlier example,higher doses of the same medication may be associated

with the appearance of a specific toxic effect such as

acute gastric hemorrhage As the dosage is increased,

more and more individuals will then begin to exhibit

that particular adverse effect The dose at which 50

percent of the group exhibits the adverse effect is

termed the median toxic dose (TD50) In animal

stud-ies, the toxic effect studied is often the death of the

ani-mal In these cases, high doses of the drug are used to

determine the median lethal dose (LD50)—the dose

that causes death in 50 percent of the animals

stud-ied.24 Of course, the LD50 is not a relevant term in

clinical use of the drug in humans, but it does serve to

provide some indication of the drug’s safety in

preclin-ical animal trials

Therapeutic Index

The median effective and toxic doses are used to

determine the therapeutic index (TI).24 The TI is

calculated as the ratio of the TD50to the ED50:

TI⫽TD 50

ED 50

In animal studies in which the median lethal dose

is known, the TI is often calculated using the LD50in

place of the TD50 In either human or animal studies,

the TI is used as an indicator of the drug’s safety.24

The greater the value of the TI, the safer the drug is

considered to be In essence, a large TI indicates that

it takes a much larger dose to evoke a toxic response

than it does to cause a beneficial effect

It should be noted, however, that the TI is arelative term Acetaminophen, a nonprescription anal-

gesic, has a TI of approximately 27 (i.e., the ratio of the

median toxic dose to the median effective dose equals

27) Prescription agents tend to have lower TIs For

instance, the narcotic analgesic meperidine (Demerol)

has a TI of 8, and the sedative-hypnotic diazepam(Valium) has a TI equal to 3 Other prescription agentssuch as cancer chemotherapeutics (methotrexate, vin-cristine, and so on) may have very low TIs, some close

to 1 However, a low TI is often acceptable in theseagents, considering the critical nature of cancer andsimilar serious conditions The consequences of notusing the drug outweighs the risks of some of the toxiceffects

To help keep the risk of toxicity to a minimumwith low-TI drugs, it is generally advisable to period-ically monitor blood levels This helps prevent con-centrations from quickly reaching toxic levels Thisprecaution is usually not necessary with high-TIdrugs, because there is a greater margin of error (i.e.,blood levels can rise quite a lot above the therapeuticconcentration before becoming dangerous)

SUMMARY

In its broadest sense, pharmacology is the study of theeffects of chemicals on living organisms Most discus-sions of clinical pharmacology deal primarily with thebeneficial effects of specific drugs on humans, and themanner in which these drugs exert their therapeuticeffects Since all drugs have the potential to produceunwanted or toxic responses, some discussion of adrug’s adverse effects is also essential in pharmacology.Drugs used therapeutically are subjected to extensivetesting prior to approval for use in humans and areclassified as either prescription or over-the-counter,depending on their dosage, effectiveness, and safetyprofile Finally, certain characteristic relationshipsexist between the dose of a drug and the response oreffect it produces Such relationships can provide use-ful information about drug efficacy and potency andabout the relative safety of different compounds

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