Professional Documents
Culture Documents
Pharmacology in Rehabilitation
Pharmacology in Rehabilitation
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.,
photosensitivity)
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
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)
Benzodiazepines -epam or -olam Diazepam, temazepam, alprazolam, Sedative-hypnotic (6), antianxiety (6),
triazolam antiseizure (9), anesthetic (11)
Glucocorticoids -sone or -olone* Cortisone, dexamethasone, prednis- Anti-inflammatory (16, 29), immuno-
one, prednisolone, triamcinolone suppressants (37)
Various other antibacterials -micin or -mycin† Streptomycin, gentamicin, Bacterial infections (33)
erythromycin
*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
Rehabilitation
4th Edition
00Ciccone(p)-FM 2/2/07 6:59 PM Page ii
Pharmacology in
Rehabilitation
4th Edition
F. A. Davis Company
1915 Arch Street
Philadelphia, PA 19103
www.fadavis.com
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.
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.
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
00Ciccone(p)-FM 2/2/07 6:59 PM Page v
v
00Ciccone(p)-FM 2/2/07 6:59 PM Page vi
Foreword
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.
vii
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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
00Ciccone(p)-FM 2/2/07 6:59 PM Page ix
Preface
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
ix
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Acknowledgments
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
text.
xi
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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
xiii
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Contents
Drug Storage, 22
Section 1. General Principles of Storage Sites, 22
Pharmacology, 1 Adverse Consequences of Drug Storage, 23
xv
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xvi Contents
Contents xvii
xviii Contents
Contents xix
xx Contents
Contents xxi
xxii Contents
Contents xxiii
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
xxiv Contents
Contents xxv
xxvi Contents
SECTION
General Principles
of Pharmacology
01Ciccone(p)-01 1/30/07 2:47 PM Page 2
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.
3
01Ciccone(p)-01 1/30/07 2:47 PM Page 4
Pharmacology
Pharmacotherapeutics Toxicology
Pharmacokinetics Pharmacodynamics
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
Trade/Brand-Name
Chemical Generic (Nonproprietary) (Proprietary)
N-Acetyl-p-aminophenol Acetaminophen Tylenol, Panadol, many others
(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 (http://www.fda.gov/cder/handbook).
01Ciccone(p)-01 1/30/07 2:47 PM Page 6
Phase III Assess safety and effective- Large number (1000–3000) 3 yrs
ness in a larger patient pop- patients targeted
ulation
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
01Ciccone(p)-01 1/30/07 2:47 PM Page 8
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
preparations.
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-
mine.
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
01Ciccone(p)-01 1/30/07 2:47 PM Page 9
Potency
One criterion used frequently when comparing drugs
Threshold is the concept of potency. Potency is related to the
dose
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
50
Drug "A"
25
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.
01Ciccone(p)-01 1/30/07 2:47 PM Page 10
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
100
50
0
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.
01Ciccone(p)-01 1/30/07 2:47 PM Page 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-
ED50
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.
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.
02Ciccone(p)-02 1/30/07 2:32 PM Page 13
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
body.
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
13
02Ciccone(p)-02 1/30/07 2:32 PM Page 14
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
Parenteral
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
absorption
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-
02Ciccone(p)-02 1/30/07 2:32 PM Page 15
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
Injection
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
02Ciccone(p)-02 1/30/07 2:32 PM Page 16
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
Topical
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
02Ciccone(p)-02 1/30/07 2:32 PM Page 17
Chapter 2 Pharmacokinetics I 17
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"
membrane
proteins
FIGURE 2–1 ▼ Schematic diagram of the cell membrane.
02Ciccone(p)-02 1/30/07 2:32 PM Page 19
Chapter 2 Pharmacokinetics I 19
ATP
ADP-Pi
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
02Ciccone(p)-02 1/30/07 2:32 PM Page 20
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
02Ciccone(p)-02 1/30/07 2:32 PM Page 22
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
following:
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
(halothane).
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.
B 420 mg 0.05 mg/mL 420 mg ÷ 0.05 Retained in plasma Aspirin; valproic acid
mg/mL ⫽ 8400 mL
⫽ 8.4 L
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
02Ciccone(p)-02 1/30/07 2:32 PM Page 24
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
SUMMARY
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.
02Ciccone(p)-02 1/30/07 2:32 PM Page 25
Chapter 2 Pharmacokinetics I 25
41. Kutchai HC. Cellular membranes and transmembrane 62. Perez-Marrero R, Tyler RC. A subcutaneous delivery
transport of solutes and water. In: Berne RM, Levy system for the extended release of leuprolide acetate
MN, eds. Principles of Physiology. 3rd ed. St Louis, MO: for the treatment of prostate cancer. Expert Opin
CV Mosby; 2000. Pharmacother. 2004;5:447–457.
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02Ciccone(p)-02 1/30/07 2:32 PM Page 28
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
29
03Ciccone(p)-03 1/30/07 2:38 PM Page 30
I. Oxidation Examples
A. Side chain (aliphatic) hydroxylation
OH
[O]
RCH2CH3→RCHCH3 Ibuprofen
B. N-oxidation
[O]
(R)2NH→(R)2NOH Acetaminophen
C. Deamination
[O]
RCH2NH2→RCHO ⫹ NH3 Diazepam
II. Reduction
A. Nitro reductions
RNO2→RNH2 Dantrolene
B. Carbonyl reductions
O OH
RCR′ → RCHR′ Methadone
III. Hydrolysis
A. Esters
O
RCOR′→RCOOH ⫹ R′OH Aspirin
B. Amides
O
RCNR′→RCOOH ⫹ R′NH2 Lidocaine
IV. Conjugation
A. Acetylation
O
RNH2 ⫹ AcetylCoA →RNHCCH3 ⫹ CoA-SH Clonazepam
B. Glycine conjugation
O
RCOOH→RCSCoA ⫹ NH2CH2COOH→
O
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
03Ciccone(p)-03 1/30/07 2:38 PM Page 31
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
03Ciccone(p)-03 1/30/07 2:38 PM Page 32
secretion
reabsorption
filtration
Polar metabolite
Nonpolar compound
excretion
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-
03Ciccone(p)-03 1/30/07 2:38 PM Page 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 (%)
100
⫽ 1500 mL/min ⫻ [(200 g/mL ⫺ 134
g/mL) ÷ 200 g/mL]
75
⫽ 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.
03Ciccone(p)-03 1/30/07 2:38 PM Page 34
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-
25
(From Katzung BG. Basic and Clinical Pharmacology. 9th ed. New York: Lange
20
15
Medical Books/McGraw-Hill; 2004, with permission.)
10
0
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.
03Ciccone(p)-03 1/30/07 2:38 PM Page 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
03Ciccone(p)-03 1/30/07 2:38 PM Page 36
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
03Ciccone(p)-03 1/30/07 2:38 PM Page 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
SUMMARY
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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implications for drug therapy. Clin Pharmacokinet. drug interactions: careful drug selection and patient
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47. Rodighiero V. Effects of liver disease on pharmacoki- cokinet. 2003;42:1193–1211.
netics. An update. Clin Pharmacokinet. 1999;37:399–431. 57. Turnheim K. When drug therapy gets old: pharmaco-
48. Schmucker DL. Liver function and phase I drug kinetics and pharmacodynamics in the elderly. Exp
metabolism in the elderly: a paradox. Drugs Aging. Gerontol. 2003;38:843–853.
2001;18:837–851. 58. Urso R, Blardi P, Giorgi G. A short introduction to
49. Schoedel KA, Tyndale RF. Induction of nicotine- pharmacokinetics. Eur Rev Med Pharmacol Sci.
metabolizing CYP2B1 by ethanol and ethanol-metabo- 2002;6:33–44.
lizing CYP2E1 by nicotine: summary and implications. 59. Wright JG, Boddy AV. All half-lives are wrong, but
Biochim Biophys Acta. 2003;1619:283–290. some half-lives are useful. Clin Pharmacokinet.
50. Schwartz JB. The influence of sex on pharmacokinet- 2001;40:237–244.
ics. Clin Pharmacokinet. 2003;42:107–121. 60. Wilkinson GR. Pharmacokinetics: the dynamics of
51. Segal JL, Hayes KC, Brunnemann SR, et al. Absorp- drug absorption, distribution, and elimination. In:
tion characteristics of sustained-release 4 aminopyri- Hardman JG, et al, eds. The Pharmacological Basis
dine (fampridine SR) in patients with chronic spinal of Therapeutics. 10th ed. New York: McGraw Hill;
cord injury. J Clin Pharmacol. 2000;40:402–409. 2001.
52. Sheweita SA. Drug-metabolizing enzymes: mecha- 61. Yang LQ, Li SJ, Cao YF, et al. Different alterations of
nisms and functions. Curr Drug Metab. 2000;1: cytochrome P450 3A4 isoform and its gene expression
107–132. in livers of patients with chronic liver disease. World J
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.
03Ciccone(p)-03 1/30/07 2:38 PM Page 40
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-
Na+
ACh ACh
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.
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
BD
Out.
In.
P P
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.
04Ciccone(p)-04 1/30/07 2:31 PM Page 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-
ATP
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
04Ciccone(p)-04 1/30/07 2:31 PM Page 44
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-
04Ciccone(p)-04 1/30/07 2:31 PM Page 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
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.
04Ciccone(p)-04 1/30/07 2:31 PM Page 46
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-
04Ciccone(p)-04 1/30/07 2:31 PM Page 47
T
N IS AG
A GO ON
IST
AGONIST ANTAGONIST
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-
04Ciccone(p)-04 1/30/07 2:31 PM Page 48
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
04Ciccone(p)-04 1/30/07 2:31 PM Page 49
Presynaptic
Terminal
Postsynaptic
Terminal Normal Synapse
Receptor Receptor
Desensitization/ Supersensitivity
Down-regulation
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
04Ciccone(p)-04 1/30/07 2:31 PM Page 50
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SECTION
Pharmacology
of the Central
Nervous System
05Ciccone(p)-05 1/30/07 2:38 PM Page 54
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.
55
05Ciccone(p)-05 1/30/07 2:38 PM Page 56
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.
05Ciccone(p)-05 1/30/07 2:38 PM Page 57
GABA (gamma-aminobutyric acid) Interneurons throughout the spinal cord, cerebel- Inhibition
lum, basal ganglia, cerebral cortex
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
Acetylcholine
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.
05Ciccone(p)-05 1/30/07 2:38 PM Page 59
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
Potential
3. Storage
7. Post-synaptic
5. Reuptake receptor
2. Synthesis
6. Degradation
8. Pre-synaptic
"Autoreceptor"
9. Membrane
FIGURE 5–2 ▼ Sites at which drugs can alter transmission at a CNS synapse.
05Ciccone(p)-05 1/30/07 2:38 PM Page 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
05Ciccone(p)-05 1/30/07 2:38 PM Page 62
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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Neuron to Brain. 4th ed. Sunderland, MA: Sinauer York: McGraw-Hill; 2003.
Associates; 2001. 41. Webster RA , ed. Neurotransmitters, Drugs, and Brain
29. Nieoullon A, Coquerel A. Dopamine: a key regulator Function. New York: John Wiley and Sons; 2001.
to adapt action, emotion, motivation and cognition. 42. Willis C, Lybrand S, Bellamy N. Excitatory amino acid
Curr Opin Neurol. 2003;(suppl 2):S3–S9. inhibitors for traumatic brain injury. Cochrane Database
30. Parnas I, Rashkovan G, Ravin R, Fischer Y. Novel Syst Rev. 2004;CD003986.
mechanism for presynaptic inhibition: GABA(A) 43. Wolburg H, Lippoldt A. Tight junctions of the blood-
receptors affect the release machinery. J Neurophysiol. brain barrier: development, composition and regula-
2000;84:1240–1246. tion. Vascul Pharmacol. 2002;38:323–337.
05Ciccone(p)-05 1/30/07 2:38 PM Page 64
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.
Benzodiazepines
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-
65
06Ciccone(p)-06 1/30/07 2:29 PM Page 66
Benzodiazepines**
Estazolam ProSom 1–2
Flurazepam Dalmane 15–30
Quazepam Doral 7.5–15
Temazepam Restoril 7.5–30
Triazolam Halcion 0.125–0.25
Others
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
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.
06Ciccone(p)-06 1/30/07 2:29 PM Page 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
␣
␥
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
06Ciccone(p)-06 1/30/07 2:29 PM Page 68
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-
06Ciccone(p)-06 1/30/07 2:29 PM Page 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-
06Ciccone(p)-06 1/30/07 2:29 PM Page 70
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.
06Ciccone(p)-06 1/30/07 2:29 PM Page 71
CH3 Buspirone
O Buspirone (BuSpar) is an antianxiety agent that was
N
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
*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.
06Ciccone(p)-06 1/30/07 2:29 PM Page 72
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
06Ciccone(p)-06 1/30/07 2:29 PM Page 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-
SUMMARY
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)
06Ciccone(p)-06 1/30/07 2:29 PM Page 74
CA S E ST U DY
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.
11. Burt DR. Reducing GABA receptors. Life Sci. 2003; 30. Kitayama M, Hirota K, Kudo M, Kudo T, Ishihara H,
73:1741–1717. Matsuki A. Inhibitory effects of intravenous anaesthetic
12. Chilmonnczyk Z, Cybulski J, Bronowska A, Les A. agents on K (⫹)-evoked glutamate release from rat
Molecular modeling of buspirone–serotonin receptor cerebrocortical slices. Involvement of voltage sensitive
interactions. Acta Pol Pharm. 2000;57:281–288. Ca (2⫹) channels and GABA (A) receptors. Naunyn
13. Chouinard G. Issues in the clinical use of benzodi- Schmiedebergs Arch Pharmacol. 2002;366:246–253.
azepines: potency, withdrawal, and rebound. J Clin Psy- 31. Kumar S, Fleming RL, Morrow AL. Ethanol regula-
chiatry. 2004;65(suppl 5):7–12. tion of gamma–aminobutyric acid A receptors: genomic
14. Costa E. From GABAA receptor diversity emerges a and nongenomic mechanisms. Pharmacol Ther. 2004;
unified vision of GABAergic inhibition. Annu Rev 101:211–226.
Pharmacol Toxicol. 1998;38:321–350. 32. Lader MH. Implications of hypnotic flexibility on pat-
15. Cumming RG, Le Couteur DG. Benzodiazepines and terns of clinical use. Int J Clin Pract Suppl. 2001;116:
risk of hip fractures in older people: a review of the 14–19.
evidence. CNS Drugs. 2003;17:825–837. 33. Lecrubier Y. Posttraumatic stress disorder in primary
16. Davidson JR. Use of benzodiazepines in social anxiety care: a hidden diagnosis. J Clin Psychiatry. 2004;65
disorder, generalized anxiety disorder, and posttrau- (suppl 1):49–54.
matic stress disorder. J Clin Psychiatry. 2004;65(suppl 34. Lee YJ. Overview of the therapeutic management of
5):29–33. insomnia with zolpidem. CNS Drugs. 2004; 18(suppl
17. Davies M. The role of GABAA receptors in mediating 1):17–23; discussion 41, 43–45.
the effects of alcohol in the central nervous system. J 35. Lenhart SE, Buysse DJ. Treatment of insomnia in hos-
Psychiatry Neurosci. 2003;28:263–274. pitalized patients. Ann Pharmacother. 2001;35:
18. Drake CL, Roehrs T, Roth T. Insomnia causes, conse- 1449–1457.
quences, and therapeutics: an overview. Depress Anxiety. 36. Longo LP, Johnson B. Addiction: part I. Benzodi-
2003;18:163–176. azepines—side effects, abuse risk and alternatives.
19. Drover DR. Comparative pharmacokinetics and phar- Am Fam Physician. 2000;61:2121–2128.
macodynamics of short acting hypnosedatives: zale- 37. Lydiard RB. The role of GABA in anxiety disorders.
plon, zolpidem and zopiclone. Clin Pharmacokinet. J Clin Psychiatry. 2003;64(Suppl 3):21–27.
2004;43:227–238. 38. Mamtani R, Cimino A. A primer of complementary
20. Dundar Y, Dodd S, Strobl J, et al. Comparative effica- and alternative medicine and its relevance in the treat-
cy of newer hypnotic drugs for the short-term man- ment of mental health problems. Psychiatr Q. 2002;73:
agement of insomnia: a systematic review and 367–381.
meta-analysis. Hum Psychopharmacol. 2004;19:305– 39. Mitler MM. Nonselective and selective benzodiazepine
322. receptor agonists—where are we today? Sleep. 2000;23
21. Evers AS, Crowder CM. General anesthetics. In: (suppl 1):S39–S47.
Hardman JG, et al., eds. The Pharmacological Basis 40. Morgan K, Dixon S, Mathers N, et al. Psychological
of Therapeutics. 10th ed. New York: McGraw-Hill; treatment for insomnia in the regulation of long-term
2001. hypnotic drug use. Health Technol Assess. 2004;8:
22. Fraser AD. Use and abuse of the benzodiazepines. 1–68.
Ther Drug Monit. 1998;20:481–489. 41. Nagel CL, Markie MB, Richards KC, Taylor JL. Sleep
23. Frighetto L, Marra C, Bandali S, et al. An assessment promotion in hospitalized elders. Medsurg Nurs. 2003;
of quality of sleep and the use of drugs with sedating 12:279–289.
properties in hospitalized adult patients. Health Qual 42. Neubauer DN. Pharmacologic approaches for the
Life Outcomes. 2004;2:17. treatment of chronic insomnia. Clin Cornerstone.
24. Gorman JM. Treating generalized anxiety disorder. J 2003;5:16–27.
Clin Psychiatry. 2003;64(suppl 2):24–29. 43. Nies AS. Clinical pharmacology of the beta-adrenergic
25. Grunstein R. Insomnia. Diagnosis and management. blockers. Med Probl Perform Art. 1986;1:25–31.
Aust Fam Physician. 2002;31:995–1000. 44. Pary R, Matuschka PR, Lewis S, et al. Generalized
26. Hajak G, Muller WE, Wittchen HU, et al. Abuse and anxiety disorder. South Med J. 2003;96:581–586.
dependence potential for the non-benzodiazepine hyp- 45. Petrovic M, Mariman A, Warie H, et al. Is there a
notics zolpidem and zopiclone: a review of case reports rationale for prescription of benzodiazepines in the
and epidemiological data. Addiction. 2003;98: elderly? Review of the literature. Acta Clin Belg.
1371–1378. 2003;58:27–36.
27. James IM. Practical aspects of the use of beta-blockers 46. Rickels K, Rynn M. Pharmacotherapy of generalized
in anxiety states: situational anxiety. Postgrad Med J. anxiety disorder. J Clin Psychiatry. 2002; 63(Suppl
1984;60(suppl 2):19–25. 14):9–16.
28. Johnston GA. Medicinal chemistry and molecular 47. Rouillon F. Long term therapy of generalized anxiety
pharmacology of GABA(C) receptors. Curr Top Med disorder. Eur Psychiatry. 2004;19:96–101.
Chem. 2002;2:903–913. 48. Rudolph U. Identification of molecular substrate for
29. Kapczinski F, Lima MS, Souza JS, Schmitt R. Antide- the attenuation of anxiety: a step toward the develop-
pressants for generalized anxiety disorder. Cochrane ment of better anti-anxiety drugs. ScientificWorld
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
77
07Ciccone(p)-07 1/30/07 2:49 PM Page 78
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
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
07Ciccone(p)-07 1/30/07 2:49 PM Page 80
Prescribing
Generic Name Trade Name Initial Adult Dose (mg/day) Limits* (mg/day)
Tricyclics
Amitriptyline Elavil, Endep, others 50–100 300
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
Mirtazapine Remeron 15 45
Paroxetine Paxil 20 50
*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
Presynaptic
terminal
Breakdown
MAO Inhibitors
MAO (inhibit breakdown)
Storage
Reuptake
Release Tricyclics &
Second-generation
drugs (inhibit reuptake)
Postsynaptic
neuron
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-
tion/desensitization.
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
07Ciccone(p)-07 1/30/07 2:49 PM Page 82
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
Mechanism
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
arrhythmias
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
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
autoreceptors
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
receptors
Mechanism
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.
07Ciccone(p)-07 1/30/07 2:49 PM Page 85
Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome 85
Desipramine ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹
Nortriptyline ⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹⫹
Protriptyline ⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹
Tranylcypromine ⫹ ⫹ ⫹⫹ ⫹ ⫹
Second-generation drugs
Bupropion 0 ⫹ 0 ⫹ ⫹⫹⫹⫹
Citalopram ⫹ 0 0 0 ⫹⫹
Fluoxetine 0 0 0 0 ⫹⫹
Fluvoxamine 0 0 0 0 ⫹⫹
Mirtazapine ⫹⫹ ⫹ ⫹⫹ ⫹ ⫹
Paroxetine ⫹ ⫹ 0 0 ⫹⫹
Sertraline 0 0 0 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.
07Ciccone(p)-07 1/30/07 2:49 PM Page 86
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
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
Chapter 7 Drugs Used to Treat Affective Disorders: Depression and Bipolar Syndrome 89
CA S E ST U DY
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.
Systematic review and meta-regression analysis. Phar- 24. Fava M. The role of the serotonergic and noradrener-
macopsychiatry. 2004;37:93–97. gic neurotransmitter systems in the treatment of psy-
7. Barden N. Implication of the hypothalamic-pituitary– chological and physical symptoms of depression. J Clin
adrenal axis in the physiopathology of depression. J Psychiatry. 2003;64(suppl 13):26–29.
Psychiatry Neurosci. 2004;29:185–193. 25. Finfgeld DL. Serotonin syndrome and the use of
8. Bauer M, Alda M, Priller J, Young LT; International SSRIs. J Psychosoc Nurs Ment Health Serv. 2004;
Group for the Study of Lithium Treated Patients 42:16–20.
(IGSLI). Implications of the neuroprotective effects 26. Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM.
of lithium for the treatment of bipolar and neurode- Lamotrigine: a review of its use in bipolar disorder.
generative disorders. Pharmacopsychiatry. 2003;36(suppl Drugs. 2003;63:2029–2050.
3):S250–S254. 27. Goodwin FK. Rationale for long-term treatment of
9. Bauer M, Whybrow PC, Angst J, et al. World Federa- bipolar disorder and evidence for long-term lithium
tion of Societies of Biological Psychiatry (WFSBP) treatment. J Clin Psychiatry. 2002;63(suppl 10):5–12.
guidelines for biological treatment of unipolar depres- 28. Goodwin FK. Rationale for using lithium in combina-
sive disorders, part 2: Maintenance treatment of major tion with other mood stabilizers in the management of
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sive disorders and subthreshold depressions. World J 5):18–24.
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10. Belmaker RH. Bipolar disorder. N Engl J Med. pain syndromes with venlafaxine. Pharmacotherapy.
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depressant strategies. Eur Neuropsychopharmacol. depressants and some important considerations. Aust N
2003;13:57–66. Z J Psychiatry. 2003;37:190–195.
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antidepressant drugs in affective and anxiety disorders allels and contrasts in diverse signaling contexts. Phar-
and pain. J Psychiatry Neurosci. 2001;26:37–43. macol Ther. 2002;96:45–66.
14. Briley M. New hope in the treatment of painful symp- 33. Gutierrez MA, Stimmel GL, Aiso JY. Venlafaxine: a
toms in depression. Curr Opin Investig Drugs. 2003 update. Clin Ther. 2003;25:2138–2154.
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15. Brown ES, Varghese FP, McEwen BS. Association of selective norepinephrine reuptake inhibitor antidepres-
depression with medical illness: does cortisol play a sant reboxetine: pharmacological and clinical profile.
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17. Cassano P, Fava M. Tolerability issues during long- brain-derived neurotrophic factor in mood disorders.
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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-
Schizophrenia
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
93
08Ciccone(p)-08 1/30/07 2:36 PM Page 94
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.
08Ciccone(p)-08 1/30/07 2:36 PM Page 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
08Ciccone(p)-08 1/30/07 2:36 PM Page 96
*Dosage range represents usual adult oral dose. Lower dosages may be indicated for older or debilitated
patients.
**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.
Fluphenazine ⫹ ⫹⫹⫹⫹ ⫹
Haloperidol ⫹ ⫹⫹⫹⫹ ⫹
Mesoridazine ⫹⫹⫹ ⫹ ⫹⫹
Molindone ⫹ ⫹⫹⫹ ⫹⫹
Perphenazine ⫹⫹ ⫹⫹⫹ ⫹⫹
Prochlorperazine ⫹⫹ ⫹⫹⫹⫹ ⫹
Thiothixene ⫹ ⫹⫹⫹⫹ ⫹
Trifluoperazine ⫹⫹ ⫹⫹⫹ ⫹⫹
Atypical antipsychotics
Aripiprazole ⫹⫹ ⫹ ⫹
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
08Ciccone(p)-08 1/30/07 2:36 PM Page 98
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
08Ciccone(p)-08 1/30/07 2:36 PM Page 99
(From Feigenbaum JC and Schneider F. Antipsychotic medications. In: Mathewson MK, ed. Pharmacotherapeutics: A Nursing
Acute Dystonic Akathisia Tardive Dyskinesia
Reactions
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
Pseudo-Parkinsonism
0 1 2 3 4 5 6 7 8 90 100 365
TIME FROM ONSET OF NEUROLEPTIC THERAPY (DAYS)
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
08Ciccone(p)-08 1/30/07 2:36 PM Page 100
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.
08Ciccone(p)-08 1/30/07 2:36 PM Page 101
CA S E ST U DY
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
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.
33. Kasckow JW, Mulchahey JJ, Mohamed S. The use of 48. Nicholson D, Chiu W. Neuroleptic malignant syn-
novel antipsychotics in the older patient with neurode- drome. Geriatrics. 2004;59:36, 38–40.
generative disorders in the long-term care setting. J 49. Oosthuizen PP, Emsley RA, Maritz JS, et al. Incidence
Am Med Dir Assoc. 2004;5:242–248. of tardive dyskinesia in first-episode psychosis patients
34. Keith SJ, Kane JM. Partial compliance and patient treated with low-dose haloperidol. J Clin Psychiatry.
consequences in schizophrenia: our patients can do 2003;64:1075–1080.
better. J Clin Psychiatry. 2003;64:1308–1315. 50. Palomo T, Archer T, Kostrzewa RM, Beninger RJ.
35. Kim JH, Byun HJ. Prevalence and characteristics of Gene-environment interplay in schizopsychotic disor-
subjective akathisia, objective akathisia, and mixed ders. Neurotox Res. 2004;6:1–9.
akathisia in chronic schizophrenic subjects. Clin Neu- 51. Remington G. Understanding antipsychotic “atypicali-
ropharmacol. 2003;26:312–316. ty”: a clinical and pharmacological moving target. J
36. Kulkarni SK, Naidu PS. Pathophysiology and drug Psychiatry Neurosci. 2003;28:275–284.
therapy of tardive dyskinesia: current concepts and 52. Serretti A, De Ronchi D, Lorenzi C, Berardi D.
future perspectives. Drugs Today. 2003;39:19–49. New antipsychotics and schizophrenia: a review on
37. Laruelle M, Kegeles LS, Abi-Dargham A. Gluta- efficacy and side effects. Curr Med Chem. 2004;
mate, dopamine, and schizophrenia: from pathophys- 11:343–358.
iology to treatment. Ann N Y Acad Sci. 2003;1003: 53. Soares-Weiser KV, Joy C. Miscellaneous treatments
138–158. for neuroleptic-induced tardive dyskinesia. Cochrane
38. Lawlor BA. Behavioral and psychological symptoms in Database Syst Rev. 2003;CD000208.
dementia: the role of atypical antipsychotics. J Clin 54. Soares-Weiser K, Rathbone J. Calcium channel block-
Psychiatry. 2004;65(suppl 11):5–10. ers for neuroleptic induced tardive dyskinesia. Cochrane
39. Lebovitz HE. Metabolic consequences of atypical Database Syst Rev. 2004;CD000206.
antipsychotic drugs. Psychiatr Q. 2003;74:277–290. 55. Stewart JT. Dysphagia associated with risperidone
40. Lee PE, Gill SS, Freedman M, et al. Atypical antipsy- therapy. Dysphagia. 2003;18:274–275.
chotic drugs in the treatment of behavioural and psy- 56. Sultzer DL. Psychosis and antipsychotic medications
chological symptoms of dementia: systematic review. in Alzheimer’s disease: clinical management and
BMJ. 2004;329:75. research perspectives. Dement Geriatr Cogn Disord.
41. Leriche L, Diaz J, Sokoloff P. Dopamine and glu- 2004;17:78–90.
tamate dysfunctions in schizophrenia: role of 57. Sussman N. Choosing an atypical antipsychotic. Int
the dopamine D3 receptor. Neurotox Res. 2004; Clin Psychopharmacol. 2002;17(suppl 3):S29–S33.
6:63–71. 58. Tariot PN, Profenno LA, Ismail MS. Efficacy of
42. Lima AR, Weiser KV, Bacaltchuk J, Barnes TR. Anti- atypical antipsychotics in elderly patients with
cholinergics for neuroleptic-induced acute akathisia. dementia. J Clin Psychiatry. 2004;65(suppl 11):
Cochrane Database Syst Rev. 2004;CD003727. 11–15.
43. Masan PS. Atypical antipsychotics in the treatment of 59. Trenton A, Currier G, Zwemer F. Fatalities associated
affective symptoms: a review. Ann Clin Psychiatry. with therapeutic use and overdose of atypical antipsy-
2004;16:3–13. chotics. CNS Drugs. 2003;17:307–324.
44. Masand PS. Side effects of antipsychotics in the elder- 60. Viejo LF, Morales V, Punal P, et al. Risk factors in neu-
ly. J Clin Psychiatry. 2000;61(suppl 8):43–49; discussion roleptic malignant syndrome. A case-control study.
50–51. Acta Psychiatr Scand. 2003;107:45–49.
45. Meltzer HY. What’s atypical about atypical antipsy- 61. Walker E, Kestler L, Bollini A, Hochman KM. Schizo-
chotic drugs? Curr Opin Pharmacol. 2004;4:53–57. phrenia: etiology and course. Annu Rev Psychol.
46. Mortimer AM. Novel antipsychotics in schizophrenia. 2004;55:401–430.
Expert Opin Investig Drugs. 2004;13:315–329. 62. Wong AH, Van Tol HH. The dopamine D4 receptors
47. Mueser KT, McGurk SR. Schizophrenia. Lancet. and mechanisms of antipsychotic atypicality. Prog Neu-
2004;363:2063–2072. ropsychopharmacol Biol Psychiatry. 2003;27:1091–1099.
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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
105
09Ciccone(p)-09 1/30/07 2:35 PM Page 106
B. Complex partial seizures (needed to differentiate Consciousness impaired; bizarre behavior; wide variety of
this from absence seizures) other manifestations; specific electroencephalography
(EEG) abnormality
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
09Ciccone(p)-09 1/30/07 2:35 PM Page 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.
09Ciccone(p)-09 1/30/07 2:35 PM Page 108
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).
09Ciccone(p)-09 1/30/07 2:35 PM Page 109
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
Tiagabine Gabitril Treatment adjunct in partial seizures in adults and children over age 12
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
Generalized seizures
Source: Gidal BE, et al. Epilepsy. In: DiPiro JT, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 5th ed.
New York: McGraw-Hill; 2002:1036.
09Ciccone(p)-09 1/30/07 2:35 PM Page 112
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)
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.
CA S E ST U DY
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.
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.
34. Sirven JI. Classifying seizures and epilepsy: a synopsis. therapy: a practical approach. Ann Med. 2003;35:
Semin Neurol. 2002;22:237–246. 207–215.
35. Specchio LM, Beghi E. Should antiepileptic drugs be 41. Waugh J, Goa KL. Topiramate: as monotherapy in
withdrawn in seizure-free patients? CNS Drugs. 2004; newly diagnosed epilepsy. CNS Drugs. 2003;17:
18:201–212. 985–992.
36. Sperling MR. The consequences of uncontrolled 42. Webster RA. The epilepsies. In: Webster RA, ed. Neu-
epilepsy. CNS Spectr. 2004;9:98–101, 106–109. rotransmitters, Drugs and Brain Function. New York:
37. Spina E, Perugi G. Antiepileptic drugs: indica- John Wiley and Sons; 2001.
tions other than epilepsy. Epileptic Disord. 2004; 6: 43. Yerby MS. Clinical care of pregnant women with
57–75. epilepsy: neural tube defects and folic acid supplemen-
38. Tatum WO, 4th, Liporace J, Benbadis SR, Kaplan tation. Epilepsia. 2003;44(suppl 3):33–40.
PW. Updates on the treatment of epilepsy in women. 44. Yerby MS, Kaplan P, Tran T. Risks and management of
Arch Intern Med. 2004;164:137–145. pregnancy in women with epilepsy. Cleve Clin J Med.
39. Tidwell A, Swims M. Review of the newer 2004;71(suppl 2):S25–S37.
antiepileptic drugs. Am J Manag Care. 2003;9: 45. Yudkoff M, Daikhin Y, Nissim I, et al. Ketogenic diet,
253–276. brain glutamate metabolism and seizure control.
40. Verrotti A, Trotta D, Salladini C, et al. Risk factors for Prostaglandins Leukot Essent Fatty Acids. 2004;70:
recurrence of epilepsy and withdrawal of antiepileptic 277–285.
09Ciccone(p)-09 1/30/07 2:35 PM Page 118
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
119
10Ciccone(p)-10 1/30/07 2:49 PM Page 120
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-
sues.48,78
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
10Ciccone(p)-10 1/30/07 2:49 PM Page 121
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.
Ropinirole
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
10Ciccone(p)-10 1/30/07 2:49 PM Page 123
Capillary
Tyrosine Endothelium
(blood-brain barrier)
Tyrosine
hydroxylase
Cerebral Capillary Cerebral Tissue
Dopamine
HO CH2 CH NH2
Levodopa Levodopa
HO COOH
dopa
decarboxylase
Dopa
Dopamine
Dopa
decarboxylase FIGURE 10–3 ▼ Selective permeability of the blood-brain barrier to
levodopa.
PERIPHERY CNS
Without Carbidopa
D-C
ASE
Levodopa Dopamine
With Carbidopa
D-C D-C
ASE ASE
Levodopa Levodopa Dopamine
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-
10Ciccone(p)-10 1/30/07 2:49 PM Page 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”).
10Ciccone(p)-10 1/30/07 2:49 PM Page 126
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
10Ciccone(p)-10 1/30/07 2:49 PM Page 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
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
Amantadine
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
dosage.
A relatively new group of drugs including entacapone
(Comtan) and tolcapone (Tasmar) were developed to
Selegiline
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
10Ciccone(p)-10 1/30/07 2:49 PM Page 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.
10Ciccone(p)-10 1/30/07 2:49 PM Page 130
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
SUMMARY
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
CA S E ST U DY
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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Chapter 11
General Anesthetics
The discovery and development of anesthetic agents be unconscious throughout the procedure and, upon
has been one of the most significant contributions in awakening, have no recollection of what occurred dur-
the advancement of surgical technique. Before the use ing the surgery. An ideal anesthetic agent must be able
of anesthesia, surgery was used only as a last resort and to produce each of the following conditions:
was often performed with the patient conscious, but
1. Loss of consciousness and sensation.
physically restrained by several large “assistants.”
2. Amnesia (i.e., no recollection of what occurred
During the past century, general and local anesthetic
during the surgery).
drugs have been used to allow surgery to be performed
3. Skeletal muscle relaxation (this requirement
in a manner that is safer, that is much less traumatic to
is currently met with the aid of skeletal mus-
the patient, and that permits lengthier and more
cle blockers used in conjunction with the
sophisticated surgical procedures.
anesthetic [see “Neuromuscular Blockers,”
Anesthetics are categorized as general or local,
later]).
depending on whether or not the patient remains con-
4. Inhibition of sensory and autonomic reflexes.
scious when the anesthetic is administered. General
5. A minimum of toxic side effects (i.e., be rela-
anesthetics are usually administered during the more
tively safe).
extensive surgical procedures. Local anesthetics are
6. Rapid onset of anesthesia; easy adjustment of
given when analgesia is needed in a relatively small,
the anesthetic dosage during the procedure; and
well-defined area, or when the patient needs to remain
rapid, uneventful recovery after administration
conscious during surgery. The use of general anesthe-
is terminated.
sia and general anesthetic agents is presented in this
chapter; local anesthetics are dealt with in Chapter 12. Current general anesthetics meet these criteria
Most physical therapists and other rehabilita- quite well, providing that the dose is high enough to
tion specialists are usually not involved in working produce an adequate level of anesthesia but not so
with patients while general anesthesia is actually being high that problems occur. The relationship between
administered. However, knowledge of how these dosage and level or plane of anesthesia is discussed in
agents work will help the therapist understand some of the next section, “Stages of General Anesthesia.”
the residual effects that may occur when the patient is
recovering from the anesthesia. This knowledge will
help the therapist understand how these effects may Stages of General Anesthesia
directly influence the therapy sessions that take place
During general anesthesia, the patient goes through a
during the first few days after procedures in which
series of stages as the anesthetic dosage and amount of
general anesthesia was used.
anesthesia reaching the brain progressively increase.
Four stages of anesthesia are commonly identified.39
General Anesthesia: Stage I. Analgesia. The patient begins to lose
somatic sensation but is still conscious and somewhat
Requirements aware of what is happening.
During major surgery (such as laparotomy, thoracoto- Stage II. Excitement (Delirium). The patient is
my, joint replacement, amputation), the patient should unconscious and amnesiac but appears agitated and
135
11Ciccone(p)-11 1/30/07 2:36 PM Page 136
restless. This paradoxical increase in the level of exci- inhaled agents is often used sequentially during length-
tation is highly undesirable because patients may injure ier surgical procedures.10 The intravenous drug is
themselves while thrashing about. Thus, an effort is injected first to quickly get the patient to stage III, and
made to move as quickly as possible through this stage an inhaled agent is then administered to maintain the
and on to stage III. patient in a stage of surgical anesthesia. Ultimately, the
Stage III. Surgical Anesthesia. As the name selection of exactly which agents will be used depends
implies, this level is desirable for the surgical procedure on the type and length of the surgical procedure and
and begins with the onset of regular, deep respiration. any possible interactions with other anesthetics or
Some sources subdivide this stage into several planes, medical problems of the patient. Specific injected and
according to respiration rate and reflex activity. 39 inhaled anesthetics are presented here.
Stage IV. Medullary Paralysis. This stage is marked
by the cessation of spontaneous respiration because
respiratory control centers located in the medulla General Anesthetics:
oblongata are inhibited by excessive anesthesia. The
ability of the medullary vasomotor center to regulate Specific Agents
blood pressure is also affected, and cardiovascular col- Inhalation Anesthetics
lapse ensues. If this stage is inadvertently reached dur-
ing anesthesia, respiratory and circulatory support Anesthetics administered by this route exist either as
must be provided or the patient will die.39 gases or as volatile liquids that can be easily mixed with
Consequently, the goal of the anesthetist is to air or oxygen and then inhaled by a patient. When
bring the patient to stage III as rapidly as possible and administered, a system of tubing and valves is usually
to maintain the patient at that stage for the duration of employed to deliver the anesthetic drug directly to the
the surgical procedure. This goal is often accom- patient through an endotracheal tube or a mask over
plished by using both an intravenous and an inhaled the face (Figure 11–1). This delivery system offers the
anesthetic agent (see next section, “General Anesthet- obvious benefit of focusing the drug on the patient
ic Agents: Classification and Use According to Route without anesthetizing everyone else in the room.
of Administration”). Finally, the anesthetic should not These systems also allow for easy adjustment of the
be administered any longer than necessary, or recovery rate of delivery and concentration of the inhaled drug.
will be delayed. This state is often accomplished by Inhaled anesthetics currently in use include halo-
beginning to taper off the dosage toward the end of the genated volatile liquids such as desflurane, enflurane,
surgical procedure so that the patient is already recov- halothane, isoflurane, methoxyflurane, and sevoflurane
ering as surgery is completed. (Table 11–1). These volatile liquids are all chemically
similar, but newer agents such as desflurane and
sevoflurane are often used preferentially because they
General Anesthetics: permit a more rapid onset, a faster recovery, and better
control during anesthesia compared to older agents
Classification and Use According such as halothane.9,15 These volatile liquids likewise
to Route of Administration represent the primary form of inhaled anesthetics. The
Specific agents are classified according to the two only gaseous anesthetic currently in widespread use is
primary routes of administration—intravenous or nitrous oxide, which is usually reserved for relatively
inhaled.11,39 Intravenously injected anesthetics offer short-term procedures (e.g., tooth extractions). Earlier
the advantage of a rapid onset, thus allowing the inhaled anesthetics, such as ether, chloroform, and
patient to pass through the first two stages of anesthe- cyclopropane, are not currently used because they are
sia very quickly. The primary disadvantage is that there explosive in nature or produce toxic effects that do not
is a relative lack of control over the level of anesthesia occur with the more modern anesthetic agents.
if too much of the drug is injected. Inhaled anesthetics
provide an easier method of making adjustments in the
Intravenous Anesthetics
dosage during the procedure, but it takes a relatively
long time for the onset of the appropriate level of anes- When given in appropriate doses, several categories of
thesia. Consequently, a combination of injected and central nervous system (CNS) depressants can serve as
Text continued on page 139
11Ciccone(p)-11 1/30/07 2:36 PM Page 137
5 7 2 1
FIGURE 11–1 ▼ Schematic diagram of a closed anesthesia system. (1) Vaporizer for volatile liq-
uid anesthetics. (2) Compressed gas source. (3) Inhalation unidirectional valve. (4) Mask. (5) Unidi-
rectional exhalation valve. (6) Rebreathing bag. (7) Carbon dioxide absorption chamber.
Gas
O
Nitrous oxide (nitrogen monoxide)
N N
Nitrous oxide
Intravenous Anesthetics
Barbiturates
H O
Methohexital (Brevital sodium)
Thiopental (Pentothal) N C C2H5
S C C
N C CH (CH2)2 CH3
H O
Thiopental
Diazepam
Opioids
O
Butorphanol (Stadol)
Fentanyl derivatives (Sublimaze, others) C O CH2 CH3
Hydromorphone (Dilaudid, Hydrostat)
Levorphanol (Levo-Dromoran)
Meperidine (Demerol) N
Morphine (many trade names) CH3
Nalbuphine (Nubain)
Oxymorphone (Numorphan) Meperidine
Pentazocine (Talwin)
Etomidate (Amidate) N
O
C2H5OC N
CHCH3
Etomidate
Ketamine (Ketalar) CI
HN
O
CH3
Ketamine
Propofol (Diprivan)
CH(CH3)2
OH
CH(CH3)2
Propofol
11Ciccone(p)-11 1/30/07 2:36 PM Page 139
general anesthetics (see Table 11–1).38,39 Barbiturate short invasive procedures, or to maintain anesthesia in
drugs such as thiopental, thiamylal, and methohexital longer procedures.22 Recovery from propofol may also
have been used commonly to induce anesthesia in be more rapid than with other anesthetics, making this
many situations. Barbiturates are noted for their fast drug useful when early mobilization of the patient is
onset (when administered intravenously) and rela- desirable.38
tive safety when used appropriately. Several other
types of drugs including benzodiazepines (diazepam,
lorazepam, midazolam) and opioid analgesics (fen-
tanyl, morphine, meperidine) have also been used to
Pharmacokinetics
induce or help maintain general anesthesia. Although Following either injection or inhalation administra-
these other agents are often used as preoperative seda- tion, general anesthetics become widely and uniformly
tives, larger doses can be used alone or in combination distributed throughout the body, largely because
with other general anesthetics to produce anesthesia of their high degree of lipid solubility. As a result, a
in short surgical or diagnostic procedures, or where great deal of the anesthetic may become temporarily
other general anesthetics may be contraindicated (e.g., stored in adipose tissues and slowly washed out
cardiovascular disease). when the patient is recovering from surgery. If the per-
Another intravenous general anesthetic is keta- son was anesthetized for an extended period of time
mine (Ketalar). This agent produces a somewhat and has large deposits of fat, this washout may take
different type of condition known as dissociative anesthe- quite some time.11,17 During this period, symptoms
sia.16,39 This term is used because of the clinical obser- such as confusion, disorientation, and lethargy may
vation that the patient appears detached or dissociated occur, presumably because the drug is being redistrib-
from the surrounding environment. The patient uted to the CNS. The patient’s age also influences
appears awake but is sedated and usually unable to anesthetic requirements and distribution, with older
recall events that occurred when the ketamine was individuals usually requiring less anesthetic for
in effect. Dissociative anesthesia is useful during rela- a given procedure.29 Since older people need small-
tively short diagnostic or surgical procedures (e.g., er concentrations of anesthetic, the chance that more
endoscopy) or during invasive procedures in children anesthetic may be administered during surgery than
or certain high-risk patients (e.g., some older adults is needed is increased and recovery will be some-
or people with low blood pressure or bronchospastic what delayed.
disease).11,16 Depending on the individual drug, elimination
A similar type of anesthesia is produced by com- occurs primarily through excretion from the lungs,
bining the opioid fentanyl with the antipsychotic drug biotransformation in the liver, or a combination of
droperidol. The combination of these two agents pro- these two methods.39 If the patient has any pulmonary
duces a condition known as neuroleptanalgesia, which is or hepatic dysfunction, elimination of the anesthetic
also characterized by a dissociation from what is hap- will be further delayed.
pening around the patient, with or without loss of
consciousness.39 An inhaled anesthetic such as nitrous
oxide can also be added to convert neuroleptanalgesia
to neuroleptanesthesia.39 Neuroleptanalgesia and neu-
Mechanisms of Action
roleptanesthesia are typically used for short surgical Although general anesthetics have been used exten-
procedures, including endoscopy or burn dressings, or sively for over 150 years, debate still exists as to
for patients who are seriously ill and may not tolerate exactly how these drugs work. Clearly these drugs are
general anesthesia using more conventional methods. able to inhibit the neuronal activity throughout the
Finally, newer intravenous anesthetics such as CNS. It appears that they can decrease activity of neu-
etomidate (Amidate) and propofol (Diprivan) are rons in the reticular activating system in the brain, and
available. Etomidate is a hypnoticlike drug that causes this action explains their ability to produce uncon-
a rapid onset of general anesthesia with a minimum of sciousness and lack of memory (amnesia) during sur-
cardiopulmonary side effects. Hence, this drug may be gery.7 General anesthetics likewise inhibit neuronal
useful in patients with compromised cardiovascular or function in the spinal cord, and this action explains
respiratory function. Propofol is a short-acting hyp- their ability to produce immobility and inhibit motor
notic that is useful as a general anesthetic in some responses to painful stimuli.7
11Ciccone(p)-11 1/30/07 2:36 PM Page 140
The exact way in which these drugs affect these on the outer surface of CNS neurons.7,14 In particular,
neurons remains somewhat speculative. In the past, it many general anesthetics bind to CNS receptors that
was believed that general anesthetics primarily affected are specific for gamma-aminobutyric acid (GABA). As
the lipid bilayer of CNS neurons. This so-called gen- discussed in Chapter 6, GABA receptors contain a
eral perturbation theory was based on the premise that chloride ion channel that, when activated by GABA,
general anesthetic molecules become dissolved direct- increases influx of chloride ions into the neuron,
ly in the nerve membrane’s lipid bilayer and serve to thereby inhibiting that neuron. By binding to specific
generally perturb membrane function by increasing GABA receptors (the GABAA subtype), general anes-
membrane fluidity and disrupting the phospholipid thetics increase the effects of GABA, thus enhancing
environment that surrounds the protein channel.7 CNS inhibition throughout the CNS.27,28 This wide-
Membrane excitability would be decreased because ion spread CNS inhibition ultimately leads to a state of
channels, including sodium channels, are unable to general anesthesia.
open and allow the influx of sodium needed to initiate Hence, many general anesthetics exert their pri-
an action potential (Fig. 11–2). The primary support mary effects by binding to inhibitory GABAA recep-
for the membrane perturbation theory was the direct tors in the brain and cord. This fact seems true for
correlation between anesthetic potency and lipid solu- both the commonly used intravenous anesthetics
bility,39 meaning that the more easily the drug dissolves (barbiturates, benzodiazepines, propofol, etomidate)
in the bilayer, the less is needed to achieve a given level as well as the typical inhaled forms (halothane, enflu-
of anesthesia. This theory was further supported by the rane, sevoflurane).19 Some of their anesthetic effects,
fact that general anesthetics all produce a similar effect, however, might also be mediated by other recep-
even though they have quite diverse chemical struc- tors. Many general anesthetics, for example, also
tures (see Table 11–1). Presumably, if drugs bind to a bind to excitatory acetylcholine receptors on CNS
certain type of receptor, they should share some struc- neurons, and inhibit the function of these receptors.
tural similarities. This combination of increased inhibition (through
More recent evidence, however, suggests that GABA receptors) and decreased excitation (through
general anesthetics bind to specific receptors located acetylcholine receptors) would certainly explain why
No Drug Anesthetized
+
(Na channel shown open) (Na+ channel closed)
A A A
A A
FIGURE 11–2 ▼ Schematic illustration of two possible ways general anesthetics may act on the
nerve membrane. In the general perturbation theory, anesthetic molecules lodge in the lipid bilayer
and inhibit sodium channel function by disrupting membrane structure. In the specific receptor theory,
anesthetics inhibit the opening of the sodium channel by binding directly to the channel protein.
11Ciccone(p)-11 1/30/07 2:36 PM Page 141
these drugs are so effective in reducing the level of offer the dual advantage of producing sedation and
consciousness and excitability throughout the brain reducing vomiting (antiemesis). Antacids and other
and cord.34,41 drugs that increase gastric pH are sometimes used to
In addition to GABA and acetylcholine receptors, decrease stomach acidity and thus reduce the risk of
other CNS receptors have been implicated in mediat- serious lung damage if gastric fluid is aspirated during
ing the effects of specific general anesthetics. Opioids, general surgery. Preoperative administration of an
for example, decrease transmission in nociceptive anti-inflammatory steroid (dexamethasone) can like-
pathways by binding to specific presynaptic and post- wise help control postoperative symptoms such as pain
synaptic opioid receptors in the brain and spinal and vomiting.4,12 In the past, anticholinergics (atro-
cord (see Chapter 14). Injected anesthetics such as pine, scopolamine) were administered to help reduce
ketamine, and certain inhaled agents (nitrous oxide), bronchial secretions and aid in airway intubation.
bind to the N-methyl-D-aspartate (NMDA) receptor However, anesthetics currently in use do not produce
in the brain, thus inhibiting the excitatory effects of excessive airway secretions (as did prior agents), so
glutamate.34,41 Other proteins that might be affected the preoperative use of anticholinergics is no longer
by anesthetics include serotonin receptors and ion critical.11
channels that are specific for sodium, potassium, or
calcium.7,35.
Hence, it is believed that general anesthetics
Neuromuscular Blockers
exert most, if not all, of their effects by binding to one Skeletal muscle paralysis is essential during surgical
or more neuronal receptors in the CNS. This idea is a procedures. The patient must be relaxed to allow
departure from the general perturbation theory proper positioning on the operating table and to pre-
described earlier; that is, that the inhaled anesthetics vent spontaneous muscle contractions from hampering
affected the lipid bilayer rather than a specific protein. the surgery.23,24 Imagine the disastrous effects that a
Continued research will continue to clarify the mech- muscular spasm in the arm would have on a delicate
anism of these drugs, and future studies may lead to procedure such as nerve repair or limb reattachment.
more agents that produce selective anesthetic effects Neuromuscular paralysis also makes it easier for the
by acting at specific receptor sites in the brain and patient to be ventilated mechanically because the tho-
spinal cord. racic wall is more compliant and does not offer as much
resistance to mechanical inflation and deflation of the
chest cavity. Hence, these drugs are used as an adjunct
to general anesthesia as well as in other situations that
Adjuvants in General require mechanical ventilation (intensive care units).
Anesthesia Most currently used general anesthetics also pro-
duce skeletal muscle relaxation, but it takes a larger
Preoperative Medications dose of the anesthetic to produce adequate muscular
Frequently, a preoperative sedative is given to a patient relaxation than is needed to produce unconsciousness
1 to 2 hours before the administration of general anes- and amnesia; that is, the patient must be well into
thesia.2,36 Sedatives are usually administered orally or stage III and almost into stage IV of anesthesia before
by intramuscular injection, and are given while the muscle paralysis is complete. Consequently, a drug
patient is still in his or her room. This approach serves that blocks the skeletal neuromuscular junction is
to relax the patient and reduce anxiety when arriving at given in conjunction with a general anesthetic to allow
the operating room. Commonly used preoperative the use of a lower dose of anesthetic while still ensur-
sedatives include barbiturates (secobarbital, pentobar- ing skeletal muscle paralysis. These drugs work by
bital), opioids (butorphanol, meperidine), and benzo- blocking the postsynaptic acetylcholine receptor
diazepines (diazepam, lorazepam) (Table 11–2). located at the skeletal neuromuscular junction.
Different sedatives are selected depending on the Several different neuromuscular blockers are cur-
patient, the type of general anesthesia used, and the rently available, and the choice of a specific agent
preference of the physician. depends primarily on the desired length of action and
A number of other medications may be used pre- the agent’s potential side effects (Table 11–3).21,23 Pos-
operatively to achieve various goals (see Table sible side effects include cardiovascular problems
11–2).5,40 Antihistamines (promethazine, hydroxyzine) (tachycardia), increased histamine release, increased
11Ciccone(p)-11 1/30/07 2:36 PM Page 142
plasma potassium levels (hyperkalemia), residual mus- down acetylcholine (the acetylcholinesterase), thereby
cle pain and weakness, and immunologic reactions prolonging its effects and hastening recovery of motor
(anaphylaxis).13,25 Selection of a specific agent is there- function. The pharmacology of acetylcholinesterase
fore designed to minimize the risk of a certain side inhibitors is addressed in more detail in Chapter 19.
effect in a specific patient; for example, a drug that Nonetheless, residual effects of the neuromuscu-
produces relatively little cardiovascular effects would lar blocker can persist in some patients long after sur-
be selected for a patient with cardiovascular disease. gery is complete.6,13 The most serious complication is
Efforts are also made to use small doses of rela- residual paralysis; that is, skeletal muscle contraction
tively short-acting agents so that the length of muscle remains depressed for several hours after the drug
paralysis is kept to a minimum.6 The paralytic effects should have worn off.8,18 In extreme cases, this resid-
of these agents should disappear by the end of the sur- ual paralysis necessitates that the patient remain in
gical procedure. If necessary, drugs such as neostig- intensive care with a mechanical ventilator to provide
mine or edrophonium can also be administered to respiratory support.
help reverse the effects of neuromuscular block- It is not always clear why certain patients do not
ade.24,30 These drugs inhibit the enzyme that breaks recover adequately from neuromuscular blockade. In
Depolarizing blockers
Succinylcholine Anectine, others 1–1.5 5–8 Ultrashort
some cases, the residual effects are attributed to genet- Depolarizing Blockers. Although these drugs also
ic differences in the enzymes responsible for metabo- inhibit transmission at the skeletal neuromuscular
lizing the neuromuscular blocker.37 If these enzymes junction, their mechanism is different from that of the
are deficient or absent, the patient cannot adequately nondepolarizing agents. These drugs initially act like
metabolize the blocker, hence paralysis continues for acetylcholine by binding to and stimulating the recep-
days or even weeks. In other patients, residual effects tor, resulting in depolarization of the muscle cell.
may occur if the patient has a concurrent neuromus- However, the enzymatic degradation of the drug is not
cular condition such as a spinal cord injury, peripheral as rapid as the destruction of acetylcholine, so the
neuropathies, intracranial lesions, or muscle patholo- muscle cell remains depolarized for a prolonged peri-
gies.26,32 od. While depolarized, the muscle is unresponsive to
Efforts should be made to use these drugs spar- further stimulation. The cell must become repolar-
ingly, and to check that their effects have worn off ized, or reprimed, before the cell will respond to a sec-
before the patient leaves the operating room. In fact, ond stimulus. This event is often referred to as phase
electric stimulation of a peripheral nerve (e.g., ulnar I blockade.37 If the depolarizing blocker remains at the
nerve) can be used to objectively determine if there is synapse, the muscle cell eventually repolarizes, but it
residual muscle paralysis.1 The muscles supplied by will remain unresponsive to stimulation by acetyl-
the nerve must show an appropriate twitch response to choline. This occurrence is referred to as phase II
a given electric stimulus to insure that the patient has blockade and is believed to occur because the drug
recovered adequately from the neuromuscular block- exerts some sort of modification on the receptor. This
ing drug.20,31 modification could be in the form of a temporary
It should also be realized that neuromuscular change in the receptor’s shape. Clinically, when these
junction blockers are an adjunct to general anesthesia drugs are first administered, they are often associated
but that these blockers do not cause anesthesia or anal- with a variable amount of muscle tremor and fasci-
gesia when used alone.26,33 The patient must receive an culation (because of the initial depolarization), but this
adequate amount of the general anesthetic throughout is followed by a period of flaccid paralysis. Although
the surgery when a neuromuscular junction blocker several drugs that act as depolarizing blockers are
is used. This idea is critical considering that the patient available, the only agent currently in clinical use is
will be paralyzed by the neuromuscular junction succinylcholine (see Table 11–3).37
blocker and unable to respond to painful stimuli if the
anesthesia is inadequate. Failure to provide adequate
anesthesia has resulted in some harrowing reports from SUMMARY
patients who were apparently fully awake during sur-
gery but unable to move or cry out.26,33 General anesthesia has been used for some time to
Two general types of neuromuscular blockers are permit surgical procedures of various types and dura-
discussed here. They are classified according to those tions. Several different effective agents are currently
that depolarize the skeletal muscle cell when binding available and are relatively safe in producing a suitable
to the cholinergic receptor and those that do not.37 anesthetic condition in the patient. General anesthet-
Nondepolarizing Blockers. These drugs act as ics are classified according to their two primary routes
competitive antagonists of the postsynaptic receptor; of administration: inhalation and intravenous infusion.
that is, they bind to the receptor but do not activate it Specific anesthetic agents and anesthetic adjuvants
(see Chapter 4). This binding prevents the agonist (preoperative sedatives, neuromuscular blockers, etc.)
(acetylcholine) from binding to the receptor; the are primarily selected according to the type of surgical
result is paralysis of the muscle cell. These drugs all procedure being performed and the overall condition
share a structural similarity to curare (the first neuro- of the patient. Health professionals should be cog-
muscular blocker), which explains their affinity and nizant of the fact that their patients may take some
relative selectivity for the cholinergic receptor at the time to fully recover from the effects of general anes-
skeletal neuromuscular junction. Specific agents, their thesia and should adjust their postoperative care
onset, and duration of action are listed in Table 11–3. accordingly.
11Ciccone(p)-11 1/30/07 2:36 PM Page 145
CA S E ST U DY
General Anesthetics about recent events and was unable to follow most com-
mands. Apparently, she was experiencing some residual
Brief History. B.W., a 75-year-old woman, fell at home effects of the general anesthesia.
and experienced a sudden sharp pain in her left hip. She was Decision/Solution. The patient’s confusion and dis-
unable to walk and was taken to a nearby hospital where orientation precluded any activities that required her cooper-
x-ray examination showed an impacted fracture of the left hip. ation, including any initial attempts at weight-bearing
The patient was alert and oriented at the time of admission. exercises. The therapist limited the initial session to passive-
She had a history of arteriosclerotic cardiovascular disease and active-assisted exercises of both lower extremities. Active
and diabetes mellitus, but her medical condition was upper-extremity exercises were encouraged within the limita-
stable. The patient was relatively obese, and a considerable tions of the patient’s ability to follow instructions. These exer-
amount of osteoarthritis was present in both hips. Two days cises were instituted to help increase metabolism and
after admission, a total hip arthroplasty was performed excretion of the remaining anesthesia. The patient was also
under general anesthesia. Meperidine (Demerol) was given placed on a program of breathing exercises in an effort to
intramuscularly as a preoperative sedative. General anesthe- facilitate excretion of the anesthesia, as well as to maintain
sia was induced by intravenous administration of thiopental respiratory function and prevent the accumulation of mucus in
(Pentothal) and sustained by inhalation of halothane the airways. As the patient’s mental disposition gradually
(Fluothane). The surgery was completed successfully, and improved, the therapist initiated partial weight bearing in the
physical therapy was initiated at the patient’s bedside on the parallel bars. From there, the patient progressed to a walker
subsequent day. and was soon able to ambulate independently using the
Problem/Influence of Medication. At the initial device. Within 1 week after the surgery, no overt residual
therapy session, the therapist found the patient to be effects of the anesthesia were noted, and the remainder of the
extremely lethargic and disoriented. She appeared confused hospital stay was uneventful.
11Ciccone(p)-11 1/30/07 2:36 PM Page 146
37. Taylor P. Agents acting at the neuromuscular junction ed. New York: Lange Medical Books/McGraw-Hill;
and autonomic ganglia. In: Hardman JG, et al, eds. 2004.
The Pharmacological Basis of Therapeutics. 10th ed. New 40. Turner KE, Parlow JL, Avery ND, et al. Prophylaxis
York: McGraw Hill; 2001. of postoperative nausea and vomiting with oral, long-
38. Tesniere A, Servin F. Intravenous techniques in ambu- acting dimenhydrinate in gynecologic outpatient
latory anesthesia. Anesthesiol Clin North America. laparoscopy. Anesth Analg. 2004;98:1660–1664.
2003;21:273–288. 41. Villars PS, Kanusky JT, Dougherty TB. Stunning the
39. Trevor AJ, White PF. General anesthetics. In: neural nexus: mechanisms of general anesthesia. AANA
Katzung BG, ed. Basic and Clinical Pharmacology. 9th J. 2004;72:197–205.
11Ciccone(p)-11 1/30/07 2:36 PM Page 148
Chapter 12
Local Anesthetics
Local anesthesia produces a loss of sensation in a spe- procedure is relatively minor, or by switching to a gen-
cific body part or region. Frequently this application eral anesthetic during a major procedure in the event
occurs before performing a relatively minor surgical of an emergency arising during surgery.
procedure. This approach involves introducing an In nonsurgical situations, local anesthetics are
anesthetic drug near the peripheral nerve that inner- sometimes used to provide analgesia. These drugs may
vates the desired area. The basic goal is to block affer- be used for short-term pain relief in conditions such as
ent neural transmission along the peripheral nerve so musculoskeletal and joint pain (e.g., bursitis, tendini-
that the procedure is painless. When a local anesthet- tis), or in more long-term situations such as pain relief
ic is introduced in the vicinity of the spinal cord, trans- in cancer or treatment of chronic pain. In addition,
mission of impulses may be effectively blocked at a local anesthetics may be used to block efferent sympa-
specific level of the cord, allowing more extensive sur- thetic activity in conditions such as reflex sympathetic
gical procedures to be performed (e.g., caesarean dystrophy syndrome. During these nonsurgical appli-
delivery) because a larger region of the body is being cations, physical therapists and other rehabilitation
anesthetized. This approach, however, is still consid- personnel will often be directly involved in treating
ered a local anesthetic because the drug acts locally at the patient while the local anesthetic is in effect. If
the spinal cord and the patient remains conscious dur- prescribed by a physician, the local anesthetic may
ing the surgical procedure. actually be administered by the physical therapist via
Using a local anesthetic during a surgical proce- phonophoresis or iontophoresis. Consequently, these
dure offers several advantages over the use of general individuals should have adequate knowledge of the
anesthesia, including a relatively rapid recovery and pharmacology of local anesthetics.
lack of residual effects.13,15 There is a virtual absence of
the postoperative confusion and lethargy often seen
after general anesthesia. In most cases of minor sur-
gery, patients are able to leave the practitioner’s office
Types of Local Anesthetics
or hospital almost as soon as the procedure is com- Commonly used local anesthetics are listed in Table
pleted. In more extensive procedures, local anesthesia 12–1. These drugs share a common chemical strategy
offers the advantage of not interfering with cardiovas- consisting of both a lipophilic and hydrophilic group
cular, respiratory, and renal functioning. This fact can connected by an intermediate chain (Fig. 12–1). A
be important in patients with problems in these phys- local anesthetic is chosen depending on factors such
iological systems. During childbirth, local (spinal) as: (1) the operative site and nature of the procedure;
anesthesia imposes a lesser risk to the neonate than (2) the type of regional anesthesia desired (such as sin-
general anesthesia.14,41 The primary disadvantages of gle peripheral nerve block or spinal anesthesia); (3) the
local anesthesia are the length of time required to patient’s size and general health; and (4) the duration
establish an anesthetic effect and the risk that analge- of action of the anesthetic.3
sia will be incomplete or insufficient for the respective The “caine” suffix (lidocaine, procaine, and so
procedure.47 The latter problem can usually be re- on) usually identifies local anesthetics.. The first clin-
solved by administering more local anesthesia if the ically useful local anesthetic identified was cocaine in
149
12Ciccone(p)-12 1/30/07 2:49 PM Page 150
Duration of
Generic Name Trade Name(s) Onset of Action Action Principle Use(s)
Articane Septocaine Rapid Intermediate Peripheral nerve block
Duration of
Generic Name Trade Name(s) Onset of Action* Action* Principle Use(s)
Procaine Novocain Intermediate Short Infiltration;
Peripheral nerve block;
Spinal
*Values for onset and duration of action refer to use during injection. Relative durations of action are as follows:
short ⫽ 30–60 min; intermediate ⫽ 1–3 hr; and long ⫽ 3–10 hr of action.
Source: USP DI, 25th Edition. Copyright 2005. Thomson MICROMEDEX. Permission granted.
tophoretic application of local anesthetics offers atic) or around a nerve plexus (brachial plexus)
12Ciccone(p)-12 1/30/07 2:49 PM Page 153
therefore be more problematic during spinal used to promote sympathetic blockade using
administration compared to the epidural route. local anesthetic drugs. With these techniques,
Central neural blockade is used whenever the goal is not to provide analgesia, but rather
analgesia is needed in a large region, and to impair efferent sympathetic outflow to the
epidural and spinal routes are used frequently affected extremity.
to administer local anesthetics during obstetric 7. Intravenous Regional Anesthesia (Bier block). Dur-
procedures (including caesarean delivery).30,44 ing intravenous regional anesthesia (also known
These routes can also be used as an alternative as Bier block), the anesthetic is injected into a
to general anesthesia for other surgical proce- peripheral vein located in a selected limb (arm
dures including lumbar spine surgery and hip or leg).9 The local vasculature can then carry the
and knee arthroplasty.23,45 The epidural and anesthetic to the nerves in that extremity, there-
intrathecal routes have also been used to admin- by producing anesthesia in the limb. A tourni-
ister anesthetics and narcotic analgesics for relief quet is also applied proximally on the limb to
of acute and chronic pain.6,19 In these instances, localize the drug temporarily within the extrem-
an indwelling catheter is often left implanted in ity, and to prevent the anesthetic from reaching
the epidural or subarachnoid space to allow the systemic circulation where it would cause
repeated or continuous delivery of the anesthet- toxic effects on the heart and CNS. This tech-
ic to the patient. The use of implanted drug nique is somewhat difficult to use because the
delivery systems in managing chronic and severe tourniquet can cause pain or increase the risk of
pain is discussed further in Chapters 14 and 17. ischemic neuropathy if left in place for more
6. Sympathetic block. Although blockade of sympa- than 2 hours.48 Intravenous regional block, how-
thetic function usually occurs during peripheral ever, can be used to anesthetize the forearm-
and central nerve blocks, sometimes the selec- hand or distal leg-ankle-foot for short periods to
tive interruption of sympathetic efferent dis- allow certain surgical procedures or to treat
charge is desirable. This intervention is conditions such as CRPS.34,35
especially useful in cases of complex regional
pain syndrome (CRPS). This syndrome, also
known as reflex sympathetic dystrophy syn-
drome (RSDS) and causalgia, involves increased
Mechanism of Action
sympathetic discharge to an upper or lower Local anesthetics work by blocking action potential
extremity, often causing severe pain and dys- propagation along neuronal axons, which is believed
function in the distal part of the extremity. As to occur from the anesthetic molecule inhibiting the
part of the treatment, a local anesthetic can be opening of membrane sodium channels.44,60 The sud-
administered to interrupt sympathetic discharge den influx of sodium into the neuron through open
to the affected extremity.33,64 One approach is (activated) ion channels depolarizes the neuron during
to inject the local anesthetic into the area sur- impulse propagation. If the sodium ion channels are
rounding the sympathetic chain ganglion that inhibited from opening along a portion of the axon,
innervates the affected limb. For example, the action potential will not be propagated past that
injection near the stellate ganglion is performed point. If the neuron is sensory in nature, this informa-
when the upper extremity is involved, and injec- tion will not reach the brain and will result in anes-
tions around the sympathetic ganglion at the L- thesia of the area innervated by that neuron.
2 vertebral level are used for lower-extremity Exactly how local anesthetics inhibit the sodium
CRPS.33 Usually a series of five injections on channel from opening has been the subject of much
alternate days is necessary to attenuate the sym- debate. Although several theories exist, the current
pathetic discharge and to provide remission consensus is that local anesthetics temporarily attach
from the CRPS episode. Alternatively, the local to a binding site or receptor located on or within the
anesthetic can be administered subcutaneously sodium channel.16,36,60 These receptors probably con-
to an affected area,38 or injected intravenously trol the opening of the channel, and when bound by
into the affected limb using regional intra- the anesthetic molecule, the sodium channel is main-
venous block techniques (see next section).35 tained in a closed, inactivated position. Several sites
Hence, several techniques are currently being have been proposed to explain exactly where the local
12Ciccone(p)-12 1/30/07 2:49 PM Page 155
+
Na+ Channel (open/ no anesthetic) Na Channel (closed/ blocked by
anesthetic)
+
Na
+
Na
+
Na
local anesthetic
FIGURE 12–3 ▼ Schematic diagram showing mechanism of action of local anesthetics on the
nerve membrane. Local anesthetics appear to bind directly to a site within the sodium channel,
thereby locking the channel in a closed position, thus preventing sodium entry and action potential
propagation.
anesthetic binds on the sodium channel protein (Fig. the first sensory information blocked as the anesthetic
12–3).36,43,60 The most likely binding site is within the takes effect. Type C fibers also transmit postganglion-
lumen or pore of the channel itself, possibly at the ic autonomic information, including sympathetic vaso-
inner, cytoplasmic opening of the channel.16,60 When motor control of the peripheral vasculature, and are
bound by the anesthetic molecule, this site may effec- most susceptible to block by local anesthetics. Other
tively lock the sodium channel shut (much in the same sensory information—such as temperature, touch, and
way that the appropriate key fitting into a door key- proprioception—is successively lost as the concentra-
hole is able to lock a door). tion and effect of the anesthetic increases. Finally,
Consequently, local anesthetics appear to bind skeletal motor function is usually last to disappear
directly to sodium channels on the nerve axon. By because efferent impulses to the skeletal muscle are
keeping these channels in a closed, inactivated state, transmitted over the large type A-alpha fibers.
the anesthetic prevents action potential propogation The exact reason for the differential susceptibili-
along the affected portion of the axon. Likewise, only ty of nerve fibers based on their axonal diameter is not
a relatively short portion of the axon (e.g., the length known. One possible explanation is that the anesthetic
of 3 nodes of Ranvier in a myelinated neuron) needs to is able to affect a critical length of the axon more
be affected by the anesthetic to block action potential quickly in unmyelinated fibers, or small myelinated
propogation.62 That is, the anesthetic does not need to neurons with nodes of Ranvier that are spaced closely
affect the entire length of the axon, but block only one together compared to larger fibers where the nodes are
specific segment of the axon to completely prevent farther apart.17 As indicated earlier, a specific length of
sensory or motor information from being transmitted the axon must be affected by the anesthetic so that
past the point of the blockade. action potentials cannot be transmitted past the point
of blockade. Other factors such as the firing rate of
each axon or the position of the axon in the nerve bun-
dle (e.g., in the outer part of the bundle versus buried
Differential Nerve Block toward the center of the nerve) may also affect suscep-
Differential nerve block refers to the ability of a given tibility to local anesthesia.62 In any event, from a clin-
local anesthetic dose to block specific nerve fiber ical perspective the smaller-diameter fibers appear to
groups depending on the size (diameter) of the be affected first, although the exact reasons for this
fibers.54, 62 In general, smaller diameter fibers seem to phenomenon remain to be determined.
be the most sensitive to anesthetic effects, with pro- The clinical importance of a differential nerve
gressively larger fibers being affected as anesthetic block is that certain sensory modalities may be blocked
concentration increases.62 This point is significant without the loss of motor function. Fortuitously, the
because different diameter fibers transmit different most susceptible modality is pain because analgesia is
types of information (Table 12–2). Thus, information usually the desired effect. If the dosage and adminis-
transmitted by the smallest fibers will be lost first, with tration of the anesthetic is optimal, it will produce
other types of transmission being successively lost as analgesia without any significant loss of skeletal muscle
the local anesthetic effect increases. The smallest function. This fact may be advantageous if motor func-
diameter (type C) fibers that transmit pain are usually tion is required, such as during labor and delivery.14 If
12Ciccone(p)-12 1/30/07 2:49 PM Page 156
Table 12–2 RELATIVE SIZE AND SUSCEPTIBILITY TO BLOCK OF TYPES OF NERVE FIBERS
Type C
Dorsal Root Pain 0.4–1.2 None 0.5–2.3 ⫹⫹⫹⫹
*Fiber types are classified according to the system established by Gasser and Erlanger. Am J Physiol. 1929;
88:581. Reproduced with permission from Katzung BG. Basic and Clinical Pharmacology. 9th ed. New York:
Lange Medical Books/McGraw Hill; 2004.
local anesthetics are used to produce sympathetic seizures can occur if sufficient amounts reach the brain
blockade, postganglionic type C fibers are the first to via the bloodstream.8,17 Central excitation is usually
be blocked, thus producing the desired effect at the followed by a period of CNS depression. This depres-
lowest anesthetic concentration. sion may result in impaired respiratory function, and
death may occur due to respiratory depression.17 The
primary cardiovascular effects associated with local
Systemic Effects anesthetics include decreased cardiac excitation, heart
rate, and force of contraction.5,17 Again, this general
of Local Anesthetics inhibitory effect on the myocardium may produce
The intent of administering a local anesthetic is to serious consequences if sufficient amounts of the local
produce a regional effect on specific neurons. Howev- anesthetic reach the general circulation.17
er, these drugs may occasionally be absorbed into the Systemic effects are more likely to occur with
general circulation and exert various effects on other long-acting anesthetics if an excessive dose is used, if
organs and tissues. Because local anesthetics inhibit absorption into the blood stream is accelerated for
action potential initiation and propogation, the most some reason, or if the drug is accidentally injected into
important systemic effects involve the CNS and car- the systemic circulation rather than into extravascular
diovascular system.8,21,27 That is, local anesthetics can tissues.17,40 Other factors that can predispose a patient
inadvertently disrupt the excitability of the CNS and to systemic effects include the type of local anesthetic
cardiac tissues if meaningful amounts of these drugs administered, as well as the route and method of
reach the systemic circulation. administration.3 Therapists and other health care pro-
Regarding CNS effects, virtually all local anes- fessionals should always be alert for signs of the sys-
thetics stimulate the brain initially, and symptoms such temic effects of local anesthetics in patients. Early
as somnolence, confusion, agitation, excitation, and symptoms of CNS toxicity include ringing/buzzing
12Ciccone(p)-12 1/30/07 2:49 PM Page 157
in the ears (tinnitus), agitation, restlessness, and de- ly after each injection so that they can perform exer-
creased cutaneous sensation around the mouth or cises and other rehabilitation techniques while the
other areas of the skin.59 Changes in heart rate (brady- anesthetic is still in effect. This strategy may help
cardia), electrocardiogram (ECG) abnormalities, or reestablish normal sympathetic function and blood
clinical signs of cardiac depression (fatigue, dizziness) flow to the affected extremity so that optimal results
may indicate cardiotoxicity. Again, early recognition are obtained from the sympathetic blockade.
of these CNS and cardiac abnormalities is essential to Finally, therapists may work with patients who
help avert fatalities due to the drug’s systemic effects. are receiving central neural blockade in the form of an
epidural or spinal injection. These procedures are
common during natural and caesarean childbirth and
in some other surgical procedures. Administration of
Significance in Rehabilitation local anesthetics into the spaces around the spinal cord
Physical therapists may encounter the use of local are also used to treat individuals with severe and
anesthetics in several patient situations because of their chronic pain—that is, patients recovering from exten-
various clinical applications. For example, therapists sive surgery, patients who have cancer, or patients with
may be directly involved in the topical or transdermal other types of intractable pain. In these situations,
administration of local anesthetics. As discussed earli- therapists may notice that an indwelling catheter has
er, repeated topical application of local anesthetics may been placed in the patient’s epidural or subarachnoid
help produce long-term improvements in motor func- space to allow repeated or sustained administration of
tion in patients with skeletal muscle hypertonicity, so the spinal anesthesia.
therapists may want to consider incorporating topical In situations where central neural blockade is
anesthetics into the treatment of certain patients with used, therapists should be especially aware that sensa-
CNS dysfunction. Therapists may also administer tion might be diminished below the level of epidural
local anesthetics transdermally, using the techniques of or spinal administration. Decreased sensation to ther-
iontophoresis and phonophoresis. Agents such as lido- mal agents and electrical stimulation will occur when
caine can be administered through this method for the the central block is in effect.10 Likewise, motor func-
treatment of acute inflammation in bursitis, tendinitis, tion may be affected in the lower extremities when
and so on. local anesthetics are administered spinally or epidural-
Therapists may also be working with patients ly.10 Hence, therapists should test sensation and motor
who are receiving local anesthetic injections for the strength before applying any physical agents or
treatment of CRPS/RSDS. Since these patients often attempting ambulation with patients who have
receive a series of anesthetic injections, therapists may received some type of central neural blockade using a
want to schedule the rehabilitation session immediate- local anesthetic.
CA S E ST U DY
Local Anesthetics sound, soft-tissue massage, and exercise. Soft-tissue
massage consisted of transverse-friction techniques applied
Brief History. R.D. is a 35-year-old man who devel- to the supraspinatus tendon. In order to improve the patient’s
oped pain in his right shoulder after spending the weekend tolerance to this technique, 5 percent lidocaine (Xylocaine)
chopping firewood. He was examined by a physical therapist solution was administered via iontophoresis prior to the
and evaluated as having supraspinatus tendinitis. Apparently, transverse-friction massage. This approach allowed R.D.
this tendinitis recurred intermittently, usually after extensive and the therapist to perform both the massage technique
use of the right shoulder. During past episodes, the tendinitis and subsequent exercises more aggressively. Under this reg-
was resistant to treatment and usually took several months imen, the supraspinatus tendinitis was resolved and the
to resolve. patient had full, pain-free use of the right shoulder within
Decision/Solution. The therapist began an aggres- 3 weeks.
sive rehabilitation program consisting of daily heat, ultra-
12Ciccone(p)-12 1/30/07 2:49 PM Page 158
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the place of ropivacaine. Curr Top Med Chem. 2001; additives for spinal anaesthesia—characteristics and
1:207–214. factors influencing the spread and duration of the
28. Grant SA, Nielsen KC, Greengrass RA, et al. Continu- block. Best Pract Res Clin Anaesthesiol. 2003;17:
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Anesth Pain Med. 2001;26:209–214. 47. Portnoy D, Vadhera RB. Mechanisms and manage-
29. Greenbaum SS. Iontophoresis as a tool for anesthesia ment of an incomplete epidural block for cesarean sec-
in dermatologic surgery: an overview. Dermatol Surg. tion. Anesthesiol Clin North America. 2003;21:39–57.
2001;27:1027–1030. 48. Rodola F, Vagnoni S, Ingletti S. An update on Intra-
30. Gogarten W. Spinal anaesthesia for obstetrics. Best venous Regional Anaesthesia of the arm. Eur Rev Med
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31. Hocking G, Wildsmith JA. Intrathecal drug spread. 49. Rogers TL, Ostrow CL. The use of EMLA cream to
Br J Anaesth. 2004;93:568–578. decrease venipuncture pain in children. J Pediatr Nurs.
32. Inoue S, Kawaraguchi Y, Kitaguchi K, Furuya H. 2004;19:33–39.
Inclusion of epinephrine to hyperbaric tetracaine and 50. Rose JB, Galinkin JL, Jantzen EC, Chiavacci RM. A
the supine position enhance the cephalad spread of study of lidocaine iontophoresis for pediatric
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2004;48:342–346. mum recommended doses of local anesthetics: a
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SECTION
Drugs Affecting
Skeletal Muscle
13Ciccone(p)-13 1/30/07 2:50 PM Page 162
Chapter 13
Skeletal Muscle Relaxants
Skeletal muscle relaxants are used to treat conditions be used to describe two different types of increased
associated with hyperexcitable skeletal muscle— excitability, which result from different underlying
specifically, spasticity and muscle spasms. Although pathologies. Spasticity occurs in many patients follow-
these two terms are often used interchangeably, spas- ing an injury to the central nervous system (CNS),
ticity and muscle spasms represent two distinct abnor- including cord-related problems (multiple sclerosis,
malities. The use of relaxant drugs, however, is similar spinal cord transection) and injuries to the brain (CVA,
in each condition because the ultimate goal is to nor- cerebral palsy, acquired brain injury). Although there is
malize muscle excitability without a profound de- considerable controversy about the exact changes in
crease in muscle function. Considering the number of motor control, most clinicians agree that spasticity
rehabilitation patients with muscle hyperexcitability is characterized primarily by an exaggerated muscle
that is associated with either spasm or spasticity, skele- stretch reflex (Fig. 13–1).40,52,79 This abnormal reflex
tal muscle relaxants represent an important class of activity is velocity-dependent, with a rapid lengthening
drugs to the rehabilitation specialist. of the muscle invoking a strong contraction in the
Drugs discussed in this chapter are used to de-
crease muscle excitability and contraction via an effect
at the spinal cord level, at the neuromuscular junction, CNS
or within the muscle cell itself. Some texts also classi- Higher Centers
fy neuromuscular junction blockers such as curare and
succinylcholine as skeletal muscle relaxants. However,
these drugs are more appropriately classified as skele-
tal muscle paralytics because they eliminate muscle
control/inhibition
contraction by blocking transmission at the myoneur- Spinal
al synapse. This type of skeletal muscle paralysis is Cord Ia afferent
used primarily during general anesthesia; using neuro-
muscular blockers as an adjunct in surgery was dis-
cussed in Chapter 11. Skeletal muscle relaxants do muscle
not typically prevent muscle contraction; they only motor spindle
attempt to normalize muscle excitability to decrease neuron
pain and improve motor function. motor neuron
Skeletal
Muscle
Increased Muscle Tone:
FIGURE 13–1 ▼ Schematic illustration of the basic components of
Spasticity Versus Muscle Spasms the stretch reflex. Normally, higher CNS centers control the sensitivity
of this reflex by inhibiting synaptic connections within the spinal cord.
Much confusion and consternation often arise from Spasticity is thought to occur when this higher center influence is lost
the erroneous use of the terms “spasticity” and because of cerebral trauma or damage to descending pathways in the
“spasm.” For the purpose of this text, these terms will spinal cord.
163
13Ciccone(p)-13 1/30/07 2:50 PM Page 164
stretched muscle. The neurophysiologic mechanisms decrease spasticity. One agent, diazepam (Valium), is
underlying spasticity are complex, but this phenome- indicated for both conditions and will appear in both
non occurs when supraspinal inhibition or control is categories. Finally, the use of botulinum toxin (Botox)
lost because of a lesion in the spinal cord or brain.40,52,54 as an alternative strategy for reducing focal spasms or
Presumably, specific upper motor neuron lesions inter- spasticity will be addressed.
rupt the cortical control of stretch reflex and alpha
motor neuron excitability. Spasticity, therefore, is not
in itself a disease but rather the motor sequela to
pathologies such as cerebral vascular accident (CVA), Agents Used to
cerebral palsy, multiple sclerosis (MS), and traumatic Treat Muscle Spasms
lesions to the brain and spinal cord (including quadri-
plegia and paraplegia).
Diazepam
Skeletal muscle spasms are used to describe the The effects of diazepam (Valium) on the CNS and its
increased tension often seen in skeletal muscle after use as an antianxiety drug are discussed in Chapter 6.
certain musculoskeletal injuries and inflammation Basically, diazepam and other benzodiazepines work by
(muscle strains, nerve root impingements, etc.) increasing the central inhibitory effects of gamma-
occur.20,96 This tension is involuntary, so the patient is aminobutyric acid (GABA); that is, diazepam binds to
unable to relax the muscle. Spasms differ from spastic- receptors located at GABAergic synapses and increases
ity because spasms typically arise from an orthopedic the GABA-induced inhibition at that synapse. Diaze-
injury to a musculoskeletal structure or peripheral pam appears to work as a muscle relaxant through this
nerve root rather than an injury to the CNS. Likewise, mechanism, potentiating the inhibitory effect of
muscle spasms are often a continuous, tonic con- GABA on alpha motor neuron activity in the spinal
traction of specific muscles rather than the velocity- cord.40,102 The drug also exerts some supraspinal seda-
dependent increase in stretch reflex activity commonly tive effects; in fact, some of its muscle relaxant proper-
associated with spasticity. The exact reasons for muscle ties may derive from the drug’s ability to produce a
spasms are poorly understood. According to some more generalized state of sedation.101
authorities, muscle spasms occur because a vicious Uses. Diazepam is one of the oldest medications
cycle is created when the initial injury causes muscular for treating muscle spasms, and has been used exten-
pain and spasm, which increases afferent nociceptive sively in treating spasms associated with musculoskele-
input to the spinal cord, further exciting the alpha tal injuries such as acute low-back strains. Diazepam
motor neuron to cause more spasms, and so on.61,96 has also been used to control muscle spasms associated
Other experts believe that muscle spasms occur with tetanus toxin; the use of valium in this situation
because of a complex protective mechanism, whereby can be life-saving as well by inhibiting spasms of the
muscular contractions are intended to support an larynx and other muscles.51,65
injured vertebral structure or peripheral joint.96 Adverse Effects. The primary side effect with
Regardless of the exact reason, tonic contraction of the diazepam is that dosages successful in relaxing skeletal
affected muscle is often quite painful because of the muscle also produce sedation and a general reduction
buildup of pain-mediating metabolites (e.g., lactate). in psychomotor ability.40,101 However, this effect may
Consequently, various skeletal muscle relaxants not be a problem and may actually be advantageous for
attempt to decrease skeletal muscle excitation and con- the patient recovering from an acute musculoskeletal
traction in cases of spasticity and spasm. Specific drugs injury. For example, a patient with an acute lum-
and their mechanisms of action are discussed here. bosacral strain may benefit from the sedative proper-
ties because he or she will remain fairly inactive,
thereby allowing better healing during the first few
Specific Agents Used days after the injury. Continued use, however, may be
to Produce Skeletal problematic because of diazepam’s sedative effects.
The drug can also produce tolerance and physical
Muscle Relaxation dependence, and sudden withdrawal after prolonged
Skeletal muscle relaxants are categorized in this chap- use can cause seizures, anxiety, agitation, tachycardia,
ter according to their primary clinical application: and even death.102 Likewise, an overdose with diaze-
agents used to decrease spasms and agents used to pam can result in coma or death as well.102 Hence, this
13Ciccone(p)-13 1/30/07 2:50 PM Page 165
drug might be beneficial for the short-term manage- It is not clear, however, exactly how these drugs
ment of acute muscle spasms, but long-term use should inhibit neurons involved in the polysynaptic pathways.
be discouraged. There is preliminary evidence that one of these com-
pounds (cyclobenzaprine) might block serotonin
receptors on spinal interneurons, thereby decreasing
Polysynaptic Inhibitors the excitatory influence of serotonin on alpha motor
A variety of centrally acting compounds have been neuron activity.50,55 Although this effect has been
used in an attempt to enhance muscle relaxation and attributed to cyclobenzaprine in animals (rats), the
decrease muscle spasms (see Table 13–1). Some exam- effect of this drug and other muscle relaxants in
ples are carisoprodol (Soma, Vanadom), chlorphen- humans remains to be determined.
esin carbamate (Maolate), chlorzoxazone (Paraflex, On the other hand, these compounds have a gen-
Parafon Forte, others), cyclobenzaprine (Flexeril), eral depressant effect on the CNS; that is, they cause a
metaxalone (Skelaxin), methocarbamol (Carbacot, global decrease in CNS excitability that results in gen-
Robaxin, Skelex), and orphenadrine citrate (Antiflex, eralized sedation. It therefore seems possible that
Norflex, others). The mechanism of action of these some of their muscle relaxant effects are caused by
drugs is not well defined.8 Research in animals has their sedative powers rather than a selective effect on
suggested that these drugs may decrease polysynaptic specific neuronal reflex pathways.11,92 This observation
reflex activity in the spinal cord, hence the term “poly- is not to say that they are ineffective, because clinical
synaptic inhibitors.” A polysynaptic reflex arc in the research has shown that these drugs can be superior to
spinal cord is comprised of several small interneurons a placebo in producing subjective muscle relax-
that link incoming (afferent) input into the dorsal ation.8,20,80,97 However, the specific ability of these
horn with outgoing (efferent) outflow onto the alpha drugs to relax skeletal muscle remains doubtful, and it
motor neuron. By inhibiting the neurons in the poly- is generally believed that their muscle relaxant proper-
synaptic pathways, these drugs could decrease alpha ties are secondary to a nonspecific CNS sedation.
motor neuron excitability and therefore cause relax- Uses. These drugs are typically used as adjuncts
ation of skeletal muscle. to rest and physical therapy for the short-term relief of
muscle spasms associated with acute, painful muscu- prodol represents a rather unique situation where the
loskeletal injuries.9,14,97 When used to treat spasms, drug itself or its metabolic byproduct (meprobamate)
these compounds are often given with a nonsteroidal can produce effects and side effects that lead to addic-
anti-inflammatory agent (NSAIDs; see Chapter 15), tion and abuse, especially in people with a history of
or sometimes incorporated into the same tablet with substance abuse.13,73 Likewise, discontinuing cariso-
an analgesic such as acetaminophen or aspirin. For prodol suddenly after long term use can lead to with-
instance, Norgesic is one of the brand names for drawal symptoms such as anxiety, tremors, muscle
orphenadrine combined with aspirin (and caffeine). twitching, and hallucinations.72
Such combinations have been reported to be more Consequently, polysynaptic inhibitors can help
effective than the individual components given sepa- provide short-term relief for muscle spasms associ-
rately.8 ated with certain musculoskeletal conditions, and they
Adverse Effects. Because of their sedative proper- may work synergistically with physical therapy and
ties, the primary side effects of these drugs are drowsi- other interventions during acute episodes of back
ness and dizziness (see Table 13–2). A variety of pain, neck pain, and so forth. Nonetheless, they have
additional adverse effects, including nausea, light- some rather serious side effects and potential for
headedness, vertigo, ataxia, and headache, may occur abuse, and the long-term use of these drugs should be
depending on the patient and the specific drug admin- discouraged.
istered (Table 13–2). Cases of fatal overdose have also
been documented for several of these drugs, including
cyclobenzaprine and metaxolone.70,86 Agents Used to
Long term or excessive use of these medica-
tions may also cause tolerance and physical depend-
Treat Spasticity
ence.14,31 In particular, carisoprodol should be used The three agents traditionally used in the treatment of
cautiously because this drug is metabolized in the spasticity are baclofen, diazepam, and dantrolene sodi-
body to form meprobamate, which is a controlled sub- um (see Table 13–3, Fig. 13–2). Two newer agents,
stance (see Chapter 1) that has sedative/anxiolytic gabapentin and tizanidine, are also available for treat-
properties but is not used extensively because it has ing spasticity in various conditions. All of these agents
strong potential for abuse.13,73 Hence, use of cariso- are addressed below.
Chlorphenesin carbamate L L R R
Chlorzoxazone M M L L
Cyclobenzaprine M M L L
Metaxalone M M M M
Methocarbamol M M L L
Orphenadrine citrate L L L L
Dantrolene sodium Adult: 25 mg/d initially; increase up to 100 mg Exerts an effect directly on the
(Dantrium) 2, 3, or 4 times per day as needed; maxi- muscle cell; may cause general-
mum recommended dose is 400 mg/day. ized weakness in all skeletal
Children (older than 5 yr of age): initially, 0.5 musculature.
mg/kg body weight BID; increase total daily
dosage by 0.5 mg/kg every 4–7 days as
needed, and give total daily amount in 4
divided dosages; maximum recommended
dose is 400 mg/d.
Diazepam (Valium) Adult: 2–10 mg TID or QID. Produces sedation at dosages that
Children (older than 6 mo of age): 1.0–2.5 mg decrease spasticity.
TID or QID (in both adults and children,
begin at lower end of dosage range and
increase gradually as tolerated and needed).
Gabapentin (Neurontin) Adult:* initially, 300 mg TID. Can be gradually Developed originally as an anticon-
increased up to 3600 mg/d based on vulsant; may also be helpful as
desired response. an adjunct to other drugs in
Children* (3–12 years of age): Initially, 10–15 treating spasticity associated
mg/kg body weight in 3 divided dosages; with spinal cord injury and multi-
increase over 3 days until desired effect or ple sclerosis.
a maximum of 50 mg/kg/d.
Tizanidine (Zanaflex) Adult: 8 mg every 6–8 hours as needed. May reduce a in spinal cord disor-
Children: The safety and effficacy of this drug ders while producing fewer
in treating spasticity in children have not side effects and less general-
been established. ized muscle weakness than
other agents (oral baclofen,
diazepam).
*Anticonvulsant dose
CH3
O
H O N
O2N CH
N CH2 CH CH2 C O
H OH CI N
NN
CI O N O
H
inhibitory effect on alpha motor neuron activity with- ness, which usually disappears within a few days.30
in the spinal cord. This inhibition apparently occurs When given to patients with spinal cord lesions, there
via inhibiting excitatory neurons that synapse with the are usually few other adverse effects. When given to
alpha motor neuron (presynaptic inhibition), as well as patients who have had a CVA or to elderly individuals,
directly affecting the alpha motor neuron itself (post- there is sometimes a problem with confusion and hal-
synaptic inhibition).40,102 The result is decreased firing lucinations. Other side effects, occurring on an indi-
of the alpha motor neuron, with a subsequent relax- vidual basis, include fatigue, nausea, dizziness, muscle
ation of the skeletal muscle. weakness, and headache. Abrupt discontinuation of
Uses. Baclofen is administered orally to treat baclofen may also cause withdrawal symptoms such as
spasticity associated with lesions of the spinal cord, hyperthermia, hallucinations, and seizures.30 Increased
including traumatic injuries resulting in paraplegia seizure activity has also been reported following
or quadriplegia and spinal cord demyelination result- baclofen overdose, and in selected patient populations
ing in MS.30,102 Baclofen is often the drug of choice such as certain children with cerebral palsy and certain
in reducing the muscle spasticity associated with MS adults with multiple sclerosis.48,81
because it produces beneficial effects with a remark-
able lack of adverse side effects when used in patients
with MS.4 The drug also does not cause as much
Intrathecal Baclofen
generalized muscle weakness as direct-acting relaxants Although baclofen is administered orally in most
such as dantrolene, which can be a major advantage of patients (Table 13–3) it can also be administered
baclofen treatment in many patients with MS.101 intrathecally in patients with severe, intractable spas-
Baclofen also appears to produce fewer side effects ticity.71,103 Intrathecal administration is the delivery of
when used appropriately to reduce spasticity second- a drug directly into the subarachnoid space surround-
ary to traumatic spinal cord lesions, thus providing a ing a specific level of the spinal cord. This places the
relatively safe and effective form of treatment.102 drug very close to the spinal cord, thus allowing
When administered systemically, baclofen is less effec- increased drug effectiveness with much smaller drug
tive in treating spasticity associated with supraspinal doses. Likewise, fewer systemic side effects occur
lesions (stroke, cerebral palsy), because these patients because the drug tends to remain in the area of the
are more prone to the adverse side effects of this drug cord rather than circulating in the bloodstream and
and because baclofen does not readily penetrate the causing adverse effects on other tissues.
blood-brain barrier.40,102 When baclofen is administered intrathecally for
Oral baclofen has also been used to reduce alco- the long-term treatment of spasticity, a small catheter
hol consumption in people who are chronic alcohol is usually implanted surgically so that the open end of
abusers.21,22 Apparently, relatively low doses of the catheter is located in the subarachnoid space and
baclofen can reduce the cravings and desire for alcohol the other end is attached to some type of programma-
consumption via the effects of this drug on CNS ble pump. The pump is implanted subcutaneously in
GABA receptors.21 Future studies will help clarify the the abdominal wall and is adjusted to deliver the drug
role of this drug in treating chronic alcoholism. at a slow, continuous rate. The rate of infusion is
Adverse Effects. When initiating baclofen thera- adjusted over time to achieve the best clinical reduc-
py, the most common side effect is transient drowsi- tion in spasticity.
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Intrathecal baclofen delivery using implantable stopping the drug due to pump failure, pump removal,
pumps has been used in patients with spasticity of or delivery catheter displacement/blockage may cause
spinal origin (spinal cord injury, multiple sclero- a withdrawal syndrome that includes fever, confusion,
sis),57,103 and in patients with spasticity resulting from delirium, and seizures.46,75,104
supraspinal (cerebral) injury, including cerebral palsy, A second major concern is the possibility that tol-
CVA, and traumatic brain injury.1,40,94 Studies involv- erance could develop with long-term, continuous
ing these patients have typically noted a substantial baclofen administration. Tolerance is the need for
decrease in rigidity (as indicated by decreased Ash- more of a drug to achieve its beneficial effects when
worth scores, decreased reflex activity, and so used for prolonged periods. Several studies have
forth).57,103 Patient satisfaction is generally favorable, reported that dosage must indeed be increased pro-
and caregivers for younger children report ease of care gressively when intrathecal baclofen systems are used
following implantation of intrathecal baclofen for periods of several months to several years.40,63 Tol-
pumps.17,43 There is growing evidence that intrathecal erance to intrathecal baclofen, however, can usually be
baclofen can also reduce pain of central origin in peo- dealt with by periodic adjustments in dosage, and tol-
ple with spasticity; that is, continuous baclofen admin- erance does not usually develop to such an extent that
istration to the subarachnoid space may inhibit the intrathecal baclofen must be discontinued.
neural circuitry that induces chronic pain in people Hence, intrathecal baclofen offers a means of
with stroke and other CNS injuries.85,90 treating certain patients with severe spasticity who
Uses. Intrathecal baclofen can result in decreased have not responded to more conventional means of
spasticity and increased comfort in many people with treatment including oral baclofen. Additional research
severe spasticity. This intervention can also result in will help determine optimal ways that this intervention
functional improvements, especially in cases where can be used to decrease spasticity. Further improve-
voluntary motor control was being masked by spastic- ments in the technologic and mechanical aspects of
ity.16 Ambulatory patients with spasticity resulting intrathecal delivery, including better pumps and
from a CVA, for example, may be able to increase their catheter systems, will also make this a safer and more
walking speed and increase their functional mobility practical method of treating these patients.
after intrathecal baclofen therapy.37,74
These functional improvements, however, may
not occur in all types of spasticity. Patients with severe
Dantrolene Sodium
spasticity of spinal origin, for example, may not expe- The only muscle relaxant available that exerts its
rience improvements in mobility or decreased disabil- effect directly on the skeletal muscle cell is dantrolene
ity.103 If these patients do not have adequate voluntary sodium (Dantrium).40,102 This drug works by impair-
motor function there is simply not enough residual ing the release of calcium from the sarcoplasmic retic-
motor ability to perform functional tasks after spastic- ulum within the muscle cell during excitation (Fig.
ity is reduced. Nonetheless, these patients may still 13–3).56,89 In response to an action potential, the
benefit from intrathecal baclofen because of decreased release of calcium from sarcoplasmic storage sites ini-
rigidity and pain, which can result in improved self- tiates myofilament cross-bridging and subsequent
care and the ability to perform daily living activi- muscle contraction. By inhibiting this release, dantro-
ties.37,74,76 lene attenuates muscle contraction and therefore
Adverse effects. Despite these benefits, intrathe- enhances relaxation.
cal baclofen is associated with a number of potential Uses. Dantrolene is often effective in treating
complications. Primary among these is the possibility severe spasticity, regardless of the underlying patholo-
of a disruption in the delivery system; that is, a pump gy.102 Patients with traumatic cord lesions, advanced
malfunction or a problem with the delivery catheter MS, cerebral palsy, or CVAs will probably experience
can occur.42,60,67,69 In particular, the catheter can a reduction in spasticity with this drug. This drug is
become obstructed, or the tip of the catheter can also invaluable in treating malignant hyperthermia,
become displaced so that baclofen is not delivered into which is a potentially life-threatening reaction occur-
the correct area of the subarachnoid space. Increased ring in susceptible individuals following exposure to
drug delivery due to a pump malfunction could cause general anesthesia, muscle paralytics used during
overdose and lead to respiratory depression, decreased surgery, or certain antipsychotic medications (a condi-
cardiac function, and coma.40 Conversely, abruptly tion also called neuroleptic malignant syndrome; see
13Ciccone(p)-13 1/30/07 2:50 PM Page 170
Dantrolene
++ Ca +
Sarcoplasmic Ca
+
Reticulum Ca ++ ++
Ca
Contractile
Filaments
Chapter 8).2,58 In this situation, dantrolene inhibits Adverse effects. Use of diazepam as an antispas-
skeletal muscle contraction throughout the body, ticity agent is limited by the sedative effects of this
thereby limiting the rise in body temperature generat- medication; that is, patients with spasticity who do not
ed by strong, repetitive skeletal muscle contractions.58 want a decrease in mental alertness will not tolerate
Dantrolene is not prescribed to treat muscle spasms diazepam therapy very well. Extended use of the drug
caused by musculoskeletal injury. can cause tolerance and physical dependence, and use
Adverse Effects. The most common side effect of of diazepam for the long-term treatment of spasticity
dantrolene is generalized muscle weakness; this makes should be avoided whenever possible.102
sense considering that dantrolene impairs sarcoplas-
mic calcium release in skeletal muscles throughout the
body, not just in the hyperexcitable tissues. Thus, the
Gabapentin
use of dantrolene is sometimes counterproductive Developed originally as an antiseizure drug (see Chap-
because the increased motor function that occurs ter 9), gabapentin (Neurontin) has also shown some
when spasticity is reduced may be offset by general- promise in treating spasticity. This drug appears to
ized motor weakness. This drug may also cause severe cause inhibition in the spinal cord in a manner similar
hepatotoxicity, and cases of fatal hepatitis have been to GABA, but the exact mechanism of this drug
reported.20,102 The risk of toxic effects on the liver remains to be determined. That is, gabapentin does
seems to be greater in women over 40 years of age, not appear to bind to the same receptors as GABA,
and in individuals receiving higher doses of this drug and this drug does not appear to directly increase the
(over 300 mg).102 Other, less serious side effects that release or effects of endogenous GABA.82,83 Nonethe-
sometimes occur during the first few days of therapy less, gabapentin may decrease spasticity by raising the
include drowsiness, dizziness, nausea, and diarrhea, overall level of inhibition in the spinal cord, thereby
but these problems are usually transient. decreasing excitation of the alpha motor neuron with
subsequent skeletal muscle relaxation. The exact way
that this drug exerts its antispasticity effects, however,
Diazepam remains to be determined.
As indicated earlier, diazepam is effective in reducing Uses. Gabapentin is effective in decreasing the
spasticity as well as muscle spasms because this drug spasticity associated with spinal cord injury102 and
increases the inhibitory effects of GABA in the CNS. multiple sclerosis.29 Additional research should clarify
Uses. Diazepam is used in patients with spastici- how this drug can be used alone or with other agents
ty resulting from cord lesions and is sometimes effec- to provide optimal benefits in spasticity resulting from
tive in patients with cerebral palsy. various spinal, and possibly cerebral, injuries.
13Ciccone(p)-13 1/30/07 2:50 PM Page 171
Adverse effects. The primary side effects of this cardiovascular side effects, and clonidine is used pri-
drug are sedation, fatigue, dizziness, and ataxia. marily for treating hypertension (see Chapter 21).
Adverse Effects. The most common side effects
associated with tizanidine include sedation, dizziness,
Tizanidine and dry mouth.40 As indicated, however, tizanidine
Tizanidine (Zanaflex) is classified as an alpha-2 adren- tends to have a more favorable side effect profile than
ergic agonist, meaning that this drug binds selectively other alpha-2 agonists, and this drug produces less
to the alpha-2 receptors in the CNS and stimulates generalized weakness than oral baclofen or diazepam.
them. Alpha-2 receptors are found at various locations Tizanidine may therefore be a better alternative to
in the brain and spinal cord, including the presynaptic these other agents in patients who need to reduce spa-
and postsynaptic membranes of spinal interneurons sticity while maintaining adequate muscle strength for
that control alpha motor neuron excitability. Stimula- ambulation, transfers, and so forth.
tion of these alpha-2 receptors inhibits the firing of
interneurons that relay information to the alpha
motor neuron; that is, interneurons that comprise Use of Botulinum Toxin
polysynaptic reflex arcs within the spinal cord.27
Tizanidine appears to bind to receptors on spinal
as a Muscle Relaxant
interneurons, decrease the release of excitatory neuro- Injection of botulinum toxin is a rather innovative
transmitters from their presynaptic terminals (presy- way to control localized muscle hyperexcitability. Bot-
naptic inhibition), and decrease the excitability of the ulinum toxin is a purified version of the toxin that
postsynaptic neuron (postsynaptic inhibition).40 Inhi- causes botulism. Systemic doses of this toxin can be
bition of spinal interneurons results in decreased exci- extremely dangerous or fatal because botulinum toxin
tatory input onto the alpha motor neuron, with a inhibits the release of acetylcholine from presynaptic
subsequent decrease in spasticity of the skeletal mus- terminals at the skeletal neuromuscular junction. Loss
cle supplied by that neuron. of presynaptic acetylcholine release results in paralysis
Uses. Tizanidine has been used primarily to con- of the muscle fiber supplied by that terminal. Systemic
trol spasticity resulting from spinal lesions (multiple dissemination of botulinum toxin can therefore cause
sclerosis, spinal cord injury),40 and this drug may also widespread paralysis, including loss of respiratory
be effective in treating spasticity in people with cere- muscle function. Injection into specific muscles, how-
bral lesions (CVA, acquired brain injury).41,62 There is ever, can sequester the toxin within these muscles,
some concern, however, that tizanidine might slow thus producing localized effects that are beneficial in
neuronal recovery following brain injury, and some certain forms of muscle hyperexcitability.
practitioners are therefore reluctant to use this drug Mechanism of action. The cellular actions of bot-
during the acute phase of stroke or traumatic brain ulinum toxin at the neuromuscular junction have
injury.102 Because it may inhibit pain pathways in the recently been clarified.84 This toxin is attracted to gly-
spinal cord, tizanidine has also been used to treat coproteins located on the surface of the presynaptic
chronic headaches and other types of chronic pain terminal at the skeletal neuromuscular junction.33
(fibromyalgia, chronic regional pain syndromes, and Once attached to the membrane, the toxin enters the
so forth).77 presynaptic terminal and inhibits proteins that are
As an antispasticity drug, tizanidine appears to be needed for acetylcholine release (Figure 13–4).84 Nor-
as effective as orally administered baclofen or mally, certain proteins help fuse presynaptic vesicles
diazepam, but tizanidine generally has milder side with the inner surface of the presynaptic terminal,
effects and produces less generalized muscle weakness thereby allowing the vesicles to release acetylcholine
than these other agents.40 Tizanidine is also superior via exocytosis. Botulinum toxin cleaves and destroys
to other alpha-2 agonists such as clonidine (Catapres) these fusion proteins, thus making it impossible for
because tizanidine does not cause as much hypoten- the neuron to release acetylcholine into the synap-
sion and other cardiovascular side effects. Clonidine tic cleft.32,84 Local injection of botulinum toxin into
exerts antispasticity as well as antihypertensive effects specific muscles will therefore decrease muscle excita-
because this drug stimulates alpha-2 receptors in the tion by disrupting synaptic transmission at the neuro-
cord and brainstem, respectively.102 Use of clonidine in muscular junction. The affected muscle will invariably
treating spasticity, however, is limited because of the undergo some degree of paresis and subsequent
13Ciccone(p)-13 1/30/07 2:50 PM Page 172
Normal
(no toxin) Botulinum toxin
ACh vesicles
BT
X
Fusion BT
X X
proteins BT
relaxation because the toxin prevents the release of but only two types are currently available for clinical
acetylcholine. use: botulinum toxin types A and B.15,23 These types
It has been suggested that botulinum toxin might differ somewhat in their chemistry, duration of action,
have other effects on neuronal excitability. This toxin, and so forth. The most commonly used therapeutic
for example, might also inhibit contraction of intra- type is botulinum toxin type A; this agent is mar-
fusal muscle fibers that are located within skeletal keted commercially under trade names such as Botox
muscle, and help control sensitivity of the stretch and Dysport. Botulinum toxin type B (Myobloc) is
reflex.33 Inhibiting these intrafusal fibers would also available, and can be useful in patients who devel-
diminish activity in the afferent limb of the stretch op immunity to the type A form of this toxin (dis-
reflex, thereby contributing to the antispasticity cussed later).
effects of this intervention.33 Botulinum toxin has been used for some time to
Through its direct action on muscle excitability, control localized muscle dystonias, including condi-
botulinum toxin may also have other neurophysiolog- tions such as spasmodic torticollis, blepharospasm,
ical effects at the spinal cord level. That is, reducing laryngeal dystonia, strabismus, and several other types
spasticity might result in complex neurophysiologic of focal dystonias.6,25,26,87,93 When used therapeutical-
changes at the spinal cord, ultimately resulting in ly, small amounts of this toxin are injected directly into
more normal control of motor function in both the the dystonic muscles, which begin to relax within a
injected muscle and its antagonist.45 In other words, few days to 1 week. This technique appears to be fair-
reduction of excessive afferent discharge from the ly safe and effective in many patients, but relief may
spastic muscle might help reestablish a more reason- only be temporary. Symptoms often return within
able level of excitation at the cord level, thus improv- 3 months after each injection, necessitating additional
ing efferent discharge to the injected muscle and its treatments.40 Still, this technique represents a method
antagonist.33,45 More research will be needed to help for treating patients with severe, incapacitating condi-
clarify how local administration of botulinum toxin tions marked by focal dystonias and spasms.
can have direct effects on the injected muscle as well More recently, there has been considerable inter-
as reflex neurophysiological effects on the spinal cord. est in using botulinum toxin to reduce spasticity in
Clinical use of botulinum toxin. Seven strains specific muscles or muscle groups. This treatment has
(serotypes) of botulinum toxin have been identified, been used to treat spasticity resulting from various dis-
13Ciccone(p)-13 1/30/07 2:50 PM Page 173
orders including cerebral palsy,10,68,78,99 traumatic patients undergoing physical rehabilitation may also
brain injury,36,66,98 CVA,19,44,49 and spinal cord injury.39 benefit from uses of this toxin. For example, patients
As with treatment of focal dystonias, the toxin is with hyperactive (neurogenic) bladder following
injected directly into selected muscles. If necessary, spinal cord injury can be treated by injecting botu-
electromyography or ultrasonography can be used to linum toxin directly into the bladder detrussor muscle
identify specific muscles and guide the injection to the or external urethral sphincter.28,59 This intervention
desired site within the muscle belly (e.g., the motor may help normalize bladder function and promote
point of the muscle).18,53,100 There is also some evi- more effective voiding.28,47 Botulinum toxin has also
dence that electrical stimulation of the nerve supply- been used to treat patients with chronic pain syn-
ing the muscle for the first few days following dromes, including chronic headache, migraine, and
injection may help increase the efficacy of the toxin, various musculoskeletal disorders (back pain, whiplash
presumably by enhancing its uptake by the presynap- injuries, and so forth).24,88 Clearly, this intervention
tic nerve terminals.38 has many potential benefits in many different clinical
Botulinum toxin injection has been documented situations, and additional research will be needed to
as a means to control severe spasticity in various clin- document how botulinum toxin can be used to reduce
ical situations. This intervention, for example, can muscle hyperexcitability and improve function in var-
help remove spastic dominance in certain patients so ious patient populations.
that volitional motor function can be facilitated. For Limitations and side effects. Botulinum toxin does
example, judicious administration of botulinum toxin not cure spasticity and there are a number of limita-
can result in improved gait and other functional activ- tions to its use. In particular, only a limited number of
ities in selected patients with cerebral palsy, stroke, or muscles can be injected during a given treat-
traumatic brain injury.7,36,49,78 Even if voluntary motor ment because only a limited amount of botulinum
function is not improved dramatically, reducing spas- toxin can be administered during each set of injections.
ticity in severely affected muscles may produce other For example, the total amount of botulinum toxin
musculoskeletal benefits. For example, injection of type A injected during each treatment session is typi-
botulinum toxin can reduce spasticity so that muscles cally between 200–300 units in adults, with propor-
can be stretched or casted more effectively, thus help- tionally smaller amounts used in children depending
ing to prevent joint contractures and decreasing the on his or her size and age.40 The typical dose of the
need for surgical procedures such as heel-cord length- type B form is 2500–5000 units. Exceeding these doses
ening and adductor release.12,98 will cause an immune response whereby antibodies
These injections can likewise enable patients to are synthesized against the toxin, making subsequent
wear and use orthotic devices more effectively. Injec- treatments ineffective because the patient’s immune
tion into the triceps surae musculature can improve the system will recognize and inactivate the toxin.34,35,91
fit and function of an ankle-foot orthosis by preventing The number of muscles that can be injected is there-
excessive plantar flexor spasticity from “pistoning” the fore often limited to one or two muscle groups; for
foot out of the orthosis.49 Injections into severely spas- example, the elbow and wrist flexors in one upper
tic muscles can also increase patient comfort and abil- extremity of an adult, or the bilateral triceps surae
ity to perform ADL and hygiene activities. Consider, musculature of a child.
for example, the patient with severe upper extremity As indicated earlier, the relaxant effects of the
flexor spasticity following a CVA. Local injection of toxin are likewise temporary, and these effects typical-
botulinum toxin into the affected muscles may enable ly diminish within 2 to 3 months after injection.91 The
the patient to extend his or her elbow, wrist, and fin- effects apparently wear off because a new presynaptic
gers, thereby allowing better hand cleansing, ability to terminal “sprouts” from the axon that contains the
dress, decreased pain, and so forth.7 originally affected presynaptic terminal. This new ter-
Finally, local botulinum toxin administration has minal grows downward, reattaching to the skeletal
been advocated as a way to control muscle hyperex- muscle and creating a new motor end plate with a new
citability in other clinical situations. There has, of source of acetylcholine. The effects of the previous
course, been considerable interest in using this toxin injection are overcome when this new presynaptic ter-
for cosmetic reasons. Injection of botulinum toxin into minal begins to function. Another injection will be
specific facial muscles can paralyze these muscles, needed to block the release from this new presynaptic
thereby reducing the appearance of wrinkles around terminal, thus allowing another 2 to 3 months of anti-
the eyes, mouth, and so forth.3,24 Nonetheless, spasticity effects. This fact raises the question of how
13Ciccone(p)-13 1/30/07 2:50 PM Page 174
such as ambulation. For example, patients who have had a CVA and use extensor spasticity in
the lower extremity to support themselves when walking may begin to fall if this spasticity is
reduced suddenly by drugs. This loss of support from the hypertonic muscles will hopefully be
replaced by a more normal form of motor function.
Therapists can therefore play a vital role in facilitating the substitution of normal physio-
logic motor control for the previously used spastic tone. This idea seems especially true when
one of the parenteral antispasticity techniques is used, such as intrathecal baclofen or botulinum
toxin injections. For example, patients who receive intrathecal baclofen through programmable
pump systems often require a period of intensive rehabilitation to enable the benefits from
decreased spasticity and increased voluntary motor function to occur. Therapists must therefore
be ready to use aggressive rehabilitation techniques to help patients adapt to the relatively rapid
and dramatic decrease in muscle tone that is often associated with antispasticity drug therapy.
Rehabilitation specialists can also play a critical role in using certain antispasticity drugs
effectively. In particular, therapists can help identify patients who are suitable candidates for
botulinum toxin injections, and help evaluate these patients pre-injection and postinjection to
determine if they achieved the desired outcomes. Rehabilitation specialists are, in fact, often in
the best position to evaluate the effects of all antispasticity drugs. By working closely with the
patient, the patient’s family, and the physician, therapists can provide valuable feedback about
the efficacy of antispasticity drugs and whether they are helping to produce improvements in
the patient’s function and well-being.
Finally, therapists may have to deal with the side effects of these drugs. Depending on the
drug in question, problems with sedation, generalized muscle weakness, and hepatotoxicity can
negate any beneficial effects from a reduction in muscle tone. Sedation, which may occur to a
variable degree with all systemic skeletal muscle relaxants, must sometimes be accommodated
in the rehabilitation program. If the patient needs to be awake and alert, treatments may have
to be scheduled at a time of the day when the sedative effects are minimal.
In situations of generalized muscle weakness (i.e., during the use of dantrolene sodium or
oral baclofen), there is often little that the physical therapist can do to resolve this problem. For
instance, the patient with paraplegia who requires adequate upper extremity strength to perform
transfers, wheelchair mobility, and ambulation with crutches and braces may find his or her abil-
ity to perform these activities compromised by the antispasticity drug. The role of the therapist
in this situation may simply be to advise the patient that voluntary muscular power is limited
and that some upper extremity strength deficits can be expected. The therapist may also work
closely with the physician in trying to find the minimum acceptable dose for that patient or in
attempting to find a better drug (e.g., switching from dantrolene to tizanidine).
CA S E ST U DY
Muscle Relaxants ue this progress and was eventually fitted with permanent leg
orthoses. During this period, spasticity had increased in his
Brief History. F.D. is a 28-year-old man who sustained lower extremities to the point where dressing and self-care
complete paraplegia below the L-2 spinal level during an auto- were often difficult. Also, the ability of the patient to put his leg
mobile accident. Through the course of rehabilitation he was braces on was often compromised by lower extremity spastic-
becoming independent in self-care, and he had begun to ity. The patient was started on oral baclofen (Lioresal) at an ini-
ambulate in the parallel bars and with crutches while wearing tial oral dosage of 15 mg/day. The daily dosage of baclofen
temporary long leg braces. He was highly motivated to contin- was gradually increased until he was receiving 60 mg/day.
13Ciccone(p)-13 1/30/07 2:50 PM Page 176
Problem/Influence of Medication. Although the Decision/Solution. The therapist conferred with the
baclofen was effective in controlling his spasticity, F.D. began patient’s physician, and the decreased voluntary muscle
to notice weakness in his arms and upper torso when he power was noted. As an alternative, the patient was switched
attempted to ambulate and transfer. This decrease in voluntary to tizanidine (Zanaflex). The dosage was adjusted until the
power in his upper extremities was caused by the generalized spasticity was adequately reduced, and no further problems
muscle weakness sometimes seen when this drug is used. were noted.
type A for upper-limb spasticity in patients after a baclofen therapy: a preliminary study. Arch Phys Med
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alcohol withdrawal syndrome and alcohol craving in 41. Gelber DA, Good DC, Dromerick A, et al. Open-label
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SECTION
Drugs Used to
Treat Pain and
Inf lammation
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Chapter 14
Opioid Analgesics
Analgesic drug therapy and certain rehabilitation In the past, the term “narcotic” was often applied
interventions share a common goal: pain relief. Con- to these compounds because—when taken—they tend
sequently, analgesics are among the drugs most to have sedative or sleep-inducing side effects and
frequently taken by patients who are treated in a reha- high doses can produce a state of unresponsiveness
bilitation setting. The vast array of drugs that are used and stupor. Narcotic is a misleading name, however,
to treat pain can be roughly divided into two cate- because it describes a side effect rather than their
gories: opioid and nonopioid analgesics. Nonopioid principal therapeutic effect.
analgesics are composed of drugs such as acetamino- Likewise, these drugs are frequently referred to as
phen, aspirin, and similar agents. These drugs are dis- “opiate” analgesics because some of these compounds
cussed in Chapter 15. are derived from opium (see the next section, “Source
Opioid analgesics are a group of naturally occur- of Opioid Analgesics”). More recently, the term “opi-
ring, semisynthetic, and synthetic agents that are char- oid” has also been instituted to represent all types of
acterized by their ability to relieve moderate-to-severe narcotic analgesiclike agents, regardless of their ori-
pain. These drugs exert their effects by binding to gin.27 Hence, most sources preferentially use the term
specific neuronal receptors that are located primarily “opioid” to describe these drugs, and clinicians should
in the central nervous system (CNS). Opioid anal- recognize that this term represents all of the mor-
gesics are also characterized by their potential ability phinelike medications.
to produce physical dependence, and these agents
are classified as controlled substances in the United
States because of their potential for abuse (see Chap- Source of Opioid Analgesics
ter 1 for a description of controlled substance classifi-
As mentioned previously, opioid analgesics can be
cation). Morphine (Fig. 14–1) is considered the
obtained from natural, synthetic, or semisynthetic
prototypical opioid analgesic, and other drugs of this
sources. Synthetic agents, as the designation implies,
type are often compared to morphine in terms of effi-
are simply formulated from basic chemical compo-
cacy and potency.44,65
nents in the laboratory. The source of naturally occur-
ring and semisynthetic narcotic analgesics is from the
opium poppy.27,65 When the extract from the seeds of
CH3N
this flower is allowed to dry and harden, the resulting
substance is opium. Opium contains about 20 biologi-
cally active compounds, including morphine and
codeine. Other derivatives from opium can also direct-
ly produce analgesia in varying degrees or can serve as
O precursors for analgesic drugs. The most notable of
HO OH these precursors is thebaine, which can be modified
chemically to yield compounds such as heroin. Like-
Morphine
wise, semisynthetic narcotic analgesics are derived
FIGURE 14–1 ▼ Structure of morphine. from these precursors. Semisynthetic opioids can also
183
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be formulated by modifying one of the other naturally exogenous drugs influence the function of the endoge-
occurring narcotic drugs, such as morphine. nous peptides, and vice versa.25,63
In addition to analgesic drugs and their precur-
sors, opium also contains compounds that do not have
Opioid Receptors
any analgesic properties. These compounds can actu-
ally antagonize the analgesic effects of opioid agonists Since their discovery, the opioid receptors have been
such as morphine. (As defined in Chapter 4, an agonist examined in considerable detail. Studies in animals
stimulates its respective receptor and exerts a physio- have suggested that rather than only one homoge-
logic response, whereas an antagonist blocks the recep- neous opioid receptor, there are at least three primary
tor, thus preventing the response.) The role of these classes known as mu, kappa, and delta receptors69,82
opioid antagonists is discussed in “Classification of (Table 14–1). Some sources also divide these primary
Specific Agents,” later in this chapter. classes into subcategories (i.e., mu1, mu2, delta1, delta2,
kappa1, kappa2, kappa3) based on how well various opi-
oids affect these receptors.65 The significance of these
subcategories, however, has been questioned some-
Endogenous Opioid what based on studies using opioid receptors that were
Peptides and Opioid Receptors cloned from rodent cell lines.27 That is, it is not clear
at the present time if the primary classes (mu, kappa,
Endogenous Opioids delta) can be subclassified based on structural or func-
Neurons at specific locations within the brain and tional differences within each primary receptor class.27
spinal cord have been identified as having receptors Nonetheless, mu opioid receptors are somewhat dis-
that serve as binding sites for morphine and other sim- tinct from kappa receptors, and kappa receptors are
ilar exogenous substances.27 Exogenous opioids exert distinct from delta receptors, and so forth. Hence,
their effects by binding to these receptors; the pro- some specialization regarding both the location and
posed mechanisms of these drug-receptor interactions the response of specific primary classes of opioid
are discussed later in “Mechanism of Action.” The dis- receptors does appear to exist (see Table 14–1).
covery of these opioid receptors also suggested the Stimulation of all three classes of opioid receptors
existence of an endogenous opioidlike substance. causes analgesia. The mu receptor, however, seems to
Rather than isolating one such compound, the search be the most important in mediating the analgesic
for an “endogenous morphine” has actually revealed effects of many opioids, including morphine.30,33 Mu
several groups of peptides with analgesic and other receptors are located in specific locations in the brain
pharmacologic properties. It is now recognized that and spinal cord, and opioids that are used clinically to
three distinct families of endogenous opioids exist: the reduce pain typically have a fairly high affinity for the
endorphins, enkephalins, and dynorphins.27,72 These mu class of opioid receptors.27 Unfortunately, some of
peptides are manufactured and released within the the more problematic side effects of opioid drugs may
body to control pain under specific conditions.29,65,81 also be mediated by stimulation of mu receptors. For
Endogenous opioids are also released during other example, stimulation of mu receptors may also cause
stressful situations, and these endogenous peptides respiratory depression and constipation, and repeated
interact with other neurochemicals (e.g., melatonin) stimulation of mu opioid receptors has been associat-
and the immune system to help individuals deal ed with the cellular changes that might lead to opioid
with various types of physical and psychological abuse and addiction.15,27
stress.23,66,67,85 The existence of several classes of opioid recep-
This chapter is not intended to elucidate all of the tors has therefore lead to the development of drugs
known details of the endogenous opioid peptide sys- that are somewhat more selective in the receptor class
tem or to illustrate how these endogenous compounds or subclass that they stimulate. In particular, drugs
can be influenced by opioid drugs. The endogenous that selectively stimulate kappa or delta receptors may
compounds described do exert their effects, however, still provide sufficient analgesia, but will be less likely
via the same receptors as the exogenous opioid drugs. to provoke problems like respiratory depression and
Obviously, there is the possibility for a great deal of opioid abuse if they avoid or even block (antagonize)
interaction between the endogenous and exogenous the mu receptors. Certain opioid drugs, for example,
opioids, and researchers continue to investigate how stimulate kappa receptors while avoiding or blocking
14Ciccone(p)-14 1/30/07 2:32 PM Page 185
Kappa () Spinal and supraspinal analgesia Sedation; constipation; psychotic effects
Delta (␦) Spinal and supraspinal analgesia Increases hormonal release (growth hormone); inhibits
neurotransmitter release (dopamine)
Mild-to-Moderate Agonists
Codeine (generic) Oral 30–45 60–120 4
IM 10–30 30–60 4
Sub-Q 10–30 — 4
antagonists, however, may produce more psychotropic tion. Other antagonists (e.g., naltrexone) are used in
effects (e.g., hallucinations, vivid dreams), and their conjunction with behavioral therapy to maintain an
maximal analgesic effect may not be as great as strong opioid-free state in individuals recovering from opioid
mu agonists.65 Consequently, these drugs are not used addiction. Hence, the primary agents used clinically as
extensively, but they do offer an alternative to strong- opioid antagonists are the following:
to-moderate opioid agonists in certain patients.
A new addition to this category is buprenorphine • nalmefene (Revex)
(Buprenex). This drug partially activates mu receptors • naloxone (Narcan)
but is an antagonist at kappa receptors. Because of • naltrexone (ReVia)
these selective effects, buprenorphine has been advo-
cated not only as an analgesic, but also as a treatment
for opioid dependence and withdrawal.26,84 The use of
Pharmacokinetics
this drug in treating opioid addiction is discussed in Some opioid analgesics can be given orally, a preferred
more detail later in this chapter. route of administration in terms of convenience and
Examples of mixed agonist–antagonists include safety. Several of these enteral drugs also come in sup-
the following: pository form, permitting rectal administration if nau-
sea and vomiting prohibit the oral route. Some
• butorphanol (Stadol)
opioids—including morphine—are now available in
• buprenorphine (Buprenex)
sustained-release enteral preparations, thus allowing
• nalbuphine (Nubain)
more prolonged effects and wider intervals between
• pentazocine (Talwin)
doses.6,12,50 Because of poor intestinal absorption or
Antagonists. These drugs block all opioid recep- significant first-pass inactivation, other agents must be
tors, with a particular affinity for the mu variety. administered parenterally, usually through subcuta-
Because of their antagonistic properties, these agents neous or intramuscular injection. Intravenous adminis-
will not produce analgesia but will displace opioid ago- tration is also used sometimes, but must be done slowly
nists from the opioid receptors and block any further and with caution. When the intravenous route is used,
effects of the agonist molecules. Consequently, these the narcotic is frequently diluted and infusion pumps
drugs are used primarily to treat opioid overdoses and are used to allow the slow, controlled administration of
addiction. Certain opioid antagonists (e.g., nalmefene, the drug. The intravenous route or other parenteral
naloxone) can rapidly (within 1 to 2 minutes) and dra- routes (epidural and intrathecal infusion) can also be
matically reverse the respiratory depression that is used to administer opioids during patient-controlled
usually the cause of death in excessive opioid inges- analgesia; this concept is addressed in Chapter 17.
14Ciccone(p)-14 1/30/07 2:32 PM Page 188
The feasibility of using other relatively new These areas include the periaqueductal gray region of
methods for administering opioids has also been the spinoreticular tract, medial thalamic nuclei, hypo-
investigated. For instance, transdermal patches have thalamus, limbic system, and several other areas.33,65,75
been developed to administer morphine, and other It is well accepted that opioids exert analgesic
opioids such as fentanyl (Duragesic Patch), a potent effects by inhibiting afferent pain transmission in
and fast-acting opioid.12,68 The patch provides a con- ascending pain pathways. By acting at the key CNS
venient method for the steady, prolonged administra- sites listed above, opioids can inhibit painful impulses
tion of these opioids into the systemic circulation. from being sent from the periphery to the brain. It is
Transdermal opioid patches also avoid the direct also believed that opioids exert some of their analgesic
administration of the drug to the gastrointestinal (GI) effects by activating descending pain pathways.27,33 That
tract, and this fact may help reduce GI problems such is, opioids can also affect efferent CNS pathways orig-
as nausea and constipation.39 inating in higher centers (rostral medulla, locus
Iontophoresis techniques (i.e., the use of electric ceruleus, midbrain periaqueductal gray area), and
current to facilitate transdermal delivery) have also enhance the ability of these descending pathways to
been advocated as a way to enhance transdermal opi- reduce painful sensations at the spinal cord level.65
oid delivery to the systemic circulation.11 By varying This effect probably occurs because opioids inhibit
the amount of electric current, iontophoresis may ulti- interneurons that normally inhibit the ability of these
mately allow the patient to control the rate of trans- descending pathways to moderate pain. This effect,
dermal administration of the opioid.10,76,78 Finally, known as disinhibition, ultimately activates the descend-
certain opioids such as fentanyl can be administered ing pathways by removing the inhibitory effect of these
systemically via lozenges or a “lollipop” that dissolves interneurons.33 By removing this inhibition, opioids
in the mouth (transmucosal delivery), or via nasal allow these descending pathways to become more
spray (intranasal administration).21,54 It will be inter- active and help control painful sensations. Hence, opi-
esting to see if these newer methods of administration oids seem to exert analgesic effects through their abil-
will gain widespread acceptance in the future. ity to decrease ascending (afferent) pain transmission,
Because of differing degrees of solubility, the dis- combined with their ability to activate descending
tribution and subsequent onset of action of specific (efferent) pathways that reduce pain.
agents varies (see Table 14–2). Opioids are ultimately
distributed throughout all tissues, and these agents
Effect of Opioids on CNS Synapses
probably exert their principal analgesic effects after
they reach the CNS. Some opioid effects may also be Opioids basically exert their analgesic effects by
mediated by peripheral receptors located at the site of inhibiting synaptic transmission in key pain pathways
painful inflammation (see “Mechanism of Action” in the spinal cord and brain. This inhibitory effect
below). Metabolic inactivation of these drugs takes is mediated by opioid receptors that are located on
place primarily in the liver, although some degree of both presynaptic and postsynaptic membranes of pain-
metabolism also occurs in other tissues such as the mediating synapses (Fig. 14–2). In the spinal cord, for
kidneys, lungs, and CNS. The kidneys excrete the example, receptors are located on the presynaptic ter-
drug metabolite and—to a lesser extent—the intact minals of primary (first-order) nociceptive afferents,
drug in the urine. and when bound by opioids, they directly decrease the
release of pain-mediating transmitters such as sub-
stance P.35,38 Opioid drug-receptor interactions also
Mechanism of Action take place on the postsynaptic membrane of the sec-
ondary afferent neuron—that is, the second-order no-
Effect of Opioids on the CNS ciceptive afferent neuron in the spinal cord.19,33 When
As discussed earlier, opioid receptors exist at specific stimulated, these receptors also inhibit pain transmis-
locations throughout the CNS and possibly in periph- sion by hyperpolarizing the postsynaptic neuron.19
eral nerve tissues as well. In the spinal cord, these Opioids therefore inhibit synaptic transmission by
receptors are concentrated on the neurons responsible decreasing neurotransmitter release from the presyn-
for transmitting nociceptive input to higher (supraspi- aptic terminal and by decreasing excitable (hyperpolar-
nal) levels.33 Opioid receptors have likewise been iden- izing) postsynaptic neurons within key pain pathways
tified in several locations of the brain that are in the spinal cord and brain. Again, these synaptic
associated with pain transmission and interpretation. effects can either limit the transmission of painful stim-
14Ciccone(p)-14 1/30/07 2:32 PM Page 189
Opioids
Pain-mediating
neurotransmitter
FIGURE 14–2 ▼ Schematic representation of how opioid analgesics may impair synaptic
transmission in pain-mediating pathways. The drug binds to specific opioid receptors on the
presynaptic and postsynaptic membranes.
uli in ascending pain pathways, or they can activate activation of the receptor leads to an opening of these
descending antinociceptive pathways by inhibiting in- channels and a loss of potassium from the postsynaptic
terneurons that control these pathways. These effects neuron.46 A relative loss of potassium from the postsy-
are mediated through opioid receptors that are located naptic neuron causes hyperpolarization because efflux
on the membrane of these neurons, but are linked to of potassium (a cation) results in a relative increase in
the internal chemistry on the presynaptic and postsy- the negative intracellular electric potential. The post-
naptic neurons through regulatory G proteins.1,65 synaptic neuron is therefore more difficult to excite
As described in Chapter 4, regulatory G proteins because the interior of the cell is more negative.
act as an intermediate link between receptor activation Finally, opioid receptors are linked via G proteins
and the intracellular effector mechanism that ultimate- to the adenyl cyclase enzyme, and stimulation of the
ly causes a change in cellular activity. In the case of receptor leads to inhibition of this enzyme and de-
opioid receptors, these G proteins interact with three creased synthesis of cyclic adenosine monophosphate
primary cellular effectors: calcium channels, potassium (cAMP). cAMP is an important second messenger that
channels, and the adenyl cyclase enzyme.27 At the regulates neurotransmitter release from the presynap-
presynaptic terminal, stimulation of opioid receptors tic terminal and may also regulate the firing threshold
activates G proteins that in turn inhibit the opening of of the postsynaptic neuron.27 Opioid-mediated inhibi-
calcium channels on the nerve membrane.65 Decreased tion of this second messenger therefore helps to ex-
calcium entry into the presynaptic terminal causes plain how these drugs alter pain transmission. Hence,
decreased neurotransmitter release because calcium opioid drugs exert their analgesic effects by interacting
influx mediates transmitter release at a chemical with receptors that are linked to several intracellular
synapse. At the postsynaptic neuron, opioid receptors effector mechanisms that ultimately lead to decreased
are linked via G proteins to potassium channels, and synaptic transmission in specific pain pathways.
14Ciccone(p)-14 1/30/07 2:32 PM Page 190
CELLULAR COMPONENTS
(monocytes, macrophages, lymphocytes) PARENTERAL SOURCE
(intraarticular injection)
Endogenous
Peptides
(endorphins,
enkephalins, Exogenous Opioids
dynorphins)
Afferent Transmission
PRIMARY SENSORY CNS
NERVE ENDING
Opioid Receptors
Decreased excitability:
decreased transmission
of nociceptive input
FIGURE 14–3 ▼ Putative mechanism of opioid action on peripheral nerve terminals. See text
for discussion.
14Ciccone(p)-14 1/30/07 2:32 PM Page 191
life offered to the patient with chronic pain clearly out- Consistent with these hypotheses is the finding that
weighs the potential risks of these drugs.28,51 continuous infusion of the opioid into the epidural or
Opioid analgesics often produce a rather unique intrathecal space provides optimal pain relief postoper-
form of analgesia as compared to the nonopioid agents. atively or in chronic, intractable pain.2,40,83 Continuous
Opioids often alter the perception of pain rather than infusion is associated with certain side effects, especial-
eliminating the painful sensation entirely. The patient ly nausea and constipation, as well as the potential for
may still be aware of the pain but it is no longer the pri- disruption of the drug delivery system.24,57,77 Problems
mary focus of his or her attention. In a sense, the with tolerance have also been reported during contin-
patient is no longer preoccupied by the pain. This type uous administration,27 but it is somewhat controversial
of analgesia is also often associated with euphoria and whether tolerance really develops when these drugs are
a sensation of floating. These sensations may be caused used appropriately in the clinical management of pain
by the stimulation of specific types of opiate receptors (see section on “Concepts of Addiction, Tolerance, and
within the limbic system (i.e., delta receptors). Physical Dependence”). Hence, the benefit-to-risk
The route of opioid administration appears to ratio for continuous epidural or intrathecal infusion is
be important in providing effective pain relief.2,7 often acceptable in patients with severe pain. This
Although the oral route is the easiest and most con- method of opioid administration continues to gain
venient, parenteral routes may be more effective in acceptance.24,57
chronic or severe, intractable pain. In particular,
administration directly into the epidural or intrathecal
space has been suggested as being optimal in relieving Use of Opioids in Patient-
pain following certain types of surgery, or in various Controlled Analgesia
types of acute or chronic pain.7,13,24,31,57,71 Since it is
Finally, some rather innovative techniques have been
impractical to reinsert a needle every time the drug is
employed whereby the patient is able to control the
needed, indwelling catheters are often implanted sur-
delivery of the analgesic.5,20,60 These techniques
gically so that the tip of the catheter lies in the epidur-
are collectively known as patient-controlled analgesia
al or intrathecal space. The free end of the catheter
(PCA) because the patient is able to periodically
can be brought out through the patient’s skin and used
administer a specific dose of the drug (by pushing a
to administer the opioid directly into the area sur-
button or some other device). PCA systems have some
rounding the spinal cord. Alternatively, the catheter
distinct advantages over conventional administration,
can be connected to some sort of a drug reservoir or
and PCAs are often used following various types of
pump that contains the opioid drug. Such devices can
surgery as well as in the treatment of certain types of
be located outside the patient’s body or implanted sur-
chronic pain.5,13,60 The use of opioids and other drugs
gically beneath the patient’s skin (e.g., in the abdomi-
in PCA systems is discussed in Chapter 17.
nal wall), and these pumps are programmed to deliver
the drug at a fixed rate into the indwelling catheter.2
Although these programmable drug delivery systems
Other Opioid Uses
do have some risks, they appear to be an effective way
of treating patients with severe, chronic pain from Opioids have several other clinical applications. These
malignant and nonmalignant sources.24 agents can be used as an anesthetic premedication or
The effectiveness of opioid analgesics also appears as an adjunct in general anesthesia. Opioids are effec-
to be influenced by the dosing schedule. The current tive in cough suppression, and the short-term use of
consensus is that orally administered opioids are more codeine and codeinelike agents in this regard is quite
effective when given at regularly scheduled intervals common. Opioid agonists decrease gastrointesti-
rather than when the patient feels the need for the nal motility and can be used to control cases of severe
drug.55,58 This may be because with regularly sched- diarrhea. This effect is probably mediated indirectly
uled dosages, plasma concentrations may be main- through an effect on the CNS, as well as through a
tained within a therapeutic range, rather than allowing direct effect on the intestine. Finally, opioid agonists
the large plasma fluctuations that may occur if the are used as an adjunct in cases of acute pulmonary
drugs are given at sporadic intervals. On the other edema. These drugs probably do not directly improve
hand, it may simply be easier to control pain in its ear- ventilatory capacity, but they do serve to reduce feel-
lier stages before the pain can reach full intensity.58 ings of intense panic and anxiety associated with the
14Ciccone(p)-14 1/30/07 2:32 PM Page 192
dyspnea inherent to this disorder. Patients feel they can This concept of addiction is often separated from the
breathe more easily following opioid administration. physiologic changes that can accompany prolonged
opioid use, namely tolerance and physical dependence.
Tolerance is the need for more of a drug to
Problems and Adverse Effects achieve a given effect, and physical dependence is the
Opioid analgesics produce a number of central and onset of withdrawal symptoms if a drug is suddenly dis-
peripheral side effects.32,48 Virtually all of these drugs continued. Tolerance and physical dependence are also
have sedative properties and induce some degree of rather complex phenomena, and a complete discussion
mental slowing and drowsiness. Patients taking opi- of the factors involved in producing these occurrences
oids for the relief of pain may also become somewhat is not possible at this time. The primary characteristics
euphoric, although the manner and degree of such of tolerance and physical dependence will be briefly
mood changes varies from individual to individual. discussed here as they relate to opioid usage.
One of the more potentially serious side effects is the
respiratory depression often seen after narcotic admin- Tolerance
istration.56 Within a few minutes after administration,
these drugs cause the breathing rate to slow down, Tolerance is defined as the need to progressively
which can last for several hours. Although not usually increase the dosage of a drug to achieve a therapeutic
a major problem when therapeutic doses are given to effect when the drug is used for prolonged periods.53
relatively healthy individuals, respiratory depression When used for the treatment of pain in some patients,
can be severe or even fatal in seriously ill patients, in the dosage of the opioid may need to be increased peri-
patients with pre-existing pulmonary problems, or in odically to continue to provide adequate relief. The
cases of overdose. Some cardiovascular problems such physiologic reasons for tolerance are complex and pro-
as orthostatic hypotension may also occur immediate- bably involve changes in the intracellular response to
ly after opioids are administered, especially when par- repeated stimulation of opioid receptors. Prolonged
enteral routes are used. exposure to opioids can also cause a decrease in the
Finally, gastrointestinal distress in the form of number and sensitivity of the opioid receptors—a phe-
nausea and vomiting is quite common with many of nomenon known as receptor downregulation and
the narcotic analgesics. Because of their antiperistaltic desensitization (see Chapter 4).14,43,80 However, these
action, these drugs can also cause constipation.48 changes in the quantity and sensitivity of opioid recep-
Because this constipating effect can be quite severe, tors do not seem to be the primary reasons for opioid
laxatives and stool softeners (see Chapter 27) can be tolerance.62 It seems more likely that tolerance is
used to prevent opioid-induced constipation in certain caused by changes in the intracellular effectors that are
people, such as with patients who are at risk for fecal coupled to the opioid receptor, namely the G proteins
impaction (e.g., people with spinal cord injuries), or and intracellular effector mechanisms.22,73 As described
with people who are taking opioids for an extended earlier, opioid receptors mediate their effects through
period of time (e.g., patients receiving opioids for regulatory G proteins that are linked to intracellular
treatment of cancer-related pain).36,70 effectors, including the adenyl cyclase enzyme. Toler-
ance to opioid drugs, therefore, seems to be caused
by long-term changes in G protein function and adenyl
Concepts of Addiction, cyclase-induced synthesis of second messengers like
Tolerance, and Physical cAMP.42,79 In a sense, tolerance occurs because the
internal biochemistry of the cell has been blunted
Dependence by repeated stimulation of the G protein-effector
When used inappropriately, opioid drugs can produce mechanisms.
addiction. The term addiction typically refers to situa- The physiologic changes that cause opioid toler-
tions in which an individual repeatedly seeks out and ance typically follow a predictable time course. Toler-
ingests certain substances for mood-altering and pleas- ance begins after the first dose of the narcotic, but the
urable experiences, such as the heroin addict who takes need for increased amounts of the drug usually be-
the drug illicitly to achieve an opioid “high.” In this comes obvious after 2 to 3 weeks of administration.
sense, addiction is a very complex phenomenon that Tolerance seems to last approximately 1 to 2 weeks
has strong psychologic implications regarding why after the drug is removed. This does not mean that the
certain chemicals cause this behavior in certain people. patient no longer has any desire for the drug, but that
14Ciccone(p)-14 1/30/07 2:32 PM Page 193
the patient will again respond to the initial dosage after longed periods, there is some debate as to whether
14 days or so. Other factors may influence the individ- these phenomena must always accompany the thera-
ual’s desire for the drug long after any physiologic peutic use of opioid drugs for the treatment of chron-
effects have disappeared (see “Physical Dependence”). ic pain. There is growing evidence that the risk of
tolerance and dependence is actually very low when
Physical Dependence opioid drugs are used appropriately to treat chronic
pain.8,18 For example, there appear to be relatively few
Physical dependence is usually defined as the onset of problems with long-term opioid use when these drugs
withdrawal symptoms when the drug is abruptly are administered to treat pain in patients who do not
removed. Withdrawal syndrome from opioid de- have a history of substance abuse, who adhere to the
pendence is associated with a number of obvious and prescribed opioid regimen, and who have pain from
unpleasant symptoms (Table 14–3). In severe depend- physiological rather than psychological causes.18,52
ence, withdrawal symptoms become evident within Some experts also feel that tolerance and physical
6 to 10 hours after the last dose of the drug, and symp- dependence will not occur if the dosage is carefully
toms reach their peak in the second or third day after adjusted to meet the patient’s needs.4,8 It is believed
the drug has been stopped. Withdrawal symptoms last that when the opioid dose exactly matches the
approximately 5 days. This does not necessarily mean patient’s need for pain control, there is no excess drug
that the individual no longer desires the drug, only to stimulate the drug-seeking behavior commonly
that the physical symptoms of withdrawal have ceased. associated with opioid addiction. The opioid is essen-
Indeed, an addict may continue to crave the drug after tially absorbed by the patient’s pain. Of course,
months or years of abstinence. patients with chronic pain may still need to have the
Physical dependence must therefore be differen- dosage increased periodically. This observation would
tiated from the more intangible concepts of addiction be explained by the fact that the pain has increased
and psychologic dependence. Psychologic dependence because the patient’s condition has worsened (e.g.,
seems to be related to pleasurable changes in mood the cancer has increased) rather than the idea that
and behavior evoked by the drug. The individual is the patient developed pharmacologic tolerance to the
motivated to continually reproduce these pleasurable drug.28,51 Thus, many practitioners feel that problems
sensations because of the feelings of well-being, relax- with addiction, tolerance, and dependence are mini-
ation, and so on. Psychologic dependence seems to mized when opioid drugs are used therapeutically.
create the drug-seeking behavior that causes the These agents are essentially being used for a specific
addict to relapse into use of the drug long after the reason—the treatment of pain—rather than for the
physiologic effects have disappeared. pleasure-seeking purpose associated with the recre-
ational use of these drugs. These drugs must, of
Tolerance and Dependence course, be used carefully and with strict regard to
During Therapeutic Opioid Use using the lowest effective dose. Hence, there is con-
sensus that opioids are very effective and important
Although tolerance and dependence can occur when-
analgesic agents and should be used under appropriate
ever opioid drugs are used indiscriminately for pro-
therapeutic conditions without excessive fear of the
patient developing addiction or becoming especially
tolerant to the drug’s effects.4,18
Table 14–3 ABSTINENCE SYNDROMES:
SYMPTOMS OF NARCOTIC
WITHDRAWAL Pharmacological Treatment
of Opioid Addiction
Body aches Runny nose
Diarrhea Shivering The inappropriate or illegal use and abuse of narcotics
Fever Sneezing such as heroin is a major problem in many countries.
Gooseflesh Stomach cramps Hence, various strategies have been employed to treat
Insomnia Sweating people who are addicted to heroin and other opioids.
Irritability Tachycardia Methadone is the primary pharmacological interven-
Loss of appetite Uncontrollable yawning tion used to treat opioid addiction. Methadone is a
Nausea/vomiting Weakness/fatigue strong opioid agonist, similar in potency and efficacy
to morphine. While giving an opioid to treat an opi-
14Ciccone(p)-14 1/30/07 2:32 PM Page 194
oid addiction may at first appear odd, methadone addiction.26,84 As indicated earlier, buprenorphine is a
offers several advantages, such as milder withdrawal mixed agonist-antagonist that partially stimulates mu
symptoms. Methadone is essentially substituted for opioid receptors while acting as a strong antagonist at
the abused opioid (e.g., heroin), and is then slowly kappa opioid receptors. By weakly stimulating the mu
withdrawn as various methods of counseling are receptors, this drug can sustain the opioid effects and
employed to discourage further drug abuse.3,74 Use of prevent sudden withdrawal. At the same time, bupre-
methadone, however, remains controversial because of norphine can block kappa receptors, thereby affecting
the rather low success rate of this intervention and the some of the cellular changes that seem to promote opi-
tendency for many subjects to relapse and return to oid addiction. Hence, this drug offers another method
opioid abuse.37 Still, methadone maintenance pro- of substituting a therapeutic agent for the abused opi-
grams are more successful than using no pharmaco- oid, with the ultimate goal being to eventually wean
logical intervention,47 and methadone remains the the patient from all opioid drugs.16
primary drug strategy used to treat opioid addiction.74 Hence, efforts continue to provide more effective
Recently, buprenorphine has been advocated as an pharmacological and nonpharmacological interven-
alternative pharmacological method for treating opioid tions for treating opioid addiction.41 As more infor-
CA S E ST U DY
Opioid Analgesics increased joint mobility achieved during the manipulative pro-
cedure.
Brief History. N.P., a 45-year-old woman, was involved Relevance to Therapy/Clinical Decision. The
in an automobile accident approximately 6 months ago. She therapist arranged the treatment schedule so that the meperi-
received multiple contusions from the accident, but no dine was reaching peak effects during the therapy session.
major injuries were sustained. Two months later, she began The patient was seen approximately 1 hour following the oral
to develop pain in the right shoulder. This pain progres- administration of the drug. The initial session was scheduled
sively increased, and she was treated for bursitis using at the patient’s bedside because the patient was still woozy
anti-inflammatory drugs. Her shoulder motion became from the anesthesia. On the following day, therapy was con-
progressively more limited; however, any movement of her tinued in the physical therapy department. However, the
glenohumeral joint caused rather severe pain. She was patient was brought to the department on a stretcher to pre-
reevaluated and a diagnosis of adhesive capsulitis was vent an episode of dizziness brought on by orthostatic
made. The patient was admitted to the hospital, and while she hypotension. On the third day, the patient’s medication was
was under general anesthesia, a closed manipulation of the changed to oxycodone (OxyContin), a mild-to-moderate opi-
shoulder was performed. When the patient recovered oid agonist. By this time, the patient was being transported to
from the anesthesia, meperidine (Demerol) was prescribed physical therapy in a wheelchair, and the therapy session also
for pain relief. This drug was given orally at a dosage of included active exercise. The patient was discharged on the
75 mg every 4 hours. Physical therapy was also initiated fourth day after the manipulative procedure. She continued to
the afternoon following the closed manipulation. Passive attend therapy as an outpatient, and full function of her right
range-of-motion exercises were used to maintain the shoulder was ultimately restored.
mation is gained about the cellular and subcellular drugs is sometimes tempered with their tendency to
mechanisms that cause addiction, we may see other produce tolerance and physical dependence, but their
agents being used to specifically treat these changes potential for abuse seems relatively low when these
and thereby offer a more effective way to prevent and drugs are used appropriately to treat pain. Opioid
treat opioid abuse. drugs therefore represent the most effective pharma-
cologic means of helping patients deal with acute and
chronic pain. The analgesic properties of these drugs
SUMMARY
often provide a substantial benefit in patients involved
Opioid analgesics represent some of the most effective in rehabilitation. Physical therapists should be aware of
methods of treating moderate-to-severe pain. When some of the side effects, such as sedation and respira-
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cellular mechanisms and proposed roles in physiologi- 83. Werawatganon T, Charuluxanun S. Patient controlled
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oid systems in a rat model of neuropathic pain. Anes- dependence: its pharmacology and social context of use
thesiology. 2003;99:449–454. in the U.S. J Psychoactive Drugs. 2004;suppl 2:119–128.
82. Wei LN, Law PY, Loh HH. Post-transcriptional regu- 85. Zadina JE. Isolation and distribution of endomorphins
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Chapter 15
Nonsteroidal
Anti-Inflammatory Drugs
199
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that is, how could one drug influence so many differ- identified as being able to produce prostaglandins.
ent systems—effectively alleviating pain and inflam- These compounds appear to be hormones that act
mation, decreasing fever, and even affecting blood locally to help regulate cell function under normal and
clotting? This issue was essentially resolved in the pathologic conditions. Other biologically active com-
early 1970s, when aspirin was found to inhibit the pounds known as the “thromboxanes” and “leukotri-
synthesis of a group of endogenous compounds known enes” are derived from the same precursor as the
collectively as the “prostaglandins.” We now know prostaglandins.2,73,80 Together, the prostaglandins,
that aspirin and the other NSAIDs exert most, if not thromboxanes, and leukotrienes are often referred to
all, of their therapeutic effects by interfering with as eicosanoids because they all are derived from 20-
the biosynthesis of prostaglandins and other related carbon fatty acids that contain several double
compounds.37,91,103 To understand the way in which bonds.66,73,88 (The term eicosanoid is derived from eicosa,
these drugs work, a brief discussion of prostaglandins meaning “20-carbon,” and enoic, meaning “containing
and similar endogenously produced substances is double bonds.”)
presented.
Eicosanoid Biosynthesis
Prostaglandins, The biosynthetic pathway of prostaglandins and other
eicosanoids is outlined in Figure 15–2. Basically, these
Thromboxanes, and Leukotrienes compounds are derived from a 20-carbon essential
Prostaglandins are a group of lipidlike compounds that fatty acid. In humans, this fatty acid is usually arachi-
exhibit a wide range of physiologic activities.37,48,68 donic acid,68,73 which is ingested in the diet and stored
With the exception of the red blood cell, virtually as a phospholipid in the cell membrane. Thus, the
every type of living cell in the human body has been cell has an abundant and easily accessible supply of this
Membrane Phospholipids
Phospholipase
COOH
Arachadonic Acid
LIPOXYGENASE CYCLOOXYGENASE
12-HPETE PGG2
5-HETE
LTA4 PGH2
LTB4 LTC4
PGI2 TXA2
LTD4
LTE4
precursor. When needed, arachidonic acid is cleaved vascular, respiratory, renal, gastrointestinal, nervous,
from the cell membrane by a phospholipase enzyme and reproductive function.48,73 The biologic effects of
(i.e., phospholipase A2). The 20-carbon fatty acid can the various eicosanoids cannot be generalized. Differ-
then be metabolized by several enzyme systems to gen- ent classes of eicosanoids, and even different members
erate a variety of biologically active compounds. One within the same class, may exert various effects on the
of the primary enzyme systems involves the cyclooxy- same system. For instance, certain prostaglandins such
genase (COX) enzyme, and a second system involves as the PGIs and PGEs tend to produce vasodilation in
the lipoxygenase (LOX) enzyme. The prostaglandins most vascular beds, whereas other prostaglandins (e.g.,
and thromboxanes are ultimately synthesized from the PGF2␣) and the thromboxanes are often vasoconstric-
cyclooxygenase pathway, and the leukotrienes come tors.30,73,96 Some of the major effects of the eicosanoids
from the lipoxygenase system (see Fig. 15–2).73 are summarized in Table 15–1.
Exactly which pathway is used in any particular All of the effects of different prostaglandins,
cell depends on the type and quantity of enzymes in thromboxanes, and leukotrienes on various systems in
that cell, as well as its physiologic status. The end the body cannot be reviewed in this chapter; this issue
products within a given pathway (i.e., exactly which has been reviewed extensively elsewhere.13,48,50,73,88 Of
prostaglandins, thromboxanes, or leukotrienes will be greater interest is the role of prostaglandins and relat-
formed) also depend on the individual cell. Any drug ed substances in pathologic conditions. In general,
inhibiting one of these enzymes will also inhibit the cells that are subjected to various types of trauma or
formation of all of the subsequent products of that disturbances in homeostasis tend to increase the pro-
particular pathway. A drug that blocks the cyclooxyge- duction of prostaglandins.50,73 This finding suggests
nase will essentially eliminate all prostaglandin and that prostaglandins and other eicosanoids may be
thromboxane synthesis in that cell. As this chapter will important in the protective response to cellular injury.
later discuss, aspirin and the other NSAIDs are In addition, prostaglandins are important in mediating
cyclooxygenase inhibitors, which is the way that these some of the painful effects of injury and inflammation,
drugs exert their therapeutic effects (see “Mechanism as well as the symptoms of other pathologic conditions.
of NSAID Action: Inhibition of Prostaglandin and Some of the better-documented conditions associated
Thromboxane Synthesis”). with excessive prostaglandin synthesis are listed here.
Aspirin and other NSAIDs do not inhibit the Inflammation. Increased prostaglandin synthe-
lipoxygenase enzyme and thus do not appreciably de- sis is usually detected at the site of local inflamma-
crease leukotriene synthesis.73 Like the prostaglandins, tion.21,66,73,101 Certain prostaglandins, such as PGE2,
leukotrienes are pro-inflammatory, but leukotrienes are thought to help mediate the local erythema and
seem to be more important in mediating airway in- edema associated with inflammation by increasing
flammation in conditions such as asthma and allergic local blood flow, increasing capillary permeability, and
rhinitis (see Chapter 26).2,20 Drugs have therefore been potentiating the permeability effects of histamine and
developed to reduce leukotriene-mediated inflamma- bradykinin.13,73 Leukotrienes, particularly LTB4, also
tion by either inhibiting the lipoxygenase enzyme (e.g., contribute to the inflammatory response by increasing
zileuton) or by blocking leukotriene receptors on res- vascular permeability, and LTB4 has a potent chemo-
piratory tissues (e.g., montelukast and zafirlukast).20,83 tactic effect on polymorphonuclear leukocytes.73,80
These antileukotriene drugs will be discussed in more Pain. Prostaglandins appear to help mediate
detail in Chapter 26. The remainder of this chapter painful stimuli in a variety of conditions (including
will focus on drugs that inhibit prostaglandin and inflammation). The compounds do not usually pro-
thromboxane production by selectively inhibiting the duce pain directly but are believed to increase the sen-
cyclooxygenase enzyme. sitivity of pain receptors to mechanical pressure and
the effects of other pain-producing substances such as
Role of Eicosanoids bradykinin.73
Fever. Prostaglandins appear to be pyretogenic;
in Health and Disease that is, they help produce the elevated body tempera-
The prostaglandins, thromboxanes, and leukotrienes ture during fever.55 Although the details are somewhat
have been shown to have a variety of effects on vir- unclear, prostaglandins produced in hypothalamic
tually every major physiologic system. Studies have blood vessels may promote fever by altering the ther-
indicated that these compounds can influence cardio- moregulatory set-point within the hypothalamus so
15Ciccone(p)-15 1/30/07 2:35 PM Page 202
that body temperature is maintained at a higher sclerosis, allergic encephalomyelitis, affective disor-
level.10 Alternatively, prostaglandin production may ders), endocrine dysfunction (Bartter syndrome, dia-
promote fever by stimulating vagal afferent neurons betes mellitus), and a variety of other problems. 7,17,40,
that originate peripherally near the diaphragm.10 77,93,110 The exact role of prostaglandins and the other
Regardless of their exact mechanism, prostaglandins eicosanoids in various diseases continues to be evaluat-
clearly play a role in promoting fever associated with ed, and the role of these compounds in health and dis-
systemic infection and other pyretogenic disorders.55 ease has become clearer with ongoing research.
Dysmenorrhea. The painful cramps that accom-
pany menstruation in some women have been attrib-
uted at least in part to increased prostaglandin
production in the endometrium of the uterus.56,70 Mechanism of NSAID Action:
Thrombus Formation. The thromboxanes, espe- Inhibition of Prostaglandin and
cially TXA2, cause platelet aggregations that result in
blood clot formation.73 It is unclear whether excessive
Thromboxane Synthesis
thrombus formation (as in deep vein thrombosis or Aspirin and the other NSAIDs are all potent inhibitors
coronary artery occlusion) is initiated by abnormal of the cyclooxygenase enzyme.37,84,91,103 Because
thromboxane production. Certainly, inhibition of cyclooxygenase represents the first step in the synthe-
thromboxane synthesis will help prevent platelet- sis of prostaglandins and thromboxanes, drugs that
induced thrombus formation in individuals who are inhibit this enzyme in any given cell will block the pro-
prone to specific types of excessive blood clotting.84 duction of all prostaglandins and thromboxanes in that
Other Pathologies. Because of their many varied cell. Considering that prostaglandins and thrombox-
physiologic effects, the eicosanoids are involved in a anes are implicated in producing pain, inflammation,
number of other pathologic conditions. Prostaglandins fever, and excessive blood clotting, virtually all of the
have been implicated in cardiovascular disorders (hy- therapeutic effects of aspirin and similar drugs can be
pertension), neoplasms (colon cancer), respiratory explained by their ability to inhibit the synthesis of
dysfunction (asthma), neurologic disorders (multiple these two eicosanoid classes.103
15Ciccone(p)-15 1/30/07 2:35 PM Page 203
The cyclooxygenase or COX enzyme system is mediate pain and inflammation while sparing the syn-
therefore the key site of NSAID action within the cell. thesis of protective prostaglandins that are synthesized
It is now realized, however, that there are at least two by COX-1. Such COX-2 selective drugs are currently
primary subtypes (isozymes) of the COX enzyme: available, and their pharmacology is addressed later in
COX-1 and COX-2.24,37,103 The COX-1 enzyme is a this chapter.
normal constituent in certain cells, and prostaglandins
synthesized by COX-1 are typically responsible for
mediating normal cell activity and maintaining home-
Aspirin: Prototypical NSAID
ostasis. For example, COX-1 enzymes located in the Acetylsalicylic acid, or aspirin, as it is commonly
stomach mucosa synthesize prostaglandins that help known (see Fig. 15–1), represents the major form of a
protect the stomach lining from gastric acid, and group of drugs known as the salicylates. Other salicy-
COX-1 enzymes in the kidneys produce beneficial lates (sodium salicylate, choline salicylate) are used
prostaglandins that help maintain renal function, espe- clinically, but aspirin is the most frequently used and
cially when kidney function is compromised.27,46,95 appears to have the widest range of therapeutic effects.
COX-1 is also the enzyme responsible for synthesizing Because aspirin has been used clinically for more than
prostaglandins and thromboxanes regulating normal 100 years, is inexpensive, and is readily available with-
platelet activity.73 out prescription, many individuals may be under the
The COX-2 enzyme, however, seems to be pro- impression that this drug is only a marginally effective
duced primarily in injured cells; that is, other chemi- therapeutic agent. On the contrary, aspirin is a very
cal mediators (cytokines, growth factors) induce the powerful and effective drug that should be considered
injured cell to synthesize the COX-2 enzyme, and a major medicine.84 As discussed previously, aspirin is
this enzyme then produces prostaglandins that medi- a potent inhibitor of all cyclooxygenase activity
ate pain and other aspects of the inflammatory (COX-1 and COX-2), and thus it has the potential to
response.19,61,84 There is also considerable evidence affect a number of conditions involving excessive
that the COX-2 form is responsible for producing prostaglandin and thromboxane production.
prostaglandins in other pathological conditions such Aspirin is the oldest and most widely used
as colorectal cancer.62,100 NSAID, and other NSAIDs are compared with aspirin
The roles of COX-1 and COX-2 enzymes therefore in terms of efficacy and safety. Hence, this discussion
seem quite different. The COX-1 enzyme is a “normal” focuses primarily on the clinical applications of aspirin
cell component that synthesizes prostaglandins to help and the problems typically associated with aspirin. For
regulate and maintain cell activity. COX-2 represents an the most part, clinical use and problems can also be
“emergency” enzyme that often synthesizes prosta- applied to most nonaspirin NSAIDs. The major simi-
glandins in response to cell injury (i.e., pain and inflam- larities and differences between aspirin and the other
mation). This difference has important implications for NSAIDs are discussed in “Comparison of Aspirin with
how NSAIDs exert their therapeutic effects and side Other NSAIDs.”
effects. Aspirin and most of the traditional NSAIDs are
nonselective—they inhibit both the COX-1 and COX-2
enzymes. These nonselective NSAIDs therefore cause Clinical Applications
primary beneficial effects (decreased pain and inflamma- of Aspirinlike Drugs
tion) by inhibiting the COX-2 enzyme. Because these
drugs also inhibit the COX-1 enzyme, they also decrease
Treatment of Pain and Inflammation
the production of the beneficial and protective Aspirin and other NSAIDs are effective in treating
prostaglandins. It is the loss of these beneficial prosta- mild-to-moderate pain of various origins, including
glandins that accounts for the primary side effects of the headache, toothache, and diffuse muscular aches and
NSAIDs; that is, loss of protective prostaglandins in the soreness. Aspirin appears to be especially useful in
stomach and kidneys result in gastric damage and de- treating pain and inflammation in musculoskeletal and
creased renal function, respectively. joint disorders.71,87,89 The safe and effective use of
It follows that drugs selectively inhibiting the aspirin in both rheumatoid arthritis and osteoarthritis
COX-2 enzyme offer certain advantages over aspirin is well documented (see Chapter 16).53,66,84 Aspirin is
and nonselective NSAIDs. Selective COX-2 inhibitors also recommended for treating the pain and cramping
should decrease the production of prostaglandins that associated with primary dysmenorrhea.70
15Ciccone(p)-15 1/30/07 2:35 PM Page 204
Aspirin and aspirinlike drugs are also used to cers), but beneficial effects in these other cancers re-
manage pain following certain types of surgery, quires additional study.3,74 It appears that certain
including arthroscopic surgery.15,16 These drugs can prostaglandins help promote tumor growth and that
serve as the primary analgesic following other types of aspirin and similar NSAIDs exert anticancer effects by
minor or intermediate surgeries, and they can be used inhibiting the synthesis of these prostaglandins.17,78
after extensive surgery to decrease the need for high Hence, aspirin continues to gain acceptance as an anti-
doses of other drugs such as opioids.12,69 Ketorolac cancer drug, especially in individuals who are at an in-
tromethamine (Toradol), for example, is a relatively creased risk for developing colon cancer.
new NSAID that has shown exceptional promise in
treating postoperative pain. This drug can be given
orally or by intramuscular injection, and it is reported
to provide analgesic effects similar to opioid drugs Problems and Adverse
(e.g., morphine) but without the associated side effects Effects of Aspirinlike Drugs
and risks.26,69 Hence, ketorolac tromethamine pro-
vides a reasonable alternative for nonopioid manage-
Gastrointestinal Problems
ment of postoperative pain and may be especially The primary problem with all NSAIDs, including
valuable when opioid side effects (sedation, respirato- aspirin, is gastrointestinal damage. Problems ranging
ry depression) are harmful or undesirable.12,26 from minor stomach discomfort to variable amounts of
upper gastrointestinal hemorrhage and ulceration are
fairly common.38,67 These effects are most likely caused
Treatment of Fever by the loss of protective prostaglandins from the
Although the use of aspirin in treating fever in chil- mucosal lining. Certain prostaglandins such as PGI2
dren is contraindicated (because of the association with and PGE2 are produced locally in the stomach, and
Reye syndrome; see “Problems and Adverse Effects of these prostaglandins help protect the gastric mucosa by
Aspirinlike Drugs”), aspirin remains the primary inhibiting gastric acid secretion, increasing the produc-
NSAID used in treating fever in adults.9 Ibuprofen is tion of mucous in the stomach lining, and maintaining
also used frequently as a nonprescription antipyretic blood flow to the gastric mucosa.84 By inhibiting the
NSAID in both adults and children. formation of these protective prostaglandins, aspirin
and most traditional NSAIDs render the stomach
more susceptible to damage from acidic gastric juices.79
Treatment of Vascular Disorders Certain patients are likewise more susceptible to
As discussed previously, aspirin inhibits platelet- gastrointestinal injury from aspirinlike drugs. Factors
induced thrombus formation through its ability to such as advanced age, a history of ulcers, use of multi-
inhibit thromboxane biosynthesis. Aspirin has there- ple NSAIDs, use of high doses of an NSAID, and use
fore been used to help prevent the onset or recurrence of other agents (anti-inflammatory steroids, anticoag-
of heart attacks in some individuals by inhibiting ulants) appear to increase the risk of serious gastroin-
thrombus formation in the coronary arteries.97,109 Sim- testinal damage.81 Helicobacter pylori, a bacterium
ilarly, daily aspirin use may help prevent transient that is sometimes present in the stomach (see Chapter
ischemic attacks and stroke by preventing cerebral 27), can also contribute to the increased risk of gastric
infarction in certain patients.97,109 The role of aspirin irritation associated with NSAIDs.4,23
in treating coagulation disorders is discussed in more Several pharmacologic and nonpharmacologic
detail in Chapter 25 strategies have been employed to manage gastroin-
testinal problems associated with aspirinlike drugs.
One strategy has been to coat the aspirin tablet so that
Prevention of Cancer dissolution and release of the drug is delayed until it
There is now considerable evidence that regular reaches the small intestine. These so-called enteric-
aspirin use decreases the risk of colorectal cancer.1,49,58 coated forms of aspirin spare the stomach from irrita-
It has been estimated, for example, that people who use tion, but the duodenum and upper small intestine may
aspirin on a regular basis have a 40 to 50 percent lower still be subjected to damage.38 Enteric-coated aspirin
risk of fatal colon cancer as compared with people who also has the disadvantage of delaying the onset of
do not use aspirin.78 Aspirin might also help prevent analgesic effects to relieve acute pain. Other methods
other types of cancers (e.g., skin, bladder, prostate can- such as buffering the aspirin tablet have also been used
15Ciccone(p)-15 1/30/07 2:35 PM Page 205
to help decrease stomach irritation. The rationale is stomach lining, whereas the COX-2 form synthesizes
that including a chemical buffer helps blunt the acidic prostaglandins that promote pain, inflammation, and
effects of the aspirin molecule on the stomach mucosa. other pathological symptoms. A COX-2 drug is there-
It is questionable, however, whether sufficient buffer fore more likely to inhibit production of the patholog-
is added to commercial aspirin preparations to actual- ical prostaglandins, while sparing the production of
ly make a difference in stomach irritation. During beneficial prostaglandins in the stomach.34,43 Indeed,
chronic aspirin therapy (e.g., treatment of arthritis), COX-2 drugs are generally associated with a reduced
taking aspirin with meals may help decrease gastroin- incidence of gastric irritation.4,25,54,57 Still, certain peo-
testinal irritation because the food in the stomach will ple can experience gastric problems with COX-2
offer some direct protection of the gastric mucosa. drugs, and these drugs may produce other serious side
The presence of food, however, will also delay drug effects. The risks and benefits of COX-2 drugs are
absorption, which may decrease the peak levels of addressed in more detail later in this chapter.
drug that reach the bloodstream.
Recently, a great deal of attention has focused on
other drugs that can prevent or treat the gastrointesti-
Other Side Effects
nal side effects associated with aspirin and the other Aspirin and similar NSAIDs can cause other toxic side
NSAIDs. Misoprostol (Cytotec) is a prostaglandin E1 effects if used improperly or if taken by patients who
analog that inhibits gastric acid secretion and prevents have preexisting diseases. For instance, serious hepato-
gastric damage.23,43 This drug has been beneficial in toxicity is rare with normal therapeutic use, but high
decreasing aspirin-induced irritation, but the clinical doses of aspirinlike drugs can produce adverse changes
use of misoprostol is limited by side effects such as in hepatic function in patients with liver disease.85,99
diarrhea.43 Omeprazole (Prilosec), esomeprazole Likewise, aspirin does not seem to cause renal disease
(Nexium), and lansoprazole (Prevacid) are drugs that in an individual with normal kidneys,84 but problems
inhibit the “proton pump” that is ultimately responsi- such as nephrotic syndrome, acute interstitial nephri-
ble for secreting gastric acid from mucosal cells into tis, and even acute renal failure have been observed
the lumen of the stomach (see Chapter 27). These pro- when aspirin is given to patients with impaired renal
ton pump inhibitors have therefore been used success- function, or people with decreased body water (volume
fully to increase healing and decrease NSAID-induced depletion).35,102
ulcers.34,43 Drugs that antagonize certain histamine Aspirinlike drugs appear to cause renal and
receptors—that is, the H2 receptor blockers—have also hepatic problems by inhibiting the synthesis of
been used to decrease gastrointestinal damage.43 As in- prostaglandins that serve a protective role in main-
dicated in Chapter 27, histamine receptor (H2) block- taining blood flow and function in the liver and kid-
ers such as cimetidine (Tagamet) and ranitidine neys.36,84 These protective prostaglandins appear to be
(Zantac) inhibit gastric acid secretion by antagoniz- important in sustaining adequate hepatic and renal
ing histamine receptors in the gastric mucosa. These function, especially when blood flow and perfusion
drugs are tolerated quite well but are generally not pressure to these organs becomes compromised. Con-
as effective in controlling NSAID-induced ulceration sequently, aspirin and aspirinlike drugs may create
as other drugs such as misoprostol and proton pump problems in other conditions such as hypovolemia,
inhibitors.54 shock, hepatic cirrhosis, congestive heart failure, and
Hence, currently available drugs such as miso- hypertension.36,84,102
prostol, proton pump inhibitors, and H2 receptor In cases of aspirin overdose, a condition known as
blockers can be used to prevent or treat gastrointesti- aspirin intoxication or poisoning may occur. This
nal damage in patients taking aspirin and other event is usually identified by a number of symptoms,
NSAIDs. These protective agents are not usually pre- including headache, tinnitus, difficulty hearing, confu-
scribed to every person taking aspirinlike drugs but are sion, and gastrointestinal distress. More severe cases
typically reserved for people who exhibit symptoms of also result in metabolic acidosis and dehydration,
gastrointestinal irritation or who are at risk for devel- which can be life-threatening. In adults, a dose
oping ulceration while undergoing NSAID therapy.64 of 10 to 30 g of aspirin is sometimes fatal, although
COX-2 selective drugs comprise an alternative much higher doses (130 g in one documented case)
strategy for reducing the risk of gastric irritation. As have been ingested without causing death.84 Of
indicated earlier, the COX-1 enzyme is responsible for course, much smaller doses can produce fatalities in
synthesizing prostaglandins that help protect the children.
15Ciccone(p)-15 1/30/07 2:35 PM Page 206
Evidence has suggested that aspirin may also be ing in clinical situations, and whether these drugs
associated with a relatively rare condition known as should be avoided for a certain period following frac-
Reye syndrome.22 This condition occurs in children ture or spinal surgery.
and teenagers, usually following a bout of influenza or The effect of NSAIDs on healing of soft tissues is
chicken pox. Reye syndrome is marked by a high fever, likewise uncertain. It was originally suggested that
vomiting, liver dysfunction, and increasing unrespon- NSAIDs might inhibit the synthesis and transport of
siveness, often progressing rapidly and leading to connective tissue components such as proteogly-
delirium, convulsions, coma, and possibly death. cans.29,51 More recent findings indicate that NSAIDs
Because aspirin is one factor that may contribute to may actually facilitate the incorporation of proteogly-
Reye syndrome, it is recommended that aspirin and cans, hylauronan, and other components into soft tis-
other aspirinlike drugs not be used to treat fever in sues.8 As such, NSAIDs may enhance the healing of
children and teenagers.84 Nonaspirin antipyretics such soft tissues in certain conditions.31 Once again, much
as acetaminophen and ibuprofen are not associated of this evidence was obtained from animal and in vitro
with Reye syndrome, so products containing these studies, and additional research will therefore be
drugs are preferred for treating fever in children and needed to determine if aspirin and other NSAIDs can
teenagers.84 affect the healing process of articular cartilage and
A small number of individuals exhibit aspirin other soft tissues.
intolerance or supersensitivity.84 These individuals
comprise approximately 1 percent of the general pop-
ulation, but the incidence is considerably higher Comparison of Aspirin
(10%–25%) in people with asthma or other hypersen-
sitivity reactions.84,94 People with aspirin intolerance
with Other NSAIDs
will display allergiclike reactions, including acute A number of drugs that bear a functional similarity to
bronchospasm, urticaria, and severe rhinitis, within a aspirin have been developed during the past several
few hours after taking aspirin and aspirinlike decades, and a comprehensive list of currently avail-
NSAIDs.45,76 These reactions may be quite severe, and able NSAIDs is shown in Table 15–2. Other NSAIDs
cardiovascular shock may occur. Likewise, sensitivity are like aspirin in that they exert their therapeutic
to aspirin often indicates a concomitant sensitivity to effects by inhibiting prostaglandin and thromboxane
other NSAIDs, including COX-2 selective drugs.92 synthesis. Although specifically approved uses of indi-
Consequently, the use of all NSAIDs is contraindicat- vidual members of this group vary, NSAIDs are used
ed in these individuals.84 in much the same way as aspirin; that is, they are
Finally, there is preliminary evidence that aspirin administered primarily for their analgesic and anti-
and other commonly used NSAIDs may inhibit heal- inflammatory effects, with some members also used as
ing of certain tissues. In particular, it has been suggest- antipyretic and anticoagulant agents. Dosages com-
ed that these drugs may inhibit bone healing after monly used to achieve analgesic or anti-inflammatory
fracture and certain types of surgery (spinal fusion).47,98 effects with some of the more common NSAIDs are
It seems that certain prostaglandins are important in listed in Table 15–3.
stimulating the early stages of bone formation follow- With respect to therapeutic effects, there is no
ing fracture or bone surgery.42 By inhibiting the syn- clear evidence that any of the commonly used NSAIDs
thesis of these prostaglandins, NSAIDS may retard are markedly better than aspirin as anti-inflammatory
bone healing and delay the formation of new bone.47 analgesics.87 The primary differences between aspirin
Much of this evidence, however, is based on laborato- and other NSAIDs are related to the side effects and
ry studies on animal models, and a definitive link safety profile of each agent (see Table 15–2).84 As a
between NSAIDs (including COX-2 drugs) and group, the nonaspirin NSAIDs tend to be associated
delayed bone healing in humans remains to be deter- with less gastrointestinal discomfort than plain aspirin,
mined.18,106 Still, some experts feel that it might be but most of these NSAIDs (with the possible exception
prudent to avoid the use of NSAIDs immediately of the COX-2 drugs; see later) are still associated with
following fracture or bone surgery.31,98 More details some degree of stomach irritation (Table 15–2).72,87
are needed to determine if traditional NSAIDs and Likewise, certain NSAIDs may offer an advantage
COX-2 selective agents are detrimental to bone heal- over aspirin or other aspirinlike drugs because they are
15Ciccone(p)-15 1/30/07 2:35 PM Page 207
Diclofenac Voltaren Substantially more potent than naproxen and several other NSAIDs;
adverse side effects occur in 20% of patients.
Diflunisal Dolobid Has potency 3–4 times greater than aspirin in terms of analgesic and
anti-inflammatory effects but lacks antipyretic activity.
Fenoprofen Nalfon GI side effects fairly common but usually less intense than those
occurring with similar doses of aspirin.
Flurbiprofen Ansaid Similar to aspirin’s benefits and side effects; also available as topical
ophthalmic preparation (Ocufen).
Ibuprofen Motrin, many others First nonaspirin NSAID also available in nonprescription form; fewer
GI side effects than aspirin but GI effects still occur in 5%–15% of
patients.
Indomethacin Indocin Relative high incidence of dose-related side effects; problems occur
in 25%–50% of patients.
Ketoprofen Orudis, Oruvail, others Similar to aspirin’s benefits and side effects but has relatively short
half-life (1–2 hours).
Mefanamic acid Ponstel No advantages; often less effective and more toxic than aspirin and
other NSAIDs.
Naproxen Anaprox, Naprosyn, others Similar to ibuprofen in terms of benefits and adverse effects
Oxaprozin Daypro Analgesic and anti-inflammatory effects similar to aspirin; may pro-
duce fewer side effects than other NSAIDs.
Phenylbutazone Cotylbutazone Potent anti-inflammatory effects but long-term use limited by high
incidence of side effects (10%–45% of patients).
Piroxicam Feldene Long half-life (45 hours) allows once-daily dosing; may be somewhat
better tolerated than aspirin.
(Continued on following page)
15Ciccone(p)-15 1/30/07 2:35 PM Page 208
Tolmetin Tolectin Similar to aspirin’s benefits and side effects but must be given fre-
quently (QID) because of short half-life (1 hour).
Diclofenac (Voltaren) Up to 100 mg for the first dose; Initially: 150–200 mg/d in 3–4 divided doses;
then up to 50 mg TID thereafter try to reduce to 75–100 mg/d in 3 divided
doses
Etodolac (Lodine) 400 mg initially; 200–400 mg 400 mg BID or TID or 300 mg TID or QID;
every 6–8 hours as needed total daily dose is typically between
600–1200 mg/d
Ibuprofen (Advil, Motrin, 200–400 mg every 4–6 hr as 1.2–3.2 g/d in 3–4 divided doses
Nuprin, others) needed
Ketoprofen (Orudis) 25–50 mg every 6–8 hr 150–300 mg/d in 3–4 divided doses
less toxic to other organs such as the liver and kidneys. fewer side effects than aspirin.108 If a patient responds
The effect on these other organs, however, seems to be equally well to a variety of NSAIDs, however, efforts
related more to the status of each patient rather than should be made to use the NSAID that will produce
the drug. That is, all NSAIDs, including aspirin, are adequate therapeutic effects at a minimal cost.84
relatively safe in people with normal liver and kidney
function when administered at moderate dosages for a
short period of time.84 A specific patient may also
respond more favorably to a specific NSAID in terms
COX-2 Selective Drugs
of therapeutic effects (decreased pain, inflammation), As discussed earlier, the cyclooxygenase enzyme that
but these responses are due to patient variability rather synthesizes prostaglandins exists in at least two forms:
than a unique characteristic of the drug. Hence, it can- COX-1 and COX-2.24,37,103 Aspirin and most other
not be generalized that the non-aspirin NSAIDs are NSAIDs are nonselective cyclooxygenase inhibitors;
significantly better or worse than aspirin in terms of that is, they inhibit both the COX-1 and COX-2 forms
either therapeutic or adverse effects.84 of the cyclooxygenase. This nonselective inhibition
The primary difference between aspirin and results in decreased synthesis of prostaglandins that
other NSAIDs is cost. Most of the NSAIDs still cause pain and inflammation (COX-2 prostaglandins),
require a physician’s prescription. The cost of pre- as well as loss of prostaglandins that are protective and
scription NSAIDs can be anywhere from 10 to 20 beneficial to tissues such as the stomach lining and kid-
times more expensive than an equivalent supply of neys (COX-1 prostaglandins). Recently, drugs have
aspirin. NSAIDs that are available in nonprescription been developed that are selective for the COX-2
form (e.g., ibuprofen) can still cost up to five times as enzyme, hence the name COX-2 inhibitors. COX-2
much as aspirin. selective drugs such as celecoxib (Celebrex) offer the
Consequently, the newer NSAIDs have not obvious advantage of inhibiting synthesis of the
always been shown to be clinically superior to aspirin, inflammatory prostaglandins, while sparing synthesis
but some agents may provide better effects in some of beneficial prostaglandins that help regulate normal
patients. Considering the interpatient variability in physiologic function.37,103
drug response, there are surely cases in which another It follows that use of COX-2 selective drugs
NSAID will produce better therapeutic effects with should decrease pain and inflammation with minimal
15Ciccone(p)-15 1/30/07 2:35 PM Page 210
or no adverse effects on the stomach and other tissues. drugs. This finding was the primary reason that cer-
The burden of evidence indicates that this fact is tain COX-2 drugs such as rofecoxib (Vioxx) and valde-
indeed true; that is, COX-2 drugs have analgesic and coxib (Bextra) were taken off the market. On the other
anti-inflammatory effects similar to other NSAIDs, hand, there is growing evidence that the risk of heart
but have a much lower incidence of gastric irrita- attack and stroke may be acceptable if COX-2 drugs
tion.33,41 Likewise, COX-2 drugs do not inhibit platelet are used appropriately.90,105,107 That is, patients must
function because prostaglandins influencing normal be screened carefully to determine individuals who are
platelet activity are under the control of the COX-1 at risk for coronary or carotid ischemia.28,60 Dosages
isozyme.73 Use of COX-2 drugs should therefore be must likewise be kept to a minimum to prevent unto-
beneficial in people who are at risk for prolonged ward cardiovascular events.
bleeding and hemorrhage. At the time of this writing, celecoxib (Celebrex) is
COX-2 drugs represent an important addition the only COX-2 selective drug that is still available. It
to the NSAID armamentarium. Although these drugs will be interesting to see if new COX-2 drugs can be
are not necessarily more effective in reducing pain developed that have an acceptable cardiovascular risk
and inflammation, they may avoid the gastritis associ- profile. Likewise, efforts continue to clearly identify
ated with aspirin and other NSAIDs. The COX-2 patients who should not take these drugs because of an
drugs are not devoid of side effects, of course, and increased risk for heart attack or ischemic stroke.
they may increase the risk of upper respiratory
tract infections. Even though these drugs are pur-
portedly easier on the stomach than traditional Acetaminophen
NSAIDs, certain patients may still experience gas- Acetaminophen (known also as paracetamol) has sev-
trointestinal (GI) problems such as diarrhea, heart- eral distinct differences from aspirin and the other
burn, stomach cramps, and upper GI bleeding. NSAIDs. Acetaminophen does appear to be equal to
Nonetheless, COX-2 drugs offer an alternative to aspirin and NSAIDs in terms of analgesic and
more traditional NSAIDs, and COX-2 agents may be antipyretic effects, but it does not have any appreciable
especially useful to patients who cannot tolerate anti-inflammatory or anticoagulant effects.44,84 One
aspirin or other NSAIDs because of gastric irritation major advantage of acetaminophen is that this drug is
or other side effects with aspirin and the more tradi- not associated with upper gastrointestinal tract irrita-
tional NSAIDs typically associated.33 tion.82 Consequently, acetaminophen has been used
widely in the treatment of noninflammatory condi-
COX-2 Drugs and the Risk tions associated with mild-to-moderate pain and in
of Heart Attack and Stroke patients who have a history of gastric damage (such as
The primary concern about COX-2 drugs is that cer- ulcers). Acetaminophen is, for example, often the first
tain patients taking specific agents may have an drug used to control pain in the early stages of
increased risk of serious cardiovascular events such as osteoarthritis and other musculoskeletal conditions
heart attack and stroke.14,75 By inhibiting the COX-2 that do not have an inflammatory component.5,104,111
form of the enzyme, these drugs inadvertently impair In addition, Reye syndrome has not been implicated
the production of prostacyclin, a prostaglandin that with acetaminophen use, so this drug is often used in
promotes vasodilation and prevents platelet-induced treating fever in children and teenagers.82
occlusion in the coronary and carotid arteries.32,63 The mechanism of action of acetaminophen is
Simultaneously, these drugs do not inhibit the pro- not fully understood. Acetaminophen does inhibit the
duction of thromboxane from the COX-1 enzyme, cyclooxygenase enzyme, and its analgesic and antipy-
and thromboxane is a prostaglandin that facilitates retic effects are probably mediated through prosta-
platelet aggregation and clot formation.39 The balance glandin inhibition. Why acetaminophen fails to exert
of prostaglandin production is therefore shifted to anti-inflammatory and anticoagulant effects, however,
favor increased platelet activity and an increased risk is unclear. One explanation is that acetaminophen
of clots in the coronary and carotid arteries in suscep- preferentially inhibits central nervous system (CNS)
tible individuals.6 prostaglandin production but has little effect on peri-
Thus, people who are prone to coronary ischemia pheral cyclooxygenase activity.10,44 This specific effect
or carotid occlusion may be at risk for heart attack or on central prostaglandins has generated the theory
ischemic stroke when taking these COX-2 selective that a third subset of cyclooxygenase enzymes known
15Ciccone(p)-15 1/30/07 2:35 PM Page 211
CA S E ST U DY
Nonsteroidal Anti- aspirin once or twice, especially when his shoulder pain kept
Inflammatory Drugs him awake at night. When he was asked specifically what
type of aspirin he had taken, he named a commercial aceta-
Brief History. D.B., a 38-year-old man, began to devel- minophen preparation. Evidently the patient was unaware
op pain in his right shoulder. He was employed as a carpenter of the difference between acetaminophen and aspirin (acetyl-
and had recently been working rather long hours building a salicylate).
new house. The increasing pain required medical attention. A Decision/Solution. The therapist explained the differ-
physician evaluated the patient, and a diagnosis of subacromi- ence between aspirin and acetaminophen to the patient,
al bursitis was made. The patient was also referred to physical pointing out that acetaminophen lacks any significant anti-
therapy, and a program of heat, ultrasound, and exercise was inflammatory effects. After consulting with the physician to
initiated to help resolve this condition. confirm that aspirin was recommended, the therapist suggest-
Problem/Influence of Medication. During the ini- ed that the patient take the recommended dosage at regular
tial physical therapy evaluation, the therapist asked if the intervals to help decrease the inflammation in the bursa, as
patient was taking any medication for the bursitis. The patient well as to provide analgesia. The patient had used aspirin in
responded that he had been advised by the physician to the past without any problems, but the therapist cautioned the
take aspirin as needed to help relieve the pain. When asked patient to contact his physician if any adverse effects were
if he had done this, the patient said that he had taken some noted (e.g., gastrointestinal distress or tinnitus).
15Ciccone(p)-15 1/30/07 2:35 PM Page 213
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drugs and new formulations. Aliment Pharmacol Ther. antiinflammatory agents and drugs employed in the
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69. Lowder JL, Shackelford DP, Holbert D, Beste TM. totoxicity of non-steroidal anti-inflammatory drugs.
A randomized, controlled trial to compare ketorolac Aliment Pharmacol Ther. 2004;20:373–380.
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Chapter 16
Pharmacologic Management
of Rheumatoid Arthritis
and Osteoarthritis
Rheumatoid arthritis and osteoarthritis represent the exacerbation and remission, rheumatoid arthritis is
two primary pathologic conditions that affect the often progressive in nature, with advanced stages lead-
joints and periarticular structures. Although the caus- ing to severe joint destruction and bone erosion.
es underlying these conditions are quite different from Specific criteria for the diagnosis of rheumatoid
one another, both conditions can cause severe pain arthritis in adults are listed in Table 16–1. In addition
and deformity in various joints in the body. Likewise, to the adult form of this disease, there is also a form of
pharmacologic management plays an important role arthritis that occurs in children known commonly as
in the treatment of each disorder. Because physical juvenile rheumatoid arthritis, or by the more recent
therapists and other rehabilitation specialists often term juvenile idiopathic arthritis (JIA). Juvenile arthri-
work with patients who have rheumatoid arthritis or tis differs from the adult form of this disease—the age
osteoarthritis, an understanding of the types of drugs of onset (younger than 16 years) and other criteria help
used to treat these diseases is important. to differentiate these two types of rheumatoid joint
This chapter will begin by describing the etiolo- disease.69,109 Drug treatment of adult and juvenile
gy of rheumatoid joint disease and the pharmacologic rheumatoid arthritis is fairly similar, however, with
treatment of rheumatoid arthritis. An analogous dis- the exception that children may not respond as well to
cussion of osteoarthritis will follow. Hopefully, these certain medications (e.g., hydroxychloroquine, gold
descriptions will provide rehabilitation specialists with compounds, penicillamine) compared to adults.79,80
an understanding of drug therapy’s role in arthritis, Consequently, in this chapter most of the discussion of
and the impact drugs can have on patients receiving the management of rheumatoid arthritis is directed
physical therapy and occupational therapy. toward the adult form.
Rheumatoid arthritis affects about 0.5 to 1.0 per-
cent of the population worldwide.38,55 This disease
occurs three times more often in women than in men,
Rheumatoid Arthritis with women between the ages of 20 and 40 especi-
Rheumatoid arthritis is a chronic, systemic disorder ally susceptible to the onset of rheumatoid joint dis-
that affects many different tissues in the body, but is ease.90,101 Rheumatoid arthritis often causes severe pain
primarily characterized by synovitis and the destruc- and suffering, frequently devastating the patient’s fam-
tion of articular tissue.49,90,100 This disease is associated ily and social life as well as his or her job situation.5,55
with pain, stiffness, and inflammation in the small syn- The economic impact of this disease is also staggering;
ovial joints of the hands and feet, as well as in larger medical costs and loss of productivity exceed $1 billion
joints such as the knee. Although marked by periods of annually in the United States.5,55 Consequently, rheu-
217
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Criterion Definition
1. Morning stiffness Morning stiffness in and around the joints, lasting at least 1 hr before maximal
improvement.
2. Arthritis of 3 or more joint areas At least 3 joint areas simultaneously have had soft tissue swelling or fluid (not
bony overgrowth alone) observed by a physician. The 14 possible areas are
right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints.†
3. Arthritis of hand joints At least 1 area swollen (as defined above) in a wrist, MCP, or PIP joint.
4. Symmetric arthritis Simultaneous involvement of the same joint areas (as defined in 2) on both
sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is accept-
able without absolute symmetry).
5. Rheumatoid nodules Subcutaneous nodules over bony prominences or extensor surfaces, or in jux-
taarticular regions, observed by a physician.
6. Serum rheumatoid factor Demonstration of abnormal amounts of serum rheumatoid factor by any
method for which the result has been positive in ⬍5% of normal control
subjects.
matoid arthritis is a formidable and serious problem in events involving a variety of immune system compo-
contemporary health care. nents such as mononuclear phagocytes, T lympho-
cytes, and B lymphocytes.38,100 These cells basically
Immune Basis for interact with each other to produce a number of arthri-
togenic mediators, including cytokines (interleukin-1,
Rheumatoid Arthritis tumor necrosis factor-alpha), eicosanoids (prostag-
The initiating factor in rheumatoid arthritis is not landins, leukotrienes), and destructive enzymes (pro-
known. It is apparent, however, that the underlying teases, collagenases).32,90,94 These substances act either
basis of this disease consists of some type of auto- directly or through other cellular components of the
immune response in genetically susceptible individu- immune system to induce synovial cell proliferation
als.29,32,94 Some precipitating factor (possibly a virus or and destruction of articular cartilage and bone.29,100
other infectious agent) appears to initiate the forma- Thus, the joint destruction in rheumatoid arthritis is
tion of antibodies that are later recognized by the host the culmination of a series of events resulting from an
as antigens.29 Subsequent formation of new antibodies inherent defect in the immune response in patients
to these antigens then initiates a complex chain of with this disease.29,32
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Overview of Drug Therapy arthritis.56 Each of these major drug categories, as well
in Rheumatoid Arthritis as specific disease-modifying drugs, is discussed in the
following sections.
The drug treatment of rheumatoid arthritis has two
goals: (1) to decrease joint inflammation and (2) to
arrest the progression of this disease. Three gen- Nonsteroidal Anti-
eral categories of drugs are available to accomplish
these goals: (1) nonsteroidal anti-inflammatory drugs
Inflammatory Drugs
(NSAIDs), (2) glucocorticoids, and (3) a diverse group Aspirin and the other NSAIDs are usually considered
of agents known as disease-modifying antirheuma- the first line of defense in treating rheumatoid arthri-
tic drugs (DMARDs) (Table 16–2).56,90 NSAIDs and tis.68,90 Although NSAIDs are not as powerful in
glucocorticoids are used primarily to decrease joint reducing inflammation as glucocorticoids, they are
inflammation, but these agents do not necessarily halt associated with fewer side effects, and they offer the
the progression of rheumatoid arthritis. DMARDs added advantage of analgesia. Consequently, NSAIDs
attempt to slow or halt the advancement of this dis- such as aspirin are often the first drugs employed in
ease, usually by interfering with the immune response treating rheumatoid arthritis; in fact, this disease can
that seems to be the underlying factor in rheumatoid often be controlled for short periods in some patients
II. Corticosteroids
Betamethasone (Celestone) Methylprednisolone (Medrol, others)
Cortisone (Cortone acetate) Prednisolone (Prelone, others)
Dexamethasone (Decadron, others) Prednisone (Deltasone, others)
Hydrocortisone (Cortef, others) Triamcinolone (Aristocort, others)
by solely using an NSAID.68 In patients who continue these drugs inhibit the COX-1 form of the enzyme
to experience progressive joint destruction despite that produces beneficial and protective prostaglandins
NSAID therapy these drugs are often combined with in certain tissues while also inhibiting the COX-2 form
disease-modifying agents (discussed later in this chap- that synthesizes prostaglandins in painful and inflamed
ter). Usually, it is not advisable to use two different tissues.84
NSAIDs simultaneously because there is an increased Newer NSAIDs, however, are known as COX-2
risk of side effects without any appreciable increase in inhibitors because these drugs inhibit the specific
therapeutic benefits. Some amount of trial and error form of COX-2 that synthesizes prostaglandins during
may be involved in selecting the best NSAID, and sev- pain and inflammation. COX-2 drugs such as celecox-
eral agents may have to be given before an optimal ib (Celebrex) spare the production of normal or pro-
drug is found. As discussed in Chapter 15, aspirin tective prostaglandins produced by COX-1 in the
appears approximately equal to the newer, more stomach, kidneys, and platelets (see Chapter 15).33,103
expensive NSAIDs in terms of anti-inflammatory and Hence, COX-2 selective drugs may be especially ben-
analgesic effects, but some of the newer drugs may eficial during long-term use in people with rheuma-
produce less gastrointestinal discomfort. In particular, toid arthritis because they may be less toxic to the
the cyclooxygenase-2 (COX-2) selective drugs (see stomach and other tissues.3 The effect of COX-2
below) may be especially helpful in people with a his- selective drugs and other NSAIDs on prostaglandin
tory of peptic ulcers or other risk factors for gastroin- biosynthesis is discussed in more detail in Chapter 15.
testinal problems.3 The choice of a specific NSAID
ultimately depends on each patient’s response to the
Adverse Side Effects
therapeutic effects and side effects of any given agent.84
Finally, acetaminophen (paracetamol) products The problems and adverse effects of aspirin and other
may provide some temporary analgesic effects in peo- NSAIDs are discussed in Chapter 15. The most com-
ple with rheumatoid arthritis, but these products are mon problem with chronic use is stomach irritation,
not optimal because they lack anti-inflammatory which can lead to gastric ulceration and hemorrhage.
effects. As discussed in Chapter 15, acetaminophen can This can be resolved to some extent by taking aspirin
be used to treat mild-to-moderate pain, but the lack of in an enteric-coated form so that release is delayed
anti-inflammatory effects makes acetaminophen fall until the drug reaches the small intestine. Other phar-
short of NSAIDs for conditions such as rheumatoid macologic interventions such as prostaglandin analogs
arthritis. Hence, patients with rheumatoid arthritis (misoprostol) and proton pump inhibitors (omepra-
usually prefer the effects of NSAIDs to acetamino- zole [Prilosec], and so forth) can also be used if gas-
phen,110 and acetaminophen products are not typically tropathy continues to be a limiting factor during
used for the routine treatment of this disease. NSAID use (see Chapter 15). Chronic NSAID use can
also produce bleeding problems (because of platelet
inhibition) and impaired renal function, especially in
Mechanism of Action
an older or debilitated patient. Despite the potential
The pharmacology of the NSAIDs was discussed in for various side effects, aspirin and other NSAIDs con-
Chapter 15. Basically, aspirin and the other NSAIDs tinue to be used extensively by people with rheumatoid
exert most or all of their anti-inflammatory and anal- arthritis and are often used for extended periods with-
gesic effects by inhibiting the synthesis of prostaglan- out serious effects.
dins.84,103 Certain prostaglandins (i.e., prostaglandin E2 As indicated earlier, COX-2 selective drugs may
[PGE2]) are believed to participate in the inflammato- reduce the risk of toxicity to the stomach, kidneys, and
ry response by increasing local blood flow and vascular other tissues because these drugs spare the production
permeability and by exerting a chemotactic effect on of normal or protective prostaglandins in these tis-
leukocytes.61 Prostaglandins are also believed to sensi- sues.3 These drugs may cause other problems such as
tize pain receptors to the nociceptive effects of other diarrhea, heartburn, gastrointestinal cramps, and an
pain mediators such as bradykinin.84 Aspirin and other increased risk of upper respiratory tract infection. As
NSAIDs prevent the production of prostaglandins by indicated in Chapter 15, COX-2 drugs have also been
inhibiting the COX enzyme that initiates prostag- associated with serious cardiovascular problems (heart
landin synthesis. As discussed in Chapter 15, aspirin attack, stroke), and these drugs should be avoided in
and most other NSAIDs inhibit all COX forms; that is, people at risk for cardiac disease.
16Ciccone(p)-16 1/30/07 2:50 PM Page 221
patients have significant bone loss before even begin- be underlying rheumatoid disease. For example, these
ning steroid therapy. Glucocorticoids have been drugs can inhibit the function of monocytes and T and
known to increase bone loss in patients with arthritis, B lymphocytes, or affect specific inflammatory media-
especially when these drugs are used at higher doses tors (e.g., cytokines) that are responsible for perpetu-
for prolonged periods.68,86 Glucocorticoids may also ating joint inflammation and destruction.90 The
cause muscle wasting and weakness, as well as hyper- pharmacology of specific DMARDs is discussed below.
tension, aggravation of diabetes mellitus, glaucoma,
and cataracts.68,89 These side effects emphasize the Antimalarial Drugs
need to limit glucocorticoid therapy as much as possi-
Originally used in the treatment of malaria, the drugs
ble in patients with arthritis.
chloroquine (Aralen) and hydroxychloroquine (Pla-
quenil) have also been used to treat rheumatoid arthri-
Disease-Modifying tis. In the past, these drugs have been used reluctantly
because of the fear of retinal toxicity (see “Adverse Side
Antirheumatic Drugs Effects”).25 There is now evidence, however, that these
Disease-modifying antirheumatic drugs (DMARDs) agents can be used safely, but they are only marginally
are defined as “medications that retard or halt the pro- effective when compared to other DMARDs. These
gression of [rheumatoid] disease.”68 These drugs com- drugs are therefore not usually the first choice, but
prise an eclectic group of agents that are now they can be used in patients who cannot tolerate other
recognized as essential in the early treatment of DMARDs, or in combination with another DMARD
rheumatoid arthritis. That is, early and aggressive use (e.g., methotrexate) for more comprehensive treat-
of DMARDs can slow the progression of this disease ment.
before there is extensive damage to affected joints. Mechanism of Action. Antimalarials exert a num-
When used in conjunction with NSAIDs and gluco- ber of effects, although it is unclear exactly which of
corticoids, DMARDs can help improve the long-term these contributes to their ability to halt the progres-
outcomes of patients with rheumatoid arthritis, and sion in rheumatoid arthritis. These drugs are known
can contribute to substantial improvements in quality- to increase pH within certain intracellular vacuoles in
of-life.12 macrophages and other immune-system cells.35 This
Hence, disease-modifying drugs are typically used effect is believed to disrupt the ability of these cells to
to control synovitis and erosive changes during the process antigenic proteins and present these antigens
active stages of rheumatoid joint disease.68 There is to T cells.107 Decreased T-cell stimulation results in
still considerable concern, however, over DMARD’s immunosuppression and attenuation of the arthritic
safety and efficacy. Older DMARDs, such as penicil- response.35 Antimalarials have also been shown to sta-
lamine and oral gold, were especially problematic, and bilize lysosomal membranes and impair DNA and
many patients who started treatment on these drugs RNA synthesis, although the significance of these
eventually discontinued drug therapy due to side effects in their role as antiarthritics remains unclear.107
effects or lack of therapeutic benefits.68 Some of the Adverse Side Effects. Chloroquine and hydro-
newer DMARDs are substantially more effective, but xychloroquine are usually considered the safest
these newer agents can still produce serious side effects DMARDs.68 The major concern is that high doses of
such as hepatic and renal toxicity.70 Despite these lim- these drugs can produce irreversible retinal damage.
itations, there has been a definite trend toward more Retinal toxicity is rare, however, when daily dosages
frequent DMARD use, and to use these drugs earlier are maintained below the levels typically used to treat
in the course of rheumatoid arthritis before excessive rheumatoid arthritis (i.e., less than 3.5 to 4.0 mg/kg
joint destruction has occurred.4,68 per day for chloroquine and less than 6.0 to 6.5 mg/kg
Disease-modifying agents currently used in treat- per day for hydroxychloroquine).60,63 Nonetheless,
ing rheumatoid arthritis are listed in Table 16–3. As ocular exams should be scheduled periodically to
the name implies, DMARDs attempt to induce remis- ensure the safe and effective use of these drugs during
sion by modifying the pathologic process inherent to prolonged administration.16 Other side effects such as
rheumatoid arthritis. In general, DMARDs inhibit headache and gastrointestinal distress can occur, but
certain aspects of the immune response thought to these are relatively infrequent and usually transient.
16Ciccone(p)-16 1/30/07 2:50 PM Page 223
Antimalarials
Chloroquine Aralen Oral: Up to 4 mg/kg of lean Periodic ophthalmic exams
body weight per day. recommended to check
for retinal toxicity.
Azathioprine Imuran Oral: 1 mg/kg body weight per Relatively high toxicity;
day; can be increased after should be used cautiously
6–8 wk up to maximum dose in debilitated patients or
of 2.5 mg/kg body weight. patients with renal disease.
Cyclophosphamide Cytoxan Oral: 1.5–2 mg/kg body weight Long-term use is limited
per day; can be increased to because of potential for
a maximum daily dose of 3 carcinogenicity.
mg/kg body weight.
Cyclosporine Neoral, Sandimmune Oral: 2.5 mg/kg body weight May cause nephrotoxicity
per day; can be increased and gastrointestinal
after 8 wk by 0.5–0.75 problems.
mg/kg body weight per day;
dose can be increased after
another 4 weeks to a maxi-
mum daily dose of 4 mg/kg
body weight per day.
Gold compounds
Auranofin Ridaura Oral: 6 mg/once each day or May have a long latency
3 mg BID (6–9 mo) before onset
of benefits.
Methotrexate Rheumatrex, others Oral: 2.5–5 mg every 12 hr for Often effective in halting
total of 3 doses/wk or 10 mg joint destruction, but
once each week. Can be long-term use may be
increased up to a maximum limited by toxicity.
of 20–25 mg/wk.
Penicillamine Cuprimine, Depen Oral: 125 or 250 mg/d; can be Relatively high incidence of
increased to a maximum of toxicity with long-term
1.5 g/d. use.
Sulfasalazine Azulfidine Oral: 0.5–1.0 g/d for the first Relatively high toxicity; may
week; dose can be increased produce serious hyper-
by 500 mg each week up sensitivity reactions and
to a maximum daily dose of blood dyscrasias.
2–3 g/d.
tential alternative in people who have failed to re- adenosine release may be especially important because
spond to other DMARDs such as methotrexate.59,70 increased amounts of endogenous adenosine can
Mechanism of Action. Leflunomide acts primarily inhibit various components of the immune response.92
by inhibiting the synthesis of RNA precursors in lym- Regardless of the exact mechanism, methotrexate has
phocytes.65,70 When stimulated, lymphocytes must become a mainstay in the management of rheumatoid
radically increase their RNA synthesis to proliferate arthritis.
and become activated during the inflammatory Adverse Side Effects. Methotrexate is a relatively
response. Leflunomide blocks a key enzyme responsi- toxic drug, and a number of adverse side effects can
ble for RNA synthesis, so that these lymphocytes can- occur.15,90 The primary problems involve the gastroin-
not progress to a more activated state and cannot cause testinal tract and include loss of appetite, nausea, and
as much joint inflammation.58,107 other forms of gastrointestinal distress (including
Adverse Side Effects. Leflunomide’s primary side intragastrointestinal hemorrhage).90 Long-term meth-
effects include gastrointestinal distress, allergic reac- otrexate use in patients with rheumatoid arthritis has
tions (skin rashes), and hair loss.57 This drug can also also been associated with pulmonary problems, hema-
affect the liver; liver function may need to be moni- tologic disorders, liver dysfunction, and hair loss.15
tored periodically.19,70 These side effects often limit the use of methotrexate
with rheumatoid arthritis, and most patients who stop
using this drug do so because of an adverse side effect
Methotrexate
rather than a loss of effectiveness.104 Methotrexate
Methotrexate (Folex, Rheumatrex) is an antimetabo- does, however, offer a favorable benefit-to-risk ratio in
lite used frequently in the treatment of cancer (see many patients and has become one of the most com-
Chapter 36). There is considerable evidence that this monly used DMARDs.
drug is also one of the most effective DMARDs.15,76
Methotrexate has been shown to slow the effects of
Penicillamine
rheumatoid arthritis as evidenced by decreased synovi-
tis, decreased bone erosion, and less narrowing of the Penicillamine (Cuprimine), a derivative of penicillin,
joint space.37 The therapeutic effects of methotrexate is officially classified as a chelating agent that is often
have also been reported to be equal to, or better than, used in the treatment of heavy metal intoxication (e.g.,
other DMARDs such as oral gold or azathioprine, and lead poisoning). In addition, this drug has been used in
methotrexate may offer an advantage in terms of a patients with severe rheumatoid arthritis, and seems to
rapid onset.68,90 Hence, methotrexate’s popularity as a be as effective as other DMARDs such as meth-
DMARD has increased during the past few years, and otrexate, sulfasalazine, and gold therapy.68,98 Penicil-
this drug is often the first DMARD used to treat lamine, however, tends to be substantially more toxic
rheumatoid arthritis in both adults and children.76 than other DMARDs, and is therefore used rarely in
Mechanism of Action. The ability of methotrexate the treatment of specific patients with rheumatoid
and similar anticancer drugs to impair DNA and RNA arthritis.68
synthesis is well known (see Chapter 36). Methotrex- Mechanism of Action. The basis for the antiar-
ate inhibits the synthesis of folic acid, thus inhibiting thritic effects of penicillamine is unknown. Reductions
the formation of nucleoproteins that serve as DNA in serum immunoglobulin M-rheumatoid factor have
precursors.20 This action inhibits cellular replication been observed with penicillamine, and this drug has
by impairing the cell’s ability to produce new genetic been shown to depress T-cell function.53 These and
material, an effect that helps attenuate tumor cell similar findings suggest that penicillamine works by
replication in cancer. Nonetheless, methotrexate’s suppressing the immune response in rheumatoid
effects on immune function and rheumatoid arthritis arthritis, but the exact mechanisms remain to be deter-
are somewhat unclear. This drug could affect immune mined.
function by inhibiting folic acid metabolism, thereby Adverse Side Effects. Penicillamine is considered
limiting the proliferation of lymphocytes and other to be fairly toxic when compared with other
cells that cause the autoimmune responses in rheuma- DMARDs.68 Side effects that have been reported as
toid disease. Methotrexate, however, also exerts other occurring more frequently include fever, joint pain,
effects, including inhibition of inflammatory cytokines skin rashes and itching, and swelling of lymph glands.
and stimulation of adenosine release.90 The effects on Other adverse effects that may occur less frequently
16Ciccone(p)-16 1/30/07 2:50 PM Page 227
are bloody or cloudy urine, swelling of feet and legs, and adalimumab can destroy cells that express TNF-
unusual weight gain, sore throat, and excessive fatigue. ␣, thus further reducing the destructive effects of this
cytokine.
There is substantial evidence that TNF-␣ inhibi-
Tumor Necrosis Factor Inhibitors
tors can retard the progression of inflammatory joint
Several agents are now available that inhibit the action disease, and promote improvements in symptoms and
of tumor necrosis factor-alpha (TNF-␣). TNF-␣ is a quality-of-life with rheumatoid arthritis.13,51 These
small protein (cytokine) that is released from cells drugs are not typically used as the initial treatment, but
involved in the inflammatory response. TNF-␣ seems can be used alone or added to other agents (e.g.,
to be a key chemical mediator that promotes inflam- methotrexate) if patients do not have an adequate
mation and joint erosion in rheumatoid arthritis.83 response to other DMARDs.45,91 There is some con-
Drugs that inhibit this chemical will therefore help cern about toxicity (see below), and these drugs must
delay the progression of this disease by decreasing be given parenterally, usually by subcutaneous injec-
TNF-␣’s destructive effects.70 tion (twice each week for etanercept; every other week
Drugs in this group include etanercept (Enbrel), for adalimumab), or by slow intravenous infusion
infliximab (Remicade), and adalimumab (Humira). (every eight weeks for infliximab). Nonetheless, TNF-
These drugs are also referred to as “biologic” ␣ inhibitors represent an important breakthrough in
DMARDs because they affect the biologic response to the drug treatment of rheumatoid arthritis.
a specific cytokine (TNF-␣).68 Etanercept was the first Mechanism of Action. As indicated, these agents
biologic DMARD— it was created by fusing human bind selectively to TNF-␣ (see Fig. 16–2).7,70,91 This
immunoglobulin (IgG) with an amino acid sequence action prevents TNF-a from binding to surface recep-
that mimics the binding portion of the TNF receptor. tors located on other inflammatory cells. TNF is
TNF-␣ recognizes the binding portion on the drug, therefore unable to activate other inflammatory cells
attaches to this portion, and therefore cannot bind to that cause inflammation and joint destruction in
the real TNF receptor. rheumatoid arthritis.70
The two newer agents (infliximab and adalimum- Adverse Side Effects. Patients taking TNF-␣
ab) were developed using monoclonal antibody tech- inhibitors may be prone to upper respiratory tract
niques. These techniques enable the drug to bind infections and other serious infections, including sep-
tightly to antigenic components on TNF-␣, thereby sis.48,51,83 This increased risk of infection probably
forming a drug-cytokine molecule that is too large to occurs because the drug inhibits a key component of
bind to the real TNF receptor. In addition, infliximab the immune response—namely, TNF-␣. These drugs
Infliximab
Etanercept Adalimumab
TNF-␣
Human Monoclonal
IgG Antibody
Joint Tissues
FIGURE 16–2 ▼ Schematic diagram illustrating the effects of tumor necrosis factor-alpha (TNF-
␣) inhibitors. Drugs such as etanercept, infliximab, and adalimumab attach directly to TNF-␣, thereby
preventing this destructive cytokine from reaching joint tissues. See text for more details.
16Ciccone(p)-16 1/30/07 2:50 PM Page 228
are therefore contraindicated in people with infec- patients with rheumatoid arthritis who have not
tions, and administration should be discontinued if an responded to other measures.54 Sulfasalazine (Azulfi-
infection develops. dine), a drug that is typically used to treat inflammato-
Other potential adverse responses include malig- ry bowel disease, may also be helpful in treating
nancy (e.g., lymphoma), liver disease, heart failure, rheumatoid arthritis because of its immunosuppressant
lupuslike disease, irritation around the injection site, effects.68 Cyclophosphamide (Cytoxan) is used prima-
and demyelinating disorders that mimic multiple scle- rily to treat cancer, but this agent can be used to sup-
rosis.34,70,88 The incidence of these adverse effects, press the immune system in severe cases of rheumatoid
however, seems to be fairly low. For the most part, arthritis.
these drugs provide an acceptable risk-to-benefit ratio In general, these drugs are more toxic and are
for most people with rheumatoid arthritis. Patients usually reserved for patients who have not responded
should, however, be screened carefully for any risk fac- to more traditional DMARDs such as methotrexate.
tors before beginning drug therapy, and should like- Drugs with immunosuppressant activity may also be
wise be monitored periodically for any potential used in combination with more traditional DMARDs
adverse reactions to these drugs. to provide optimal benefits in certain patients. Com-
bination drug therapy in rheumatoid arthritis is
addressed in the next section.
Anakinra
Anakinra (Kineret) blocks the effects of interleukin-1 DMARD Combinations Used
on joint tissues. Like TNF-␣, interleukin-1 is a
cytokine that promotes inflammation and joint
in Rheumatoid Arthritis
destruction in rheumatoid arthritis.23,36 By blocking There has been a great deal of interest in using sever-
interleukin-1 receptors on joint tissues, anakinra pre- al DMARDs simultaneously to achieve optimal effects
vents the destructive events mediated by this cytokine. in treating rheumatoid arthritis. The strategy of com-
This drug appears to be moderately effective in limit- bination therapy is to attack the underlying disease
ing the progression of rheumatoid arthritis, and it is process from several pharmacologic vantage points,
generally well tolerated.36 Hence, anakinra is another much in the same way that combination therapies are
option that can be used alone or in combination with used in other disorders such as hypertension (Chapter
other DMARDs such as methotrexate.23 21) and cancer (Chapter 36). Although the benefits of
Mechanism of Action. As indicated, anakinra is an combining DMARDs have been questioned, most
antagonist (blocker) that is specific for the interleukin- practitioners currently advocate a combination of
1 receptor found on joint tissues, other tissues, and two or more drugs so that optimal benefits can be
organs.23 By blocking this receptor, the drug prevents achieved with a relatively low dose of each drug.42,68
interleukin-1 from binding to this receptor and exert- Likewise, the best way to combine specific DMARDs
ing destructive effects on joint tissues. is still being investigated, with various combinations
Adverse Side Effects. Patients receiving anakinra of new and old DMARDs being studied for efficacy
may be more susceptible to bacterial infections and and toxicity.40,67 At present, methotrexate is typically
other infectious agents.70 This drug is administered the cornerstone of treatment, with other DMARDs
via subcutaneous injection, and irritation at the injec- added, depending on the needs of each patient.76 For
tion site is fairly common, but is usually not severe. example, a triple combination of methotrexate with
More serious systemic allergic reactions may occur in hydroxychloroquine and sulfasalazine has been advo-
a small number of patients.70 cated as an effective treatment for many patients.39 In
addition, some of the newer biologic agents such as
the TNF-␣ inhibitors (etanercept, infliximab,
Other DMARDs
adalamimab) and interleukin-1 inhibitors (anakinra)
Because of the autoimmune basis of rheumatoid have been added to methotrexate to provide an effec-
arthritis, various other drugs that affect the immune tive combination in patients who have not responded
response are used on a limited basis. For instance, to use of only one drug.31,68
cyclosporine (Sandimmune), an immunosuppressant The drawback of combination therapy is, of
agent that is used to prevent rejection of organ trans- course, the potential for increased toxicity and drug
plants (see Chapter 37), is sometimes used to treat interactions when several DMARDs are used simulta-
16Ciccone(p)-16 1/30/07 2:50 PM Page 229
neously.68 This fact is understandable, considering but rather an intrinsic defect in the joint cartilage.
that many DMARDs have a relatively high risk of tox- This defect causes a slow, progressive deterioration of
icity when used alone, and combining these drugs will articular cartilage that is accompanied by degenerative
certainly increase the risk of adverse drug reactions. bony changes, including thickening of the subchondral
There is, however, evidence that the incidence of side bone, creation of subchondral bone cysts, and forma-
effects is not necessarily greater when DMARD com- tion of large bony protrusions (osteophytes) at the
binations are used compared with a single drug such as joint margins.14 Osteoarthritis typically occurs in large
methotrexate.68,99 Hence, combination therapy con- weight-bearing joints such as the knees and hips, as
tinues to gain acceptance, and the use of two or three well as some of the smaller joints in the hands and
DMARDs early in the course of the disease may pro- feet.18 Patients are described as having primary osteo-
vide patients with the best hope for halting the pro- arthritis when there is no apparent reason for the onset
gression of rheumatoid arthritis.99 Continued research of joint destruction; in secondary osteoarthritis, a fac-
will hopefully lend additional insight to the best way tor such as previous joint trauma, infection, or meta-
that DMARDs can be combined to safely and effec- bolic disease is responsible for triggering articular
tively treat patients with rheumatoid arthritis. changes.14 Obesity, genetic susceptibility, and joint
vulnerability (malalignment, weakness, and so forth)
have also been implicated as predisposing factors in
Dietary Implications for osteoarthritis.30
Rheumatoid Arthritis Clearly, osteoarthritis is a different form of joint
disease than rheumatoid arthritis. Hence, treatment of
There is an ongoing search for other pharmaco- these conditions also differs somewhat. As discussed
logic and nonpharmacologic interventions that can previously, rheumatoid arthritis is characterized by a
help arrest the progression of rheumatoid joint severe inflammatory response that is perpetuated by a
disease. There is some evidence, for example, that cellular immune reaction. Thus, drug therapy in
dietary manipulation can alleviate the symptoms of rheumatoid disease consists of agents that are focused
rheumatoid arthritis.72 Diets that are high in fish oil on directly relieving these inflammatory symptoms
and certain fatty acids (e.g., gammalinolenic acid) have (i.e., NSAIDs or glucocorticoids) or drugs that
been advocated for patients with rheumatoid arthritis attempt to arrest the cellular immune response that
because these diets may supply precursors that enhance causes this inflammation (DMARDs). Treatment of
the biosynthesis of certain endogenous anti-inflamma- joint inflammation is not a major focus of drug thera-
tory and immunosuppressant compounds.81,85 Foods py in osteoarthritis, however. A mild inflammatory
that have antioxidant properties (e.g., fruits, vegeta- synovitis does occur in osteoarthritis, but this is sec-
bles) may also have beneficial effects in people with ondary to the articular damage inherent to this dis-
rheumatoid arthritis.81 On the other hand, diets that ease.14 Also, drug therapy represents one of the
are rich in meat and protein may exacerbate rheuma- primary interventions in rheumatoid arthritis, where-
toid arthritis and similar inflammatory diseases.21 as treatment of osteoarthritis should be focused more
Hence, dietary changes used in combination with drug directly on nonpharmacologic measures such as phys-
therapy may provide additional benefits for some peo- ical therapy, weight loss, and joint replacement in the
ple with rheumatoid arthritis. advanced stages of this disease.93
Hence, drug therapy in osteoarthritis is focused
primarily on helping patients manage their pain and
maintain an active lifestyle. When joint pain begins to
Osteoarthritis be a problem, simple analgesics such as acetaminophen
Osteoarthritis far exceeds rheumatoid arthritis as the and NSAIDs have been the major form of drug thera-
most common form of joint disease. The prevalence of py. Newer pharmacologic strategies are also emerging
osteoarthritis increases with age.2 Approximately 50 to that attempt to slow or reverse the pathologic changes
80 percent of people aged 65 years have osteoarthritis in osteoarthritis. These newer strategies use disease-
to some extent, and virtually everyone over 75 years modifying osteoarthritic drugs (DMOADs) rather
has some degree of osteoarthritic joint disease.14 In than drugs that treat only the symptoms of osteoarthri-
contrast to rheumatoid joint disease, osteoarthritis tis.28,90 Two types of DMOADs will be addressed:
does not seem to be caused by an immune response, drugs that attempt to directly improve the viscosity
16Ciccone(p)-16 1/30/07 2:50 PM Page 230
and function of synovial fluid (viscosupplementation) preliminary evidence, in fact, that some of the NSAIDs
and agents that serve as precursors to the normal may actually impair bone healing following fractures
constituents of joint tissues (glucosamine and chon- or surgery, but their effects on cartilage formation and
droitin sulfate). soft tissue repair remain unclear (see Chapter 15).26,46
At the present time, however, acetaminophen and
NSAIDs remain the cornerstone of the pharmacolog-
Acetaminophen and NSAIDs ic treatment of joint pain in osteoarthritis.
Acetaminophen is often the first drug used to treat os-
teoarthritis.9,10 As indicated in Chapter 15, acetamin- Viscosupplementation
ophen is as effective as NSAIDs in controlling pain,
but acetaminophen does not have anti-inflammatory Viscosupplementation is a clinical procedure that is
effects. The lack of anti-inflammatory effects is of less being used increasingly in the treatment of
concern when acetaminophen is used in osteoarthritis osteoarthritis. This technique uses a substance known
because the inflammatory symptoms are milder. Aceta- as hyaluronan to restore the lubricating properties of
minophen is therefore successful in reducing pain, and synovial fluid in osteoarthritic joints.6,41 Hyaluronan is
because this drug does not cause gastric irritation, acet- a polysaccharide that can be injected into an arthritic
aminophen is often considered the drug of choice in joint to help restore the normal viscosity of the syn-
mild-to-moderate osteoarthritis.9,108 Hence, acetamin- ovial fluid.6 This treatment helps reduce joint stresses,
ophen provides a relatively safe and effective form of thus limiting the progression of articular destruction
analgesia for patients with osteoarthritis, especially seen in osteoarthritis.106 Viscosupplementation has
when this drug needs to be administered for long peri- therefore been shown to reduce pain and improve
ods of time.9 function in osteoarthritis.1,95
NSAIDs are also used for the symptomatic treat- When used to treat osteoarthritis, viscosupple-
ment of pain in osteoarthritis.10,75 These drugs are mentation typically consists of 2 to 10 weekly injec-
used primarily for their analgesic properties, although tions of hyaluronan Hyalgan, Synvisc, others. Patients
the anti-inflammatory effects of NSAIDs can help often experience a decrease in pain within days after
control the mild synovitis that typically occurs in injection, and pain continues to diminish within the
advanced osteoarthritis secondary to joint destruc- first weeks after treatment. Duration of relief is vari-
tion.75 If the primary goal is pain reduction, however, able, but most patients who respond to viscosupple-
NSAIDs do not provide any advantage over acetamin- mentation experience beneficial effects for 6 months to
ophen. As indicated earlier, acetaminophen is often a 1 year after a series of injections.74
better choice than traditional NSAIDs because most Hence, viscosupplementation may temporarily
NSAIDs cause gastric irritation. The newer COX-2 attenuate the progressive changes in joint structure and
selective NSAIDs (see Chapter 15) do not appear to function typically seen in osteoarthritis. Although
cause as much gastric irritation as other NSAIDs, and these benefits are relatively transient, viscosupplemen-
these COX-2 drugs may be a valuable alternative to tation can delay the need for more invasive surgical
acetaminophen and traditional NSAIDs in the long- treatments such as joint replacement. This interven-
term treatment of osteoarthritis. COX-2 drugs, how- tion is also tolerated fairly well, although a pseudosep-
ever, may increase the risk of serious cardiovascular tic reaction that produces local pain and swelling may
problems (heart attack, stroke), and patients should be occur.41,106 Future clinical studies will be needed to
screened carefully for cardiovascular risk factors determine how viscosupplementation can be used most
before beginning treatment with COX-2 drugs.44 effectively in the comprehensive treatment of people
Regardless of the exact drug used, there is no with osteoarthritis.
doubt that the analgesia produced by NSAIDs or acet-
aminophen plays a valuable role in the management of
osteoarthritis. These drugs allow the patient to main-
Glucosamine and Chondroitin Sulfate
tain a more active lifestyle and to participate in various It has been suggested that dietary supplements such
activities, including exercise programs and other forms as glucosamine and chondroitin sulfate may help pro-
of physical therapy and occupational therapy. Howev- tect articular cartilage and halt or reverse joint degen-
er, these drugs do not alter the progressive course of eration in osteoarthritis. These two compounds are
joint destruction and osteoarthritic changes. There is key ingredients needed for the production of several
16Ciccone(p)-16 1/30/07 2:50 PM Page 231
components of articular cartilage and synovial fluid, in- nover may be more likely to experience positive effects
cluding glycosaminoglycans, proteoglycans, and hyalu- because these supplements will provide the necessary
ronic acid.71,112 It seems reasonable that increased substrates to sustain this turnover and maintain joint
amounts of these ingredients should facilitate the integrity.22
repair of joint tissues, improve synovial fluid viscosity, Consequently, it appears that glucosamine and
and help restore joint function in conditions like chondroitin supplements are certainly worth a trial for
osteoarthritis. Hence, several products containing glu- many patients with osteoarthritis. Some gastrointesti-
cosamine, or glucosamine combined with chondroitin nal problems may occur, but these supplements are
sulfate, are currently available as nonprescription usually well tolerated. Although these supplements are
dietary supplements. These supplements typically con- available over-the-counter in the United States, peo-
tain oral dosages of 1500 mg/d glucosamine and 1200 ple with osteoarthritis should consult their physician
mg/d chondroitin sulfate.82 and pharmacist before self-administration. Likewise,
Several recent studies suggest that chondroitin patients should be educated on the proper dosage, and
and glucosamine supplements can decrease pain and should be reminded that these products may need to
improve function in some patients with osteoarthri- be consumed for several weeks or months before ben-
tis.47,62,64 Radiographic studies also indicate that these eficial effects become apparent. Long-term studies on
supplements can reduce joint space narrowing in knee the effects of these supplements are currently being
osteoarthritis, thus providing some protective effects conducted, and clinicians should try to stay abreast of
on joint structure.78,82 These benefits may not occur in any new information about the potential benefits of
all patients—patients with a high rate of cartilage tur- glucosamine and chondroitin.
cillamine, and these effects may also become a problem during rehabilitation. A variety of other
side effects can occur, depending on the particular DMARD being used and the sensitivity of
the patient. Therapists should be aware of any changes in patient response, not only when a new
drug is being started but also during the prolonged use of DMARDs.
Finally, the use of DMOADs (viscosupplementation, glucosamine, chondroitin) to restore
joint function in osteoarthritis is fairly new, and it is not clear if these techniques will have any
side effects that will have a direct impact on physical rehabilitation. Likewise, it remains to be
seen if there are any rehabilitation techniques (exercise, physical agents) that could enhance the
effectiveness of DMOADs. It is hoped that these techniques will work synergistically with phys-
ical therapy to improve function in patients with osteoarthritic joints.
CA S E ST U DY
Rheumatoid Arthritis legs. The therapist noticed this while preparing the patient for
her paraffin treatment. It seemed that these rashes might be
Brief History. A.T., a 75-year-old woman, was diag- occurring as a side effect of the auranofin. The therapist
nosed with rheumatoid joint disease several years ago. She brought this to the attention of the physician, who concurred
is currently being seen three times each week in physical that this was probably a side effect of the gold therapy.
therapy as an outpatient for a program of paraffin and active Decision/Solution. The patient was temporarily
exercise to her wrists and hands. Resting splints were also removed from auranofin therapy to see if this skin reaction
fabricated for both hands, and these are worn at night to would subside. In the interim, the therapist discontinued
prevent joint deformity. The patient was also instructed in a paraffin so that the rashes and itching would not be exacer-
home exercise program to maintain joint mobility in both bated. To continue to provide gentle heat, a warm whirlpool
upper extremities. Pharmacologic management in this patient (100⬚F) was substituted for the paraffin bath. Also, the night
originally consisted of NSAIDs, beginning with aspirin and splints were temporarily discontinued to prevent irritation to
later switching to ibuprofen. Six months ago, she was also the affected areas. After 2 weeks, the skin rashes had virtual-
placed on auranofin (Ridaura), which was instituted in an ly disappeared, and the original physical therapy program was
attempt to halt the progressive arthritic changes. This orally resumed. After another week, the physician restarted
administered gold compound was given at a dosage of 3 mg DMARD therapy in the form of low dose methotrexate com-
twice each day. bined with etanercept (Enbrel). This combination was intend-
Problem/Influence of Medication. The combina- ed to provide a more comprehensive antiarthritic regimen,
tion of an NSAID and a disease-modifying drug, along with while reducing the chance of the allergic response that is
the physical therapy program, seemed to be helping to common with gold compounds. No other adverse effects
decrease the patient’s pain and joint stiffness. However, she were noted, and the patient continued to notice improve-
began to develop skin rashes and itching on her arms and ments in her arthritic condition.
there is some concern about the efficacy and safety of the synovial fluid in osteoarthritic joints. Dietary sup-
these drugs, DMARDs have been a welcome addition plements containing glucosamine and chondroitin sul-
to the rather limited arsenal of drugs used to treat fate may also help provide constituents that protect
rheumatoid arthritis. joint structure and function, and some people with
Drug treatment of osteoarthritis differs some- osteoarthritis have benefited from their long-term
what from that of rheumatoid arthritis, with manage- use. In any event, drug therapy along with nonphar-
ment of pain by using NSAIDs and acetaminophen macologic measures such as physical therapy can pro-
constituting the major forms of drug therapy. A newer vide an effective way of dealing with the potentially
technique known as viscosupplementation has also devastating effects of rheumatoid arthritis and
been used to help restore the lubricating properties of osteoarthritis.
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effects of nonsteroidal anti-inflammatory drugs on 64. McAlindon TE, LaValley MP, Gulin JP, Felson DT.
bone healing: a concise review. J Clin Pharmacol. Glucosamine and chondroitin for treatment of
2003;43:807–815. osteoarthritis: a systematic quality assessment and
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in rheumatoid arthritis: the challenges of study design. 66. Morrow JD, Roberts LJ. Lipid-derived autacoids:
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Chapter 17
Patient-Controlled Analgesia
Patient-controlled analgesia (PCA) was first intro- systems are often a preferred method of managing
duced into clinical practice in the early 1980s as an pain in contemporary practice.
alternative way to administer analgesic medications.
The basic principle behind PCA is that the patient can
self-administer small doses of the drug (usually an opi- Pharmacokinetic
oid) at relatively frequent intervals to provide optimal
pain relief.32 These small doses are typically delivered
Basis for PCA
intravenously or into the spinal canal by some type of To provide optimal management of pain, analgesic
machine (pump) that is controlled by the patient. drugs should be delivered into the bloodstream or
Patient-controlled analgesia has several advantages other target tissues (epidural space, within joints, and
over more traditional dosing regimens. In particular, so forth) in a predictable and fairly constant manner.
PCA systems often provide equivalent or increased The goal is to maintain drug levels within a fairly well-
analgesic effects with a lower incidence of side effects defined range, or therapeutic window.32 Such a thera-
while using less of the drug.9,32 This fact has generat- peutic window for systemic (intravenous) dosages is
ed a great deal of interest and increased use of PCA in represented schematically by the shaded area in Figure
a variety of clinical situations. For instance, PCA sys- 17–1. If drug levels are below this window, the anal-
tems have been used to help manage acute pain fol- gesic is below the minimum analgesic concentration,
lowing surgery, and PCAs have also been used to treat and the patient is in pain. Drug levels above the win-
pain in patients with cancer and other conditions asso- dow may produce adequate analgesia but may also
ciated with chronic pain.10,19 produce side effects such as sedation. The traditional
Hence, PCA continues to gain acceptance as an method of administering analgesics is to give relative-
optimal method for treating pain. Because PCA is used ly large doses with relatively large time intervals
extensively to treat acute and chronic pain, rehabilita- between each dosage. For instance, opioid analgesics
tion specialists should be aware of some of the funda- are typically injected intramuscularly every 3 to 4
mental principles governing PCA. This chapter begins hours to manage severe pain, thus creating large fluc-
by discussing the basic concepts and strategies of PCA, tuations in the amount of drug present in the body.
followed by some of its practical aspects, including the The dark solid lines in Figure 17–1 illustrate these
types of analgesics used, the possible routes of admin- large fluctuations. As illustrated in Figure 17–1, this
istration, and the types of machines used to administer traditional method of administration is associated with
the drugs. An indication of why PCA is often clinical- long periods of time when the drug concentration falls
ly superior to more traditional methods of analgesia is below the therapeutic window, allowing pain to occur,
then presented. Finally, potential problems associated or above the therapeutic window, causing sedation.
with PCA and the specific ways that PCA can affect Figure 17–1 also illustrates why PCA systems are
patients receiving physical therapy and occupational better at maintaining drug levels within the therapeu-
therapy are discussed. It is hoped that this will provide tic (analgesic) window. Systems using some form of
the reader with a better understanding of why PCA PCA deliver small doses of the analgesic on a relative-
237
17Ciccone(p)-17 2/2/07 6:59 PM Page 238
Analgesia Sedation
minimal minimal
analgesic analgesic
concentration concentration
dose dose dose
Pain
600 800 1000 1200 1400
Time (hours)
FIGURE 17–1 ▼ Pharmacokinetic model for PCA using opioid drugs. Conventional intramuscular
injection is indicated by the long solid lines, PCA is indicated by the short dashed lines, and the thera-
peutic window for analgesia is indicated by the shaded area. (From Ferrante, et al. Anesth Analg.
1988;67: 457–461; with permission.)
ly frequent basis, as indicated by the dashed lines. analgesic to the therapeutic window, as illustrated by
Drug levels are maintained within the analgesic range; the shaded area in Figure 17–1.
there are shorter periods of time when the drug con-
centration falls below the therapeutic window (i.e.,
below the shaded area), and there is virtually no time
Demand Dose
when side effects occur because the concentration The amount of drug that is self-administered by the
rises above the therapeutic window. Hence, analgesia patient each time he or she activates the PCA delivery
can be achieved more effectively with a reduced inci- mechanism is known as the demand dose. The magni-
dence of side effects. tude of these doses for some commonly used opioid
analgesics is listed in Table 17–1.
Background Infusion Rate most patients, but may still be used in specific cases
such as patients who need larger amounts of opioids to
In some patients, a small amount of the analgesic is control pain, especially during sleep.34
infused continuously to maintain a low, background
level of analgesia. Demand doses are superimposed on
the background infusion whenever the patient feels an Successful Versus Total Demands
increase in pain (e.g., the so-called breakthrough pain Successful demands occur when the patient activates
that may occur when the patient coughs or changes the PCA delivery system and actually receives a
position). The use of background infusion basically demand dose of the drug. Demands made during the
combines the technique of continuous infusion with lockout interval are not considered successful, but are
PCA, which may provide optimal analgesia with min- added to the number of successful demands to indicate
imal side effects.38 Background infusion, for example, the total demands. A large number of unsuccessful
can maintain adequate analgesia even when patients demands may indicate that the PCA parameters are
are asleep or otherwise unable to activate the pump not effective in providing adequate analgesia. There-
manually. fore, most PCA systems record the number of total
Nonetheless, routine use of background infusion demands so that the demand dose can be adjusted if a
has been questioned, especially when opioids are large number of unsuccessful demands are being made.
administered systemically (intravenously) by PCA. It
appears that background infusions may not provide
any additional analgesic benefits in most patients, but Types of Analgesics
they can lead to an increased risk of side effects such
as respiratory depression because patients ultimately
Used for PCA
receive a larger total amount of opioid (i.e., the back- Opioid analgesics (see Chapter 14) are the primary
ground infusion plus the demand doses).8,34 Hence, medications used during PCA.9 Opioids such as mor-
background infusion rates have been discouraged for phine, meperidine, tramadol, fentanyl, and fentanyl
17Ciccone(p)-17 2/2/07 6:59 PM Page 240
derivatives (alfentanil, remifentanil) are powerful anal- (IV) line. The catheter is then connected to a PCA
gesics that act primarily on the spinal cord and brain pump (see later), and small intermittent doses of the
to inhibit the transmission and perception of nocicep- analgesic are administered through the catheter and
tive impulses. Opioids must be used cautiously be- delivered directly into the systemic circulation. This
cause these drugs can cause serious side effects and technique is often effective in allowing the patient to
have the potential for patient overdose. As explained regulate his or her level of analgesia for a short period
earlier, PCA often provides a safer and more effective of time (e.g., for the first few days after surgery).
way to administer these powerful drugs by preventing When PCIA is needed for longer periods, a
large fluctuations in plasma opioid levels. catheter can be implanted surgically in a large central
Likewise, a number of nonopioid analgesics have vein, with the tip of the catheter advanced to the right
been combined with opioids during systemic (intra- atrium of the heart. The catheter is then tunneled
venous) PCA to decrease the amount of opioid needed through subcutaneous tissues and brought out
for adequate analgesia. This “opioid sparing” effect can through the patient’s skin to allow administration of
be achieved by combining morphine or other opioids PCA. Alternatively, the catheter can be connected to a
with ketorolac (an NSAID; see Chapter 15), ketamine small container known as an access port, which is
(an anesthetic agent; see Chapter 11), or droperidol (an implanted subcutaneously within the patient’s body
antipsychotic; see Chapter 8).15,33,43 Alternatively, a (Fig. 17–2). This type of catheter-port system is used
very low dose of an opioid receptor antagonist (block- to provide a method of IV drug delivery that is locat-
er) such as naloxone (see Chapter14) can also be ad- ed primarily within the patient’s body. Injections can
ministered along with the opioid during PCA. be made through the skin and into the port through a
Preliminary evidence suggests that a low dosage of the self-sealing silicone rubber septum located on the
opioid antagonist may block certain opioid side effects port. When these ports are used during PCA, the
(nausea, pruritus) while still allowing an adequate level external PCA source is connected to the port via a spe-
of analgesia.11,36 cial (Huber) needle that is inserted through the skin
Local anesthetics such as bupivacaine and ropiva- and into the port (see Fig. 17–2). The analgesic drug
caine have also been used during PCA (see Chapter is then given from the PCA pump through a catheter
12). These drugs, which block transmission along into the port and ultimately into the systemic circula-
afferent sensory neurons, can be administered epidu- tion. This provides an effective way of getting small,
rally to block sensation at the spinal cord level. Local frequent doses of the drug into the bloodstream with
anesthetics are often administered when an epidural less risk of infection or intravenous catheter displace-
PCA is used during labor and childbirth.23 These ment. This type of PCA-port delivery also enables the
drugs have also been mixed with opioids to
provide optimal epidural PCA during labor or follow-
ing surgery.2,4,25 Local anesthetics can also be applied
to a specific site such as the subacromial space or Self-sealing septum
around a specific peripheral nerve. This technique,
known as patient controlled regional anesthesia
(PCRA), is discussed later. Hence, local anesthetics
serve as an alternative or adjunct to opioids during Skin line
several types of PCA.
patient to be disconnected from the PCA delivery sys- means “within a sheath”; see Chapter 2). Although
tem for short periods of time by removing the needle intrathecal administration can be used in certain situ-
from the port. This allows the patient to bathe or get ations, the epidural route seems to be the preferred
dressed without risking damage to the indwelling method during PCA because it is safer and there is less
port-IV system.17 risk of damaging the meninges.
If PCEA is intended for short-term use, the
Epidural PCA catheter can be externalized through the skin on the
midline of the patient’s back and held in place by sur-
Patient controlled epidural analgesia (PCEI) is
gical tape. For long-term use, the catheter is often
achieved by administering drugs directly into the area
tunneled through the subcutaneous tissues in the
outside of the membranes (meninges) surrounding the
patient’s abdominal wall, after which the catheter can
spinal cord.9 This is typically done by inserting a small
either be brought out through the skin on the patient’s
catheter so that the tip of the catheter lies in the
side (see Fig. 17–3) or connected to some type of
epidural space at a specific level of the spinal cord (Fig.
implanted access port or drug reservoir. In either case,
17–3). Alternatively, the tip of the catheter can be
PCEA is achieved by using a pump to deliver the drug
placed in the subarachnoid space—this type of deliv-
through the catheter and into the area directly sur-
ery is known as spinal or intrathecal administration.
rounding the spinal cord.
That is, the drug is delivered into the space between
Administration of drugs into the epidural space
the middle (arachnoid) layer of the meninges and the
is obviously more difficult than simple intravenous
inner (pia mater) meningeal membrane (intrathecal
delivery using a peripheral vein. Epidural delivery
does, however, offer advantages in terms of providing
more effective analgesia with a smaller amount of
drug. For instance, it is estimated that epidural mor-
phine is 5 to 10 times more potent than IV morphine,
indicating that less drug needs to be administered by
the epidural route to achieve adequate analgesia.17
This fact makes sense, considering that PCEA admin-
isters the drug closer and more directly to the spinal
cord compared with the amount of drug that must be
added to the bloodstream via PCIA so that enough
medication eventually reaches the spinal cord via the
Insertion Site systemic circulation. Likewise, there have been
- Epidural numerous studies that directly compared PCEA with
- Intrathecal other parenteral administration routes, including
Exit Site PCIA. Although these studies varied in the type of
analgesic drugs used and the clinical indication (i.e.,
pain control following various types of surgery), they
routinely found that PCEA provided superior pain
control without a significant increase in side
effects.6,26,40,49 By improving pain control after surgery,
PCEA can also facilitate early recovery and rehabilita-
tion in situations such as total knee arthroplasty.24
Implanted
Pump Transdermal PCA
Patient controlled transdermal analgesia (PCTA) is
one of the newest variations on PCA. PCTA uses a
FIGURE 17–3 ▼ Schematic illustration of PCA spinal delivery. The delivery system consisting of a small patch that is
catheter delivers the analgesic into either the epidural or intrathecal
approximately the size of a credit card.29,45 This patch
(subarachnoid) space. Catheters for long-term use are tunneled under
the skin (dashed line) and can either be connected directly to an is adhered to the patient’s skin, usually on the arm or
implanted PCA pump, or exit the anterior-lateral flank for connection to upper chest. The patch is impregnated with an opioid
an external pump. such as fentanyl, and the patient can self-administer a
17Ciccone(p)-17 2/2/07 6:59 PM Page 242
small dose of the drug by pushing a button located on these perineural applications can help control pain fol-
the patch. One such system is now commercially avail- lowing various types of surgery.21,28 These regional
able, and will deliver 40 g of fentanyl over a 10 administration techniques can, of course, also be
minute period each time the patient activates the accomplished by delivering a single (one-shot) dose of
patch.29,44 the medication, or via continuous infusion of the local
Hence, PCTA is similar to other iontophoresis anesthetic into the affected site.9 Nonetheless, use of
techniques that use a small amount of electric current some type of patient-controlled pump offers the addi-
to facilitate transdermal delivery. PCTA, however, tional benefit of allowing the patient to regulate the
offers the additional benefit of allowing the patient amount of medication, and may improve patient satis-
to activate drug delivery, thus helping to match the faction because the patient is more engaged in his or
amount of medication delivered to each patient’s her own pain control. Hence, PCRA can be used alone
specific needs. Because no needle is required, this tech- or incorporated into more traditional analgesic regi-
nique also offers the obvious advantage of a noninva- mens as an effective way to control local pain in a vari-
sive method for PCA. Patients can likewise remain ety of situations.
more mobile because there is no IV line connect-
ing the patient to a PCA pump.13 Moreover, several
studies have documented that PCTA using fentanyl PCA Pumps
can provide pain control that is superior to placebo
and comparable to standard postoperative analgesic The increase in popularity and use of PCA has largely
techniques such as morphine PCIA.14,45 Thus, PCTA been because of the development of infusion devices
is one of the more exciting innovations in pain control, that can administer the analgesic in a safe and accurate
and future research will help clarify how this technique manner. These devices, or pumps, vary in technologic
can be used effectively as an analgesic technique. sophistication and cost, but they all share common
features (some are summarized in Table 17–2).37 PCA
pumps essentially allow the practitioner to set specific
parameters of drug delivery (demand dose, lockout
Regional PCA interval, etc.). The pump must then provide features
Patient controlled regional analgesia (PCRA) occurs to safeguard the patient against pump malfunction and
when the patient self-administers the medication to warn the patient or caregiver if drug delivery is
directly into a specific anatomical site, such as a interrupted.
peripheral joint, near a peripheral nerve, or into a Pumps used for PCA fall into two basic categories:
wound. This technique helps localize the drug to the external and internal (implantable).39 The most basic
site of administration, thereby providing adequate pain type of external pump is a simple syringe driver (Fig.
control with minimal effects on other tissues and 17–4). A syringe containing the medication is placed in
organs. Although this technique has been used to a viselike machine that advances the syringe a small
administer analgesic medications such as morphine, amount when the patient activates the pump. A second
PCRA typically uses some type of local anesthetic such type of pump uses some sort of peristaltic action that
as bupivacaine or ropivacaine. Hence, this technique is sequentially compresses a piece of tubing to milk the
really analogous to patient-controlled regional anesthe- medication through the tubing toward the patient. A
sia rather than a strictly analgesic intervention. third pump, known as a cassette system, works by
Regardless, PCRA is an innovative way to provide safe drawing the medication into a fluid container within
and effective pain control. the pump and expelling the selected amount of med-
PCRA is typically accomplished by inserting a ication out of the chamber into tubing that leads to the
small catheter into the affected site, and then attach- patient. In most cases, these external pumps are acti-
ing the catheter to some type of pump that enables the vated when the patient pushes a button located on the
patient to self-administer small amounts of medication end of a pendant that is connected to the pump (see
as needed. For example, a PCA system has been used Fig. 17–4).
to deliver local anesthetics such as bupivacaine and Disposable models of external PCA pump are
ropivacaine into the subacromial space following acro- also available, offering a simple and less costly method
mial decompression surgery.3,27 Likewise, PCRA can for pain management.32,42 Rather than using sophisti-
be used to deliver a local anesthetic to the area around cated electronic controls, these disposable pumps
a peripheral nerve (sciatic, popliteal, and so forth), and are typically activated when the patient squeezes a
17Ciccone(p)-17 2/2/07 6:59 PM Page 243
Abbott LifeCare
Feature Abbott AMP II 4100 PCA Plus II Baxter 6060 Baxter PCA II
Ambulatory Use Yes No Yes No
Size (inches) 6.75 ⫻ 4.0 ⫻ 2.3 8.25 ⫻ 13.4 ⫻ 6.0 4.7 ⫻ 3.9 ⫻ 2.3 13.0 ⫻ 6.3 ⫻ 2.8
Power source Wall plug in AC; 2 ⫻ Wall plug in AC; one 2 ⫻ 9-volt alkaline Four D-cell alkaline bat-
9-volt alkaline bat- 8-volt sealed or lithium batter- teries; AC power kit
tery; NiCd recharge- lead-acid battery ies; external lead- with two recharge-
able battery pack acid battery pack able NiCd batteries
Comments Meets all basic Performs adequately, Meets most require- Meets most require-
requirements for but has a number ments; has a mix ments and offers
performance, safety, of minor draw- of minor advan- some advantages,
and ease of use. backs in its ease tages and disad- but also has some
of use and safety vantages; ease of drawbacks, most
features. use is only fair. notably in its data
logs and alarms.
Source: Adapted from Patient-controlled analgesic infusion pumps. Health Devices. 2001;30:168, 169, 182;
with permission.
small bulb containing a small dose (i.e., the demand best serve the patient’s needs, as well as cost and avail-
dose) of medication. As with other PCA pumps, safe- ability of a given type of pump. Advances in pump
guards are built in to limit how often these demand technology will continue to improve the available
doses can be administered. Thus, disposable PCA devices, and future developments will undoubtedly
pumps offer a cost-effective alternative that patients provide devices that are even more efficient in provid-
can use in the hospital or after discharge following ing PCA.
surgery.32,42
Internal, or implantable, pumps are placed surgi-
cally beneath the patient’s skin and connected to a
catheter leading to the patient’s bloodstream or Comparison of PCA
perispinal spaces (epidural or intrathecal). This basi- to Traditional Methods
cally creates a closed system within the patient’s body. of Analgesic Administration
These pumps typically contain a reservoir filled with
medication. The reservoir can be refilled by inserting From the pharmacokinetic perspective discussed
a Huber needle through the skin and into the pump previously, it is apparent that giving small, frequent
via a resealable septum located on the outside of the doses of analgesic through PCA is superior to admin-
pump (Fig. 17–5). Some implantable pumps use a istering large doses at infrequent intervals. Many
rotatory peristaltic mechanism to milk the medication clinical studies have attempted to verify this by com-
out of the pump. Other pumps use a bellows system to paring PCA using opioid drugs with traditional intra-
compress a chamber within the pump, thus expelling a muscular (IM) opioid injection. Although some studies
given quantity of the drug. Implantable pumps are have not shown any clear advantages or disadvantages
often programmed through the skin with some sort of of PCIA,34 most controlled trials indicate that PCA
electronic control device. administered either intravenously or epidurally pro-
The type of pump that is selected depends prima- vides improved analgesia without a substantial increase
rily on which method (external or implantable) will in side effects.5,6,7,12,22,46
17Ciccone(p)-17 2/2/07 6:59 PM Page 244
administering analgesics or adjusting the rate of anal- of opioids are given via PCA.9,32 In fact, the risk of res-
gesic delivery. Intramuscular injection, for instance, piratory depression is believed to be negligible when
requires that the nurse be available at the proper time opioids are administered through spinal routes
to inject the proper amount of the correct drug into (epidural and intrathecal).17 Hence, there does not
the correct patient. This clearly takes the locus of con- seem to be an increase in the side effects commonly
trol out of the patient’s hands and makes the patient seen when PCA techniques are used to administer opi-
feel more dependent on an outside person to provide oids, and the side effects commonly associated with
pain relief. When PCA systems are used appropriate- these drugs may even be reduced during certain types
ly, pain control is literally in the patient’s hands. Like- of PCA application.
wise, continuous infusion often requires frequent The incidence of side effects during PCA with
adjustments by a qualified person who must attempt to local anesthetics is not well defined. Local anesthetics
match the dose of analgesic to the patient’s pain level. could conceivably cause sensory loss and motor weak-
This is especially difficult if pain levels are changing, ness below the level of administration during PCEA.
such as in the patient recovering from surgery. With The possibility of these effects is directly dependent
PCA, the patient is able to automatically adjust the on the dose and type of local anesthetic, and efforts are
amount of analgesia according to his or her pain. usually made to use lower doses of agents such as
Again, this underscores a key advantage of PCA: it is bupivacaine and ropivacaine because these drugs tend
superior to more traditional methods of analgesia to produce sensory effects with minimal motor loss.
because the person most qualified to judge his or her Also, local anesthetic side effects can be minimized
pain is empowered to self-administer the analgesic during PCEA by combining the local anesthetic with
according to his or her own needs. an opioid, thus decreasing the total amount of each
drug.9 Some degree of sensory and motor loss will also
occur when local anesthetics are administered into
Problems and Side other peripheral sites, especially when these agents are
administered near specific peripheral nerves (i.e., per-
Effects of PCA ineural PCRA). Hence, transient sensory and motor
Pharmacologic Side Effects loss must always be considered as a potential side
effect when local anesthetics are used during PCA.
Side effects typically seen when opioids are used for
PCA include sedation, pruritus, and gastrointestinal
problems (nausea, vomiting). The incidence of these
Problems with PCA Delivery
side effects, however, is not significantly increased dur- Other problems that can occur with PCA systems
ing PCA versus more traditional methods of opioid include errors on the part of the operator (nurse, physi-
administration such as intermittent intramuscular dos- cian, etc.) or the patient, and mechanical problems
ing.18 Respiratory depression is another common side with the pump-delivery system.18 These problems are
effect of opioid use, but again, there is no increased summarized in Table 17–3. Operator errors typically
incidence of this problem when appropriate amounts occur because the pump is not programmed correctly
Table 17–3 SUMMARY OF PROBLEMS THAT CAN OCCUR DURING PCA THERAPY
or some other error occurs in loading the analgesic.18 during PCA, as evidenced by an increase in analgesic
Errors on the part of the patient can occur if the side effects, or that the analgesic is being underdeliv-
patient is not properly educated in PCA use or if the ered, as indicated by inadequate pain control.
patient lacks adequate cognitive skills to use the PCA
correctly. Problems can likewise occur if the patient
intentionally tries to administer more drug than neces-
SUMMARY
sary to adequately control pain; that is, the patient PCA allows the patient to self-administer a small
attempts to use the PCA as a form of drug abuse. amount of analgesic medication on a relatively fre-
Although the safeguards provided by the device (small quent basis. This technique has been used to adminis-
demand dose, appropriate lockout interval) should pre- ter drugs such as opioids and local anesthetics. PCA
vent addiction, these PCA systems are not usually as can often provide better pain control with smaller
successful in controlling pain in people with a history quantities of the drug and a lower incidence of side
of opioid addiction. Finally, mechanical problems, effects. The patient is allowed to self-administer a
including pump malfunction and clogging or displace- small dose of the drug by pressing a button that is
ment of the delivery tubing, may preclude delivery of connected to some type of pump. These PCA pumps
the analgesic. Members of the health-care team should vary in cost, level of sophistication, and location
be alert for signs that the drug is being overdelivered (external versus surgically implanted), but all pumps
CA S E ST U DY
Patient-Controlled Analgesia and he seemed to understand how to use this device
properly.
Brief History. S.G., a 61-year-old man, was being Problem/Influence of Drug Therapy. When seen at
treated for severe osteoarthritis in the right knee. Following an bedside on the day following surgery, the patient was in obvi-
unsuccessful course of conservative therapy, S.G. was admit- ous discomfort. Pain was rated in the 8- to 9-cm range of the
ted to the hospital for a total knee replacement. The surgery VAS. The patient stated that he had been using the PCA as
was performed successfully, and PCA was instituted for post- instructed and that the device had been recording his suc-
operative pain management. PCA consisted of an external cessful attempts with an audible signal. Upon closer inspec-
syringe pump connected to an IV catheter. The analgesic, tion, however, the therapist noticed that the syringe was not
meperidine (Demerol), was used at a concentration of 10 properly engaged in the pump mechanism. Hence, the
mg/mL. Parameters for PCA were set by the physician to syringe was not being propelled forward, and the demand
allow a demand dose of 1 mL (10 mg) with a lockout interval dose was not being administered.
of 10 minutes. An initial or loading dose of 10 mg was also Decision/Solution. The PCA malfunction was brought
provided at the conclusion of the surgery. Physical therapy to the attention of the nursing staff, and the problem was
was initiated at the patient’s bedside on the afternoon follow- quickly rectified. The syringe containing the opioid had appar-
ing surgery. The therapist found the patient groggy, but the ently been refilled earlier in the day and had not been installed
patient was coherent and able to understand simple com- properly in the pump’s syringe driver. The patient was given
mands. Pain, as assessed by a visual analog scale (VAS), was an initial 10-mg infusion, and PCA was then resumed accord-
rated in the 4- to 5-cm range of a 10-cm scale (10 cm being ing to the original dosing parameters. The remainder of the
equivalent to the “worst pain imaginable”). The patient patient’s recovery was uneventful, and he was able to partici-
was observed using his PCA during the therapy session, pate actively and enthusiastically in the rehabilitation sessions.
are capable of being programmed to prevent the control and enhance the patient’s recovery. Human
patient from exceeding certain dosing parameters. error or mechanical malfunction during PCA, howev-
PCA systems continue to increase in popularity er, may cause excessive or inadequate drug delivery, so
and are now used in a variety of clinical situations to therapists should also be alert for any signs that
manage acute and chronic pain. Rehabilitation spe- patients are receiving too much or too little analgesic
cialists should be aware that PCA can improve pain during PCA.
10. Carr DB, Reines HD, Schaffer J, et al. The impact 26. Halpern SH, Muir H, Breen TW, et al. A multicenter
of technology on the analgesic gap and quality of randomized controlled trial comparing patient-
acute pain management. Reg Anesth Pain Med. 2005; controlled epidural with intravenous analgesia for pain
30:286–291. relief in labor. Anesth Analg. 2004;99:1532–1538.
11. Cepeda MS, Alvarez H, Morales O, Carr DB. Addition 27. Harvey GP, Chelly JE, AlSamsam T, Coupe K.
of ultralow dose naloxone to postoperative morphine Patient-controlled ropivacaine analgesia after arthro-
PCA: unchanged analgesia and opioid requirement scopic subacromial decompression. Arthroscopy. 2004;
but decreased incidence of opioid side effects. Pain. 20:451–455.
2004;107:41–46. 28. Ilfeld BM, Thannikary LJ, Morey TE, et al. Popliteal
12. Chang AM, Ip WY, Cheung TH. Patient-controlled sciatic perineural local anesthetic infusion: a compari-
analgesia versus conventional intramuscular injection: son of three dosing regimens for postoperative analge-
a cost effectiveness analysis. J Adv Nurs. 2004;46: sia. Anesthesiology. 2004;101:970–977.
531–541. 29. Koo PJ. Postoperative pain management with a
13. Chelly JE. An iontophoretic, fentanyl HCl patient- patient-controlled transdermal delivery system
controlled transdermal system for acute postoperative for fentanyl. Am J Health Syst Pharm. 2005;62:
pain management. Expert Opin Pharmacother. 2005; 1171–1176.
6:1205–1214. 30. Lebovits AH, Zenetos P, O’Neill DK, et al. Satisfac-
14. Chelly JE, Grass J, Houseman TW, et al. The safety tion with epidural and intravenous patient-controlled
and efficacy of a fentanyl patient-controlled transder- analgesia. Pain Med. 2001;2:280–286.
mal system for acute postoperative analgesia: a multi- 31. Ledin Eriksson S, Gentele C, Olofsson CH. PCEA
center, placebo-controlled trial. Anesth Analg. 2004; compared to continuous epidural infusion in an
98:427–433. ultra-low-dose regimen for labor pain relief: a ran-
15. Chen JY, Wu GJ, Mok MS, et al. Effect of adding domized study. Acta Anaesthesiol Scand. 2003;47:
ketorolac to intravenous morphine patient-controlled 1085–1090.
analgesia on bowel function in colorectal surgery 32. Lehmann KA. Recent developments in patient-
patients—a prospective, randomized, double-blind controlled analgesia. J Pain Symptom Manage. 2005;
study. Acta Anaesthesiol Scand. 2005;49:546–551. 29 (suppl):S72–S89.
16. Choiniere M, Rittenhouse BE, Perreault S, et al. Effi- 33. Lo Y, Chia YY, Liu K, Ko NH. Morphine sparing
cacy and costs of patient-controlled analgesia versus with droperidol in patient-controlled analgesia.
regularly administered intramuscular opioid therapy. J Clin Anesth. 2005;17:271–275.
Anesthesiology. 1998;89:1377–1388. 34. Macintyre PE. Intravenous patient-controlled analge-
17. Chrubasik J, Chrubasik S, Martin E. Patient-controlled sia: one size does not fit all. Anesthesiol Clin North
spinal opiate analgesia in terminal cancer. Has its time America. 2005;23:109–123.
really arrived? Drugs. 1992;43:799–804. 35. Maurer K, Bonvini JM, Ekatodramis G, et al. Contin-
18. Cohen MR, Smetzer J. Patient-controlled analgesia uous spinal anesthesia/analgesia vs. single-shot spinal
safety issues. J Pain Palliat Care Pharmacother. 2005; anesthesia with patient-controlled analgesia for elec-
19:45–50. tive hip arthroplasty. Acta Anaesthesiol Scand. 2003;47:
19. Colwell CW, Jr. The use of the pain pump and 878–883.
patient-controlled analgesia in joint reconstruction. 36. Maxwell LG, Kaufmann SC, Bitzer S, et al. The
Am J Orthop. 2004;33(suppl):10–12. effects of a small-dose naloxone infusion on opi-
20. Conner M, Deane D. Patterns of patient-controlled oid-induced side effects and analgesia in children
analgesia and intramuscular analgesia. Appl Nurs Res. and adolescents treated with intravenous patient-
1995;8:67–72. controlled analgesia: a double-blind, prospective,
21. Duflo F, Qamouss Y, Remond C, et al. Patient- randomized, controlled study. Anesth Analg.
controlled regional analgesia is effective in children: a 2005;100:953–958.
preliminary report. Can J Anaesth. 2004;51:928–930. 37. Patient-controlled analgesic infusion pumps. Health
22. Etches RC. Patient-controlled analgesia. Surg Clin Devices. 2001;30:157–185.
North Am. 1999;79:297–312. 38. Ready LB. Acute perioperative pain. In: Miller RD,
23. Evron S, Glezerman M, Sadan O, et al. Patient- ed. Anesthesia. 5th ed. Philadelphia: Churchill Liv-
controlled epidural analgesia for labor pain: effect ingston; 2000.
on labor, delivery and neonatal outcome of 0.125% 39. Rosenthal K. Implantable pumps deliver innovative
bupivacaine vs 0.2% ropivacaine. Int J Obstet Anesth. pain management. Nurs Manage. 2003;34:46–49.
2004;13:5–10. 40. Senagore AJ, Delaney CP, Mekhail N, et al. Random-
24. Farag E, Dilger J, Brooks P, Tetzlaff JE. Epidural ized clinical trial comparing epidural anaesthesia and
analgesia improves early rehabilitation after total patient-controlled analgesia after laparoscopic segmen-
knee replacement. J Clin Anesth. 2005;17:281–285. tal colectomy. Br J Surg. 2003;90:1195–1199.
25. Gogarten W, Van de Velde M, Soetens E, et al. A 41. Sucato DJ, Duey-Holtz A, Elerson E, Safavi F. Postop-
multicentre trial comparing different concentrations erative analgesia following surgical correction for ado-
of ropivacaine plus sufentanil with bupivacaine plus lescent idiopathic scoliosis: a comparison of continuous
sufentanil for patient-controlled epidural analgesia epidural analgesia and patient-controlled analgesia.
in labour. Eur J Anaesthesiol. 2004;21:38–45. Spine. 2005;30:211–217.
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42. Sumikura H, van de Velde M, Tateda T. Comparison 46. Walder B, Schafer M, Henzi I, Tramer MR. Effi-
between a disposable and an electronic PCA device for cacy and safety of patient-controlled opioid anal-
labor epidural analgesia. J Anesth. 2004;18:262–266. gesia for acute postoperative pain. A quantitative
43. Sveticic G, Eichenberger U, Curatolo M. Safety of systematic review. Acta Anaesthesiol Scand. 2001;45:
mixture of morphine with ketamine for postoperative 795–804.
patient-controlled analgesia: an audit with 1026 47. Werawatganon T, Charuluxanun S. Patient controlled
patients. Acta Anaesthesiol Scand. 2005;49:870–875. intravenous opioid analgesia versus continuous epidur-
44. Viscusi ER. Emerging techniques for postoperative al analgesia for pain after intra-abdominal surgery.
analgesia in orthopedic surgery. Am J Orthop. 2004; Cochrane Database Syst Rev. 2005;CD004088.
33(suppl):13–16. 48. White PF. Mishaps with patient-controlled analgesia.
45. Viscusi ER, Reynolds L, Chung F, et al. Patient- Anesthesiology. 1987;66:81–83.
controlled transdermal fentanyl hydrochloride vs 49. Yavuz L, Eroglu F, Ozsoy M. The efficacy of intrave-
intravenous morphine pump for postoperative pain: nous versus epidural tramadol with patient-controlled
a randomized controlled trial. JAMA. 2004;291: analgesia (PCA) in gynecologic cancer pain. Eur J
1333–1341. Gynaecol Oncol. 2004;25:215–218.
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SECTION
Autonomic and
Cardiovascular
Pharmacology
18Ciccone(p)-18 2/2/07 6:58 PM Page 252
Chapter 18
Introduction to
Autonomic Pharmacology
The human nervous system can be divided into two marily from neurons located in the thoracic and upper
major functional areas: the somatic nervous system lumbar regions of the spinal cord. The parasympathetic,
and the autonomic nervous system (ANS). The somat- or craniosacral, division is composed of neurons origi-
ic division is concerned primarily with voluntary func- nating in the midbrain, brainstem, and sacral region of
tion—that is, control of the skeletal musculature. The the spinal cord. There are many other anatomic and
ANS is responsible for controlling bodily functions functional characteristics differentiating these two
that are largely involuntary, or automatic, in nature. divisions these are briefly discussed later in this chap-
For instance, the control of blood pressure (BP) and ter. For a more detailed discussion of the anatomic and
other aspects of cardiovascular function is under the functional organization of the ANS, the reader is
influence of the ANS. Other involuntary, or vegeta- referred to several excellent sources listed at the end of
tive, functions such as digestion, elimination, and this chapter.7,9,11,17
thermoregulation are also controlled by this system.
Considering the potential problems that can
occur in various systems, such as the cardiovascular
Preganglionic and
and digestive systems, the use of therapeutic drugs to Postganglionic Neurons
alter autonomic function is one of the major areas of The somatic nervous system uses one neuron to reach
pharmacology. Drugs affecting autonomic function from the central nervous system (CNS) to the periph-
are prescribed routinely to patients, including those ery. In the somatic motor system, for instance, the
seen for physical therapy and occupational therapy. alpha motor neuron begins in the spinal cord and
The purpose of this chapter is to review some of the extends all the way to the skeletal muscle; that is, it
primary anatomic and physiologic aspects of the ANS. does not synapse until it reaches the muscle cell. In
This review is intended to provide rehabilitation spe- both the sympathetic and parasympathetic divisions,
cialists with a basis for understanding the pharmaco- however, two neurons are used in sequence to reach
logic effects and clinical applications of the autonomic from the CNS (i.e., brain or spinal cord) to the periph-
drugs, which are discussed in subsequent chapters. eral organ or tissue that is being supplied. The first
neuron begins somewhere in the CNS and extends a
certain distance toward the periphery before synapsing
Anatomy of the Autonomic with a second neuron, which completes the journey to
Nervous System: Sympathetic the final destination. The synapse of these two neu-
rons is usually in one of the autonomic ganglia (see
and Parasympathetic Divisions “Sympathetic Organization” and “Parasympathetic
The ANS can be roughly divided into two areas: the Organization”). Hence, the first neuron in sequence is
sympathetic and parasympathetic nervous systems.6,9 termed the preganglionic neuron and the second is
The sympathetic or thoracolumbar, division arises pri- referred to as the postganglionic neuron.
253
18Ciccone(p)-18 2/2/07 6:58 PM Page 254
In both the sympathetic and parasympathetic di- As in the sympathetic division, parasympathetic
visions, preganglionic fibers are myelinated type B preganglionic neurons synapse in the periphery with a
fibers, and postganglionic fibers are the small, unmye- postganglionic fiber. This synapse usually takes place
linated type C fibers. In the sympathetic division, in a terminal ganglion that is located directly in the
preganglionic neurons tend to be short, while the organ or tissue supplied by the postganglionic neuron.
sympathetic postganglionic neurons are long. The Consequently, the parasympathetic ganglia are usually
opposite is true for the parasympathetic division—pre- embedded directly in the innervated organ or tissue.
ganglionic neurons are long and postganglionic neu-
rons are short. The location of preganglionic and Functional Aspects of
postganglionic fibers in each autonomic division is the Sympathetic and
presented here.
Parasympathetic Divisions
Except for skeletal muscle, virtually all tissues in the
Sympathetic Organization body are innervated in some way by the ANS.9 Table
The cell bodies for the sympathetic preganglionic 18–1 summarizes the innervation and effects of the
fibers arise from the intermediolateral gray columns of sympathetic and parasympathetic divisions on some of
the thoracic and upper lumbar spinal cord. The pre- the major organs and tissues in the body. As indicated
ganglionic fibers leave the spinal cord via the ventral in Table 18–1, some organs, such as the heart, are
root of the spinal nerve and end in a sympathetic gan- innervated by both sympathetic and parasympathetic
glion. The sympathetic ganglia are located in three neurons. Other tissues, however, may only be supplied
areas: (1) the paired paravertebral, or chain, ganglia, by the sympathetic division. The peripheral arterioles,
which lie bilaterally on either side of the vertebral col- for instance, are innervated by the sympathetic divi-
umn; (2) a group of unpaired prevertebral ganglia, sion but receive no parasympathetic innervation.
which lie anterior to the aorta (e.g., the celiac plexus, If an organ is innervated by both the sympathetic
the superior and inferior mesenteric ganglia); and (3) and parasympathetic divisions, a physiologic antago-
a small number of terminal ganglia, which lie directly nism typically exists between these divisions. That is, if
in the tissue that is innervated (e.g., the bladder and both divisions innervate the tissue, one division usual-
rectum). ly increases function, whereas the other decreases
When the preganglionic fiber reaches one of the activity. For instance, the sympathetics increase heart
sympathetic ganglia, it synapses with a postganglionic rate and stimulate cardiac output, whereas the para-
fiber. Actually, one sympathetic preganglionic neuron sympathetics cause bradycardia. However, it is incor-
may synapse with many postganglionic fibers. (The rect to state that the sympathetics are always excitatory
ratio of preganglionic to postganglionic fibers in in nature and that the parasympathetics are always
the sympathetic chain ganglia is usually 1:15 to 20.)17 inhibitory. In tissues such as the gastrointestinal tract,
The postganglionic fiber then leaves the ganglion to the parasympathetics tend to increase intestinal motil-
travel to the effector tissue that it supplies (i.e., the ity and secretion, whereas the sympathetics slow down
heart, peripheral arteriole, sweat gland, and so forth). intestinal motility. The effect of each division on any
tissue must be considered according to the particular
organ or gland.
Parasympathetic Organization One generalization that can be made regarding
Parasympathetic preganglionic neurons originate in sympathetic and parasympathetic function is that the
the midbrain and brainstem (cranial portion) or the sympathetic division tends to mobilize body energy,
sacral region of the spinal cord. Neurons comprising whereas the parasympathetic division tends to con-
the cranial portion of the parasympathetics exit the serve and store it. Typically, sympathetic discharge is
CNS via cranial nerves III, VII, IX, and X. Cranial increased when the individual is faced with some
nerve X (vagus nerve) is particularly significant be- stressful situation. This situation initiates the classic
cause it contains approximately 75 percent of the effer- fight-or-flight scenario in which the person must
ent component of the entire parasympathetic division. either flee or defend himself or herself. Sympathetic
Neurons composing the preganglionic fibers of the discharge causes increased cardiac output, decreased
sacral portion exit the spinal cord via the pelvic splan- visceral blood flow (thus leaving more blood available
chnic nerves. for skeletal muscle), increased cellular metabolism,
18Ciccone(p)-18 2/2/07 6:58 PM Page 255
Urinary bladder
Detrusor Relaxation (beta-2) Contraction (musc)
Trigone and sphincter Contraction (alpha-1) Relaxation (musc)
Sweat glands Increased secretion (musc‡) No parasympathetic innervation
*The primary receptor subtypes mediating each response are listed in parentheses (e.g., alpha-1, beta-2).
†
Note that all organ responses to parasympathetic stimulation are mediated via muscarinic (musc) receptors.
‡
Represents response due to sympathetic postganglionic cholinergic fibers.
and several other physiologic changes that facilitate trointestinal tract. When the sympathetic division is
vigorous activity. In contrast, the parasympathetic activated, effects are commonly observed on many tis-
division tends to have the opposite effect. Parasympa- sues throughout the body. The more diffuse sympa-
thetic discharge slows down the heart and brings thetic reactions routinely produce a simultaneous
about changes that generally encourage inactivity. effect on the heart, total peripheral vasculature, gener-
Parasympathetic discharge tends to increase intestinal al cellular metabolism, and so on.
digestion and absorption, an activity that stores ener-
gy for future needs.
Finally, activation of the sympathetic division Function of the
tends to result in a more massive and diffuse reaction
than does parasympathetic activation. Parasympathetic
Adrenal Medulla
reactions tend to be fairly discrete and to affect only The adrenal medulla synthesizes and secretes norepi-
one organ or tissue. For instance, the parasympathetic nephrine and epinephrine directly into the blood-
fibers to the myocardium can be activated to slow stream. Typically, the secretion from the adrenal
down the heart without a concomitant emptying of the medulla contains about 20 percent norepinephrine
bowel through an excitatory effect on the lower gas- and 80 percent epinephrine.7 These two hormones are
18Ciccone(p)-18 2/2/07 6:58 PM Page 256
fairly similar in action, except that epinephrine tors) located in the large arteries of the thorax and
increases cardiac function and cellular metabolism to a neck monitor changes in BP and heart rate. A sudden
greater extent because it has a higher affinity for cer- drop in BP is sensed by the baroreceptors, and
tain receptors than norepinephrine (i.e., epinephrine this information is relayed to the brainstem. In the
binds more readily to the beta subtype of adrenergic brainstem, this information is integrated, and a com-
receptors; see “Autonomic Receptors”).7 pensatory increase occurs in sympathetic discharge to
The adrenal medulla is innervated by sympathet- the heart and peripheral vasculature, and parasympa-
ic neurons. During normal, resting conditions, the thetic outflow to the heart is decreased. The result is
adrenal medulla secretes small amounts of epinephrine an increase in cardiac output and an increase in
and norepinephrine. During periods of stress, howev- peripheral vascular resistance, which effectively brings
er, a general increase in sympathetic discharge causes BP back to the appropriate level. The baroreceptor
an increased release of epinephrine and norepineph- reflex also works in the opposite fashion—if BP were
rine from the adrenal medulla. Since these hormones to suddenly increase, a decrease in sympathetic out-
are released directly into the bloodstream, they tend to flow and an increase in cardiac parasympathetic dis-
circulate extensively throughout the body. Circulating charge would ultimately bring a return to normal
epinephrine and norepinephrine can reach tissues that pressure levels.
are not directly innervated by the sympathetic neurons, The baroreceptor response is just one example of
thus augmenting the general sympathetic effect. Also, the type of reflex activity employed by the ANS. The
the circulating epinephrine and norepinephrine are control of other involuntary functions usually follows
removed from the body more slowly than norepineph- a similar pattern of peripheral monitoring, central
rine that is produced locally at the sympathetic post- integration, and altered autonomic discharge. Body
ganglionic nerve terminals. As a result, adrenal release temperature, for instance, is monitored by thermore-
of epinephrine and norepinephrine tends to prolong ceptors located in the skin, viscera, and hypothalamus.
the effect of the sympathetic reaction. When a change in body temperature is monitored by
Consequently, the adrenal medulla serves to aug- these sensors, this information is relayed to the hypo-
ment the sympathetic division of the ANS. In situa- thalamus and appropriate adjustments are made in
tions where a sudden increase in sympathetic function autonomic discharge in order to maintain thermal
is required (i.e., the fight-or-flight scenario), the adre- homeostasis (e.g., sweating is increased or decreased
nal medulla works with the sympathetics to produce a and blood flow is redistributed). Many other auto-
more extensive and lasting response. nomic reflexes that control visceral and involuntary
functions operate in a similar manner.
Integration of autonomic responses is often fairly
Autonomic Integration complex and may occur at several levels of the CNS.
Some reflexes, such as emptying of the bowel and blad-
and Control der, are integrated primarily at the level of the sacral
Most of the autonomic control over various physiolog- spinal cord. Other reflexes, such as the baroreceptor
ic functions is manifested through autonomic reflexes; reflex, are integrated at higher levels in the so-called
that is, homeostatic control of BP, thermoregulation, vasomotor center located in the brainstem. Also, the
and gastrointestinal function depend on the automatic hypothalamus is important in regulating the ANS, and
reflex adjustment in these systems through the sympa- many functions including body temperature, water
thetic and/or parasympathetic divisions.9 Autonomic balance, and energy metabolism are controlled and
reflexes are based on the following strategy: a periph- integrated at the hypothalamus. To add to the com-
eral sensor monitors a change in the particular system. plexity, higher levels of the brain such as the cortex and
This information is relayed to a certain level of the limbic system may also influence autonomic function
CNS, where it is integrated. An adjustment is made in through their interaction with the hypothalamus,
the autonomic discharge to the specific organ or tissue, brainstem, and spinal cord. This information is impor-
which will alter its activity to return physiologic func- tant pharmacologically because drugs that act on the
tion back to the appropriate level. CNS have the potential to alter autonomic function by
A practical example of this type of autonomic influencing the central integration of autonomic
reflex control is the so-called baroreceptor reflex, responses. Drugs that affect the cortex, limbic system,
which is important in the control of BP. In this and brainstem may indirectly alter the response of
particular example, pressure sensors (i.e., barorecep- some of the autonomic reflexes by altering the rela-
18Ciccone(p)-18 2/2/07 6:58 PM Page 257
tionship between afferent input and efferent sympa- postganglionic neurons use norepinephrine and are
thetic and parasympathetic outflow. referred to as adrenergic. (Norepinephrine is some-
times referred to as noradrenaline; hence the term
“adrenergic.”) An exception to this scheme is the pres-
Autonomic Neurotransmitters ence of certain sympathetic postganglionic fibers that
use acetylcholine as their neurotransmitter. These
Acetylcholine and Norepinephrine sympathetic cholinergic neurons innervate sweat
glands and certain blood vessels in the face, neck, and
There are four sites of synaptic transmission in the
lower extremities.
efferent limb of the ANS: (1) the synapse between
the preganglionic and postganglionic neurons in the
sympathetic division, (2) the analogous preganglio-
nic-postganglionic synapse in the parasympathetic
Other Autonomic Neurotransmitters
division, (3) the synapse between the sympathetic post- In recent years, it has become apparent that several
ganglionic neuron and the effector cell, and (4) the nonadrenergic, noncholinergic neurotransmitters may
parasympathetic postganglionic–effector cell synapse. also be present in the ANS. Purinergic substances such
Figure 18–1 summarizes the chemical neurotransmit- as adenosine and adenosine triphosphate have been
ter that is present at each synapse. implicated as possible transmitters in the gastroin-
As indicated in Figure 18–1, the transmitter at the testinal tract, cardiovascular system, and several other
preganglionic-postganglionic synapse in both divisions organs and systems influenced by autonomic nerves.3,16
is acetylcholine, as is the transmitter at the parasympa- Several peptides such as substance P, vasoactive intes-
thetic postganglionic–effector cell synapse. The trans- tinal polypeptide, and angiotensin II have been identi-
mitter at the sympathetic postganglionic–effector cell fied as possibly participating in the autonomic control
synapse is usually norepinephrine. A small number of of various organs and systems.10,11,13 Nitric oxide may
sympathetic postganglionic fibers, however, also use also help regulate various peripheral autonomic re-
acetylcholine as their neurotransmitter. sponses, and this substance may also control CNS
Consequently, all preganglionic neurons and autonomic activity.12,15,18
parasympathetic postganglionic neurons are said to be It is still uncertain whether all of these nona-
cholinergic in nature because of the presence of acetyl- drenergic, noncholinergic substances are true neuro-
choline at their respective synapses. Most sympathetic transmitters. They may act as cotransmitters that are
Sympathetic Pathways
ACH NE
Nicotinic
Cholinergic Adrenergic
Receptor Receptor
(⬀1, ⬀2, 1, 2) Effector
CNS
Cell
Parasympathetic Pathways
ACH ACH
Nicotinic Muscarinic
Cholinergic Cholinergic
Receptor Receptor
released from the synaptic terminal along with the neurons in both the sympathetic and parasympathetic
classic autonomic transmitters (i.e., acetylcholine and pathways (see Fig. 18–1). This fact is significant phar-
norepinephrine). These other substances, however, macologically because any drug that affects these nico-
may simply be produced locally and serve to modulate tinic receptors will affect activity in both divisions of
synaptic activity without actually being released from the ANS. The cholinergic nicotinic receptor located
the presynaptic terminal. Additional information will in the ANS is sometimes referred to as a type I (or
be necessary to fully identify the role of these and NN) nicotinic receptor to differentiate it from the type
other nonadrenergic, noncholinergic substances as II (or NM) nicotinic receptors, which are located at the
autonomic neurotransmitters. skeletal neuromuscular junction.
Muscarinic cholinergic receptors are located at all
of the synapses between cholinergic postganglionic
Autonomic Receptors neurons and the terminal effector cell, including all
the parasympathetic terminal synapses, as well as the
Since there are two primary neurotransmitters in-
sympathetic postganglionic cholinergic fibers, that
volved in autonomic discharge, there are two primary
supply sweat glands and some specialized blood ves-
classifications of postsynaptic receptors. Cholinergic
sels. Current research suggests that there may be five
receptors are located at acetylcholine synapses, and
subtypes of muscarinic receptors, that is, muscarinic
adrenergic receptors are located at norepinephrine
subtypes can be classified as M1, M2, M3, and so forth,
synapses. As indicated in Figure 18–2, each type of
based on their structural and chemical characteris-
receptor has several subclassifications. The location
tics.9,19,22 Specific subtypes seem to predominate at
and functional significance of these classifications and
certain organ systems. For example, the M1, M2, M4,
subclassifications are presented here.
and M5 receptors seem to be important in CNS
responses,20 whereas the M3 subtype may be more
prevalent in smooth muscle and heart tissue.19,21 The
Cholinergic Receptors exact role of these muscarinic receptor subtypes con-
Cholinergic receptors are subdivided into two cate- tinues to be elucidated through ongoing research, and
gories: nicotinic and muscarinic. Although acetyl- future studies will lend more insight to how each
choline will bind to all cholinergic receptors, certain receptor subtype participates in normal function and
receptors bind preferentially with the drug nicotine. specific diseases in humans.
Other receptors have a specific affinity for muscarine, Thus, cholinergic muscarinic receptors ultimately
a naturally occurring compound found in certain poi- mediate the effect on the tissue itself. Table 18–2 sum-
sonous mushrooms. Thus the terms “nicotinic” and marizes the primary physiologic responses when mus-
“muscarinic’ were derived. carinic receptors are stimulated on various tissues in
Nicotinic cholinergic receptors are located at the the body. Note that the specific response to stimula-
junction between preganglionic and postganglionic tion of a muscarinic cholinergic receptor depends on
ACH NE
Cholinergic Adrenergic
Receptor Receptor
FIGURE 18–2 ▼ Receptor classifications and subclassifications for acetylcholine (ACh) and
norepinephrine (NE), the two primary neurotransmitters used in the autonomic nervous system.
18Ciccone(p)-18 2/2/07 6:58 PM Page 259
Adrenergic
the tissue in question. Stimulation of muscarinic recep- beta-3 receptors.9 These divisions are based on the
tors on the myocardium, for instance, causes a decrease different sensitivities of each receptor subcategory to
in heart rate, whereas stimulation of muscarinic recep- different endogenous and exogenous agents. Alpha-1
tors in the intestinal wall leads to increases in smooth receptors, for instance, bind more readily with certain
muscle contraction and glandular secretion. agonists and antagonists, whereas alpha-2 receptors
bind preferentially with other agents. Specific agents
that bind to each adrenergic receptor subcategory are
Adrenergic Receptors
identified in Chapter 20.
As shown in Figure 18–2, the adrenergic receptors are In the ANS, the various types of adrenergic re-
subdivided into two primary categories: alpha- and ceptors are found on the effector cell in the innervat-
beta-adrenergic receptors. Alpha receptors are further ed tissue. In other words, these receptors are located
subdivided into alpha-1 and alpha-2 receptors, and at the terminal synapse between sympathetic postgan-
beta receptors are subdivided into beta-1, beta-2, and glionic adrenergic neurons and the tissue they supply.
18Ciccone(p)-18 2/2/07 6:58 PM Page 260
The basic characteristics of each adrenergic receptor 2C.4,14 The functional and pharmacological signifi-
subtype are briefly outlined here. cance of these different alpha-2 receptor subtypes
Alpha-1 Receptors. A primary location of these continues to be elucidated.
receptors is the smooth muscle located in various tis- Beta-1 Receptors. These receptors predominate
sues throughout the body. Alpha-1 receptors are locat- in the heart and kidneys (see Table 18–2).9,24 The car-
ed on the smooth muscle located in the peripheral diac beta-1 receptors have received a tremendous
vasculature, intestinal wall, radial muscle of the iris, amount of attention with regard to pharmacologic
ureters, urinary sphincter, and spleen capsule. The antagonism of their function through the use of the
response of each tissue when the alpha-1 receptor is so-called beta blockers.
stimulated varies depending on the tissue (see Table Beta-2 Receptors. Beta-2 receptors are found pri-
18-2). Research also suggests that there might be marily on the smooth muscle of certain vasculatures,
three subtypes of alpha-1 receptors, identified as the bronchioles, the gallbladder, and the uterus.9 Their
alpha-1A, alpha-1B, and alpha-1D receptors.4 Much presence in bronchiole smooth muscle is especially
of this research, however, has focused on the charac- important in the pharmacologic management of respi-
teristics of alpha-1 receptor subtypes in various animal ratory conditions such as asthma (see Chapter 26).
models. Studies are currently underway to determine These receptors are also responsible for mediating
the exact location and functional significance of these changes in the metabolism of skeletal muscle and liver
alpha-1 receptor subtypes in humans. cells. Beta-2 receptors are also located on the heart,
Alpha-2 Receptors. The alpha-2 receptors were although the predominant effects on cardiac tissue
originally identified by their presence on the presynap- seem to be mediated through the beta-1 subtype.
tic terminal of certain adrenergic synapses.2 These Beta-3 Receptors. Although it was originally
presynaptic alpha-2 receptors appear to modulate the thought that only two subtypes of beta receptors exist-
release of neurotransmitters from the presynaptic ed, we now know that a third subtype, the beta-3
terminal; that is, they seem to decrease the release of receptor, plays a functional role in certain tissues. In
norepinephrine and other chemicals, thus serving as particular, beta-3 receptors are located on adipose tis-
a form of negative feedback limiting the amount of sue, and stimulation of beta-3 receptors increases lipol-
neurotransmitter released from the presynaptic termi- ysis (see Table 18-2).9 In addition, beta-3 receptors are
nal.1,2 As discussed in Chapter 13, alpha-2 receptors also found on the heart and some smooth muscles, and
have also been found on spinal interneurons, and stim- the functional significance of beta-3 receptors at these
ulation of these alpha-2 receptors may cause decreased locations continues to be investigated.5,23
neurotransmitter release and diminished stimulation of In summary, adrenergic receptors can be subclas-
the interneurons that influence the alpha motor neu- sified according to their location and affinity for spe-
ron. Thus, alpha-2 stimulants (agonists) such as tizani- cific pharmacologic agents. Table 18–2 summarizes
dine have been used to decrease neuronal excitability the receptor subtypes that are located on the primary
in the spinal cord and thereby decrease muscle hyper- organs and tissues in the body, and the associated
excitability in conditions such as spasticity. Also, alpha- response when the receptor is stimulated. Exactly
2 receptors have been found postsynaptically on which receptor subtype is located on any given tissue
certain CNS adrenergic synapses involved in the con- depends on the tissue in question. Note that some tis-
trol of sympathetic discharge.9 Stimulation of these sues may have two or more different subtypes of
centrally located alpha-2 receptors is believed to inhib- adrenergic receptor (e.g., skeletal muscle arterioles
it sympathetic discharge from the brainstem. The appear to have alpha-1 and beta-2 receptors). Also, the
importance of central alpha-2 receptors in controlling response of a tissue when the receptor is stimulated is
cardiovascular function and the possible use of alpha-2 dependent on the specific receptor-cell interaction.
agonists to control BP are discussed in Chapter 21. Stimulation of the vascular alpha-1 receptor, for
Alpha-2 receptors are also located in the gastrointesti- instance, results in smooth-muscle contraction and
nal tract and pancreas, and stimulation of these recep- vasoconstriction, whereas stimulation of the intestinal
tors at these sites causes decreased intestinal motility alpha-1 receptor results in relaxation and decreased
and decreased insulin secretion, respectively. intestinal motility. This difference is caused by the
As is the case with alpha-1 receptors, we now way the receptor is coupled to the cell’s internal bio-
believe that at least three subtypes of alpha-2 receptors chemistry at each location. As discussed in Chapter 4,
may exist, namely alpha-2A, alpha-2B, and alpha- the surface receptor at one cell may be coupled to the
18Ciccone(p)-18 2/2/07 6:58 PM Page 261
cell’s internal enzymatic machinery so that it stimu- affect beta-2 receptors as well. Finally, organs and tis-
lates cell function. The same receptor subtype at a dif- sues in the body do not contain only one subtype
ferent tissue will be linked to inhibitory enzymes that of receptor. For example, the predominant receptor
slow down cell function. Refer to Chapter 4 for a in the bronchioles is the beta-2 subtype, but some
more detailed description of how surface receptors are beta-1 receptors are also present. Thus, a patient using
coupled to cell function. a beta-1–specific drug such as metoprolol (Lopressor)
may experience some respiratory effects as well.8
Consequently, the many side effects and benefi-
Pharmacologic Significance cial effects of autonomic drugs can be attributed to the
of Autonomic Receptors interaction of various agents with different receptors.
The significance of autonomic receptor subtypes as
Perhaps no area of research has contributed more to well as the use of specific cholinergic and adrenergic
pharmacology than the identification, classification, drugs in treating various problems are covered in
and subclassification of autonomic receptors. The more detail in Chapters 19 and 20.
realization that various tissues have distinct subtypes
of receptors has enabled the use of drugs affecting cer-
tain tissues and organs while causing minimal effects
SUMMARY
on other tissues. For instance, a beta-1 antagonist (i.e., The ANS is primarily responsible for controlling
a drug that specifically blocks the beta-1 adrenergic involuntary, or vegetative, functions in the body. The
receptor) will slow down heart rate and decrease sympathetic and parasympathetic divisions of the ANS
myocardial contractility without causing any major often function as physiologic antagonists to maintain
changes in the physiologic functions that are mediat- homeostasis of various activities, including BP control,
ed by the other autonomic receptors. thermoregulation, digestion, and elimination. The pri-
However, several limitations of autonomic drugs mary neurotransmitters used in synaptic transmission
must be realized. First, a drug that binds preferential- within the ANS are acetylcholine and norepinephrine.
ly to one receptor subtype will bind to that receptor at These chemicals are found at specific locations in each
all of its locations. For example, a muscarinic antago- autonomic division, as are their respective cholinergic
nist that decreases activity in the gastrointestinal tract and adrenergic receptors. The two primary types of
may also decrease bronchial secretions in the lungs autonomic receptors (cholinergic and adrenergic) are
and cause urinary retention because of relaxation of subdivided according to differences in drug affin-
the detrusor muscle of the bladder. Also, no drug is ity. Receptor subtypes are located in specific tissues
entirely specific for only one receptor subtype. For throughout the body and are responsible for mediating
instance, the so-called beta-1–specific antagonists the appropriate tissue response. Most autonomic drugs
atenolol and metoprolol have a much greater affinity exert their effects by interacting in some way with
for beta-1 receptors than for beta-2 receptors.8 At autonomic synaptic transmission so that a fairly selec-
high enough concentrations, however, these drugs will tive and isolated effect is achieved.
10. Johns EJ. Angiotensin II in the brain and the auto- 17. Standring S, ed. Gray’s Anatomy. 39th ed. New York:
nomic control of the kidney. Exp Physiol. 2005;90: WB Saunders; 2005.
163–168. 18. Stern JE. Nitric oxide and homeostatic control: an
11. Katzung BG. Introduction to autonomic pharmacolo- intercellular signalling molecule contributing to auto-
gy. In: Katzung BG, ed. Basic and Clinical Pharmacology. nomic and neuroendocrine integration? Prog Biophys
9th ed. New York: Lange Medical Books/McGraw Mol Biol. 2004;84:197–215.
Hill; 2004. 19. Uchiyama T, Chess-Williams R. Muscarinic receptor
12. Mohan RM, Golding S, Heaton DA, et al. Targeting subtypes of the bladder and gastrointestinal tract. J
neuronal nitric oxide synthase with gene transfer to Smooth Muscle Res. 2004;40:237–247.
modulate cardiac autonomic function. Prog Biophys 20. Volpicelli LA, Levey AI. Muscarinic acetylcholine
Mol Biol. 2004;84:321–344. receptor subtypes in cerebral cortex and hippocampus.
13. Pan HL. Brain angiotensin II and synaptic transmis- Prog Brain Res. 2004;145:59–66.
sion. Neuroscientist. 2004;10:422–431. 21. Wang Z, Shi H, Wang H. Functional M3 muscarinic
14. Philipp M, Brede M, Hein L. Physiological sig- acetylcholine receptors in mammalian hearts. Br J
nificance of alpha(2)-adrenergic receptor sub- Pharmacol. 2004;142:395–408.
type diversity: one receptor is not enough. Am J 22. Yamada M, Basile AS, Fedorova I, et al. Novel insights
Physiol Regul Integr Comp Physiol. 2002;283: into M5 muscarinic acetylcholine receptor function by
R287–R295. the use of gene targeting technology. Life Sci.
15. Sartori C, Lepori M, Scherrer U. Interaction between 2003;74:345–353.
nitric oxide and the cholinergic and sympathetic nerv- 23. Yamaguchi O. Beta3-adrenoceptors in human detrusor
ous system in cardiovascular control in humans. Phar- muscle. Urology. 2002;59(suppl 1):25–29.
macol Ther. 2005;106:209–220. 24. Zheng M, Zhu W, Han Q, Xiao RP. Emerging con-
16. Scislo TJ, O’Leary DS. Purinergic mechanisms of the cepts and therapeutic implications of beta-adrenergic
nucleus of the solitary tract and neural cardiovascular receptor subtype signaling. Pharmacol Ther. 2005;
control. Neurol Res. 2005;27:182–194. 108:257–268.
19Ciccone(p)-19 1/30/07 2:37 PM Page 263
Chapter 19
Cholinergic Drugs
This chapter discusses drugs that affect the activity at or pharmacodynamic criteria, and these criteria will be
cholinergic synapses—that is, synapses using acetyl- discussed in more detail in this chapter.
choline as a neurotransmitter. Cholinergic synapses are
important in a number of physiologic systems. As dis-
cussed in Chapter 18, acetylcholine is one of the pri-
mary neurotransmitters in the autonomic nervous
Cholinergic Receptors
system (ANS), especially in the parasympathetic auto- Many autonomic cholinergic drugs affect synaptic
nomic division. Consequently, many drugs discussed in activity by interacting with the acetylcholine recep-
this chapter are administered to alter the response of tor located on the postsynaptic membrane. At each
various tissues to autonomic parasympathetic control. cholinergic synapse, postsynaptic receptors are re-
Acetylcholine is also the neurotransmitter at the skele- sponsible for recognizing the acetylcholine molecule
tal neuromuscular junction. Certain cholinergic stimu- and transducing the chemical signal into a postsynap-
lants are used to treat a specific problem at the skeletal tic response. As discussed in Chapter 18, cholinergic
neuromuscular junction (i.e., myasthenia gravis). receptors can be subdivided into muscarinic and nico-
Cholinergic synapses are also found in specific areas of tinic receptors according to their affinity for certain
the brain, and some anticholinergic drugs are used to drugs.12
decrease the symptoms of diverse problems such as Muscarinic cholinergic receptors are generally
parkinsonism and motion sickness. Consequently, found on the peripheral tissues supplied by parasympa-
these drugs are used in a variety of clinical situations. thetic postganglionic neurons—that is, on effector
The purpose of this chapter is to present an organs such as the gastrointestinal tract, urinary blad-
overview of drugs sharing a common mode of action; der, heart, eye, and so on. Acetylcholine synapses found
that is, influencing cholinergic activity. Considering in specific areas of the central nervous system (CNS)
the diverse clinical applications of cholinergic and also use the muscarinic subtype of cholinergic receptor.
anticholinergic agents, physical therapists and occupa- Nicotinic cholinergic receptors are located in the auto-
tional therapists will likely encounter patients taking nomic ganglia (i.e., the NN nicotinic subtype) and at
these drugs. Knowledge of the pharmacodynamics of the skeletal neuromuscular junction (the NM nicotinic
these medications will enable the rehabilitation spe- subtype). Refer to Chapter 18 for a more detailed dis-
cialist to understand the therapeutic rationale behind cussion of cholinergic receptor subclassification.
drug administration as well as the patient’s response to The existence of different varieties of choliner-
the drug. gic receptors is important pharmacologically. Some
Autonomic cholinergic drugs can be divided into drugs are relatively specific for a certain choliner-
two general categories: cholinergic stimulants and gic receptor subtype, whereas others tend to bind
anticholinergic drugs. Cholinergic stimulants effec- rather indiscriminately to all cholinergic receptors.
tively increase activity at acetylcholine synapses, Obviously, specific drugs are preferable because they
whereas anticholinergic drugs decrease synaptic activ- tend to produce a more precise response with fewer
ity. Cholinergic stimulants and anticholinergic agents side effects. As this chapter will point out, however,
can be further characterized according to functional specificity is only a relative term, and drugs that bind
263
19Ciccone(p)-19 1/30/07 2:37 PM Page 264
preferentially to one receptor subtype may produce a true cholinergic agonists, and they function in a man-
variety of responses. ner similar to the acetylcholine molecule. By defini-
tion, acetylcholine itself is a direct-acting cholinergic
stimulant. Exogenously administered acetylcholine is
Cholinergic Stimulants not used therapeutically, however, because it is
Cholinergic stimulants increase activity at acetyl- degraded rapidly and extensively by the acetyl-
choline synapses. Chemically, many agents are capable cholinesterase enzyme, which is found ubiquitously
of potently and effectively stimulating cholinergic throughout the body.
activity. However, only a few drugs exhibit sufficient As mentioned previously, there are many pharma-
safety and relative specificity for use in clinical situa- cologic agents that can directly stimulate cholinergic
tions. These clinically relevant drugs can be subdivid- receptors. A certain degree of drug specificity is desir-
ed into two categories depending on their mechanism able, however, when considering these agents for ther-
of action. Direct-acting cholinergic stimulants exert apeutic purposes. For instance, drugs that have a
their effects by binding directly with the cholinergic greater specificity for the muscarinic cholinergic
receptor (Fig. 19–1). Indirect-acting cholinergic stim- receptor are more beneficial. These muscarinic
ulants increase synaptic activity by inhibiting the cholinergic stimulants will primarily affect the periph-
acetylcholinesterase enzyme located at the cholinergic eral tissues while exerting a minimal effect on the
synapse (Fig. 19–1). Table 19–1 lists specific direct- cholinergic receptors located in the autonomic ganglia
acting and indirect-acting cholinergic stimulants; the and the neuromuscular junction. (Recall that the
rationale for their use is presented below. cholinergic receptors found in the autonomic ganglia
and at the skeletal neuromuscular junction are the NN
Direct-Acting Cholinergic Stimulants and NM, respectively.)
Consequently, only a few agents are suitable for
Direct-acting stimulants bind directly to the choliner-
clinical use as direct-acting cholinergic stimulants. For
gic receptor to activate it, which in turn initiates a cel-
systemic administration, bethanechol (Duvoid, others)
lular response. These stimulants may be considered
is the primary direct-acting cholinergic stimulant (see
Table 19–1). Bethanechol appears to preferentially
stimulate muscarinic cholinergic receptors, especially
Indirect Cholinergic Stimulants
those on gastrointestinal and bladder tissues.5 Hence,
this drug is sometimes used to increase gastrointesti-
nal or bladder contractions, especially when motility
Cholinesterase in these tissues is reduced following abdominal sur-
Enzyme
gery. Other direct-acting cholinergic stimulants such
Acetylcholine as carbachol and pilocarpine are limited to topical use
in ophthalmologic conditions, especially glaucoma.
These antiglaucoma drugs produce too many side
effector cell
effects if administered systemically, but are relatively
specific when administered directly to the eye. Like-
wise, methacholine is a direct-acting cholinergic stim-
ulant that can be administered locally to the lungs via
inhalation to test for airway hyperresponsiveness
presynaptic when diagnosing patients for asthma. Clinical applica-
terminal tions of direct-acting cholinergic stimulants are sum-
marized in Table 19–1.
Indirect-Acting
Direct Cholinergic Stimulants
Cholinergic Stimulants
Indirect-acting stimulants increase activity at cholin-
FIGURE 19–1 ▼ Mechanism of action of cholinergic stimulants.
Direct-acting stimulants bind directly to the postsynaptic cholinergic ergic synapses by inhibiting the acetylcholinesterase
receptor. Indirect-acting stimulants inhibit the cholinesterase enzyme, enzyme.21 This enzyme is normally responsible for
thus allowing acetylcholine to remain in the synaptic cleft. destroying acetylcholine after this neurotransmitter
19Ciccone(p)-19 1/30/07 2:37 PM Page 265
Physostigmine Antilirium, Eserine, Isopto Eserine Glaucoma, reversal of CNS toxicity caused by
anticholinergic drugs
*Agents used to treat glaucoma and other visual disturbances are administered topically, that is, directly to the
eye. Agents used for other problems are given systemically by oral administration or injection.
is released from the presynaptic terminal. Indirectact- cholinesterase enzyme varies depending on the indi-
ing stimulants inhibit the acetylcholinesterase, thus vidual agent. The net effect is similar, however, in that
allowing more acetylcholine to remain at the synapse. the enzyme’s ability to degrade acetylcholine is dimin-
The result is an increase in cholinergic synaptic trans- ished by these drugs.
mission. Unlike the systemic direct-acting cholinergic
Because of their effect on the acetylcholinesterase stimulants (e.g., bethanechol), cholinesterase inhibi-
enzyme, indirect-acting stimulants are also referred tors display a relative lack of specificity regarding
to as cholinesterase inhibitors or anticholinesterase agents. which cholinergic synapses they stimulate. These
The exact way in which these drugs inhibit the acetyl- drugs tend to inhibit the acetylcholinesterase found at
19Ciccone(p)-19 1/30/07 2:37 PM Page 266
all cholinergic synapses. Thus, they may exert a stim- er cortical functions.7 Although there is no cure for
ulatory effect on the peripheral muscarinic cholinergic this disease, indirect cholinergic stimulants such as
synapses, as well as the cholinergic synapses found at tacrine (Cognex), donepezil (Aricept), galantamine
the autonomic ganglia, at the skeletal neuromuscular (Remingl), and rivastigmine (Exelon) (see Table 19–1)
junction, and within certain aspects of the CNS. In may help decrease some of the symptoms during the
appropriate doses, however, certain agents exert some early stages of Alzheimer disease.7,10 By inhibiting
degree of specificity at peripheral versus CNS synaps- acetylcholine breakdown, these drugs prolong the
es. Indirect-acting stimulants such as neostigmine, for effects of any acetylcholine released from neurons that
example, tend to predominantly affect the skeletal are still functioning in the cerebral cortex.
neuromuscular junction and peripheral tissues con- Regrettably, these drugs do not alter the progres-
taining muscarinic receptors. In contrast, newer sion of Alzheimer disease, and they tend to lose effec-
agents such as tacrine and donepezil show more speci- tiveness as the disease progresses into the advanced
ficity for cholinergic synapses in certain regions of the stages.7 This loss of effectiveness makes sense when
brain—hence, these newer drugs have been used to one considers that these drugs can only prolong the
boost cholinergic function in conditions such as effects of endogenously released acetylcholine; they
Alzheimer disease. Still, none of the indirect-acting will have no effect when cortical neurons degenerate
cholinergic stimulants affect only one type of tissue, to the point where acetylcholine is no longer being
and some adverse side effects can be caused by their synthesized and released within the brain. Nonethe-
relatively nonspecific activity. less, drugs such as tacrine, donepezil, and other CNS
The primary indirect-acting cholinergic stimu- cholinesterase inhibitors can help patients retain bet-
lants currently in use are neostigmine and pyridostig- ter cognitive function during the early stages of
mine. Several other agents are also used therapeutically Alzheimer disease, which can help sustain a better
to treat systemic conditions such as myasthenia gravis, quality-of-life for patients for as long as possible.7
ophthalmologic disorders such as glaucoma, and Gastrointestinal and Urinary Bladder Atony. After
diminished acetylcholine activity associated with surgical manipulation or other trauma to the viscera,
degenerative brain syndromes such as Alzheimer dis- there is often a period of atony (i.e., lack of tone) in the
ease. These indirect-acting agents are summarized in smooth muscle of these organs. As a result, intestinal
Table 19–1. peristalsis is diminished or absent, and the urinary
bladder becomes distended, leading to urinary reten-
Clinical Applications of tion. Under normal circumstances, acetylcholine
released from parasympathetic postganglionic neurons
Cholinergic Stimulants would stimulate smooth-muscle contraction in these
Direct- and indirect-acting cholinergic stimulants are tissues. Consequently, cholinergic agonists (i.e., drugs
used to treat the decrease in smooth-muscle tone that that mimic or enhance the effects of acetylcholine) are
sometimes occurs in the gastrointestinal tract and uri- administered to treat this problem. Bethanechol and
nary bladder following abdominal surgery or trauma. neostigmine, a direct-acting and an indirect-acting
Indirect-acting stimulants are also used in the treat- cholinergic stimulant, respectively, are the drugs most
ment of glaucoma and myasthenia gravis, in Alzheimer frequently used to treat this condition until normal
disease, and to reverse the effects from an overdose gastrointestinal and urinary function is resumed.
of other drugs such as neuromuscular blocking agents Glaucoma. Glaucoma is an increase in intraocular
and anticholinergics. Each of these applications is pressure brought on by an accumulation of aqueous
briefly discussed here. humor within the eye.16 If untreated, this increased
Alzheimer Disease. Alzheimer disease is a pro- pressure leads to impaired vision and blindness.
gressive neurodegenerative disorder that affects older Cholinergic stimulation via the parasympathetic sup-
adults. This disorder is characterized by neuronal atro- ply to the eye increases the outflow of aqueous humor,
phy and other pathological changes in neuron struc- thus preventing excessive accumulation. If evidence of
ture and function throughout the brain (neurofibrillary increased intraocular pressure exists, cholinergic stim-
tangles, formation of plaques, and so forth). Included ulants are among the drugs that may be used to treat
in this neuronal degeneration are cholinergic neurons this problem.15,16 Direct-acting and indirect-acting
that are critical in memory, cognition, and other high- cholinergic drugs (see Table 19–1) are usually applied
19Ciccone(p)-19 1/30/07 2:37 PM Page 267
topically to the eye by placing the drug directly within cholinesterase enzyme at the neuromuscular junction,
the conjunctival sac to treat glaucoma. This applica- thus allowing endogenously released acetylcholine to
tion concentrates the action of the drug, thus limiting remain active at the synaptic site and effectively over-
the side effects that might occur if these agents were come the neuromuscular blockade until the curarelike
given systemically. These agents are not typically the agents have been metabolized.
first drugs used to treat glaucoma, but they can be used Reversal of Anticholinergic-Induced CNS Toxicity.
if other agents are not effective.6,15 Indirect-acting cholinergic stimulants (e.g., physostig-
Myasthenia Gravis. Myasthenia gravis is a disease mine) are sometimes used to reverse the toxic effects
affecting the skeletal neuromuscular junction and is of anticholinergic drugs on the CNS. An overdose of
characterized by skeletal muscle weakness and pro- anticholinergic drugs may produce toxic CNS effects
found fatigability.14,23 As the disease progresses, fatigue such as delirium, hallucinations, and coma. By inhibit-
increases in severity and in the number of muscles ing acetylcholine breakdown, indirect-acting stimu-
involved. In advanced stages, the patient requires res- lants enable endogenously released acetylcholine to
piratory support because of a virtual paralysis of the overcome the anticholinergic drug effects.
respiratory musculature. In myasthenia gravis, the
number of functional cholinergic receptors located Adverse Effects of
postsynaptically at the neuromuscular junction is
diminished.23 As a result, acetylcholine released from
Cholinergic Stimulants
the presynaptic terminal cannot sufficiently excite the Cholinergic stimulants are frequently associated with a
muscle cell to reach threshold. Thus, the decreased number of adverse side effects caused by the relative
receptivity of the muscle cell accounts for the clinical nonspecificity of these drugs. Even bethanechol, which
symptoms of weakness and fatigue. is relatively specific for muscarinic receptors, may
Myasthenia gravis appears to be caused by an stimulate muscarinic receptors on many different tis-
autoimmune response whereby an antibody to the sues. For example, administering bethanechol to
neuromuscular cholinergic receptor is produced.23 increase gastrointestinal motility may also result in
Although no cure is available, cholinesterase inhibitors bronchoconstriction if this drug reaches muscarinic
such as ambenonium, neostigmine, and pyridostig- receptors in the upper respiratory tract. Many indirect-
mine may help alleviate the muscular fatigue associat- acting stimulants (i.e., the cholinesterase inhibitors)
ed with this disease. These indirect-acting cholinergic show even less specificity and may increase synaptic
agonists inhibit the acetylcholinesterase enzyme at the activity at all synapses that they reach, including nico-
neuromuscular junction, allowing the endogenous tinic cholinergic synapses.
acetylcholine released from the presynaptic terminal to The adverse effects associated with both the
remain at the myoneural junction for a longer period direct- and indirect-acting cholinergic stimulants
of time. The endogenously released acetylcholine is mimic the effects that occur during exaggerated
able to provide adequate excitation of the skeletal mus- parasympathetic activity. This notion is logical consid-
cle cell and thus allow a more sustained muscular con- ering that the parasympathetic autonomic division
traction. exerts its effects on peripheral tissues by releasing
Reversal of Neuromuscular Blockage. Drugs that acetylcholine from postganglionic neurons. Conse-
block transmission at the skeletal neuromuscular junc- quently, the primary adverse effects of cholinergic
tion are often used during general anesthesia to main- stimulants include gastrointestinal distress (nausea,
tain skeletal muscle paralysis during surgical vomiting, diarrhea, abdominal cramping), increased
procedures (see Chapter 11). These skeletal muscle salivation, bronchoconstriction, bradycardia, and diffi-
paralytic agents include curarelike drugs (e.g., tubocu- culty in visual accommodation. Increased sweating and
rarine, gallamine, pancuronium). Occasionally, the vasodilation of facial cutaneous blood vessels (flushing)
neuromuscular blockage caused by these drugs must may also occur because of an effect on the respective
be reversed. For instance, an accelerated recovery tissues supplied by special sympathetic postganglionic
from the paralytic effects of these neuromuscular neurons that release acetylcholine. The incidence of
blockers may be desired at the end of the surgical pro- these side effects varies from patient to patient, but the
cedure. Consequently, indirect-acting cholinergic onset and severity increases as higher drug doses are
stimulants are sometimes used to inhibit the acetyl- administered.
19Ciccone(p)-19 1/30/07 2:37 PM Page 268
O CH3
Anticholinergic Drugs
H3C C O CH2 CH2 N+ CH 3
In contrast to drugs that stimulate cholinergic activity,
anticholinergic drugs attempt to diminish the response CH3
of tissues to cholinergic stimulation. In general, these
drugs are competitive antagonists of the postsynaptic
cholinergic receptors; that is, they bind reversibly to acetylcholine
the cholinergic receptor but do not activate it. This
binding blocks the receptor from the effects of endoge-
nously released acetylcholine, thus diminishing the cel-
N CH3
lular response to cholinergic stimulation. (See Chapter
4 for a more detailed description of the mechanism by
which drugs function as competitive antagonists.) HOCH2
Anticholinergic drugs can be classified as antimus-
O
C
carinic or antinicotinic agents, depending on their
C O
specificity for the two primary subtypes of cholinergic
receptors. This chapter focuses on the antimuscarinic
agents, with the antinicotinic drugs being discussed H
elsewhere in this text. Mecamylamine and trimetha-
phan, for example, are drugs that are relatively specific
for the nicotinic receptor located in the autonomic atropine
ganglia (the NN subtype). These NN antagonists are
sometimes used to treat extremely high blood pressure. FIGURE 19–2 ▼ Structures of acetylcholine and atropine. Atropine
The use of antinicotinic drugs in treating hypertensive and similar agents antagonize the effects of acetylcholine by blocking
emergencies is discussed in Chapter 21. Antinicotinic muscarinic cholinergic receptors.
drugs that block the skeletal neuromuscular junction
(i.e., the NM antagonists) are sometimes used as an some degree of specificity of these drugs, which may
adjunct in general anesthesia and are used to pro- be because of differences in the muscarinic receptor at
duce skeletal muscle paralysis during surgery. These gastrointestinal versus central synapses. Indeed, there
so-called neuromuscular blockers are discussed in is evidence that as many as five muscarinic receptor
Chapter 11. subtypes may exist at different locations in the body;
these subtypes are designated M1, M2, M3, M4, and M5
Source and Mechanism of Action of receptors.24,25,26,28 Some drugs may be more selective
for a certain receptor subtype than for others. This
Antimuscarinic Anticholinergic Drugs drug-receptor specificity is far from complete, howev-
The prototypical antimuscarinic anticholinergic drug er, and virtually every antimuscarinic drug will antag-
is atropine (Fig. 19–2). Atropine is a naturally occur- onize cholinergic receptors on a number of tissues,
ring substance that can be obtained from the extract of which leads to various side effects (see “Side Effects of
plants such as belladonna and jimsonweed. Other nat- Anticholinergic Drugs”). Perhaps as more is learned
ural, semisynthetic, and synthetic antimuscarinic anti- about muscarinic receptor subtypes, more selective
cholinergic agents have been developed that are anticholinergic drugs may be developed.
similar in structure or function to atropine.
As mentioned previously, antimuscarinic anti- Clinical Applications of
cholinergic drugs all share the same basic mechanism
of action: they block the postsynaptic cholinergic mus-
Antimuscarinic Drugs
carinic receptor. However, certain antimuscarinic The primary clinical applications of antimuscarinic
agents seem to preferentially affect some tissues more anticholinergic drugs include the treatment of certain
than others. For instance, certain antimuscarinics seem gastrointestinal disorders. These drugs may also be
to preferentially antagonize gastrointestinal mus- helpful in managing Parkinson disease. In addition,
carinic receptors, whereas others have a predominant they have been used to treat a variety clinical disorders
effect on CNS cholinergic synapses. This fact suggests involving other physiologic systems.5 The clinical ap-
19Ciccone(p)-19 1/30/07 2:37 PM Page 269
Hyoscyamine Cystospaz, Levsin, others Peptic ulcer, irritable bowel syndrome, urinary bladder
hypermotility, preoperative antisecretory agent
*Clinical uses listed for a specific agent reflect that agent’s approved indication(s). Actual clinical use, however,
may be limited because anticholinergics have often been replaced by agents that are more effective and better
tolerated. Anticholinergic drugs used specifically to treat Parkinson disease are listed in Table 10–2, Chapter 10.
plications of antimuscarinic agents are discussed here, neurons generally produces an increase in gastric se-
and specific drugs used in various clinical situations cretions and an increase in gastrointestinal motility.
are outlined in Table 19–2. Consequently, certain antimuscarinic anticholinergics
Gastrointestinal System. Stimulation of the gas- tend to reverse this stimulation by blocking the effects
trointestinal tract via parasympathetic cholinergic of endogenously released acetylcholine. Clinically,
19Ciccone(p)-19 1/30/07 2:37 PM Page 270
these drugs are used as an adjunct in peptic ulcer. The seem to preferentially block the central muscarinic
rationale is that they will limit secretion of gastric acid, cholinergic synapses involved in parkinsonism. This
thus reducing irritation of the stomach mucosa. Also, does not mean that the drugs do not affect other
antimuscarinic anticholinergic drugs have been peripheral muscarinic receptors. Indeed, antiparkin-
approved for treatment of irritable bowel syndrome. sonian drugs are associated with a number of side
This condition is characterized by hyperactivity of gas- effects such as dry mouth, constipation, and urinary
trointestinal smooth muscle and includes problems retention, which are caused by their antagonistic effect
such as irritable colon and spastic colon. These on muscarinic receptors located outside of the brain.
antimuscarinic agents are sometimes referred to as Their primary effect, however, is to decrease the influ-
antispasmodics because of their reported ability to ence of central cholinergic synapses in parkinsonism.
decrease gastrointestinal smooth-muscle tone or Cardiovascular System. Atropine is sometimes
spasms. used to block the effects of the vagus nerve (cranial
Drugs used to treat peptic ulcer and irritable nerve X) on the myocardium. Release of acetylcholine
bowel syndrome are listed in Table 19–2. Although from vagal efferent fibers slows heart rate and the
these agents are approved for use in these conditions, conduction of the cardiac action potential throughout
considerable doubt exists as to how effective they are the myocardium. Atropine reverses the effects of
in actually resolving these gastrointestinal disorders. excessive vagal discharge and is used to treat the symp-
Their use in treating peptic ulcer has essentially been tomatic bradycardia that may accompany myocardial
replaced by other agents such as the H2 histamine infarction.4 Atropine may also be useful in treating
receptor blockers and proton pump inhibitors (see other cardiac arrhythmias such as atrioventricular
Chapter 27), but antimuscarinic anticholinergics may nodal block and ventricular asystole.
still be used if other drugs are ineffective or poorly Motion Sickness. Antimuscarinics (scopolamine
tolerated.5 These drugs will not cure peptic ulcer or in particular) are frequently used in the treatment of
prevent its recurrence when the medication is discon- motion sickness.22 Scopolamine appears to block
tinued. In essence, they only treat a symptom of the cholinergic transmission from areas of the brain and
problem (e.g., increased gastric secretion), without brainstem that mediate motion-related nausea and
really addressing the cause of the increased secretion vomiting (i.e., the vestibular system and reticular for-
(e.g., emotional stress). mation).8 These drugs are often administered trans-
Finally, antimuscarinic anticholinergic drugs used dermally via small patches that adhere to the skin.18
to treat gastrointestinal problems are often combined Preoperative Medication. Atropine and related
with other agents, such as antianxiety drugs. Librax, antimuscarinics are occasionally used preopera-
for instance, is the trade name for a combination of tively to decrease respiratory secretions during general
chlordiazepoxide and clidinium (an antianxiety agent anesthesia. Their use in this capacity has declined
and an anticholinergic agent, respectively). These considerably, however, because the newer inhala-
combination products are supposedly better at reliev- tion forms of general anesthesia do not stimulate
ing gastrointestinal problems where emotional factors bronchial secretions to the same extent as earlier
are also present. general anesthetics (see Chapter 11).5 Anticholinergic
Parkinson Disease. The pharmacologic manage- medications can sometimes be used preoperatively
ment of Parkinson disease is discussed in detail in with other agents (sedatives, antianxiety agents, and
Chapter 10. Consequently, the use of anticholinergic so forth) to help control postoperative nausea and
drugs in this disorder will only be mentioned briefly vomiting.9,19 Antimuscarinics may also be administered
here. Parkinsonism is a movement disorder caused by to prevent bradycardia during surgery, especially in
a deficiency of the neurotransmitter dopamine in the children.
basal ganglia. This deficiency leads to an overactivity Urinary Tract. Atropine and several synthetic
of central cholinergic synapses. Hence, anticholiner- antimuscarinics have been used to alleviate urinary
gic drugs should be beneficial in helping to resolve frequency and incontinence caused by hypertonicity of
this increase in central cholinergic influence.11 the urinary bladder.13,17 Increased bladder tone results
Certain anticholinergic drugs such as benz- if the normal reflex control of bladder function is
tropine, biperiden, and trihexyphenidyl are approved disrupted (i.e., the so-called neurogenic bladder syn-
for use in treating Parkinson disease (see Chapter 10, drome) or a urinary tract infection irritates the bladder.
Table 10–2 for a more complete list). These drugs Some people might also exhibit increased urinary
19Ciccone(p)-19 1/30/07 2:37 PM Page 271
frequency and nocturia without any obvious patholog- tered anticholinergic agent cannot be targeted for one
ical findings, a condition known as overactive blad- specific organ without also achieving a response in
der.13,17 Regardless of the cause, antimuscarinics can other tissues as well. For instance, an antimuscarinic
help reduce bladder hypertonicity by inhibiting drug administered to decrease motility in the gastroin-
contraction of the bladder detrusor muscle, thus allow- testinal tract may also affect other tissues containing
ing the bladder to fill more normally, with a decrease muscarinic receptors (e.g., the bladder, bronchial
in frequency of urination and a lesser chance of incon- smooth muscle, eye, heart). As higher doses are admin-
tinence. istered for any given problem, the chance of addition-
Respiratory Tract. Stimulation of the upper respi- al effects in tissues other than the target organ is also
ratory tract via the vagus causes bronchoconstriction. increased.
Anticholinergic drugs that block the effects of vagal- Consequently, antimuscarinic anticholinergic
released acetylcholine will relax bronchial smooth drugs are associated with a number of side effects.
muscle. Consequently, atropine and some synthetic Exactly which symptoms (if any) will be encountered
derivatives (ipratropium, tiotropium) have been used depends on a number of factors such as the specific
to treat bronchospasms occurring in patients with anticholinergic agent, the dosage of the drug, and the
asthma and chronic obstructive pulmonary disease individual response of each patient. The most common
(COPD).3,5,20 Although anticholinergics are not usual- side effects include dryness of the mouth, blurred
ly the initial drugs used to treat bronchoconstriction, vision, urinary retention, constipation, and tachycar-
they may be used in combination with other drugs or dia. Each of these side effects is caused by the blockade
as a second choice for patients who are unable to tol- of muscarinic receptors on the tissue or organ related
erate more conventional forms of bronchodilators to the effect. Some patients also report symptoms such
such as the adrenergic agonists.5 The use of anti- as confusion, dizziness, nervousness, and drowsiness,
cholinergics in treating respiratory disorders is dis- presumably because of an interaction of antimuscarinic
cussed in more detail in Chapter 26. drugs with CNS cholinergic receptors. These CNS-
Eye. Atropine and similar antimuscarinics block related symptoms occur more frequently with anti-
the acetylcholine-mediated contraction of the pupil- cholinergic drugs that readily cross the blood-brain
lary sphincter muscle, thus causing dilation of the barrier.
pupil (mydriasis).1 During an ophthalmologic exam,
these drugs may be applied topically in order to dilate
the pupil, thus allowing a more detailed inspection of
internal eye structures such as the retina.
SUMMARY
Cholinergic Poisoning. Cholinergic poisoning can Drugs affecting acetylcholine-mediated responses
occur in several situations such as eating wild mush- are classified as cholinergic stimulants and anticholin-
rooms, being exposed to certain pesticides, or being ergic drugs. Cholinergic stimulants increase choliner-
exposed to certain types of chemical warfare.2,27 This gic activity by binding to the acetylcholine receptor
type of poisoning often occurs because organophos- and activating the receptor (direct-acting stimulants)
phates and similar toxic compounds inhibit the acetyl- or by inhibiting the acetylcholinesterase enzyme,
cholinesterase enzyme throughout the body, thereby thus allowing more acetylcholine to remain active
causing severe overstimulation of nicotinic and mus- at the cholinergic synapse (indirect-acting stimu-
carinic receptors in organs and physiologic systems. lants). Anticholinergic drugs inhibit cholinergic activ-
These potentially life-threatening occurrences typi- ity by acting as competitive antagonists; that is,
cally require emergency treatment with atropine or an they bind to the cholinergic receptor but do not
analogous anticholinergic agent. In cases of severe activate it.
poisoning, fairly high doses of these drugs must often Cholinergic stimulants and anticholinergic drugs
be administered for several days. affect many tissues in the body and are used to treat a
variety of clinical problems. Cholinergic stimulants
are often administered to increase gastrointestinal and
Side Effects of Anticholinergic Drugs urinary bladder tone, to treat conditions such as glau-
Considering the diverse uses of the previously named coma, myasthenia gravis, and Alzheimer disease, and
anticholinergics, these drugs can obviously affect a to reverse the neuromuscular blockade produced by
number of different tissues. A systemically adminis- curarelike drugs. Anticholinergic drugs are used prin-
19Ciccone(p)-19 1/30/07 2:37 PM Page 272
cipally to decrease gastrointestinal motility and secre- diverse clinical applications of cholinergic stimulants
tions, and to decrease the symptoms of Parkinson and anticholinergics, physical therapists and occupa-
disease, but they may also be used to treat problems in tional therapists may frequently encounter patients
several other physiologic systems. Because of the abil- taking these drugs. Rehabilitation specialists should be
ity of cholinergic stimulants and anticholinergic drugs aware of the rationale for drug administration as well
to affect different tissues, these drugs may be associat- as possible side effects of cholinergic stimulants and
ed with a number of side effects. Considering the anticholinergic agents.
Chapter 20
Adrenergic Drugs
The purpose of this chapter is to describe drugs that therapy will be taking adrenergic agonists or antago-
either stimulate activity at norepinephrine synapses nists. In this chapter, the basic pharmacodynamic
(adrenergic agonists) or inhibit norepinephrine influ- mechanisms, clinical applications, and adverse effects
ence (adrenergic antagonists). To be more specific, of these drugs are introduced. The relevance of specif-
this chapter will focus on drugs primarily influencing ic adrenergic drugs to physical rehabilitation is
activity in the sympathetic nervous system through addressed in more detail in subsequent chapters cate-
their effect on adrenergic synapses. Norepinephrine is gorizing their use according to specific disorders
usually the neurotransmitter at the junction between (hypertension, angina, asthma, etc.).
sympathetic postganglionic neurons and peripheral Many adrenergic agonists and antagonists exert
tissues. Consequently, most of the adrenergic agonists their effects by binding directly to the appropriate
discussed in this chapter will be used to augment sym- postsynaptic receptor. Since a great deal of the speci-
pathetic responses, while the adrenergic antagonists ficity (or lack of specificity) of these drugs depends on
will be used to attenuate sympathetic-induced activity. the drug-receptor interaction, adrenergic receptor
In fact, adrenergic agonists are sometimes referred to classes and subclasses are briefly reviewed here.
as sympathomimetic, and antagonists are referred to
as sympatholytic, because of their ability to increase
and decrease sympathetic activity, respectively. Adrenergic Receptor
As in Chapter 19, drugs discussed here are cate-
gorized according to a common mode of action rather
Subclassifications
than according to common clinical applications. Most As discussed in Chapter 18, adrenergic receptors can
drugs introduced in this chapter will appear through- be divided into two primary categories: alpha and beta
out this text when they are classified according to their receptors. Each category can then be subdivided, so
use in treating specific problems. For instance, the that five receptor subtypes are commonly identified:
beta-selective adrenergic antagonists (i.e., beta block- alpha-1, alpha-2, beta-1, beta-2, and beta-3.16 Alpha-1
ers; see “Beta Antagonists”) are collectively intro- receptors have been further categorized as alpha 1a,
duced. Individual beta blockers, however, are also 1b, and 1d receptors, and alpha-2 receptors have been
discussed in subsequent chapters with regard to their subdivided into alpha 2a, 2b, and 2c receptors. The
use in specific problems such as hypertension (see functional significance of these subclassifications
Chapter 21), angina pectoris (see Chapter 22), cardiac remains unclear, so drugs affecting alpha receptors will
arrhythmias (see Chapter 23), and congestive heart be categorized according to the primary alpha receptor
failure (see Chapter 24). that they affect (i.e., alpha-1 or alpha-2). Adrenergic
The drugs described in this chapter are used to receptor subtypes are located on specific tissues
treat a variety of disorders, ranging from severe car- throughout the body, and the response mediated by
diovascular and respiratory problems to symptoms of each receptor depends on the interaction between that
the common cold. Because these drugs are widely used receptor and the respective tissue. Refer to Chapter 18
in cardiovascular disease and other disorders, many for a more detailed description of adrenergic receptor
patients seen in physical therapy and occupational locations and responses.
273
20Ciccone(p)-20 1/30/07 2:37 PM Page 274
The primary uses of adrenergic agonists and anta- type is beneficial. Use of selective versus nonselective
gonists according to their selectivity for individual adrenergic drugs is considered in “Adrenergic Ago-
receptor subtypes are summarized in Table 20–1. In nists” and “Adrenergic Antagonists” in this chapter.
general, a specific agonist is used to mimic or increase “Receptor selectivity”, however, is a relative term.
the receptor-mediated response, whereas the antago- Even though an adrenergic drug is reported to be
nist is used to decrease the receptor-mediated response. selective for only one receptor subtype, a certain affin-
Clinically useful adrenergic agonists and antago- ity for other receptor subtypes may also occur to a less-
nists display variable amounts of specificity for each er degree. A beta-1–specific drug, for instance, binds
receptor subtype. Some drugs are fairly specific and preferentially to beta-1 receptors but may also show
bind to only one receptor subtype (e.g., a specific some slight affinity for beta-2 receptors. Selectivity is
alpha-1 agonist like phenylephrine preferentially stim- also dose-related, with the relative degree of receptor
ulates the alpha-1 subtype). Other drugs show a mod- selectivity decreasing as higher doses are administered.
erate amount of specificity, perhaps affecting one Consequently, some side effects of the so-called selec-
major receptor category. An example is the nonselec- tive drugs may be caused by stimulation of other
tive beta antagonist propranolol, which blocks beta-1 receptor subtypes, especially at higher drug doses.
and beta-2 receptors but has little or no effect on alpha
receptors. Finally, other drugs such as epinephrine are
rather nonspecific and affect alpha and beta receptors
equally. In some clinical situations, administering a
Adrenergic Agonists
selective drug may be desirable, whereas in others, a Drugs that stimulate the adrenergic receptors are pre-
drug that interacts with more than one receptor sub- sented below according to their relative specificity for
Alpha-2 receptor
CNS synapses (inhibitory) Hypertension No significant clinical use
Spasticity
Beta-1 receptor
Heart: increased heart rate and force Cardiac decompensation Hypertension
of contraction Arrhythmia
Angina pectoris
Heart failure
Prevention of reinfarction
Beta-2 receptor
Bronchioles: bronchodilation Prevent bronchospasm No significant clinical use
Uterus: relaxation Prevent premature labor
*Primary clinical condition(s) that the agonists or antagonists are used to treat. See text for specific drugs in
each category and a discussion of treatment rationale.
20Ciccone(p)-20 1/30/07 2:37 PM Page 275
each receptor subtype. The drugs that primarily acti- Oxymetazoline (Afrin, Visine, many others). This
vate alpha receptors are discussed first, followed by drug is used in nose drops and nasal sprays to decrease
beta-selective drugs, and drugs that have mixed alpha- nasal congestion through alpha-1–mediated vasocon-
and beta-agonist activity. striction. Higher or systemic doses may also cause
hypotension, presumably because central nervous sys-
tem (CNS) alpha-2 receptors are stimulated in a man-
Alpha Agonists ner similar to clonidine (see “Alpha-2–Selective
Alpha-1–Selective Agonists Agonists”). Oxymetazoline can also be administered as
eye drops to decrease redness and minor eye irritation.
General Indications Phenylephrine (Neo-Synephrine, others). Like
Alpha-1 agonists bind directly to and activate the methoxamine, phenylephrine can be administered sys-
alpha-1 receptor located primarily on vascular smooth temically to treat hypotension, and phenylephrine can
muscle, thus leading to smooth-muscle contraction also be used to terminate certain episodes of supraven-
and vasoconstriction. Because of their vasoconstrictive tricular tachycardia. In addition, phenylephrine is
properties, these drugs are able to increase blood pres- administered topically to treat nasal congestion and is
sure by increasing peripheral vascular resistance. Con- found in many over-the-counter spray decongestants.
sequently, certain alpha-1 agonists are administered Pseudoephedrine (Drixoral, Sudafed, many others).
systemically to treat acute hypotension occurring in Pseudoephedrine is administered orally for its decon-
emergencies such as shock or during general anesthe- gestant effects, is found in many over-the-counter
sia. A second common clinical application of these preparations, and is commonly used to help relieve
drugs is the treatment of nasal congestion (i.e., runny cold symptoms.
nose and stuffy head feelings associated with the com- Xylometazoline (Otrivin, others). This drug is used
mon cold). In appropriate doses, alpha-1 agonists primarily as a nasal spray to decrease congestion dur-
preferentially constrict the vasculature in the nasal and ing colds and allergies.
upper respiratory mucosa, thus decreasing the conges-
tion and mucosal discharge. A third application of Adverse Effects
alpha-1 agonists is to decrease heart rate during
attacks of paroxysmal supraventricular tachycardia. By The primary side effects associated with alpha-1–
increasing peripheral vascular resistance, these drugs specific agonists are caused by excessive stimulation of
bring about a reflex decrease in heart rate through the alpha-adrenergic responses. Some of the more fre-
cardiac baroreceptor reflex. quent side effects include increased blood pressure,
headache, and an abnormally slow heart rate (because
of reflex bradycardia). Some patients also report chest
Specific Agents pain, difficulty breathing, and feelings of nervousness.
These side effects are quite variable and are usually
Mephenteramine (Wyamine). This alpha-1 stimu- dose-related (i.e., they occur more frequently at high-
lant is used primarily to maintain or restore blood er doses).
pressure during hypotensive episodes that may occur
during spinal anesthesia. It is typically administered by
intravenous or intramuscular injection. Alpha-2–Selective Agonists
Methoxamine (Vasoxyl). This drug is used prima-
General Indications
rily to increase and maintain blood pressure in severe,
acute hypotension, especially during general anesthe- Alpha-2–selective drugs are used primarily in the
sia and spinal anesthesia. It is usually administered by treatment of hypertension and spasticity. When treat-
injection (intramuscularly or intravenously) to allow a ing hypertension, these drugs stimulate alpha-2 recep-
rapid onset. tors located in the brain and brainstem. When
Midodrine (ProAmatine). Midodrine can be stimulated, these central alpha-2 receptors exert an
administered orally to treat resistant cases of orthosta- inhibitory effect on sympathetic discharge from the
tic hypotension. This drug can also prevent hypoten- vasomotor center in the brainstem.34 Diminished sym-
sion in patients undergoing dialysis, and it can offset pathetic discharge results in a decrease in blood pres-
the hypotensive effects of certain psychotropic drugs sure. The use of alpha-2 agonists in lowering blood
(e.g., antipsychotic medications). pressure is discussed in more detail in Chapter 21.
20Ciccone(p)-20 1/30/07 2:37 PM Page 276
Alpha-2 receptors have also been identified on anesthesia, and an analgesic. In particular, this drug can
interneurons in the spinal cord. Stimulation of these be combined with other analgesics (opioids) for treat-
receptors causes interneuron inhibition, and a subse- ing severe pain in people with cancer. Clonidine’s anal-
quent decrease in excitability of motor neurons sup- gesic effects are probably mediated by stimulation of
plied by the interneurons.6,8 Alpha-2 agonists have alpha-2 receptors located in the spinal cord. Because of
therefore been used to normalize neuronal activity in its effects on alpha-2 receptors in the spinal cord,
conditions such as spasticity; the use of these drugs as clonidine has antispasticity effects. Use of this drug in
antispasticity agents is discussed in more detail in spasticity, however, is often limited because it also
Chapter 13. causes hypotension.
Consequently, alpha-2 agonists appear to exert Guanabenz (Wytensin). Guanabenz is used pri-
their antihypertensive effects and antispasticity effects marily to decrease blood pressure via its effect on
by preferentially stimulating alpha-2 receptors in the alpha-2 receptors in the brainstem. This drug is simi-
brain and spinal cord, respectively. In both situations, lar to clonidine in efficacy and clinical use.
it is unclear whether alpha-2 agonists exert their pri- Guanfacine (Tenex). This drug is similar to guan-
mary effects on presynaptic or postsynaptic receptors. abenz, and is typically used to treat advanced or resist-
Stimulation of presynaptic alpha-2 receptors located ant cases of high blood pressure.
at adrenergic synapses results in a decrease in norepi- Methyldopa (Aldomet). Methyldopa has been
nephrine release from the presynaptic terminal.8 Sim- used as an antihypertensive drug for some time, but its
ilarly, alpha-2 receptors have also been identified mechanism of action is poorly understood. Currently,
postsynaptically at specific central synapses, and these methyldopa is believed to exert its effects by being
postsynaptic receptors are believed to directly inhibit converted to alpha-methylnorepinephrine in the
neuronal excitation.35 Thus, alpha-2 agonists may body.26 Alpha-methylnorepinephrine is a potent alpha-
exert their effects by stimulating either central presy- 2 agonist that lowers blood pressure by stimulating
naptic or postsynaptic receptors, or by acting on inhibitory central adrenergic receptors in a manner
inhibitory presynaptic and postsynaptic receptors similar to clonidine and guanabenz.
simultaneously. Alpha-2 receptors may also exist on Tizanidine (Zanaflex) Tizanidine is used primarily
other tissues such as the eye, and the use of alpha-2 for treating spasticity.14,24 This drug is similar to cloni-
agonists continues to expand as more is learned about dine, but has less vasomotor effects and is therefore
the location and function of these receptors. less likely to cause hypotension and other cardiovascu-
lar problems. As indicated earlier, tizanidine stimu-
lates alpha-2 receptors in the spinal cord, which
Specific Agents
results in decreased excitatory input onto the alpha
Brimonidine (Alphagan). This drug is adminis- motor neuron. Decreased excitation of the alpha
tered locally to the eye to treat glaucoma. It stimulates motor neuron results in decreased spasticity of the
ocular alpha-2 receptors, which decreases intraocular skeletal muscle supplied by that neuron.
pressure by decreasing vitreous humor production and
increasing drainage of vitreous humor from the eye. Adverse Effects
Clonidine (Catapres, Duraclon). Clonidine is used Use of alpha-2–specific drugs may be associated with
as an antihypertensive as well as an analgesic. Cloni- some relatively minor side effects such as dizziness,
dine’s antihypertensive effects occur because the drug drowsiness, and dry mouth. More pronounced adverse
stimulates alpha-2 receptors in the vasomotor center of effects such as difficult breathing, an unusually slow
the brainstem and decreases sympathetic discharge to heart rate, and persistent fainting may indicate a toxic
the heart and vasculature. Clonidine, however, is not accumulation or overdose of these drugs.
usually successful when used alone in long-term treat-
ment of essential hypertension. This drug is usually
reserved for use in short-term management or in com-
Beta Agonists
bination with other antihypertensive drugs, especially Beta-1–Selective Agonists
in patients who are unable to tolerate alpha-1 antago-
General Indications
nists such as prazosin (Minipress) (see “Alpha Antago-
nists”). Clonidine also has sedative properties and has The beta-1 receptor is located primarily on the myo-
been used as an antianxiety drug, an adjunct in general cardium, and stimulation of the receptor results in in-
20Ciccone(p)-20 1/30/07 2:37 PM Page 277
nists actually result in beneficial outcomes for the and methamphetamine (Desoxyn) are known for their
newborn child, and these drugs may actually be harm- powerful sympathomimetic effects. These drugs
ful to the mother (see “Adverse Effects” below).9 appear to increase norepinephrine release, decrease
Hence, it is not clear if beta-2 agonists will be used to norepinephrine reuptake and breakdown at adrenergic
prevent preterm labor in the future. synapses, thus increasing activity at synapses with nor-
epinephrine-sensitive receptors (i.e., alpha-1, alpha-2,
Adverse Effects and beta-1 receptors). These drugs may also exert
similar effects on certain dopaminergic synapses.
The primary side effects associated with beta-2– Amphetamines are used on a limited basis to treat
specific drugs include nervousness, restlessness, and attention-deficit disorder in children and to increase
trembling. These adverse symptoms may be caused by mental alertness in adults with narcolepsy. Use of
stimulation of central beta-adrenergic receptors. these drugs to suppress appetite or to combat normal
There is also some suggestion that excessive use of sleepiness is discouraged because of their high poten-
beta-2 agonists may cause increased airway hyperre- tial for abuse, and these drugs are classified in the
sponsiveness, which could lead to severe and possibly United States as schedule II controlled substances (see
fatal asthmatic attacks.21,33 This fact has generated Chapter 1 for a description of controlled substance
debate about the safe and effective use of these drugs classification).
in treating asthma; contemporary use of beta-2 ago- Ephedrine (generic). Ephedrine appears to
nists along with other antiasthmatic drugs is described directly stimulate alpha-1, alpha-2, and beta-1 adreno-
in Chapter 26. When used to prevent premature labor, ceptors, and may also stimulate these receptors indi-
drugs such as ritodrine have also been associated with rectly by increasing the release of norepinephrine at
increases in maternal heart rate and systolic blood synapses that use these receptor subtypes. This drug is
pressure, as well as maternal pulmonary edema. These used primarily for its alpha-1 effects and can be used
changes in maternal cardiopulmonary function can be to treat severe, acute hypotension. When treating
quite severe and may be fatal to the mother. hypotension in emergency situations (e.g., shock),
ephedrine is administered systemically by injection
Drugs with Mixed Alpha- (intravenously, intramuscularly, or subcutaneously).
and Beta-Agonist Activity Because of its ability to stimulate alpha-1 receptors in
the nasal mucosa, ephedrine is also used as a nasal
General Indications decongestant. As a decongestant, ephedrine is typical-
Several drugs are available that display a rather mixed ly combined with other agents (antitussives, antihista-
agonistic activity with regard to adrenergic receptor mines) to form cough/cold products. Ephedrine is also
subtypes. Some drugs, like epinephrine, appear to be sometimes administered as a bronchodilator (beta-2
able to stimulate all four adrenergic receptor subtypes. agonist effect), but the use of this drug in asthma and
Other drugs, such as norepinephrine, bind to both related conditions has generally been replaced by safer
types of alpha receptors, bind to beta-1 receptors to a agents (see Chapter 26). Finally, ephedrine has been
lesser extent, and show little or no affinity for beta-2 administered to produce a general excitatory effect on
receptors. Another group of indirect adrenergic ago- central adrenergic receptors and has been used to treat
nists (ephedrine, metaraminol) appear to act as nonse- conditions associated with a decrease in CNS arousal
lective agonists because of their ability to increase the (e.g., narcolepsy).
release of norepinephrine from presynaptic storage Epinephrine (Adrenalin, Bronkaid Mist, Primatene
sites. Because of the ability of many of these multiple- Mist, others). Epinephrine appears to directly stimu-
receptor drugs to affect a number of adrenoceptor late all adrenergic receptor subtypes and is adminis-
subtypes, their clinical uses are quite varied. Specific tered for a variety of reasons. Epinephrine is found in
agents with mixed agonistic activity and their respec- many antiasthmatic inhalation products because of its
tive applications are presented below. ability to stimulate beta-2 receptors on the bronchi.
Because it stimulates vascular alpha-1 receptors, epi-
nephrine may be applied topically to produce local
Specific Agents
vasoconstriction and control bleeding during minor
Amphetamines. Drugs such as amphetamine surgical procedures (e.g., suturing superficial wounds).
(generic), dextroamphetamine (Dexedrine, others), Likewise, epinephrine may be mixed with a local anes-
20Ciccone(p)-20 1/30/07 2:37 PM Page 279
thetic when the anesthetic is injected during minor receptors that inhibits contraction of the bladder.
surgical and dental procedures. The vasoconstriction Phenylpropanolamine is taken orally for nasal decon-
produced by epinephrine prevents the anesthetic from gestion, appetite suppression, or urinary incontinence.
being washed away by the local blood flow, thus pro-
longing the anesthetic’s effects. Because of a potent Adverse Effects
ability to stimulate the heart (beta-1 effect), epineph-
Because of the general ability of many of the drugs
rine is frequently administered during cardiac arrest to
previously described to produce CNS excitation, some
reestablish normal cardiac rhythm. Finally, epineph-
of the primary side effects are nervousness, restless-
rine is often the drug of choice in treating anaphylac-
ness, and anxiety. Because these agents also tend to
tic shock. Anaphylactic shock is a hypersensitive
allergic reaction marked by cardiovascular collapse stimulate the cardiovascular system, prolonged or
(decreased cardiac output, hypotension) and severe excessive use may also lead to complications such as
bronchoconstriction. Epinephrine is ideally suited to hypertension, arrhythmias, and even cardiac arrest.
treat this problem because of its ability to stimulate When used to treat bronchospasm, prolonged admin-
the heart (beta-1 effect), vasoconstrict the periphery istration via inhalation may also cause some degree of
(alpha-1 effect), and dilate the bronchi (beta-2 effect). bronchial irritation with some agents.
Metaraminol (Aramine). Metaraminol appears to
act like ephedrine; that is, metaraminol directly stim- Adrenergic Antagonists
ulates alpha-1, alpha-2, and beta-1 receptors, and indi-
rectly stimulates them by increasing the release of Adrenergic antagonists or blockers bind to adrenergic
presynaptic norepinephrine. This drug is usually receptors but do not activate them. These agents are
administered by injection (intramuscularly, intra- often referred to as sympatholytic drugs because of
venously, or subcutaneously) to treat hypotension their ability to block the receptors that typically medi-
occurring in shock or general anesthesia. ate sympathetic responses (i.e., alpha and beta recep-
Norepinephrine (Levophed). Norepinephrine tors). Clinically useful adrenergic antagonists usually
stimulates both types of alpha receptors as well as show a fairly high degree of specificity for one of
beta-1 receptors but displays very little agonistic activ- the major receptor classifications. They tend to bind
ity toward beta-2 receptors. It is usually administered preferentially to either alpha- or beta-adrenergic
intravenously to treat hypotension during shock or receptors. Specific drugs may show an additional
general anesthesia. degree of specificity within the receptor class. For
Phenylpropanolamine (Acutrim, Dexatrim, Propa- instance, a beta blocker may bind rather selectively to
gest, others). The exact mechanism of this drug is only beta-1 receptors, or it may bind equally to both
unclear. Although it may directly stimulate alpha and beta-1 and beta-2 receptors.
beta receptors, this drug probably exerts its effects by The general clinical applications of alpha and
increasing the release of presynaptic norepinephrine; beta antagonists are presented below. Specific agents
thus, phenylpropanolamine is an indirect-acting, non- within each major group are also discussed.
selective agonist. Because of its alpha-1 agonist prop-
erties, phenylpropanolamine can be used as a nasal Alpha Antagonists
decongestant. Phenylpropanolamine also appears to
General Indications
act as an appetite suppressant (“diet” drug) by increas-
ing the release of norepinephrine within the hypothal- Alpha antagonists are administered primarily to
amus. In this regard, it is similar to amphetaminelike reduce peripheral vascular tone by blocking the alpha-
compounds, which may also suppress feeding behavior 1 receptors located on vascular smooth muscle. When
by increasing adrenergic influence in the brain. Its use stimulated by endogenous catecholamines (norepi-
as a diet drug, however, has generated substantial con- nephrine, epinephrine), the alpha-1 receptor initiates
cern because it may be abused by some individuals, and vasoconstriction.
because excessive use may lead to hemorrhagic Consequently, alpha antagonists are used in con-
stroke.17 Hence, efforts have been made to curtail the ditions where peripheral vasodilation would be bene-
availability of this drug, especially in over-the-counter ficial. A principal application of these agents, for
products. Finally, this drug can help treat urinary instance, is in treating hypertension.26,39 These drugs
incontinence, presumably because of an effect on alpha seem to attenuate the peripheral vasoconstriction me-
20Ciccone(p)-20 1/30/07 2:37 PM Page 280
diated by excessive adrenergic influence, thus decreas- of smooth muscle in the vasculature and other tissues.
ing blood pressure through a decrease in peripheral It was developed as an antihypertensive, and can be
vascular resistance. These agents may also be used in taken orally to reduce blood pressure because it
patients with a pheochromocytoma, a tumor that pro- decreases peripheral vascular resistance.5,39 In addi-
duces large quantities of epinephrine and norepineph- tion, doxazosin may have beneficial effects on the plas-
rine. Alpha antagonists are often administered prior to ma lipid profile (decreased total cholesterol, decreased
and during the removal of such a tumor, thus prevent- triglycerides), and may decrease insulin resistance in
ing the hypertensive crisis that may occur from exces- people with type 2 diabetes mellitus (see Chapter
sive alpha-1 stimulation from catecholamines released 32).7,19,36 Hence, this drug is useful in treating high
from the tumor. Similarly, alpha antagonists have been blood pressure in people with metabolic problems
used to successfully prevent and treat the sudden including various hyperlipidemias and glucose intoler-
increase in blood pressure occurring during an auto- ance. In addition, doxazosin has been successful in
nomic crisis. These drugs have been used to promote reducing urinary retention in men with BPH. As indi-
vasodilation in conditions of vascular insufficiency, cated above, this drug relaxes smooth muscle in the
including peripheral vascular disease and Raynaud prostate and urethra, thereby allowing urine to flow
phenomenon. However, the success of these drugs in more freely during micturition.
treating vascular insufficiency has been somewhat Ergot alkaloids. Ergotamine (Ergomar, others)
limited. and similar drugs such as dihydroergotamine (D. H. E.
Certain alpha-1 blockers such as doxazosin have 45) and ergonovine (Ergotrate), exert several pharma-
been used extensively in treating benign prostatic cological effects. At higher doses, these drugs act as
hyperplasia (BPH).23,32 Alpha-1 receptors located on competitive alpha antagonists, hence their inclusion
smooth muscle in the prostate capsule, neck of the here. However, these drugs appear to produce vaso-
bladder, and urethra cause muscle constriction that constriction in blood vessels that have low vascular
restricts urine flow and the ability to empty the blad- tone and vasodilation in blood vessels that have high
der. By blocking these receptors, alpha-1 antagonists vascular tone. Exactly how they accomplish these
relax these smooth muscles and allow men with BPH rather contradictory effects is unclear, but these drugs
to void urine more easily and completely.12,32 essentially function as partial agonists because they dis-
A group of drugs known collectively as ergot play agonistic (stimulatory) activity in vessels with low
derivatives display some alpha-blocking ability as well tone and antagonistic (inhibitory) activity in vessels
as other unique properties. Ergot alkaloids and with high tone. These drugs, however, can also block
ergoloid mesylates and are used clinically for diverse serotonin and dopamine receptors. Hence, they exert a
problems, including the treatment of vascular number of complex effects throughout the body, and it
headache and improvement of mental function in pre- is difficult to attribute their therapeutic effects to only
senile dementia. one type of receptor. In the past, these drugs were used
Because the primary uses of alpha antagonists primarily for their ability to prevent or abort vascular
involve their ability to decrease vascular tone, the clin- headaches (migraine, cluster headaches) by vasocon-
ically useful alpha antagonists tend to be somewhat stricting cerebral vessels.37,38 Their antimigraine effects,
alpha-1 selective. Alpha-2 receptors should not be however, may be due to their antagonistic effect on vas-
selectively antagonized because this event may ulti- cular serotonin receptors rather than an effect on cere-
mately lead to an increase in peripheral vascular tone bral alpha-1 receptors. Hence, use of these drugs in
through an increase in sympathetic discharge. Certain treating headaches has been replaced in many patients
alpha-2 receptors are located in the brainstem, and with serotonin-selective antagonists such as sumatrip-
stimulation of these receptors appears to decrease tan (Imitrex) and rizatriptin (Maxalt). Alpha-1 blockers
sympathetic outflow from the vasomotor center. are also used to prevent or treat postpartum hemor-
Thus, blocking these centrally located alpha-2 recep- rhage because they stimulate the uterus to contract,
tors is counterproductive when a decrease in vascular thereby helping compress and occlude bleeding vessels
tone is desired. in the uterine wall. Occasionally, these drugs can also
be used to diagnosis angina pectoris because they cause
transient constriction of the coronary arteries.
Specific Agents
Ergoloid mesylate These compounds, which
Doxazosin (Cardura). This drug shows a high appear under trade names such as Gerimal and
degree of alpha-1 selectively, and promotes relaxation Hydergine, exhibit some ability to produce peripheral
20Ciccone(p)-20 1/30/07 2:37 PM Page 281
vasodilation by blocking peripheral alpha-1 receptors. alpha-1 receptors, these drugs tend to decrease blood
The primary clinical application of ergoloid mesylates pressure by decreasing peripheral vascular resistance.
is to increase mental acuity and alertness in geriatric As blood pressure falls, a compensatory increase in
patients with dementia related to Alzheimer disease.27 cardiac output is initiated via the baroreceptor reflex.
These drugs supposedly increase mental function by The increased cardiac output is mediated in part by an
increasing cerebral blood flow or by increasing oxygen increase in heart rate, hence the reflex tachycardia. A
utilization in the brain. The mechanism of action of second major problem with these drugs is orthostatic
these drugs is probably a moot point, however, hypotension. Dizziness and syncope following changes
because there is little evidence that they produce any in posture are quite common due to the decrease in
significant clinical benefits in treating Alzheimer peripheral vascular tone. With alpha antagonists, or-
dementia.27 These drugs are usually administered oral- thostatic hypotension may be a particular problem just
ly or sublingually. after drug therapy is initiated, in geriatric patients, or
Phenoxybenzamine (Dibenzyline). Phenoxybenza- following exercise.
mine is a noncompetitive alpha-1 blocker that binds
irreversibly to the alpha-1 receptor. This drug tends to
have a slow onset, but its effects last much longer than Beta Antagonists
those of the competitive blockers (e.g., phentolamine
General Indications
and prazosin). Phenoxybenzamine is used primarily to
control blood pressure prior to and during the Beta antagonists are generally administered for their
removal of a pheochromocytoma. This drug is not effect on the beta-1 receptors that are located on the
typically used for the long-term management of heart.31 When stimulated, these receptors mediate an
hypertension, however, because it produces several increase in cardiac contractility and rate of contrac-
side effects including reflex tachycardia. Other indica- tion. By blocking these receptors, beta antagonists
tions for phenoxybenzamine include treatment of reduce the rate and force of myocardial contractions.
urinary retention in benign prostatic hypertrophy Consequently, beta antagonists are frequently used to
and treatment of vasospastic disease (Raynaud phe- decrease cardiac workload in conditions such as
nomenon). Phenoxybenzamine is usually adminis- hypertension and certain types of angina pectoris.
tered orally. Beta blockers may also be used to normalize heart rate
Phentolamine (Regitine). Phentolamine is a com- in certain forms of cardiac arrhythmias. Specific clini-
petitive alpha antagonist used primarily to control cal applications of individual beta blockers are sum-
blood pressure during management of pheochromocy- marized in Table 20–2.
toma. The drug is usually administered via intravenous Another important function of beta blockers is
or intramuscular injection. Phentolamine is not usual- their ability to limit the extent of myocardial damage
ly used to treat essential hypertension because with following a heart attack and to reduce the risk of fatal-
prolonged use, effectiveness tends to decrease and ity following myocardial infarction.11 Apparently,
patients begin to develop adverse side effects. these drugs help reduce the workload of the damaged
Prazosin (Minipress). Prazosin is a competitive heart, thus allowing the heart to recover more
alpha-1 antagonist that has emerged as one of the pri- completely following infarction. Likewise, there is
mary alpha-1 selective agents. It tends to produce substantial evidence that some beta blockers can
vasodilation in both arteries and veins, and is used pri- help improve cardiac function in certain types of heart
marily in the long-term management of essential failure3,13,15; this idea is addressed in more detail in
hypertension.38 Prazosin has also been used to reduce Chapter 24.
alpha-1 receptor mediated activity in congestive heart Clinically useful beta antagonists are classified as
failure, Raynaud phenomenon, pheochromocytoma, beta-1–selective if they predominantly affect the beta-
and BPH. Prazosin is administered orally. 1 subtype; they are classified as beta-nonselective if
Terazosin (Hytrin). This drug is similar to doxa- they have a fairly equal affinity for beta-1 and beta-2
zosin. receptors (see Table 20–2). Beta-1–selective drugs are
also referred to as cardioselective because of their pref-
erential effect on the myocardium. Even if a beta
Adverse Effects Of Alpha-1 Antagonists
antagonist is nonselective (i.e., blocks both beta-1 and
One of the primary adverse effects associated with beta-2 receptors), the beta-1 blockade is clinically
alpha antagonists is reflex tachycardia. By blocking beneficial. When stimulated, beta-2 receptors, which
20Ciccone(p)-20 1/30/07 2:37 PM Page 282
*Only indications listed in the United States product labeling are included in this table. All drugs are fairly similar
pharmacologically, and some may be used for appropriate cardiovascular conditions not specifically listed in
product labeling.
are found primarily on bronchial smooth muscle, tions.18,20,25 Primary indications and relative selectivity
cause bronchodilation. Blocking these beta-2 recep- of these drugs are summarized in Table 20–2. Clinical
tors may lead to smooth-muscle contraction and bron- applications of specific beta blockers are discussed in
choconstriction. Thus, drugs that selectively block more detail in Chapters 21 through 24.
beta-2 receptors have no real clinical significance
because they promote bronchoconstriction.2
Specific Agents
Currently, a number of beta blockers are used
clinically; the selection of a specific agent depends on Acebutolol (Sectral). Acebutolol is described as a rela-
factors such as cardioselectivity, duration of action tively cardioselective beta blocker that tends to bind
(half-life), and several other ancillary properties of preferentially to beta-1 receptors at low doses, but
each drug.1,10 Certain beta blockers, for instance, pro- binds to both types of beta receptors as the dosage
duce added effects such as mild peripheral vasodila- increases. This drug also exerts mild to moderate
tion or stabilization of cardiac membranes that can intrinsic sympathomimetic activity, which means that
be beneficial in treating certain cardiovascular condi- acebutolol not only blocks the beta receptor from
20Ciccone(p)-20 1/30/07 2:37 PM Page 283
the effects of endogenous catecholamines, but also dolol is used primarily in the long-term management
stimulates the receptor to some extent (i.e., it acts as of hypertension, but this drug may also be used to pre-
a partial beta agonist). This advantage protects the vent certain types of angina pectoris.
beta receptor from excessive endogenous stimulation Propranolol (Inderal). Propranolol, the classic
while still preserving a low level of background sym- nonselective beta blocker, is approved for use in
pathetic activity. Primary clinical applications are for hypertension, angina pectoris, cardiac arrhythmias,
treatment of hypertension and prevention and treat- and prevention of myocardial reinfarction. In addi-
ment of cardiac arrhythmias. The drug is usually tion, propranolol has been used in the prevention of
administered orally. vascular headache and as an adjunct to alpha blockers
Atenolol (Tenormin). Like acebutolol, atenolol is in treating pheochromocytoma. Propranolol is usually
regarded as beta-1 selective, but tends to be less beta- administered orally for the long-term management of
specific at higher doses. The drug is administered the previously listed conditions, but it may be admin-
orally for the long-term treatment of hypertension istered via intravenous injection for the immediate
and chronic, stable angina. Atenolol is also adminis- control of arrhythmias.
tered immediately following a myocardial infarction Sotalol (Betapace). This drug is a nonselective
to prevent reinfarction and to promote recovery of the beta blocker that is administered primarily to treat
myocardium. arrhythmias, although it is sometimes used as an anti-
Betaxolol (Kerlone). This drug is a relatively hypertensive or antianginal agent. It is administered
beta-1 selective agent that is administered orally for orally.
treating hypertension. Timolol (Blocadren). This nonselective beta
Bisoprolol (Zebeta). This drug is similar to betax- blocker is administered orally for the treatment of
olol. hypertension and prevention of myocardial reinfarc-
Carteolol (Cartrol). Carteolol is a nonselective tion. It may also be used to treat angina or prevent
beta blocker that also has moderate intrinsic sympath- vascular headaches.
omimetic activity. It is typically administered orally to
treat hypertension.
Adverse Effects
Labetalol (Normodyne, Trandate). Labetalol is a
nonselective beta blocker. This drug appears to have When nonselective beta blockers are used, some
some alpha-1–selective blocking effects. Labetalol is antagonism of beta-2 receptors also occurs.2,31 The
used primarily in the management of hypertension antagonism of beta-2 receptors on bronchiole smooth
and, while usually given orally, may be injected intra- muscle often leads to some degree of bronchoconstric-
venously in emergency hypertensive situations. tion and an increase in airway resistance. Although this
Metoprolol (Lopressor, Toprol-XL). Metoprolol is event is usually not a problem in individuals with nor-
considered a cardioselective beta blocker and has been mal pulmonary function, patients with respiratory
approved for treating hypertension, preventing angina problems such as asthma, bronchitis, and emphysema
pectoris, and preventing myocardial reinfarction. As may be adversely affected by nonselective beta antago-
an antihypertensive and antianginal, metoprolol is nists. In these patients, one of the beta-1–selective
usually administered orally. In the prevention of rein- drugs should be administered.
farction, metoprolol is initiated by intravenous injec- Selective and nonselective beta blockers are also
tion and then followed up by oral administration. associated with several other adverse effects. The most
Nadolol (Corgard). Nadolol is a nonselective beta serious of these effects results from excessive depres-
blocker that is administered orally as an antihyperten- sion of cardiac function.30 By slowing down the heart
sive and antianginal agent. This drug has an advantage too much, these agents can lead to cardiac failure,
over other nonselective beta blockers (propranolol) in especially if there is some preexisting cardiac disease.
that nadolol often needs to be taken only once each Because of their antihypertensive properties, beta
day. blockers may produce orthostatic hypotension, and
Penbutolol (Levatol). This drug is similar to car- dizziness and syncope may occur following abrupt
teolol. changes in posture. Patients taking beta blockers for
Pindolol (Visken). Pindolol is a nonselective beta prolonged periods have also been reported to have an
blocker that exhibits the highest level of intrinsic sym- increase in centrally related side effects such as depres-
pathomimetic activity of all the beta blockers. Pin- sion, lethargy, and sleep disorders.17,29 These behav-
20Ciccone(p)-20 1/30/07 2:37 PM Page 284
ioral side effects may be due to the interaction of beta Guanethidine (Ismelin). Similar in action and
blockers with CNS receptors. effects to guanadrel, this drug is actively transported
Various other relatively minor side effects have into the presynaptic terminal by the norepinephrine
also been reported, including gastrointestinal distur- pump, where it inhibits norepinephrine release
bances (nausea, vomiting) and allergic responses and later replaces stored norepinephrine. Unlike gua-
(fever, rash). However, these are fairly uncommon and nadrel, guanethidine selectively affects postganglionic
tend to be resolved by adjusting the dosage or specific sympathetic adrenergic nerve terminals and does
medication type. not affect release of norepinephrine from the adre-
nal medulla. Guanethidine is usually administered
orally for the management of moderate-to-severe
Other Drugs That Inhibit hypertension.
Adrenergic Neurons Metyrosine (Demser). Metyrosine inhibits the en-
General Indications zyme initiating catecholamine synthesis (epinephrine,
norepinephrine); this drug is used to diminish cate-
Several agents are available that inhibit activity at cholamine stores prior to removal of a catecholamine-
adrenergic synapses by interfering with the release of producing tumor (pheochromocytoma).
norepinephrine. Rather than directly blocking the Rauwolfia alkaloids. This chemical group includes
postsynaptic receptor, these drugs typically inhibit or reserpine (Serpalan), deserpidine (Harmonyl), and rau-
deplete the presynaptic terminal of stored norepi- wolfia serpentina (Raudixin, Rauval, others). These
nephrine. These drugs are used primarily to decrease drugs all inhibit the synthesis of catecholamines (nor-
peripheral adrenergic influence and to treat problems epinephrine, epinephrine) as well as 5-hydroxytrypta-
such as hypertension and cardiac arrhythmias. mine (serotonin) in peripheral and CNS sympathetic
nerve endings. This inhibition eventually causes a de-
pletion of presynaptic neurotransmitter stores in sever-
Specific Agents
al tissues including postganglionic nerve terminals,
Bretylium (Bretylol). Bretylium appears to direct- adrenal medulla, and brain. Unlike guanethidine and
ly inhibit the release of norepinephrine from adrener- guanadrel, these agents do not appear to actually re-
gic nerve terminals. With prolonged use, this drug place the presynaptic neurotransmitter, but simply
may also replace presynaptic norepinephrine in a prevent more transmitter from being resynthesized.
manner similar to guanadrel and guanethidine (see the Reserpine and the other rauwolfia alkaloids are admin-
next two agent listings in this section). Bretylium is istered orally to treat mild-to-moderate hypertension.
used primarily in the treatment of cardiac arrhythmias The antihypertensive effects of these drugs are caused,
(Chapter 23). In addition to its effect on norepineph- in part, by the inhibition of peripheral adrenergic
rine release, bretlium also appears to have a direct sta- nerve terminals, although some of their antihyperten-
bilizing effect on cardiac muscle cells that contributes sive effects may also be because of the inhibition of
to this drug’s antiarrhythmic properties. While usual- CNS catecholamine activity.
ly given orally for the long-term management of ven-
tricular arrhythmias, bretylium is also injected
Adverse Effects
intravenously for the emergency treatment of ventric-
ular tachycardia and ventricular fibrillation. Orthostatic hypotension is occasionally a problem
Guanadrel (Hylorel). Guanadrel is taken up by the with the aforementioned drugs, and dizziness and syn-
presynaptic terminal and appears to directly inhibit cope sometimes occur after a sudden change in pos-
the release of norepinephrine. With prolonged use, ture. Some patients also experience gastrointestinal
guanadrel slowly replaces norepinephrine in the disturbances including nausea, vomiting, and diarrhea.
presynaptic vesicles. This substitution of guanadrel for Peripheral edema as evidenced by swelling in the feet
norepinephrine further inhibits activity at postsynap- and legs has also been reported.
tic adrenergic synapses by creating a false neurotrans-
mitter. Guanadrel also replaces stored norepinephrine
in the adrenal medulla, thus decreasing adrenal influ-
SUMMARY
ence on cardiovascular function. Guanadrel is admin- This chapter classifies and describes a variety of drugs
istered orally for the management of hypertension. according to their stimulatory (agonistic) or inhibitory
20Ciccone(p)-20 1/30/07 2:37 PM Page 285
(antagonistic) effects on adrenergic function. In gen- treatment of asthma and premature labor because of
eral, adrenergic agonists are administered according their ability to relax bronchiole and uterine smooth
to their ability to evoke specific tissue responses via muscle, respectively.
specific adrenergic receptors. Alpha-1–adrenergic Alpha-adrenergic antagonists are used primarily
agonists are used as antihypotensive agents because of as antihypertensive drugs because of their ability to
their ability to increase peripheral vascular resistance; block vascular alpha-1 receptors. Beta-adrenergic
they may also be used as nasal decongestants because antagonists (beta blockers) are administered primarily
of their ability to vasoconstrict the nasal mucosa. Ago- for their inhibitory effects on myocardial function and
nists selective for alpha-2 receptors are administered are used in the prevention and treatment of hyperten-
to treat hypertension and spasticity because of their sion, angina pectoris, arrhythmias, and myocardial
ability to inhibit neuronal activity in the brainstem reinfarction. Many of the drugs introduced in this
and spinal cord, respectively. Cardioselective beta-1 chapter are discussed further in chapters that deal with
agonists are used primarily for their ability to stimu- the specific clinical conditions (e.g., hypertension,
late the heart, and beta-2 agonists are used in the asthma, and other disorders).
due to acquired brain injury. Arch Phys Med Rehabil. symptoms and benign prostatic hyperplasia. J Urol.
2001;82:1155–1163. 2004;171:1029–1035.
25. Naccarelli GV, Lukas MA. Carvedilol’s antiarrhythmic 33. Sitkauskiene B, Sakalauskas R. The role of beta(2)-
properties: therapeutic implications in patients with adrenergic receptors in inflammation and allergy. Curr
left ventricular dysfunction. Clin Cardiol. 2005;28: Drug Targets Inflamm Allergy. 2005;4:157–162.
165–173. 34. Tank J, Diedrich A, Szczech E, et al. Alpha-2 adrener-
26. Oates JA, Brown NJ. Antihypertensive agents and the gic transmission and human baroreflex regulation.
drug therapy of hypertension. In: Hardman JG, et al, Hypertension. 2004;43:1035–1041.
eds. The Pharmacological Basis of Therapeutics. 10th ed. 35. Trendelenburg AU, Philipp M, Meyer A, et al. All
New York: McGraw-Hill; 2001. three alpha-2-adrenoceptor types serve as autorecep-
27. Olin J, Schneider L, Novit A, Luczak S. Hydergine for tors in postganglionic sympathetic neurons. Naunyn
dementia. Cochrane Database Syst Rev. 2001;CD000359. Schmiedebergs Arch Pharmacol. 2003;368:504–512.
28. Ooi H, Colucci W. Pharmacological treatment of heart 36. Ueshiba H, Miyachi Y. Effect of doxazosin on insulin
failure. In: Hardman JG, et al, eds. The Pharmacological resistance in hypertensive patients with obesity. Horm
Basis of Therapeutics. 10th ed. New York: McGraw-Hill; Metab Res. 2003;35:532–536.
2001. 37. Villalon CM, Centurion D, Valdivia LF, de Vries P,
29. Patten SB, Barbui C. Drug-induced depression: a sys- Saxena PR. Migraine: pathophysiology, pharmacology,
tematic review to inform clinical practice. Psychother treatment and future trends. Curr Vasc Pharmacol.
Psychosom. 2004;73:207–215. 2003;1:71–84.
30. Peel C, Mossberg KA. Effects of cardiovascular med- 38. Zhang L, Hay JW. Cost-effectiveness analysis of
ications on exercise responses. Phys Ther. 1995;75: rizatriptan and sumatriptan versus Cafergot in the
387–396. acute treatment of migraine. CNS Drugs. 2005;
31. Reiter MJ. Cardiovascular drug class specificity: 19:635–642.
beta-blockers. Prog Cardiovasc Dis. 2004;47:11–33. 39. Zusman R. Patients with uncontrolled hypertension
32. Roehrborn CG, Schwinn DA. Alpha1-adrenergic or concomitant hypertension and benign prostatic
receptors and their inhibitors in lower urinary tract hyperplasia. Clin Cardiol. 2004;27:63–69.
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Chapter 21
Antihypertensive Drugs
Hypertension is a sustained, reproducible increase in cialists dealing with hypertensive patients are usually
blood pressure. Hypertension is one of the most com- treating a problem other than the increased blood
mon diseases affecting adults living in industrialized pressure (i.e., hypertension is not the reason the
nations. In the United States, for example, hyperten- patient is referred to physical therapy and occupation-
sion occurs in approximately 30% of the general pop- al therapy). Due to the prevalence of hypertension,
ulation aged 20 and over.44 The prevalence of this however, many patients receiving therapy for other
disease can be even higher in certain subpopulations problems will also be taking antihypertensive drugs, so
(e.g., 41% in African Americans), and the incidence of knowledge of the pharmacology of these agents is
hypertension increases with age.44 ,45 If left untreated, essential.
the sustained increase in blood pressure associated The pharmacologic management of hypertension
with hypertension can lead to cardiovascular problems has evolved to where blood pressure can be controlled
(stroke, heart failure), renal disease, and blind- for extended periods in most patients. There are cur-
ness.15,22,108,111 These and other medical problems ulti- rently several major categories of antihypertensive
mately lead to an increased mortality rate in agents, and new drugs are continually being added to
hypertensive individuals. the antihypertensive arsenal. Each group of antihyper-
Although there is a general consensus regarding tensive drugs is discussed under the appropriate sec-
the adverse effects of hypertension, some debate exists tion in this chapter, as well as how several different
as to exactly how much of an increase in blood pres- drugs can be used together when treating hyperten-
sure constitutes hypertension. Generally, diastolic val-
ues greater than 90 mm Hg and/or systolic values
greater than 140 mm Hg warrant a diagnosis of hyper- Table 21–1 CLASSIFICATION OF BP
tension. A more detailed classification scheme is
shown in Table 21–1. Patients are classified as prehy- Category Systolic BP Diastolic BP
pertensive, stage 1, or stage 2 depending on the extent (mm Hg) (mm Hg)
of their elevated blood pressure. As might be expect- Optimal ⬍120 ⬍80
ed, the incidence of morbidity and mortality increases Prehypertension 120–139 80–89
as the hypertension becomes more severe. Hence, Hypertension
pharmacologic and nonpharmacologic methods are Stage 1 140–159 90–99
implemented to decrease blood pressure to an optimal Stage 2 ⱖ160 ⱖ100
diastolic value of 80 mm Hg or less and an optimal
systolic value less than 120 mm Hg (see Table 21–1). BP ⫽ blood pressure.
Source: From The Seventh Report of the Joint National Com-
Hypertension is often described as a silent killer mittee on Prevention, Detection, Evaluation, and Treatment of
because of the lack of symptoms throughout most of High Blood Pressure (JNC-VII). JAMA. 2003;289:2560–2571,
the disease course. Patients may feel fine into the with permission.
advanced stages of hypertension. Rehabilitation spe-
287
21Ciccone(p)-21 1/30/07 2:51 PM Page 288
but may be caused by a subtle, complex interaction Increased blood pressure may also invoke adap-
of many factors. The exact way in which these fac- tive changes in the peripheral vasculature so that
tors interact probably varies from person to person, so peripheral vessels become less compliant and vascular
that the cause of this disease really must be regarded resistance increases.99,111 That is, increased pressure on
individually rather than being based on one common the vascular wall actually causes thickening of the wall,
etiology. which further increases the resistance to blood flow
Despite the fact that the actual cause of hyperten- through the thickened vessels. The peripheral vascula-
sion is unknown, studies in humans and in animal ture may also become more reactive to pressor sub-
models that mimic essential hypertension have sug- stances such as norepinephrine and angiotensin II.99
gested that the sympathetic nervous system may be a Hypertension is likewise associated with a defect in the
final common pathway in mediating and perpetuating production of vasoactive substances by the cells lining
the hypertensive state. That is, the factors described the peripheral vasculature (i.e., the vascular endotheli-
earlier may interact in such a way as to cause a general um). The vascular endothelium normally produces
increase in sympathetic activity, which then becomes several vasoactive substances including vasodilators
the common denominator underlying the elevated (nitric oxide, bradykinin, prostaglandin I2) and vaso-
blood pressure in essential hypertension.9,38,39 In- constrictors (angiotensin II, endothelin-I).13,54,76
creased sympathetic activity should produce a hyper- These endothelial-derived substances help maintain
tensive effect because of the excitatory effect of local control over vascular resistance.54 In hyperten-
sympathetic neurons on the heart and peripheral vas- sion, however, there may be a defect in the production
culature. Increased sympathetic drive may initially of these substances, especially a decreased production
increase blood pressure by increasing cardiac output. of nitric oxide.13,54 A relative deficiency of this
In later stages, cardiac output often returns to normal vasodilator would result in increased vascular resist-
levels, with the increased blood pressure being due to ance, which helps increase the hypertensive condition.
an increase in vascular resistance. The reasons for the The possible factors involved in initiating and
shift from elevated cardiac output to elevated periph- maintaining essential hypertension are summarized in
eral vascular resistance are somewhat unclear. A sus- Figure 21–1. Ultimately, certain environmental factors
tained increase in sympathetic activity, however, may may turn on the sympathetic division of the autonom-
be the initiating factor that begins a sequence of events ic nervous system in susceptible individuals. Increased
ultimately resulting in essential hypertension. sympathetic discharge then creates a vicious cycle
Once blood pressure does become elevated, whereby increased sympathetic effects—in conjunc-
hypertension seems to become self-perpetuating to tion with the increased blood pressure itself—help
some extent. Mechanisms that control blood pressure perpetuate hypertension. Exactly how various factors
(the baroreceptor reflex), for example, may decrease in initiate the increased sympathetic discharge is not fully
sensitivity, thus blunting the normal response to ele- understood and may in fact vary from patient to
vated pressure.60,96 Increased sympathetic discharge to patient. It is hoped that future studies will elaborate on
the kidneys and altered renal hemodynamics may also the exact role of factors causing essential hypertension
cause changes in renal function contributing to the and that treatment can then be focused on preventing
sustained increase in blood pressure.40,41,57 Moreover, the changes that initially increase blood pressure.
it is apparent that hypertension is often associated
with metabolic abnormalities, including impaired glu-
cose metabolism (due to insulin resistance), hyperin-
sulinemia, dyslipidemia, and abdominal obesity.61,82,101
Drug Therapy
This cluster of problems, known commonly as meta- Several major categories of drugs exist for the treat-
bolic syndrome, places the patient at risk for type 2 ment of essential hypertension. These categories
diabetes mellitus (see Chapter 32). Although the exact include diuretics, sympatholytic drugs, vasodilators,
link between hypertension and metabolic syndrome angiotensin-converting enzyme inhibitors, and calci-
is not clear, it is apparent that chronic elevations in um channel blockers. The primary sites of action
blood pressure can lead to metabolic impairments and effects of each category are summarized in Table
that further jeopardize the health of patients with this 21–2. The mechanism of action, rationale for use, spe-
disease.32,101 cific agents, and adverse effects of drugs in each cate-
21Ciccone(p)-21 1/30/07 2:51 PM Page 290
Genetic Factors
Decreased Baroreceptor
Diet Sensitivity
Central Activity
hypothalamus
brainstem
Structural/Functional
Change in Heart and
Vasculature
gory are discussed in the next few sections of this through their ability to simply decrease the amount of
chapter. fluid in the vascular system.
Diuretics are often the first type of drugs used to
treat hypertension.35,79 They are relatively inexpensive
Diuretics and seem to work well in a large percentage of patients
with mild-to-moderate hypertension.70 Likewise, a
Mechanism of Action large clinical trial recently suggested that thiazide
and Rationale for Use diuretics might be superior to calcium channel block-
ers and angiotensin converting enzyme inhibitors in
Diuretics increase the formation and excretion of preventing major cardiac events such as myocardial
urine. These drugs are used as antihypertensive agents infarction, stroke, and heart failure in people with
because of their ability to increase the renal excretion hypertension.3 Hence, diuretics have been a mainstay
of water and sodium, thus decreasing the volume of in the treatment of hypertension for many years, and
fluid within the vascular system. This situation is they remain one of the primary methods for treating
somewhat analogous to the decrease in pressure that this condition in a large number of people. The use of
would occur inside a balloon if some of the air inside diuretics alone and in conjunction with other antihy-
were allowed to leak out. Consequently, diuretics ap- pertensives is discussed in more detail in “Stepped-
pear to have a rather direct effect on blood pressure Care Approach to Hypertension.”
21Ciccone(p)-21 1/30/07 2:51 PM Page 291
Sympatholytics Various sites within the sym- Decrease sympathetic influence on the
pathetic division of the heart and/or peripheral vasculature
autonomic nervous system
Inhibition of the renin- Peripheral vasculature and ACE inhibitors: prevent the conversion
angiotensin system (ACE certain organs with a func- of angiotensin I to angiotensin II.
inhibitors and angiotensin tional renin-angiotensin Angiotensin II receptor blockers: block
II receptor blockers) system (heart, kidneys) the effects of angiotensin II on the vas-
culature and various other tissues
Calcium channel blockers Limit calcium entry into vas- Decrease vascular smooth-muscle contrac-
cular smooth muscle and tion; decrease myocardial force and rate
cardiac muscle of contraction
“loop diuretic”). They exert their diuretic effect by Loop and thiazide diuretics may also impair glu-
inhibiting the reabsorption of sodium and chloride cose and lipid metabolism, and it has been suggested
from the nephron, thereby preventing the reabsorp- that high doses of these agents may predispose some
tion of the water that follows these electrolytes. Spe- patients to type 2 diabetes mellitus.1,13 Although the
cific types of loop diuretics are listed in Table 21–3. exact risk of such metabolic disturbances is not known,
Potassium-Sparing Diuretics. Several different the long-term use of these drugs has been ques-
drugs with diuretic properties are classified as potassi- tioned.67 Nonetheless, concerns about metabolic side
um-sparing because they are able to prevent the secre- effects can be minimized if low doses are adminis-
tion of potassium into the distal tubule. Normally, a tered.13
sodium-potassium exchange occurs in the distal tubule, Other less serious, but bothersome, side effects of
where sodium is reabsorbed and potassium is secreted. diuretic therapy include gastrointestinal disturbances
Potassium-sparing agents interfere with this exchange and weakness-fatigue. Orthostatic hypotension may
in various ways (depending on the specific drug) so that occur because of the relative fluid depletion produced
potassium is spared from secretion and sodium remains by these drugs. Changes in mood and confusion may
in the tubule, where it is excreted. Although these also occur in some patients.
agents do not produce a diuretic effect to the same
extent as the loop and thiazide diuretics, potassium-
sparing drugs have the advantage of reducing potassi- Sympatholytic Drugs
um loss and thus preventing hypokalemia. Specific
potassium-sparing drugs are listed in Table 21–3. As discussed previously, the preponderance of evidence
indicates that an increase in sympathetic activity may
be an underlying factor in essential hypertension. Con-
Adverse Effects of Diuretics sequently, drugs that interfere with sympathetic dis-
The most serious side effects of diuretics are fluid charge (i.e., sympatholytic agents) should be valuable
depletion and electrolyte imbalance.13,88 By the very as antihypertensive agents. These sympatholytic drugs
nature of their action, diuretics decrease extracellular can be classified according to where and how they
fluid volume as well as produce sodium depletion interrupt sympathetic activity. Sympatholytic drugs
(hyponatremia) and potassium depletion (hypokale- used to treat hypertension include beta-adrenergic
mia). Hypokalemia is a particular problem with the blockers, alpha-adrenergic blockers, presynaptic adre-
thiazide and loop diuretics, but occurs less frequently nergic neurotransmitter depletors, centrally acting
when the potassium-sparing agents are used. Hypo- drugs, and ganglionic blockers (Table 21–4). Each of
kalemia and other disturbances in fluid and electrolyte these categories is discussed here.
balance can produce serious metabolic and cardiac
problems and may even prove fatal in some individu- Beta Blockers
als. Consequently, patients must be monitored closely,
Mechanism of Action and Rationale for Use
and the drug dosage should be maintained at the low-
est effective dose. Also, potassium supplements are Beta-adrenergic blockers have been used extensively to
used in some patients to prevent hypokalemia. decrease blood pressure and are a mainstay of antihy-
Fluid depletion may also be a serious problem pertensive therapy in many patients.4,81 Beta blockers
during diuretic therapy. A decrease in blood volume exert their primary effect on the heart, where they
may cause a reflex increase in cardiac output and decrease heart rate and force myocardial contraction.
peripheral vascular resistance because of activation of In hypertensive patients, these drugs lower blood pres-
the baroreflex (see Chapter 18). This occurrence may sure by slowing down the heart and reducing cardiac
produce an excessive demand on the myocardium, output. This statement, however, is probably an over-
especially in patients with cardiac disease. Decreased simplification of how beta blockers produce an antihy-
blood volume may also activate the renin-angiotensin pertensive effect. In addition to their direct effect on
system, thereby causing further peripheral vasocon- the myocardium, beta blockers also produce a general
striction and increased cardiac workload. Again, the decrease in sympathetic tone.19,39 Although their exact
effects of fluid depletion may be especially serious in effects on sympathetic activity remain to be deter-
patients with certain types of heart failure. mined, beta blockers may decrease sympathetic activi-
21Ciccone(p)-21 1/30/07 2:51 PM Page 293
Specific Agents
Alpha Blockers
Mechanism of Action and Rationale for Use
Beta-adrenergic blockers that are approved for use in
hypertension are listed in Table 21–4. These drugs are Drugs that block the alpha-1–adrenergic receptor on
all effective in decreasing blood pressure, but certain vascular smooth muscle will promote a decrease in
beta blockers have additional properties that make vascular resistance.37,110 Since the total peripheral vas-
21Ciccone(p)-21 1/30/07 2:51 PM Page 294
neurons may be used effectively in some individuals diovascular stimulation and blood pressure.21,104 Con-
with hypertension. Some agents, such as reserpine, sequently, centrally acting drugs offer a rather unique
inhibit the presynaptic synthesis and storage of norep- approach to hypertension because these drugs limit
inephrine in peripheral and CNS adrenergic neu- sympathetic activity at the source (brainstem vasomo-
rons.21 Other agents (guanadrel, guanethidine) replace tor center) rather than at the periphery (cardiovascu-
norepinephrine in peripheral sympathetic neurons, lar neuroeffector junction).
thus creating a false neurotransmitter.21,74 In either
case, depletion of norepinephrine from the presynap- Specific Agents
tic terminal decreases sympathetic-mediated excita-
tion of the heart and peripheral vasculature, resulting The primary drugs in this category are clonidine, gua-
in decreased blood pressure. nabenz, guanfacine, and methyldopa (see Table 21–4).
Clonidine, guanabenz, and guanfacine act directly on
the alpha-2 receptor, whereas methyldopa acts as an
Specific Agents
alpha-2 agonist after being converted in vivo to alpha-
Drugs that inhibit the presynaptic synthesis and stor- methylnorepinephrine. As indicated, monoxidine and
age of norepinephrine are discussed in Chapter 20. rilmenidine act primarily on imidazoline receptors.
The drugs in this category used to treat hyperten-
sion are listed in Table 21–4. These drugs are often Adverse Effects
used in conjunction with other agents in the stepped-
care approach to hypertension (see “Stepped-Care At therapeutic doses, these drugs are associated with
Approach to Hypertension”). some troublesome but relatively minor side effects
including dry mouth, dizziness, and sedation. The
incidence of sedation seems to be related to these
Adverse Effects drug’s alpha-2 stimulatory effects. Hence, agents that
Orthostatic hypotension is sometimes a problem with are more selective for imidazoline receptors may seem
these agents. Other bothersome side effects include better tolerated because patients are more alert and
gastrointestinal disturbances such as nausea, vomiting, have less psychomotor slowing.104
and diarrhea.
Ganglionic Blockers
Centrally Acting Agents Mechanism of Action and Rationale for Use
Mechanism of Action and Rationale for Use
Drugs that block synaptic transmission at autonomic
Several drugs currently available seem to inhibit sym- ganglia will dramatically and effectively reduce blood
pathetic discharge from the brainstem. Sympathetic pressure by decreasing systemic sympathetic activi-
discharge from the vasomotor center appears to be ty.21,95 These agents are essentially nicotinic cholin-
influenced by two types of neuronal receptors located ergic antagonists (see Chapter 18), which block
in the brainstem: alpha-2 adrenergic receptors and transmission at the junction between presynaptic and
imidazoline type I1 receptors. Stimulation of these postsynaptic neurons in sympathetic and parasympa-
receptors results in a decrease in sympathetic discharge thetic pathways. Because of the effect of these agents
to the heart and vasculature. Centrally acting sympa- on both divisions of the autonomic nervous system,
tholytics are therefore characterized as agonists for ganglionic blockers are used sparingly in treating
either one or possibly both types of these receptors. hypertension. In the past, these drugs were used to
Clonidine, for example is considered to primarily be reduce blood pressure in hypertensive emergencies.100
an alpha-2 agonist, although this drug also has some Their routine use, however, has been largely replaced
ability to stimulate imidazoline receptors.21 Newer by vasodilators (nitroprusside; see “Vasodilators”) and
agents in this category (monoxidine, rilmenidine) other agents that are safer and produce fewer side
seem to be more selective for imidazoline recep- effects.28,33 Still, ganglionic blockers may be used to
tors.51,62,94,104 In either case, stimulation of these cen- decrease blood pressure rapidly in certain emergencies
trally located receptors results in a decrease in such as acute aortic dissection or autonomic crisis in
sympathetic outflow and a subsequent decrease in car- people with spinal cord injury.95,100
21Ciccone(p)-21 1/30/07 2:51 PM Page 296
Specific Agents
Table 21–5 ANTIHYPERTENSIVE
Ganglionic blockers currently used to decrease blood VASODILATORS, ACE
pressure in a hypertensive crisis are listed in Table INHIBITORS, ANGIOTENSIN
21–4. II RECEPTOR BLOCKERS,
AND CALCIUM CHANNEL
BLOCKERS
Adverse Effects
As might be expected, ganglionic blockers produce a Vasodilators
multitude of side effects because of the inhibition of Diazoxide (Hyperstat) Minoxidil (Loniten)
both sympathetic and parasympathetic responses. Hydralazine (Apresoline) Nitroprusside (Nipride,
Some adverse effects include gastrointestinal discom- Nitropress)
fort (nausea, constipation), urinary retention, visual
disturbances, and orthostatic hypotension. At higher ACE inhibitors
doses, they may even exhibit some neuromuscular Benazepril (Lotensin) Moexipril (Univasc)
blocking activity. These and other side effects may be Captopril (Capoten) Perindopril (Aceon)
quite severe in some patients. Fortunately, ganglionic Enalapril (Vasotec) Quinapril (Accupril)
blockers are usually not used for extended periods Fosinopril (Monopril) Ramipril (Altace)
because the patient is placed on other antihypertensive Lisinopril (Prinivil, Zestril) Trandolapril (Mavik)
drugs when the hypertensive crisis is resolved.
Angiotensin II receptor blockers
Candesartan (Atacand) Telmisartan (Micardis)
Vasodilators Irbesartan (Avapro) Valsartan (Diovan)
Losartan (Cozaar)
Mechanism of Action
and Rationale for Use Calcium channel blockers
Amlodipine (Norvasc) Nicardipine (Cardene)
Drugs that directly vasodilate the peripheral vascula-
Bepridil (Vascor) Nifedipine (Adalat,
ture will produce an antihypertensive effect by
Diltiazem (Cardizem) Procardia)
decreasing peripheral vascular resistance.13 Although
Felodipine (Plendil) Nimodipine (Nimotop)
other drugs such as the alpha blockers may ultimately
Isradipine (DynaCirc) Verapamil (Calan, Isoptin)
produce vasodilation by interrupting adrenergic sup-
ply to the vasculature, the vasodilators exert an inhibi- ACE ⫽ angiotensin converting enzyme.
tory effect directly on vascular smooth-muscle cells.
Vasodilators are believed to inhibit smooth-muscle
contraction by increasing the intracellular production
of second messengers such as cyclic guanosine mono- such as severe preeclampsia or malignant hyperten-
phosphate (cGMP; see Chapter 4). Increased amounts sion.56,100 Other vasodilators include diazoxide (Hyper-
of cGMP inhibit the function of the contractile pro- stat) and nitroprusside (Nipride, Nitropress), but these
cess in the vascular smooth-muscle cell, thus leading drugs are usually given only in emergency situations to
to vasodilation. treat a patient in hypertensive crisis.28
Nitric oxide also produces vasodilation in vascular
smooth muscle. As indicated earlier, hypertension may
Specific Agents be perpetuated by a defect in the production of nitric
The primary vasodilators used in hypertension are oxide by the vascular endothelium. In follows that pro-
hydralazine (Apresoline) and minoxidil (Loniten) viding nitric oxide directly or administering precursors
(Table 21–5). These drugs are not usually the first for nitric oxide production may help reduce vascular
medications used in patients with hypertension, but resistance and decrease arterial pressure in specific
tend to be added to the drug regimen if other agents hypertensive syndromes.6 To date, inhaled nitric oxide
(diuretics, beta blockers) fail.89 Hydralazine is likewise has been used to treat acute pulmonary hypertension
used to lower blood pressure in emergency situations associated with respiratory distress syndrome in new-
21Ciccone(p)-21 1/30/07 2:51 PM Page 297
borns and adults.10,52 Likewise, researchers are trying and other hairy body surfaces. This increased hair
to determine if nitric oxide could be used to treat sys- growth is often a cause for the discontinuation of this
temic (essential) hypertension, or if other drugs could drug in women. Some men, however, have applied
be used to increase the production of endogenous minoxidil cutaneously to treat baldness, and a topical
nitric oxide in people with hypertension.6 Future stud- preparation of this drug (Rogaine) is marketed as a
ies are needed to determine if manipulation of nitric potential hair-growth stimulant.
oxide levels in the peripheral vasculature is a possible
way to treat essential hypertension.
Inhibition of the
Renin-Angiotensin System
Adverse Effects
Mechanism of Action
Although vasodilators are effective in lowering blood
and Rationale for Use
pressure, these drugs are associated with a number of
adverse effects. Reflex tachycardia often occurs because The renin-angiotensin system involves several endo-
baroreflex responses attempt to compensate for the fall genous components that help regulate vascular tone in
in vascular resistance that these drugs produce. This various organs and tissues.25,84,109 In systemic circula-
side effect is analogous to the increased heart rate tion, the renin-angiotensin system acts by a sequence
occurring when alpha blockers are used to decrease of events summarized in Figure 21–2. Renin is an
peripheral vascular resistance. Other common reac- enzyme produced primarily in the kidneys. When
tions include dizziness, postural hypotension, weak- blood pressure falls, renin is released from the kidneys
ness, nausea, fluid retention, and headache. Minoxidil into the systemic circulation. Angiotensinogen is a
also increases hair growth on the face, ears, forehead, peptide that is produced by the liver and circulates
Angiotensin
Renin
(from kidneys)
Angiotensin I
Angiotensin
converting enzyme
(in lungs, other tissues)
Angiotensin II
FIGURE 21–2 ▼ The renin-angiotensin system and the effects of angiotensin II. Angiotensin
converting enzyme inhibitors interrupt this system by blocking the conversion of angiotensin I to
angiotensin II, and angiotensin II receptor blockers prevent angiotensin II from stimulating car-
diovascular tissues. From: Ciccone. Medications. In: DeTurk WE, Cahalin LP, eds. Cardiovascular
and Pulmonary Physical Therapy. New York: McGraw-Hill; 2004: 193, with permission.
21Ciccone(p)-21 1/30/07 2:51 PM Page 298
continually in the bloodstream. When renin contacts related cardiovascular events (stroke, myocardial
angiotensinogen, angiotensinogen is transformed into infarction, heart failure).25
angiotensin I. The circulating angiotensin I is then Fortunately, two pharmacologic strategies have
transformed by angiotensin-converting enzyme into been developed to inhibit the effects of abnormal
angiotensin II. The converting enzyme is located in renin-angiotensin system activation. The first strategy
the vasculature of many tissues, especially the lung. involves drugs that inhibit the enzyme that converts
Angiotensin II is an extremely potent vasoconstrictor. angiotensin I to angiotensin II. These drugs are com-
Consequently, the fall in blood pressure that activated monly referred to as angiotensin converting enzyme
the renin-angiotensin system is rectified by the in- (ACE) inhibitors. ACE inhibitors decrease the hyper-
crease in vascular resistance caused by angiotensin II. tensive effects of angiotensin II by limiting the pro-
Angiotensin II, or possibly its by-product angiotensin duction of this compound. More recently, a second
III, also increases aldosterone secretion from the adre- strategy has emerged in the form of drugs that block
nal cortex. Aldosterone directly increases sodium reab- angiotensin II receptors on various tissues.103,105
sorption from the kidneys, which creates osmotic Angiotensin II stimulates vascular and other tissues by
forces in the kidneys that encourage water reabsorp- binding to a protein receptor (specifically, the AT1
tion, thus helping maintain plasma volume. angiotensin II receptor) on these tissues.103 Newer
The sequence of events just described illustrate drugs, known as angiotensin II blockers or antago-
the role of the systemic renin-angiotensin system in nists, have been developed to block these receptors,
normal blood pressure regulation. Exactly what goes thereby negating the harmful effects of angiotensin II
wrong with this system in patients with essential on vascular and other tissues.
hypertension is not fully understood. Some patients ACE inhibitors and angiotensin II blockers have
display increased levels of circulating renin, hence been an important addition to the antihypertensive
their classification as having high-renin hypertension. drug arsenal. These drugs can be used alone or in con-
Why plasma renin production is elevated in these junction with other drugs for the long-term control of
patients, however, is often unclear. In addition to prob- high blood pressure.69,105 In fact, these drugs appear
lems in circulating levels of renin and angiotensin II, to have several advantages over other antihyperten-
there may also be problems with the renin-angiotensin sives, such as a lower incidence of cardiovascular side
system in specific tissues or organs. For instance, a effects (i.e., less reflex tachycardia and orthostatic
complete, functioning renin-angiotensin system has hypotension).64,105 The ability of these drugs to inhib-
been identified within the brain84,106 and in the heart it angiotensin II-induced vascular hypertrophy and
and vascular walls.86 This fact suggests that some of the remodeling is also recognized as an important benefit
hypertensive effects of this system may be mediated during the treatment of high blood pressure.25,103
through CNS mechanisms or by changes directly in These drugs are likewise extremely beneficial in de-
the vascular tissues. creasing morbidity and mortality associated with con-
Nonetheless, activation of the renin-angiotensin gestive heart failure, and use of these drugs in heart
system is extremely detrimental in people with high failure will be addressed in Chapter 24.
blood pressure. Excess production of angiotensin II
causes vascoconstriction that perpetuates the hyper-
tensive condition. More importantly, angiotensin II is
Specific Agents
a powerful stimulant of vascular tissue growth, and ACE inhibitors and angiotensin II blockers used to
sustained production of angiotensin II results in the treat hypertension are listed in Table 21–5. These
thickening and hypertrophy of the vascular wall.59 The drugs have been shown to be effective in many cases of
thickened vascular wall causes a decrease in the lumen mild-to-moderate essential hypertension, and they
of the vessel, thereby causing additional resistance to may be used alone or in combination with beta block-
blood flow and increased hypertension. Angiotensin II ers or diuretics.
may have other detrimental effects on the vasculature,
including inflammation of the vascular endothelium
and increased lipid accumulation within the vascular
Adverse Effects
wall.14,53 Excessive production of angiotensin II is ACE inhibitors are generally well-tolerated in most
therefore associated with several detrimental changes patients. Some individuals may experience an allergic
in the vascular wall that can lead to hypertension and reaction as evidenced by skin rash. This reaction usu-
21Ciccone(p)-21 1/30/07 2:51 PM Page 299
ally disappears when the dosage is reduced or when tered to certain hypertensive patients (older patients,
administration is discontinued. Patients may also expe- patients with diabetes, patients with unstable angi-
rience a persistent, dry cough that is annoying but rel- na).66,107 The risk of infarction, however, seems mini-
atively harmless. Although the incidence is rare, ACE mal if long-acting or sustained-release formulations
inhibitors may cause hematological effects (neutrope- are used, presumably because these formulations do
nia, agranulocytosis) and renal problems (glomeru- not cause a sudden change in blood pressure as do
lonephritis, renal failure) in susceptible patients; these their shorter-acting counterparts.27 Likewise, other
drugs should be use cautiously in certain patients with studies suggested that calcium channel blockers may
preexisting blood or kidney diseases. Other problems increase the risk of cancer, presumably because these
(gastrointestinal discomfort, dizziness, chest pain) may drugs interfere with the normal role that calcium plays
occur in some patients, but adverse effects are relative- in regulating cell growth and turnover.63 Subsequent
ly rare. studies, however, have failed to establish a clear link
Angiotensin II blockers are likewise well tolerat- between calcium channel blockers and cancer.63,92
ed; these drugs do not cause the cough associated with Consequently, calcium channel blockers still play
ACE inhibitors.64 Hence, angiotensin II blockers may an important role in the antihypertensive arsenal, but
be an effective alternative in patients who experience practitioners are more cautious about using these
side effects such as coughing.13 drugs to lower blood pressure in certain patients.107 As
mentioned above, the longer-acting or sustained-
release forms of these drugs are somewhat safer and
Calcium Channel Blockers should be used whenever possible.29,90
with certain drugs such as the short-acting form of A stepped-care approach is generally regarded as
nifedipine. Other bothersome side effects include an effective way to use different types of antihyperten-
dizziness, headache, and nausea. sive drugs.31 However, the stepped-care approach is
not a set protocol—it only acts as a guideline for drug
administration. It has also been suggested that initial
Stepped-Care treatment should be more aggressive in many patients,
and that two agents should be used concurrently dur-
Approach to Hypertension ing initial treatment.16,72 That is, treatment may be
In many hypertensive patients, more than one type of more successful if two antihypertensive drugs from
drug must be given to successfully control blood pres- different categories are used in the first step rather
sure.31,113 In general, the more severe the hyperten- than a single drug.46,113 Clearly, specific programs can
sion, the greater the need for a combination of several (and should) be tailored to individual patients by pro-
agents. To provide some type of rationale for effective viding various drugs at each step.16,46
drug use, a stepped-care approach is often implement-
ed. The object of a stepped-care approach is to begin
drug therapy with certain types of drugs and then, if Nonpharmacologic
additional drugs are needed, to follow a logical pro-
gression in each patient. One type of stepped-care sys- Treatment of Hypertension
tem is outlined in Table 21–6. Typically, drug therapy Although several effective and relatively safe drugs
is initiated with either a thiazide diuretic, a beta block- exist for treating hypertension, the use of nondrug
er, an ACE inhibitor, or a calcium channel blocker methods in decreasing blood pressure should not be
(step 1). If blood pressure is not adequately controlled, overlooked, especially in cases of mild or borderline
other types of antihypertensive drugs are instituted as hypertension.73,93 Certain dietary modifications, such
outlined in steps 2 through 4 (see Table 21–6). as sodium restriction, low-fat diets, and diets high in
certain fish oils, have been helpful in some patients.47,71
Decreasing the use of alcohol and tobacco may also
Table 21–6 STEPPED-CARE APPROACH help lower blood pressure. Generally, a decrease in
TO HYPERTENSION body weight will produce an antihypertensive
effect26,71; regular exercise may help decrease blood
STEP 1: In patients with mild hypertension, drug pressure by decreasing body weight or by mechanisms
therapy is usually initiated with a single agent unrelated to weight loss.8,75 Many forms of behavior
(monotherapy) from one of the following classes: a modification and stress management techniques have
diuretic, a beta blocker, an angiotensin converting also been suggested as nonpharmacologic methods of
enzyme (ACE) inhibitor, or a calcium channel blocker. blood pressure control.
Considerable debate exists as to whether or not
STEP 2: If a single drug is unsuccessful in reducing mild hypertension should be treated initially with
blood pressure, a second agent is added. The second drugs, or if a trial with one or more nonpharma-
drug can be from one of the initial classes not used in cologic technique should be employed first.73 This
step 1, or it can be from a second group that includes decision must be made on an individual basis with
the centrally acting agents (clonidine, guanabenz), consideration given to the patient’s lifestyle and
presynaptic adrenergic inhibitors (reserpine, guanethi- chance of compliance with a nondrug approach.
dine), alpha-1 blockers (prazosin, doxazosin), and There is ample evidence, however, that optimal results
vasodilators (hydralazine, minoxidil). are obtained when lifestyle changes are combined with
antihypertensive drug therapy.73,74 Hence, changes in
STEP 3: A third agent is added, usually from one of
lifestyle and behavior should be encouraged in all
the classes listed in step 2 that has not already been
hypertensive patients, regardless of whether drug
used. Three different agents from three different class-
therapy is initiated. Patients should be encouraged to
es are often administered concurrently in this step.
quit smoking, lose weight, manage stress, and modify
STEP4: A fourth drug is added from still another class. their diet, even if blood pressure is reduced pharma-
cologically.
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CA S E ST U DY
Hypertension tive beta blocker (metoprolol, [Lopressor] 200 mg/d), and a
vasodilator (minoxidil, [Loniten] 20 mg/d).
Brief History. H.C. is a 55-year-old man who works as While rushing to a business luncheon, H.C. was hit by an
an attorney for a large corporation. He is consistently faced automobile as he was crossing the street. He was admitted to
with a rather demanding work schedule, often working 12- to the hospital, where radiologic examination revealed a fracture
14-hour days, 6 days each week. In addition, he is 25 to 30 of the right pelvis. Further examination did not reveal any
pounds overweight and is a habitual cigarette smoker. He has other significant internal injuries. The pelvic fracture appeared
a long history of high blood pressure, which has been man- stable at the time of admission, and internal fixation was not
aged fairly successfully over the past 15 years through the use required. H.C. remained in the hospital and was placed on
of different drugs. Currently, H.C. is in step 3 of the stepped- bed rest. Two days after admission, a physical therapist was
care approach to hypertensive therapy, and three drugs are called in to consult on the case. The physical therapist sug-
being administered to control his blood pressure. He is receiv- gested a progressive ambulation program using the facility’s
ing a diuretic (furosemide, [Lasix] 100 mg/d), a cardioselec- therapeutic pool. The buoyancy provided by the pool would
21Ciccone(p)-21 1/30/07 2:51 PM Page 302
allow a gradual increase in weight bearing while protecting cern because the patient’s active leg muscle contractions facil-
the fracture site. itated venous return, and the buoyancy of the water decreased
Problem/Influence of Medication. To guard against the effects of gravity on venous pooling in the lower extremi-
patient hypothermia, the water temperature in the therapeutic ties. In fact, only at the end of the rehabilitation session, when
pool was routinely maintained at 95⬚F. The therapist was con- the patient came out of the pool, did hypotension became
cerned that immersing the patient in the pool would cause a potential problem. The patient was still experiencing periph-
excessive peripheral vasodilation. Because the patient was eral vasodilation because of the residual effects of the warm
taking a vasodilating drug (minoxidil), the additive effect of the water, but he no longer had the advantage of active muscle
warm pool and vasodilating agent might cause profound contractions and water buoyancy to help maintain his blood
hypotension because of a dramatic decrease in total peripher- pressure. To prevent a hypotensive episode at the end of the
al resistance. Also, because this patient was taking a car- session, the therapist placed the patient supine on a stretcher
dioselective beta blocker (metoprolol), his heart would not be as soon as he came out of the water. Also, the patient’s legs
able to sufficiently increase cardiac output to offset the were quickly toweled dry, and vascular support stockings
decreased peripheral resistance. were placed on the patient’s legs. These precautions allowed
Decision/Solution. When the patient was in the pool, the patient to progress rapidly through his rehabilitation with-
the therapist monitored heart rate and blood pressure at fre- out any adverse incidents. When he was eventually discharged
quent, regular intervals. Blood pressure did decrease when the from the hospital, he was ambulating with crutches, with par-
patient was ambulating in the pool, but not to a point of con- tial weight bearing on the side of the pelvic fracture.
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Chapter 22
Treatment of Angina Pectoris
Angina pectoris is pain that occurs in the chest region metabolic, electrophysiologic, and contractile changes
during ischemic heart disease. Attacks of angina pec- in the heart. The painful symptoms inherent to angi-
toris begin suddenly and are often described as a sen- na pectoris seem to result from the accumulation of
sation of intense compression and tightness in the metabolic by-products such as lactic acid. Presumably,
retrosternal region, with pain sometimes radiating to these metabolic by-products act as nociceptive sub-
the jaw or left arm. In many patients, episodes of angi- stances and trigger the painful compressive sensations
na pectoris are precipitated by physical exertion. Some characteristic of angina pectoris.
forms of angina, however, may occur spontaneously Although angina pectoris is believed to be caused
even when the patient is at rest or asleep. by the buildup of lactic acid and other metabolites, the
The basic problem in angina pectoris is that the exact mechanisms responsible for mediating anginal
supply of oxygen to the heart is insufficient to meet pain remain unknown. Also, the emotional state of the
myocardial demands at a given point in time, which patient and other factors that influence central pain
results in an imbalance between myocardial oxygen perception play an obvious role in angina pectoris.20,34
supply and demand (Fig. 22–1).6,34 This imbalance In fact, the majority of anginal attacks may be silent
leads to myocardial ischemia, which results in several in many patients, and myocardial ischemia may fre-
Imbalance
Myocardial Ischemia
Clinical Angina
FIGURE 22–1 ▼ Myocardial ischemia equation. (Adapted from: Miller AB. Mixed ischemic
subsets. Comparison of the mechanism of silent ischemia and mixed angina. Am J Med. 1985;79
[suppl 3a]:25, with permission.)
307
22Ciccone(p)-22 1/30/07 2:38 PM Page 308
their ability to decrease cardiac work, thus decreasing sons for this tolerance are not fully understood and
myocardial oxygen demand. may involve a decrease in the ability to convert nitro-
glycerin to nitric oxide, a decrease in the responsive-
ness of the vasculature to nitric oxide, an increased
Specific Agents sensitivity to endogenous vasoconstrictors, or a com-
Nitroglycerin (Nitro-Bid, Nitrostat, Nitro-Dur, many bination of these and other factors.33,41,53 Tolerance to
others). In addition to being used as a powerful explo- nitrate drugs is rather short-lived, however, and nor-
sive, nitroglycerin is perhaps the most well known mal responses to nitrate drugs can be restored within
antianginal drug. The explosive nature of this agent is only a few hours after withdrawing these agents.47
rendered inactive by diluting it with lactose, alcohol, Consequently, patients may benefit from hav-
or propylene glycol. Nitroglycerin is administered for ing at least an 8-hour interval each day when they do
both the prevention and treatment of anginal attacks not wear their patches. Daily administration, for exam-
and is available in oral, buccal, sublingual, and trans- ple, might be optimized by wearing the patch for 12 to
dermal forms (see Table 22–1). 14 hours followed by a 10- to 12-hour nitrate-free
Sublingual administration of nitroglycerin is the interval.47 This method of intermittent nitroglycerin
best method to treat an acute attack of angina. Placed administration may provide beneficial effects with less
under the tongue, the drug is rapidly absorbed through chance of developing drug tolerance.1 The drawback,
the oral mucosa into the systemic circulation. Thera- of course, is that the patient will be more susceptible to
peutic effects usually begin within 2 minutes when angina attacks during the nitrate-free interval. Hence,
nitroglycerin is administered sublingually. Sublingual intermittent nitrate use must be monitored carefully in
administration also spares the nitroglycerin from the each patient to make sure that the patch provides ade-
first-pass effect because the drug is able to reach the quate protection during the part of day or night when
systemic circulation before first passing through the angina is likely to occur, without leaving the patient
liver, where it is inactivated (see Chapter 2). especially vulnerable during the nondrug interval.
Extended-release versions of this drug, which can Nitroglycerin ointment is another way to provide
be taken buccally (between the cheek and gum), have continuous transdermal administration.47 The oint-
been developed for the prevention of angina. Like- ment is applied directly to the skin on the patient’s
wise, nitroglycerin can be delivered via an aerosol chest or back, in much the same way as any topical
form that is sprayed on or under the tongue (lingual ointment or skin cream. Although somewhat messy
spray). Oral preparations have also been developed, and inconvenient, nitroglycerin ointment may be
but this method of administration is limited because— helpful in preventing angina in certain situations, such
as previously mentioned—nitroglycerin undergoes as when the patient is sleeping.31 This method is not
extensive first-pass degradation in the liver when as popular as transdermal patches, however, because
absorbed directly from the intestines. patches are more convenient and easier to apply. Like-
For prophylaxis of angina, nitroglycerin can also wise, tolerance may occur if nitroglycerin is applied
be administered transdermally via ointment or med- continually through topical ointments.
icated patches placed on the skin (see Table 22–1). Isosorbide Dinitrate Like nitroglycerin, isosor-
Nitroglycerin-impregnated patches or disks are ap- bide dinitrate is used for the treatment of acute
plied cutaneously like a small bandage, with the drug episodes of angina as well as for the prevention of
slowly and continuously absorbed through the skin anginal attacks. The antianginal and hemodyna-
and into the systemic circulation.31 Transdermal mic effects last longer with isosorbide dinitrate, how-
administration of nitroglycerin using these patches has ever, so this drug is often classified as a long-acting
been regarded favorably because of its ease and con- nitrate.31 For acute attacks, isosorbide dinitrate is
venience. By providing fairly continuous and sustained administered sublingually, buccally, or by chewable
administration, nitroglycerin can also help prevent the tablets (see Table 22–1). For prevention of angina, oral
onset of an anginal episode in many patients. tablets are usually given.
One problem associated with the nitroglycerin Isosorbide Mononitrate This drug is another
patch is that continuous nitroglycerin administration long-acting nitrate that is similar in structure and
will cause drug tolerance, thus reducing the antiangi- function to isosorbide dinitrate. It is typically given
nal effectiveness of this medication.8,33 The exact rea- orally for prevention of anginal attacks.
22Ciccone(p)-22 1/30/07 2:38 PM Page 310
Amyl Nitrite This drug is supplied in small ers help maintain an appropriate balance between
ampules that can be broken open to inhale during myocardial oxygen supply and demand by preventing
acute anginal attacks. Absorption of the drug through an increase in myocardial oxygen demand.
the nasal membranes causes peripheral vasodilation Consequently, beta blockers are given to certain
and decreased cardiac preload and afterload. Clinical patients with angina to limit the oxygen demands of
use of inhaled amyl nitrite is very limited, however, the heart.12,31 This prophylactic administration pre-
and this type of antianginal treatment has generally vents the onset of an anginal attack. The use of beta
been replaced by safer and more convenient methods blockers in specific forms of angina is reviewed later in
of nitrate administration (e.g., nitroglycerin patches). this chapter.
Diltiazem (Cardizem, Dilacor). Like the other feelings of warmth, and dizziness may occur in some
calcium channel blockers, diltiazem is able to vasodi- patients. Peripheral edema, as evidenced by swelling in
late the coronary arteries and the peripheral vascula- the feet and legs, may also occur, and nausea is fairly
ture. Diltiazem also produces some depression of common. Nonselective calcium channel blockers that
electrical conduction in the sinoatrial and atrioven- affect the myocardium (e.g., bepridil, diltiazem, vera-
tricular nodes, an effect that may cause slight brady- pamil) can cause disturbances in cardiac rhythm. As
cardia. This bradycardia can be worsened by beta indicated, reflex tachycardia can also be a problem,
blockers or in patients with myocardial conduction especially with nifedipine and other dihydropyridine
problems, and diltiazem should probably be avoided calcium channel blockers (“-ipine” drugs) that selec-
in these individuals.32,45 tively decrease vascular resistance without simultane-
Nifedipine (Adalat, Procardia) and Other Dihy- ously inhibiting heart rate.
dropyridines. Nifedipine and similar drugs are mem- There has been some concern about the safety of
bers of the dihydropyridine class of calcium channel the calcium channel blockers. In particular, reports
blockers. This class is distinguished by drugs with an indicated that certain calcium channel blockers, such
-ipine suffix, including felodipine (Plendil), isradipine as the short-acting form of nifedipine, may be associ-
(DynaCirc), and nicardipine (Cardene). These drugs ated with an increased risk of myocardial infarction in
are relatively selective for vascular smooth muscle as certain patients (older patients with hypertension,
compared to cardiac striated muscle, and they vasodi- patients with unstable angina).21,29
late the coronary arteries and peripheral vasculature The short-acting or immediate-release form of
without exerting any direct effects on cardiac exci- nifedipine and other “-ipine” calcium channel block-
tability or contractility.31 These drugs are therefore ers can be problematic because these drugs may cause
advantageous when treating patients with angina who a fairly rapid decrease in peripheral vascular resistance
also have certain types of cardiac arrhythmias or prob- and blood pressure.46 A rapid fall in vascular resistance
lems with cardiac excitation and conduction.9 Nifedip- and blood pressure can precipitate reflex hemodynam-
ine and similar drugs may, however, produce reflex ic changes (increased heart rate, decreased myocardial
tachycardia, which is a compensatory increase in heart perfusion), which leads to ischemia and infarction in
rate occurring when peripheral vascular resistance susceptible patients. Sustained-release or longer-act-
decreases because of the drug-induced vasodilation. ing forms of nifedipine and similar agents may be
Other nondihydropyridine drugs (diltiazem, vera- somewhat safer because they do not cause as rapid a
pamil) also lower vascular resistance, but reflex tachy- change in vascular resistance as the short-acting
cardia is prevented because these drugs also have an drugs.11,24
inhibitory effect on heart rate (negative chronotropic Preliminary studies also suggested that calcium
effect). If reflex tachycardia does occur with nifedip- channel blockers my increase the risk of cancer.10,28
ine, this problem can be controlled by using sustained- Intracellular calcium levels are important in regulating
release or long-acting forms of these drugs (see cell division. By modifying calcium influx, calcium
“Adverse Side Effects”). channel blockers could conceivably accelerate cell
Verapamil (Calan, Isoptin). Verapamil has been proliferation and lead to cancerous growths. Fortu-
used to treat angina because of its ability to vasodilate nately, the carcinogenic potential of these drugs has
the coronary vessels. Verapamil, however, seems to be not been proven conclusively by subsequent studies.21
moderately effective compared to the other antiangi- Hence, calcium channel blockers continue to be used
nal drugs, and verapamil also depresses myocardial cautiously but effectively in large numbers of patients.
excitability and decreases heart rate.9,32 Because of its
negative effects on cardiac excitation, verapamil is
probably more useful in controlling certain cardiac Use of Anticoagulants
arrhythmias (see Chapter 23).
in Angina Pectoris
Angina pectoris is typically associated with some
Adverse Side Effects degree of coronary artery occlusion. To help prevent
The primary problems associated with the calcium further blockage of the coronary arteries, certain anti-
channel blockers are related to the peripheral vasodila- coagulant drugs can be administered so that a partial-
tion produced by these agents. Headache, flushing or ly occluded artery does not become completely
22Ciccone(p)-22 1/30/07 2:38 PM Page 313
blocked and cause myocardial infarction.15,52 The Aspirin is administered orally, and is often used
most common agents used in this situation are heparin for the long-term management of platelet-induced
and platelet inhibitors such as aspirin.23,52 The phar- clotting in people with angina. Aspirin, however, only
macology and anticoagulant effects of these drugs are produces a moderate amount of platelet inhibition,
discussed in detail in Chapter 25, and their use in and stronger antiplatelet drugs are also available.
angina is addressed briefly here. Drugs such as clopidogrel (Plavix), for example, block
Heparin is often used during the initial or acute the effects of adenosine diphosphate (ADP) on the
phase of unstable angina to prevent clot formation at platelet, thereby reducing the ability of ADP to acti-
atherosclerotic plaques that may have ruptured in the vate the platelet.19,27 These stronger antiplatelet drugs
coronary arteries.14,15 Heparin is a fast-acting antico- can be used alone or added to aspirin therapy in
agulant that leads to the inhibition of thrombin, a key patients who are at high risk for infarction.3,50
component of the clotting mechanism. With regard Heparin and antiplatelet drugs are therefore used
to their use in angina, low molecular weight heparins in various forms of angina to help prevent infarction.
(LMWH) such as enoxaparin (Lovenox) seem to When administered with the traditional anti-anginal
be especially advantageous because they produce a medications, these anticoagulants can help decrease
more predictable anticoagulant response and are morbidity and mortality in people with ischemic heart
tolerated better than more traditional (unfractionated) disease. For more details on the effects of anticoagu-
heparin.14,23,56 Heparin must, however, be adminis- lant medications, please refer to Chapter 25.
tered parenterally, and LMWHs are usually given via
subcutaneous injection.
Aspirin and other drugs that reduce platelet activ- Treatment of Specific
ity are essential in preventing platelet-induced clotting
in the coronary arteries and other vascular tissues.50 As
Types of Angina Pectoris
discussed in Chapter 15, aspirin inhibits the biosyn- All forms of angina pectoris are not the same. Tradi-
thesis of prostaglandins, and certain prostaglandins tionally, angina has been subclassified according to
are responsible for activating platelets during the clot- factors that precipitate the angina and the pathophys-
ting process. In angina pectoris, aspirin administration iologic mechanisms responsible for producing
can prevent platelets from becoming activated in par- myocardial ischemia.6 The major forms of angina and
tially occluded coronary vessels, and therefore helps the primary drugs used to treat each type are discussed
maintain blood flow through these vessels.36 here and summarized in Table 22–4.
Variant angina Myocardial oxygen supply decreases due to Treated primarily with a calcium channel
coronary vasospasm; may occur while blocker
patient is at rest
Unstable angina Myocardial oxygen supply decreases at the May require a combination of drugs—
same time oxygen demand increases; can that is, a calcium channel blocker plus
occur at any time secondary to athero- a beta blocker. Anticoagulant drugs
sclerotic plaque rupture within the coro- are also helpful in preventing throm-
nary artery bogenesis and coronary occlusion
22Ciccone(p)-22 1/30/07 2:38 PM Page 314
ety of emotional or environmental stimuli may trigger important, however, is the recognition that unstable
coronary vasospasm.18,30 In many patients, however, angina is often associated with coronary artery throm-
the reason for this spontaneous coronary vasoconstric- bosis, and that anticoagulant and antiplatelet therapy is
tion is unknown. critical in preventing this type of angina from pro-
Calcium channel blockers are usually the drugs of gressing to myocardial infarction.44,47 Hence, anticoag-
choice in treating the variant form of angina.18,51 ulant drugs are often administered in the early stages of
These drugs limit the entry of calcium into the coro- unstable angina, with antiplatelet drugs (aspirin, clopi-
nary vessels, thus attenuating or preventing the dogrel) being continued indefinitely to help prevent
vasospasm underlying variant angina.9 If calcium chan- coronary occlusion.54,55 Likewise, lipid lowering drugs
nel blockers are not tolerated, long-acting nitrates may such as the statins (see Chapter 25) are instrumental in
be used instead. Calcium channel blockers are espe- providing long term benefits and preventing coronary
cially effective in treating variant angina, however, and occlusion in patients with unstable angina.40,42
most patients with this form of angina respond well to
these agents. If patients do not respond to a single cal-
cium channel blocker, long-acting nitrates may be
added for management of severe variant angina.18,51 Nonpharmacologic
Management of Angina Pectoris
The primary drugs used to treat angina (nitrates, beta
Unstable Angina blockers, calcium channel blockers) are effective and
The more severe form of angina is often classified relatively safe for long-term use. These agents, how-
as “unstable” angina. This type of angina is often ini- ever, really only treat a symptom of heart disease,
tiated by sudden rupture of atherosclerotic plaques namely, the pain associated with myocardial ischemia.
within the coronary arteries, which precipitates coro- Traditional antianginal drugs do not cure any cardiac
nary vasoconstriction and thrombus formation.4,6 conditions, nor do they exert any beneficial long-term
Plaque rupture can be brought on by exertion, or it effects on cardiac function. Consequently, efforts are
may occur spontaneously when the patient is at rest. made in many patients with angina to resolve the
The primary defect in unstable angina, therefore, is a underlying disorder responsible for causing an imbal-
decrease in myocardial oxygen supply, although ance in myocardial oxygen supply and demand.
myocardial oxygen demand may be increasing simul- Nonpharmacologic treatment usually begins by
taneously if the patient is exercising. Because unstable identifying any potentiating factors that might initiate
angina is also associated with thrombosis and or exacerbate anginal attacks. For instance, hyperten-
increased platelet aggregation in the affected coronary sion, congestive heart failure, anemia, and thyrotoxi-
arteries, this type of angina is often a precursor to cosis may all contribute to the onset of angina. In some
acute myocardial infarction.6 Together, unstable angi- cases, treatment of one of these potentiating factors
na and myocardial infarction comprise the category of may effectively resolve the angina, thus making subse-
acute coronary syndromes.2,38 Unstable angina is quent drug therapy unnecessary. Lifestyle changes,
therefore regarded as the most serious and potentially including exercise, weight control, giving up smoking,
dangerous form of angina.43 and stress management, may also be helpful in
Various traditional antianginal drugs have been decreasing or even eliminating the need for antiangi-
used alone or in combination to treat the ischemic nal drugs. Finally, a number of surgical techniques that
symptoms of unstable angina.35,47 Beta blockers, for try to increase coronary blood flow may be attempted.
example, are among the primary drugs because they Revascularization procedures such as coronary artery
decrease cardiac workload and thereby prevent subse- bypass and coronary artery angioplasty may be suc-
quent damage to the ischemic myocardium.12,31 Beta cessful in increasing myocardial oxygen supply, thus
blockers can likewise be combined with the two other attenuating anginal attacks in some patients. Regard-
types of traditional antianginal medications (nitrates less of what strategy is pursued, a permanent solution
and calcium channel blockers), depending on the to the factors that precipitate myocardial ischemia
specific needs and responses of each patient.47 Most should be explored in all patients with angina pectoris.
22Ciccone(p)-22 1/30/07 2:38 PM Page 316
CA S E ST U DY
Antianginal Drugs past decade despite oral antidiabetic medication and insulin
treatment. He also has a history of stable (classic) angina
Brief History. T.M. is a 73-year-old man who is retired that has been managed by nitroglycerin. The patient self-
from his job as an accountant. He has a long history of type 2 administers a nitroglycerin tablet sublingually (0.4 mg per
diabetes mellitus, which has progressively worsened over the tablet) at the onset of an anginal attack. Recently, the patient
22Ciccone(p)-22 1/30/07 2:38 PM Page 317
was admitted to the hospital for treatment of a gangrenous were monitored and he was placed in a supine position on a
lesion on his left foot. When this lesion failed to respond to mat table. The drug was administered sublingually while the
conservative treatment, a left below-knee amputation was patient remained supine, and his chest pain subsided.
performed. Following the amputation, the patient was referred Decision/Solution. Evidently, the exertion and appre-
to physical therapy for strengthening and a preprosthetic hension of merely being transported to the physical therapy
evaluation. department was sufficient to trigger an attack of angina in this
Problem/Influence of Medication. A program of patient. The fact that his medication was not readily available
general conditioning and strengthening was initiated at the created a rather anxious situation, which was fortunately
patient’s bedside the day following surgery. On the third day, resolved without any serious incident. To prevent a repeat of
the therapist decided to bring the patient to the physical ther- this predicament, the therapist contacted the nursing staff and
apy department for a more intensive program, including requested that the patient always bring his medication with
standing activities with the parallel bars. The patient arrived in him to physical therapy. On subsequent occasions when the
the department via wheelchair and began complaining imme- patient did experience the onset of angina, he was immediate-
diately of chest pains. The patient had not brought his nitro- ly placed in a supine position and the drug was administered
glycerin tablets with him to the therapy session. The therapist sublingually. The patient was placed supine to prevent any
immediately phoned the nursing floor, and the patient’s med- orthostatic hypotension that may occur with nitroglycerin. He
ication was rushed to the physical therapy department. While was eventually fitted with a temporary prosthesis and trans-
waiting for the nitroglycerin to arrive, the patient’s vital signs ferred to an extended-care facility to continue rehabilitation.
13. Fihn SD, Williams SV, Daley J, et al. Guidelines for beta-adrenergic blocking drugs. J La State Med Soc.
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treatment. Ann Intern Med. 2001;135:616–632. 33. Munzel T, Daiber A, Mulsch A. Explaining the phe-
14. Gouin-Thibault I, Pautas E, Siguret V. Safety profile nomenon of nitrate tolerance. Circ Res. 2005;97:
of different low-molecular weight heparins used at 618–628.
therapeutic dose. Drug Saf. 2005;28:333–349. 34. Noronha B, Duncan E, Byrne JA. Optimal medical
15. Granger CB, Weaver WD. Reducing cardiac events management of angina. Curr Cardiol Rep. 2003;5:
after acute coronary syndromes. Rev Cardiovasc Med. 259–265.
2004;5(suppl 5):S39–S46. 35. O’Connor R, Persse D, Zachariah B, et al. Acute coro-
16. Hashimoto S, Kobayashi A. Clinical pharmacokinetics nary syndrome: pharmacotherapy. Prehosp Emerg Care.
and pharmacodynamics of glyceryl trinitrate and its 2001;5:58–64.
metabolites. Clin Pharmacokinet. 2003;42:205–221. 36. Parmley WW. Optimum treatment of stable angina
17. Jain A, Wadehra V, Timmis AD. Management of stable pectoris. Cardiovasc Drugs Ther. 1998;12(suppl 1):
angina. Postgrad Med J. 2003;79:332–336. 105–110.
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Care. 2004;13:350–354. ications on exercise responses. Phys Ther. 1995;75:
19. Kerr JL, Oppelt TF, Rowen RC. Role of clopidogrel 387–396.
in unstable angina and non-ST-segment elevation 38. Pollack CV, Jr, Gibler WB. 2000 ACC/AHA guide-
myocardial infarction: from literature and guidelines lines for the management of patients with unstable
to practice. Pharmacotherapy. 2004;24:1037–1049. angina and non-ST-segment elevation myocardial
20. Ketterer MW, Mahr G, Cao JJ, et al. What’s ′′unsta- infarction: a practical summary for emergency physi-
ble′′ in unstable angina? Psychosomatics. 2004;45: cians. Ann Emerg Med. 2001;38:229–240.
185–196. 39. Romero M, Sanchez I, Pujol MD. New advances
21. Kizer JR, Kimmel SE. Epidemiologic review of the in the field of calcium channel antagonists: cardio-
calcium channel blocker drugs. An up-to-date perspec- vascular effects and structure-activity relationships.
tive on the proposed hazards. Arch Intern Med. 2001; Curr Med Chem Cardiovasc Hematol Agents. 2003;1:
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22. Klein WW, Jackson G, Tavazzi L. Efficacy of mono- 40. Rondina MT, Muhlestein JB. Early initiation of statin
therapy compared with combined antianginal drugs in therapy in acute coronary syndromes: a review of the
the treatment of chronic stable angina pectoris: a evidence. J Interv Cardiol. 2005;18:55–63.
meta-analysis. Coron Artery Dis. 2002;13:427–436. 41. Schulz E, Tsilimingas N, Rinze R, et al. Functional
23. Korkmaz ME. Low-molecular-weight heparins in and biochemical analysis of endothelial (dys)func-
acute coronary syndromes. Curr Vasc Pharmacol. tion and NO/cGMP signaling in human blood vessels
2003;1:259–271. with and without nitroglycerin pretreatment. Circula-
24. Kumar S, Hall RJ. Drug treatment of stable angina tion. 2002;105:1170–1175.
pectoris in the elderly: defining the place of calcium 42. Schwartz GG, Olsson AG. The case for intensive
channel antagonists. Drugs Aging. 2003;20:805–815. statin therapy after acute coronary syndromes. Am J
25. Lettino M, Falcone C, Tavazzi L. Therapeutic Cardiol. 2005;96:45F–53F.
approach in patients with stable angina. Ital Heart J. 43. Shah PK. Pathophysiology of plaque rupture and the
2005;6:1–8. concept of plaque stabilization. Cardiol Clin. 2003;21:
26. Li H, Cui H, Liu X, Zweier JL. Xanthine oxidase cat- 303–314.
alyzes anaerobic transformation of organic nitrates to 44. Shin J, Edelberg JE, Hong MK. Vulnerable atheroscle-
nitric oxide and nitrosothiols: characterization of this rotic plaque: clinical implications. Curr Vasc Pharmacol.
mechanism and the link between organic nitrate and 2003;1:183–204.
guanylyl cyclase activation. J Biol Chem. 2005;280: 45. Spaulding C, Cabanes L, Weber S. Pharmacological
16594–16600. and therapeutic basis for combined administration of
27. Manoharan G, Adgey AA. Current management of beta blockers and calcium channel blockers in the
unstable angina: lessons from the TACTICS-TIMI treatment of stable chronic angina. Br J Clin Pract
18 trial. Am J Cardiovasc Drugs. 2002;2:237–243. Suppl. 1997;88:17–22.
28. Mason RP. Effects of calcium channel blockers on cel- 46. Stason WB, Schmid CH, Niedzwiecki D, et al. Safety
lular apoptosis: implications for carcinogenic potential. of nifedipine in angina pectoris: a meta-analysis.
Cancer. 1999;85:2093–2102. Hypertension. 1999;33(1):24–31.
29. Massie BM. The safety of calcium-channel blockers. 47. Talbert RL. Ischemic heart disease. In: DiPiro JT, et
Clin Cardiol. 1998;21(suppl 2):II12–II17. al, eds. Pharmacotherapy: A Pathophysiologic Approach.
30. Mayer S, Hillis LD. Prinzmetal’s variant angina. Clin 5th ed. New York: McGraw-Hill; 2002.
Cardiol. 1998;21:243–246. 48. Thadani U. Current medical management of chronic
31. Michel T. Treatment of myocardial ischemia. In: stable angina. J Cardiovasc Pharmacol Ther. 2004;9
Brunton L, et al, eds. The Pharmacologic Basis of Thera- (suppl 1):S11–S29.
peutics. 10th ed. New York: McGraw-Hill; 2006. 49. Toda N. Vasodilating beta-adrenoceptor blockers as
32. Mills TA, Kawji MM, Cataldo VD, et al. Profound cardiovascular therapeutics. Pharmacol Ther. 2003;100:
sinus bradycardia due to diltiazem, verapamil, and/or 215–234.
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50. Tran H, Anand SS. Oral antiplatelet therapy in 54. Wiviott SD, Braunwald E. Unstable angina and non-
cerebrovascular disease, coronary artery disease, ST-segment elevation myocardial infarction: part I.
and peripheral arterial disease. JAMA. 2004;292: Initial evaluation and management, and hospital care.
1867–1874. Am Fam Physician. 2004;70:525–532.
51. Van Spall HG, Overgaard CB, Abramson BL. Coro- 55. Wiviott SD, Braunwald E. Unstable angina and non-
nary vasospasm: a case report and review of the litera- ST-segment elevation myocardial infarction: part II.
ture. Can J Cardiol. 2005;21:953–957. Coronary revascularization, hospital discharge, and
52. Wallentin L. Prevention of cardiovascular events after post-hospital care. Am Fam Physician. 2004;70:
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293–300. 56. Yan AT, Goodman SG. Low-molecular-weight
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Mechanisms underlying nitrate-induced endothelial 2004;19:309–316.
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studies. Heart Fail Rev. 2002;7:335–345. coronary angiogram. Herz. 2005;30:17–25.
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Chapter 23
Treatment of Cardiac
Arrhythmias
321
23Ciccone(p)-23 1/30/07 2:52 PM Page 322
the efflux of potassium ions. The cardiac action poten- the cell, which causes the cell to become more
tial, however, has several features that distinguish it and more positive until it reaches threshold and
from action potentials recorded in other nerves and phase 0 is initiated again.37
muscles.5,37 The cardiac action potential is typically
Action potentials recorded from various cardiac
divided into several phases (see Fig. 23–1). The ionic
cells may vary somewhat from the action potential
movement that occurs in each phase is outlined here.
described previously. Some cells, for instance, totally
Phase 0. Rapid depolarization occurs because of the lack phase 1 and have a slower phase 0. Such cells
sudden influx of sodium ions into the cell. At are said to have a slow response as opposed to the fast
some threshold level, the cell membrane sud- response just described. Also, action potentials from
denly becomes permeable to sodium ions the nodal cells (see the next section, “Normal Cardiac
because of the opening of sodium channels or Rhythm”) differ somewhat from the fast response
gates, similar to the spike seen in skeletal mus- cells. Nonetheless, the fundamental ionic fluxes
cle depolarization. occurring during cardiac action potentials are similar
Phase 1. An early, brief period of repolarization in all cardiac cells. This ionic activity is pharmaco-
occurs because specific potassium channels in logically significant because various antiarrhythmic
the cell membrane open to allow potassium drugs will affect the movement of sodium and other
to leave the cell. ions in an attempt to establish and maintain normal
Phase 2. The action potential undergoes a plateau cardiac rhythm.
phase, primarily because the calcium channels
open, and there is a slow, prolonged influx of
calcium ions into the cell. There is no net Normal Cardiac Rhythm
change in the charge within the cell because the
Certain cardiac cells are able to initiate and maintain a
efflux of positively charged potassium ions that
spontaneous automatic rhythm. Even in the absence
occurred in phase 1 is balanced by the influx of
of any neural or hormonal input, these cells will auto-
positively charged calcium ions. Thus, the cell’s
matically generate an action potential. They are usu-
potential remains relatively constant for a brief
ally referred to as pacemaker cells in the myocardium.
period, which creates the distinctive plateau that
Pacemaker cells have the ability to depolarize sponta-
can be seen in Figure 23–1. The phase 2 plateau
neously because of a rising phase 4 in the cardiac
is important in cardiac cells because it prolongs
action potential (see Fig. 23–1). As described previ-
the cell’s effective refractory period (i.e., the
ously, the resting cell automatically begins to depolar-
time interval between successive action poten-
ize during phase 4 until the cell reaches threshold and
tials). The plateau basically enables the heart
an action potential is initiated.
to enter a period of rest (diastole) so that the
Pacemaker cells are found primarily in the sinoa-
cardiac chambers can fill with blood before
trial (SA) node and the atrioventricular (AV) node
the next contraction (systole).
(Fig. 23–2). Although many other cardiac cells also
Phase 3. At the end of the plateau, repolarization is
have the ability to generate an automatic rhythm, the
complete. This is primarily because of the clos-
pacemaker cells in the SA node usually dominate and
ing (inactivation) of the calcium channels, which
control cardiac rhythm in the normal heart.
terminates the entry of calcium into the cell.
Repolarization is completed by the unopposed
exit of potassium ions. Normal Conduction of
Phase 4. Phase 4 consists of a slow, spontaneous
depolarization in certain cardiac cells (such as
the Cardiac Action Potential
the one shown in Fig. 23–1). This spontaneous The cardiac action potential is normally conducted
depolarization probably occurs because of the throughout the heart in a coordinated and predictable
continuous leak of sodium ions into the cell, pattern (Fig. 23–2).5 The action potential originates in
combined with a gradual decrease in potassium the SA node and is conducted throughout both
exit from the cell. This combination of sodium atria via the atrial muscle cells. While spreading
entry and decreased potassium exit causes a pro- through the atria, the action potential reaches the
gressive accumulation of positive charge within AV node. From the AV node, the action potential
23Ciccone(p)-23 1/30/07 2:52 PM Page 323
Bundle of His
Sinoatrial node
Atrioventricular node
FIGURE 23–2 ▼ Schematic representation of the conduction system of the heart. Conduction
normally follows the pathways indicated by the dashed lines. Impulses originate in the sinoatrial node
and are transmitted to the atrioventricular node. Impulses are then conducted from the atrioventricu-
lar node to the ventricles by the bundle of His and bundle branches.
is passed on to the ventricles via a specialized con- the cardiac cell membrane.19,36,42 Thus, inherited
ducting system known as the bundle of His. The bundle alterations in ion channel function can affect cardiac
of His is composed primarily of specialized conduct- action potential initiation or conduction, especially
ing cells known as Purkinje fibers. As the bundle when the heart is damaged (e.g., ischemic) or exposed
leaves the AV node, it divides into left and right to other factors that stress the heart.32,34,35
branches, which supply the respective ventricles. The Regardless of what the initiating factor is in pro-
action potential is distributed to all parts of the ventri- ducing arrhythmias, the mechanism underlying a dis-
cles via the bundle branches and Purkinje fibers (see turbance in cardiac rhythm can be attributed to one of
Fig. 23–2). the three basic abnormalities listed below.5
1. Abnormal impulse generation. The normal auto-
matic rhythm of the cardiac pacemaker cells has
Mechanisms of been disrupted. Injury and disease may directly
render the SA and AV cells incapable of main-
Cardiac Arrhythmias taining normal rhythm. Also, cells that do not
The origin of the cardiac action potential and system normally control cardiac rhythm may begin to
of action potential propagation represents normal car- compete with pacemaker cells, thus creating
diac excitation and conduction. Any number of factors multiple areas of automaticity.
can disrupt the normal cardiac excitation process, thus 2. Abnormal impulse conduction. The conduction of
resulting in arrhythmic contractions. Such factors impulses throughout the myocardium has been
include disease, metabolic and electrolyte imbalances, interrupted. Various diseases and local damage
abnormal autonomic influence on the heart, toxicity may result in the delay or failure of an action
to other drugs (e.g., digitalis), and myocardial potential to reach certain areas. These conduc-
ischemia and infarction.10,20,24,32,33 In addition, it is tion impairments or heart blocks can prevent a
now recognized that genetic factors can predispose smooth and synchronous contraction, thus cre-
individuals to certain arrhythmias.13,35,36 Specifically, ating an abnormal rhythm.
mutations is certain genes can cause altered expression 3. Simultaneous abnormalities of impulse generation
and function of channel proteins that control move- and conduction. A combination of both previous-
ments of sodium, potassium, or calcium ions across ly listed factors may cause cardiac arrhythmias.
23Ciccone(p)-23 1/30/07 2:52 PM Page 324
tible to proarrhythmic effects of class I agents.4 Class I Class III: Drugs That
drugs are also associated with a variety of side effects Prolong Repolarization
such as dizziness, visual disturbances, and nausea.5
These symptoms are often important, however, Mechanism of Action and Rationale for Use
because they may indicate the presence of arrhythmias Class III agents delay repolarization of cardiac cells,
even when the pulse or electrocardiogram (ECG) is which prolongs the effective refractory period of the
not being directly monitored. Hence, class I drugs are cardiac action potential.5,28 This delay lengthens the
still important in treating certain arrhythmias, but they time interval before a subsequent action potential can
are used less and with more caution than in the past.8,9 be initiated, thus slowing and stabilizing the heart
rate. The effects of class III drugs are complex, but
Class II: Beta Blockers their ability to lengthen the cardiac action potential is
Mechanisms of Action and Rationale for Use most likely mediated by inhibition of potassium efflux
during repolarization.5 That is, these drugs limit the
Drugs that block beta-1 receptors on the myocardium ability of potassium to leave the cell during phase 2
are one of the mainstays in arrhythmia treatment. Beta and 3 of the action potential, which prolongs repolar-
blockers are effective because they decrease the excita- ization and prevents the cell from firing another
tory effects of the sympathetic nervous system and action potential too rapidly. Class III drugs are used to
related catecholamines (norepinephrine and epineph- treat ventricular arrhythmias such as ventricular
rine) on the heart.5,28 This effect typically decreases tachycardia and ventricular fibrillation, and supraven-
cardiac automaticity and prolongs the effective refrac- tricular arrhythmias such as postoperative atrial fibril-
tory period, thus slowing heart rate.5 Beta blockers lation.22,30 Interest in using these drugs and
also slow down conduction through the myocardium, developing new class III agents has increased recently
and are especially useful in controlling function of the because they affect both atrial and ventricular prob-
atrioventricular node.21 Hence, these drugs are most lems and are relatively safe compared to other agents
effective in treating atrial tachycardias such as atrial such as the class I drugs.11,38,40
fibrillation.23 Some ventricular arrhythmias may also
respond to treatment with beta blockers.
Specific Agents
Specific Agents Class III drugs currently in use include amiodarone,
bretylium, dofetilide, and ibutilide (see Table 23–2).
Individual beta blockers are presented in Chapter 20.
These drugs all exert their primary effects by prolong-
Beta blockers shown to be effective in treating arrhyth-
ing repolarization in cardiac cells. Amiodarone, how-
mias include acebutolol, atenolol, esmolol, metoprolol,
ever, also appears to have some properties similar to
nadolol, propranolol, sotalol, and timolol (see Table
drugs in other classes, and may help control arrhyth-
23–2). Choice of a specific beta blocker depends to a
mias by inhibiting sodium channel function (class I
large extent on the exact type of arrhythmia present
effect), by beta blockade (class II effect), or even by
and the individual patient’s response to the drug.
blocking calcium channels (class IV effect).5
Adverse Side Effects
Adverse Side Effects
Nonselective beta blockers affect beta-2 receptors on
the lungs as well as beta-1 receptors on the heart, and An initial increase in cardiac arrhythmias (proarrhyth-
these nonselective agents can increase bronchocon- mic effect) may occur when class III drugs are insti-
striction in patients with asthma and chronic obstruc- tuted. The most important proarrhythmia is known as
tive pulmonary disease. Hence, a drug that is more torsades de pointes, which is a form of ventricular
specific for beta-1 receptors is preferred in these tachycardia that can be fatal.11,40 Specific class III
patients. Beta blockers can also produce excessive agents are associated with various other side effects.
slowing of cardiac conduction in some patients, result- Amiodarone, for example, is associated with pul-
ing in an increase in arrhythmias. Severe adverse reac- monary toxicity and liver damage. Other class III
tions are rare, however, and beta blockers are drugs may have a more favorable side-effect profile
well-tolerated by most patients when used appropri- but may not be as effective as amiodarone in control-
ately to treat arrhythmias. ling arrhythmias. Side effects of class III drugs there-
23Ciccone(p)-23 1/30/07 2:52 PM Page 327
fore vary from agent to agent, and any untoward vasodilation and lead to dizziness and headaches in
effects should be monitored carefully. some patients.
CA S E ST U DY
Antiarrhythmic Drugs ing the drug. This consideration is important because the
exercise prescription for any given patient must take into
Brief History. M.R. is a 48-year-old man with a history account the patient’s maximal exercise capacity. Typically,
of coronary artery disease and cardiac rhythm disturbances. patients exercise at some submaximal percentage of their
Specifically, he has experienced episodes of paroxysmal maximal ability. If maximal exercise capacity is influenced by
supraventricular tachycardia, with his heart rate often exceed- the beta blocker, the exercise prescription must be adjusted
ing 180 beats per minute. He has been treated for several accordingly.
years with the nonspecific beta blocker propranolol (Inderal). Decision/Solution. Prior to beginning the rehabilita-
Oral propranolol (60 mg/d) has successfully diminished his tion program, the patient underwent a graded exercise test
episodes of tachycardia. In an effort to improve his myocardial (GXT). All patients with cardiac disorders should undergo a
function and overall cardiovascular fitness, M.R. recently GXT before beginning a cardiac rehabilitation program.
enrolled as an outpatient in a cardiac rehabilitation program. Patients taking beta blockers and other drugs that affect car-
Under the supervision of a physical therapist, he attended diac function must also be tested under the conditions in
cardiac training sessions three times each week. A typical which they will eventually be exercising. The GXT accurately
session consisted of warm-up calisthenics, bicycle ergometry, determined the patient’s exercise workload while he was tak-
and cool-down stretching activities. Each session lasted ing his normal dosage of propranolol. Consequently, the pre-
approximately 45 minutes. scribed exercise workload was adjusted by the therapist for
Problem/Influence of Medication. Propranolol and the effect of the beta blocker.
the other beta blockers are successful in reducing various During the cardiac rehabilitation sessions, the therapist
supraventricular arrhythmias. These drugs, however, also periodically monitored heart rate, blood pressure, and ECG.
attenuate the cardiac response to exercise. Heart rate and No significant episodes of arrhythmias were noted, and the
cardiac output are lower at any absolute workload, and max- patient progressed rapidly through the program. He was
imal heart rate and cardiac output are attenuated by beta eventually discharged from the formal program with instruc-
blockade. Consequently, the exercise response of a patient tions of how to continue his rehabilitation exercises at home
taking a beta blocker will be less than if the patient is not tak- and at a local health club.
23Ciccone(p)-23 1/30/07 2:52 PM Page 329
References 18. Hume JR, Grant AO. Agents used in cardiac arrhyth-
mias. In: Katzung BG, ed. Basic and Clinical Pharmacol-
1. Adamson PB, Barr RC, Callans DJ, et al. The perplex- ogy. 9th ed. New York: Lange Medical
ing complexity of cardiac arrhythmias: beyond electri- Books/McGraw-Hill; 2004.
cal remodeling. Heart Rhythm. 2005;2:650–659. 19. Ji S, Cesario D, Valderrabano M, Shivkumar K. The
2. Agarwal A, York M, Kantharia BK, Ezekowitz M. molecular basis of cardiac arrhythmias in patients with
Atrial fibrillation: modern concepts and management. cardiomyopathy. Curr Heart Fail Rep. 2004;1:98–103.
Annu Rev Med. 2005;56:475–494. 20. Khan IA. Long QT syndrome: diagnosis and manage-
3. Albrecht CA. Proarrhythmia with non-antiarrhythmics. ment. Am Heart J. 2002;143:7–14.
A review. Cardiology. 2004;102:122–139. 21. Khan IA, Nair CK, Singh N, et al. Acute ventricular
4. Balser JR. Inherited sodium channelopathies: novel rate control in atrial fibrillation and atrial flutter. Int J
therapeutic and proarrhythmic molecular mechanisms. Cardiol. 2004;97:7–13.
Trends Cardiovasc Med. 2001;11:229–237. 22. Khan MH. Oral class III antiarrhythmics: what is new?
5. Bauman JL, Schoen MD. Arrhythmias. In: DiPiro JT, Curr Opin Cardiol. 2004;19:47–51.
et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 23. Kuhlkamp V, Bosch R, Mewis C, Seipel L. Use of
5th ed New York: McGraw-Hill; 2002. beta-blockers in atrial fibrillation. Am J Cardiovasc
6. Berne RM, Levy MN. Cardiovascular Physiology. 8th ed. Drugs. 2002;2:37–42.
St Louis: Mosby; 2001. 24. Leonardi M, Bissett J. Prevention of atrial fibrillation.
7. Brennan TD, Haas GJ. The role of prophylactic Curr Opin Cardiol. 2005;20:417–423.
implantable cardioverter defibrillators in heart failure: 25. Marcus GM, Sung RJ. Antiarrhythmic agents in facili-
recent trials usher in a new era of device therapy. Curr tating electrical cardioversion of atrial fibrillation and
Heart Fail Rep. 2005;2:40–45. promoting maintenance of sinus rhythm. Cardiology.
8. Campbell TJ, Williams KM. Therapeutic drug moni- 2001;95:1–8.
toring: antiarrhythmic drugs. Br J Clin Pharmacol. 26. Marine JE, Dong J, Calkins H. Catheter ablation ther-
1998;46:307–319. apy for atrial fibrillation. Prog Cardiovasc Dis. 2005;48:
9. Chaudhry GM, Haffajee CI. Antiarrhythmic agents 178–192.
and proarrhythmia. Crit Care Med. 2000;28(suppl): 27. Nattel S, Kneller J, Zou R, Leon LJ. Mechanisms of
N158–N164. termination of atrial fibrillation by Class I antiarrhyth-
10. Chiang CE. Congenital and acquired long QT syn- mic drugs: evidence from clinical, experimental, and
drome. Current concepts and management. Cardiol mathematical modeling studies. J Cardiovasc Electro-
Rev. 2004;12:222–234. physiol 2003;14(suppl):S133–S139.
11. Elming H, Brendorp B, Pehrson S, et al. A benefit-risk 28. Nattel S, Singh BN. Evolution, mechanisms, and clas-
assessment of class III antiarrhythmic agents. Expert sification of antiarrhythmic drugs: focus on class III
Opin Drug Saf. 2004;3:559–577. actions. Am J Cardiol. 1999;84(suppl 9A):11R–19R.
12. Elmslie KS. Calcium channel blockers in the treatment 29. Ohmura K, Kobayashi Y, Miyauchi Y, et al. Electrocar-
of disease. J Neurosci Res. 2004;75:733–741. diographic and electrophysiological characteristics of
13. Francis J, Antzelevitch C. Brugada syndrome. Int J atrial fibrillation organized into atrial flutter by oral
Cardiol. 2005;101:173–178. administration of class I antiarrhythmic agents. Pacing
14. Gillinov AM, Wolf RK. Surgical ablation of atrial fib- Clin Electrophysiol. 2003;26:692–702.
rillation. Prog Cardiovasc Dis. 2005;48:169–177. 30. Purerfellner H. Recent developments in cardiovascular
15. Grossman E, Messerli FH. Calcium antagonists. Prog drug therapy: treatment of atrial arrhythmias with new
Cardiovasc Dis. 2004;47:34–57. class III drugs and beyond. Curr Med Chem Cardiovasc
16. Gutierrez A, Lopez JE. Update in atrial fibrillation. Hematol Agents. 2004;2:79–91.
P R Health Sci J. 2004;23:279–284. 31. Roden DM. Mechanisms and management of proar-
17. Guyton AC, Hall JE. Cardiac arrhythmias and their rhythmia. Am J Cardiol. 1998;82(4A):49I–57I.
electrocardiographic interpretation. In: Textbook of 32. Roden DM, Viswanathan PC. Genetics of acquired
Medical Physiology. 11th ed. Philadelphia: WB Saun- long QT syndrome. J Clin Invest. 2005;115:
ders; 2006. 2025–2032.
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33. Roffi M, Cattaneo F, Brandle M. Thyrotoxicosis and 39. Tamargo J, Caballero R, Delpon E. Pharmacological
the cardiovascular system. Minerva Endocrinol. 2005; approaches in the treatment of atrial fibrillation. Curr
30:47–58. Med Chem. 2004;11:13–28.
34. Rubart M, Zipes DP. Mechanisms of sudden cardiac 40. Tsikouris JP, Cox CD. A review of class III antiar-
death. J Clin Invest. 2005;115:2305–2315. rhythmic agents for atrial fibrillation: maintenance
35. Sarkozy A, Brugada P. Sudden cardiac death and inher- of normal sinus rhythm. Pharmacotherapy. 2001;21:
ited arrhythmia syndromes. J Cardiovasc Electrophysiol. 1514–1529.
2005;16(suppl 1):S8–S20. 41. Van Gelder IC, Brugemann J, Crijns HJ. Current
36. Schwartz PJ. Management of long QT syndrome. Nat treatment recommendations in antiarrhythmic therapy.
Clin Pract Cardiovasc Med. 2005;2:346–351. Drugs. 1998;55:331–346.
37. Seifter J, Ratner A, Sloane D. The electrical activity 42. Viswanathan PC, Balser JR. Inherited sodium channe-
of the heart. In: Concepts in Medical Physiology. Philadel- lopathies: a continuum of channel dysfunction. Trends
phia: Lippincott, Williams and Wilkins; 2005 Cardiovasc Med. 2004;14:28–35.
38. Singh BN, Wadhani N. Antiarrhythmic and proarrhy- 43. Willems R, Heidbuchel H. Nonpharmacologic
thmic properties of QT-prolonging antianginal drugs. treatment of atrial fibrillation in elderly persons.
J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S85–S97. Am J Geriatr Cardiol. 2005;14:68–72.
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Chapter 24
Treatment of Congestive
Heart Failure
Congestive heart failure is a chronic condition in recent advances in medical treatment, approximately
which the heart is unable to pump a sufficient quantity 50 percent of patients die within 5 years after they are
of blood to meet the needs of peripheral tissues.13,16 diagnosed with heart failure.34
Essentially, the heart’s pumping ability has been com- Consequently, effective treatment of congestive
promised by some form of myocardial disease or dys- heart failure is a critical and challenging task. Pharma-
function. The congestive aspect of heart failure arises cotherapy represents one of the primary methods of
from the tendency for fluid to accumulate in the lungs treating congestive heart failure, and the drugs dis-
and peripheral tissues because the heart is unable to cussed in this chapter play a vital role in the optimal
maintain proper circulation. The pathophysiology management of this disease. As with other cardiac
of congestive heart failure is fairly complex; the possi- problems, the prevalence of congestive heart failure
ble causes and mechanisms are addressed in more necessitates that members of the health care commu-
detail below in “Pathophysiology of Congestive Heart nity be aware of the pharmacologic management of
Failure.” this disease. Rehabilitation specialists will often treat
The primary symptoms associated with conges- patients with heart failure, and therapists should be
tive heart failure are peripheral edema and a decreased cognizant of the drugs used to treat this problem.
tolerance for physical activity.39,60 Dyspnea and short-
ness of breath are also common, especially if the left
heart is failing and pulmonary congestion is present Pathophysiology of
(see the next section). In severe cases, cyanosis devel- Congestive Heart Failure
ops because the heart cannot deliver oxygen to periph-
eral tissues.
Vicious Cycle of Heart Failure
Congestive heart failure represents one of the The mechanisms underlying chronic heart failure are
major illnesses present in industrialized nations.32,34,53 complex and may include biochemical disturbances in
In the United States, approximately 5 million people the cardiac cell, altered genetic expression of myocar-
have been diagnosed with this disease,34 and the inci- dial proteins, and systemic changes in hemodynamic
dence of heart failure (number of new cases each year) and neurohormonal factors.10,16,60 Heart failure also
is approximately 400,000 to 700,000.39 The preva- tends to be self-perpetuating because an aberration in
lence of heart failure also increases in the elderly, and cardiac function often initiates a vicious cycle leading
the number of people with heart failure will undoubt- to further decrements in cardiac function.53 Figure
edly increase as a larger percentage of our population 24–1 illustrates the way in which a vicious cycle might
reaches advanced age.53 This disease is likewise asso- be generated by the interaction of cardiac and neuro-
ciated with serious consequences, and the prognosis humoral factors. The sequence of events depicted in
for congestive heart failure is often poor.32,53 Despite Figure 24–1 is discussed briefly here.
331
24Ciccone(p)-24 2/2/07 6:58 PM Page 332
Cardiac Lesion:
ischemia hypertension
infarction valve disease
myopathy other
FIGURE 24–1 ▼ Vicious cycle of congestive heart failure. An initial cardiac lesion begins a self-
perpetuating decrease in myocardial performance.
1. Decreased cardiac performance. Any number decrease, several neural and humoral changes
of factors that affect cardiac pumping ability occur, increasing cardiac contractility and
may be responsible for initiating a change helping maintain blood pressure. In particular,
in myocardial performance. Factors such as the sympathetic nervous system and renin-
ischemic heart disease, myocardial infarction, angiotensin system are activated, and secre-
valve dysfunction, and hypertension may all tion of aldosterone and antidiuretic hormone
compromise the heart’s pumping ability.29,53,71 increases.2,15,42,61 Although these compensa-
Also, cardiomyopathy may result from other tions are initially helpful in maintaining cardiac
diseases and infections.13 function, they actually place more stress on the
2. Neurohumoral compensations. The body responds failing heart.18 This increased stress initiates a
to the decreased cardiac pumping ability in a vicious cycle because it causes more damage to
number of ways. In the early stages of failure, the myocardium, which further compromises
cardiac output decreases, and the delivery of cardiac pumping ability, causing more neurohu-
oxygen and nutrients to tissues and organs is moral activation, more stress to the heart, and
diminished. To compensate for this initial so on (see Fig. 24–1).
24Ciccone(p)-24 2/2/07 6:58 PM Page 333
3. Increased cardiac workload. The neurohumoral function and heart failure with normal ejection frac-
changes previously described contribute to tion.63 In diastolic heart failure, systolic function may
peripheral vasoconstriction, as well as a gen- appear normal at rest, but increased stress on the
eral increase in sodium and water retention.15 myocardium leads to progressive changes in cellular
These effects place additional strain on the function and cardiac remodeling that are detrimental
heart by increasing cardiac preload (the volume to cardiac function.
of blood returning to the heart) and cardiac Diastolic heart failure is more common in
afterload (the pressure that the heart must older adults, especially older women.51 The patho-
pump against).13 physiology of this type of heart failure might also dif-
4. Changes in myocardial cell function. The increased fer from heart failure associated with left ventricular
workload on the heart can lead to, or cause or systolic dysfunction, with hypertension being rela-
exaggerated alterations, in cell function. tively more important in the cause of diastolic heart
Increased cardiac workload may lead to further failure.35 Drug therapy for diastolic heart failure
structural damage to the already compromised therefore focuses on lowering blood pressure and
myocardial cell.25,28 Also, studies on the using other agents to reduce stress on the heart (see
molecular basis of heart failure have suggested “Agents that Decrease Cardiac Workload”).31 The
that alterations in calcium transport, contractile causes of systolic and diastolic heart failure continue
protein function, energy production and utiliza- to be investigated, and future research will help clari-
tion, free-radical production, and beta-receptor fy the factors responsible for specific forms of cardiac
density may occur.2,28,60 Continued stress on dysfunction.
the heart may exacerbate these changes, leading
to more cellular dysfunction and inappro-
priate adaptive changes in myocardial cell struc- Congestion in Left and
ture and function, which ultimately leads to Right Heart Failure
abnormal changes in the size, shape, and func-
The primary problem in advanced heart failure is that
tion of the heart (cardiac remodeling).25,50,67
the heart is unable to push blood forward through the
Increased dysfunction on the cellular level
circulatory system, thus causing pressure to build up
therefore leads to pathological remodeling,
in the veins returning blood to the heart. In effect,
resulting in a further decrease in cardiac per-
blood begins to back up in the venous system, increas-
formance, thus completing the cycle shown
ing the pressure gradient for fluid to move out of the
in Figure 24–1.
capillary beds. The net movement of fluid out of the
The changes in cardiac function previously capillaries causes the edema or congestion typically
described represent a simplification of the interaction found in advanced stages of heart failure.
of central and peripheral factors in congestive heart Although heart disease commonly affects the
failure. This description does, however, illustrate entire myocardium, congestive heart failure is some-
the primary problems that occur in this disease, as well times divided into left and right heart failure (Fig.
as the manner in which heart failure tends to self- 24–2). In left heart failure, the left atrium and ventricle
perpetuate. are unable to adequately handle the blood returning
Likewise, heart failure is not always associated from the lungs. This causes pressure to build up in the
with systolic dysfunction and an obvious decline in pulmonary veins, and fluid accumulates in the lungs.
cardiac pumping ability. In approximately half the Consequently, left heart failure is associated with pul-
cases of symptomatic heart failure, systolic function monary edema (see Fig. 24–2 A).
and cardiac output may appear normal when the In right heart failure, the right atrium and ventri-
patient is at rest.53,63 In this type of heart failure, car- cle are unable to handle blood returning from the sys-
diac function is impaired because the left ventricle is temic circulation. This causes fluid to accumulate in
stiff and unable to relax during the filling phase, the peripheral tissues, and ankle edema and organ
resulting in increased pressures at the end of dias- congestion (liver, spleen) are typical manifestations
tole.31 This condition is often described as “diastolic” (see Fig. 24–2 B). If both left and right heart failure
heart failure, but it is also identified by other names occur simultaneously, congestion is found in the lungs
such as heart failure with preserved left ventricular as well as the periphery.
24Ciccone(p)-24 2/2/07 6:58 PM Page 334
pulmonary
distended
edema
neck veins
pleural
effusion enlarged liver
and spleen
ankle
edema
A B
FIGURE 24–2 ▼ Effects of congestive heart failure. (A) Left-sided heart failure results primarily in
pulmonary edema. (B) Right-sided heart failure results in peripheral edema (swollen ankles, enlarged
organs). (Adapted from: Kent TH, Hart MN. Introduction to Human Disease. 2nd ed. Norwalk, CT:
Appleton-Century-Crofts; 1987: 141, with permission.)
Angiotensin II receptor blockers** Reduce angiotensin II–induced peripheral vascular resistance and
Eprosartan (Teveten) cardiovascular hypertrophy/remodeling by blocking angiotensin II
Losartan (Cozaar) receptors on the heart and vasculature
Valsartan (Diovan)
Beta adrenergic blockers Prevent sympathetic-induced overload on the heart by blocking the
Acebutolol (Sectral) effects of epinephrine and norepinephrine on the myocardium; some
Atenolol (Tenormin) agents (e.g., carvedilol) may also produce peripheral vasodilation
Carteolol (Cartrol)
Carvedilol (Coreg)
Labetolol (Normodyne, Trandate)
Metoprolol (Lopressor)
(others, see Table 20–2)
Diuretics*** Decrease the volume of fluid the heart must pump by promoting the
excretion of excess sodium and water; also reduce fluid accumulation
(congestion) in the lungs and other tissues
heart failure as well as the number of hospitalizations transports sodium out of the cell and potassium
and other aspects of morbidity associated with this into it. Sodium enters the cardiac cell during
disease.19,36,53 Digitalis must, however, be used cau- the depolarization phase of each action poten-
tiously and specifically in certain cases of congestive tial, and the sodium-potassium pump is respon-
heart failure, rather than as a panacea for all forms sible for removing this sodium from the cell
of this disease.19,60 Specifically, digitalis is often added (see Chapter 23 for a description of ion move-
to the pharmacological regimen in patients with ments during cardiac excitation). Inhibition of
heart failure who remain symptomatic despite treat- the sodium-potassium pump therefore causes
ment with other agents such as diuretics, angiotensin- sodium to accumulate within the cell.
converting enzyme (ACE) inhibitors, and beta block- 2. An increase in intracellular sodium concentra-
ers (see the respective headings later in this chap- tion leads to an increase in intracellular calci-
ter).19,37 In such patients, combining digitalis with um.51 During cardiac excitation, calcium ions
these drugs will clearly provide better clinical effects normally enter the myocardial cell through
than can be achieved by using digitalis alone.14,37 specific calcium channels during each action
potential (see Chapter 23). An enzyme known
as the sodium-calcium exchange protein
Effects and Mechanism of Action
removes some of the calcium that enters. This
Mechanical Effects enzyme uses the ionic gradient for sodium entry
to help remove calcium from the cell, thus
Digitalis and the other cardiac glycosides increase the
exchanging sodium entry for calcium exit from
heart’s mechanical pumping ability by bringing about
the cell. Because intracellular sodium concen-
an increase in intracellular calcium concentration.
tration has increased, there is a smaller driving
Increased intracellular calcium enhances contractility
force (electrochemical gradient) for sodium to
by facilitating the interaction between thick (myosin)
enter the cell. If less sodium enters, there is a
and thin (actin) filaments in the myocardial cell.60,66
reduction in the ability of the sodium-calcium
Digitalis probably increases intracellular calcium con-
exchange protein to remove calcium. Hence,
centration by a complex mechanism, which is illustrat-
intracellular calcium concentration increases.
ed in Figure 24–3. Details of this mechanism are also
3. The increased availability of calcium within the
briefly outlined below.
cardiac cell enables it to store more calcium in
1. Digitalis exerts its primary effect by inhibiting the sarcoplasmic reticulum.60 As in any type of
the sodium-potassium pump on the myocardial muscle cell, calcium is normally stored within
cell membrane.66 The sodium-potassium pump the sarcoplasmic reticulum and released during
is an active transport system that normally each action potential to facilitate actin-myosin
24Ciccone(p)-24 2/2/07 6:58 PM Page 337
+
Digitalis 'd Na entry
1 Cardiac Cell
Na+ – K+
ATPase
NCX
2
Na+ ++
Na+ 'd Ca exit;
++
'd intracellular Ca
SR
3
++
'd Ca storage
++
4 'd Ca release during excitation
FIGURE 24–3 ▼ Proposed mechanism of digitalis action on the sarcomere located within the
myocardial cell. Digitalis inhibits the Na⫹, K⫹-ATPase (1) resulting in increased intracellular sodium
(Na⫹). Increased intracellular sodium alters the Na⫹, Ca⫹⫹ exchange (NCX) mechanism so that
intracellular Ca⫹⫹ also increases (2). As intracellular calcium increases, more calcium is available
for storage in the sarcoplasmic reticulum (SR) (3). During cardiac excitation, more calcium is
released from storage sites in the sarcoplasmic reticulum, which facilitates contractile protein
binding, resulting in increased myocardial contractility (4). See text for additional details.
interaction and initiate muscle contraction. tion through the myocardium. In fact, digitalis is used
Because more calcium is stored in the cardiac to prevent and treat certain arrhythmias such as atrial
cell, the sarcoplasmic reticulum releases more tachycardia and atrial fibrillation (see Chapter 23).8
calcium during each action potential, thereby Some of these electrical properties may be caused by
initiating greater actin-myosin interaction and the direct effect of digitalis on the sodium-potassium
a stronger cardiac contraction. pump and can be attributed to alterations in sodium,
potassium, and calcium fluxes. As indicated, digitalis
also decreases excessive sympathetic stimulation of the
Autonomic and Electrophysiologic Effects
heart, and this effect helps normalize cardiac excitation
In addition to its effects on cardiac contractility, digi- and conduction. Digitalis likewise causes reflex stimu-
talis has a direct inhibitory effect on sympathetic nerv- lation of the vagus nerve, thus further slowing heart
ous system activity.37,60 This effect is beneficial because rate and conduction.60 The autonomic and electrical
it decreases stress on the failing heart by decreasing properties of digitalis therefore improve cardiac exci-
excessive sympathetic stimulation of the heart and tation and function, and these effects generally com-
peripheral vasculature2. Therapeutic levels of digitalis plement the mechanical effects of this drug in treating
likewise stabilize heart rate and slow impulse conduc- congestive heart failure.
24Ciccone(p)-24 2/2/07 6:58 PM Page 338
ing positive inotropic effects, and there is concern that ACE inhibitors
these agents may actually result in more serious side
Angiotensin-converting enzyme (ACE) inhibitors
effects, including an increase in patient mortality com-
have been used successfully to treat hypertension (see
pared with other drug treatments.1,4,9 Therefore,
Chapter 21) and are now recognized as critical in
inamrinone and milrinone have limited use in treating
treating congestive heart failure.14,17,33 ACE inhibitors
heart failure and are usually administered in severe or
interrupt the renin-angiotensin system and help
acute cases of heart failure, or in patients with severe
decrease morbidity and mortality in patients with con-
heart failure who are awaiting a heart transplant.4,6,9,26
gestive heart failure by improving the patient’s neuro-
It is hoped that newer forms of phosphodiesterase
hormonal and hemodynamic function.60,70 The ACE
inhibitors will be developed in the future that are safer
inhibitors commonly used in congestive heart failure
and more effective than the existing drugs.43,54
include captopril (Capoten), enalapril (Vasotec), and
several similar drugs listed in Table 24–1. In severe
Dopamine and Dobutamine congestive heart failure, these drugs are often given in
Dopamine and dobutamine are sometimes used to combination with diuretics and digitalis.
stimulate the heart in cases of acute or severe heart ACE inhibitors are now considered one of the
failure (see Chapter 20). Dopamine and dobutamine mainstays of treatment in congestive heart failure.
exert a fairly specific positive inotropic effect, presum- These drugs are the first agents shown to prolong the
ably through their ability to stimulate beta-1 receptors life span of people with this disease 60; that is, digital-
on the myocardium.60 Other beta-1 agonists (epineph- is, diuretics, and other drugs commonly used to treat
rine, prenalterol, etc.) will also increase myocardial heart failure may all produce symptomatic improve-
contractility, but most of these other beta-1 agonists ments, but the use of ACE inhibitors alone or in com-
will also increase heart rate or have other side effects bination with these drugs actually results in decreased
that prevent their use in congestive heart failure. mortality.32,60
Dopamine and dobutamine are usually reserved for The use of ACE inhibitors in treating heart
patients with advanced cases of congestive heart fail- failure has therefore increased dramatically over the
ure who do not respond to other positive inotropic last several years.53 There is evidence that these drugs
drugs (e.g., digitalis).6,72 should be used even more extensively and in higher
doses, especially in the early stages of this disease.32,48
By reducing the detrimental effects of angiotensin
Agents That Decrease II on the vascular system, early use of ACE inhibitors
Cardiac Workload may prevent or delay the progression of this disease
(see the next section, “Effects and Mechanism of
Drugs Affecting the Renin- Action of ACE Inhibitors”).
Angiotensin System
Effects and Mechanism of Action of ACE Inhibitors
As discussed previously in this chapter, the renin-
angiotensin system is often activated in congestive As discussed in Chapter 21, ACE inhibitors suppress
heart failure. Activation of this system results in the enzyme that converts angiotensin I to angiotensin
increased production of a powerful vasoconstrictor II in the bloodstream. Angiotensin II is a potent vaso-
known as angiotensin II (see Chapter 21 for details of constrictor. By inhibiting the formation of angiotensin
the renin-angiotensin system). Excess production of II, ACE inhibitors limit peripheral vasoconstriction.
angiotensin II is extremely detrimental to the cardio- This effect results in a decrease in cardiac workload
vascular system because it causes increased workload primarily by decreasing the pressure against which the
on the heart and abnormal structural changes (remod- heart must pump (cardiac afterload).13,41 Decreased
eling) of the heart and vasculature. Fortunately, two cardiac afterload eases the strain on the failing heart,
drug strategies have been developed to deal with resulting in improved cardiac performance and
abnormal activation of the renin-angiotensin system. increased exercise tolerance.39
These strategies are the ACE inhibitors and angioten- Angiotensin II also promotes abnormal growth
sin II receptor blockers—each strategy is addressed and remodeling of the heart, and this substance is
below. thought to be responsible for many of the pathologi-
24Ciccone(p)-24 2/2/07 6:58 PM Page 340
cal changes in left ventricular function in heart fail- thus inhibiting angiotensin II–induced damage of the
ure.5,14 Angiotensin II likewise stimulates growth and cardiovascular system. It appears that ARBs are as
hypertrophy of vascular tissues, which results in the effective as ACE inhibitors in treating heart failure
thickening of peripheral blood vessels’ walls.21,49 This and preventing mortality.24,46,47 It has also been sug-
thickening reduces the size of the vessel lumen, which gested that combining an ARB with an ACE inhibitor
further increases cardiac afterload because the heart might provide more benefits than using either drug
must force blood into these narrowed vessels. ACE alone.5,24,52 This idea remains controversial, however,
inhibitors therefore prevent angiotensin II–induced because some studies failed to observe a supplemental
cardiovascular remodeling, which helps reduce the effect when an ARB was added to ACE inhibitor in the
workload on the heart and prevents the progression of treatment of patients with heart failure.17,59
heart failure.11,60 Consequently, ARBs are used primarily as an
By directly inhibiting angiotensin II formation, alternative for people who are unable to tolerate tradi-
ACE inhibitors also inhibit aldosterone secretion.42 tional ACE inhibitors.17,46,47 Future studies comparing
Angiotensin II promotes aldosterone secretion from ACE inhibitors with these newer angiotensin II recep-
the adrenal cortex (it is probably a by-product of tor blockers should help clarify which type of drug—or
angiotensin II—that is, angiotensin III, which directly perhaps a combination of the two—provides optimal
stimulates aldosterone secretion). Aldosterone in- treatment in heart failure.17
creases renal sodium reabsorption, with a subsequent
increase in water reabsorption (i.e., the exact opposite
Adverse Side Effects of Drugs Affecting
effect produced by a diuretic). Inhibition of aldos-
the Renin-Angiotensin System
terone secretion is beneficial in congestive heart fail-
ure because vascular fluid volume does not increase Adverse effects with ACE inhibitors are relatively rare.
and overtax the failing heart. Consequently, ACE In fact, one of the primary advantages of these drugs
inhibitors may help decrease cardiac workload in con- over more toxic compounds such as digitalis is the low
gestive heart failure by both hemodynamic mecha- incidence of serious effects. ACE inhibitors are occa-
nisms (prevention of vasoconstriction by angiotensin sionally associated with bothersome side effects such as
II) and fluid-electrolyte mechanisms (inhibition of skin rashes, gastrointestinal discomfort, and dizziness;
aldosterone secretion). these effects are often transient or can be resolved with
Finally, ACE inhibitors exert some of their bene- an adjustment in dosage. Some patients taking ACE
ficial effects by increasing bradykinin levels in the inhibitors develop a persistent dry cough, and this side
bloodstream.17,70 Bradykinin is a vasodilator, and in- effect is often the reason for discontinuing the drug
creased levels of this compound decrease cardiac or seeking an alternative treatment. As indicated
workload in people with heart failure. Normally, ACE above, the newer angiotensin II receptor blockers can
is responsible for the enzymatic destruction of be used as an alternative to ACE inhibitors if patients
bradykinin in the bloodstream. ACE inhibitors reduce are not able to tolerate a dry cough or other ACE
the breakdown of bradykinin, thereby prolonging the inhibitor–induced side effects.
vasodilating effects of this substance.17,70
Hence, ACE inhibitors reduce the detrimental
effects of excess angiotensin II and aldosterone, and
Beta Blockers
prolong the beneficial effects of bradykinin. These In the past, beta blockers were considered detrimental
effects work in combination to sustain cardiovascular in patients with heart failure.60 As indicated in Chap-
health in people with heart failure. ter 20, these drugs decrease heart rate and myocardial
contraction force by blocking the effects of epineph-
rine and norepinephrine on the heart. Common sense
Angiotensin II Receptor Blockers
dictated that a decrease in myocardial contractility
Angiotensin II receptor blockers (ARBs) represent a would be counterproductive in heart failure, and beta
second strategy for treating disorders associated with blockers were therefore contraindicated in heart fail-
the renin-angiotensin system.24 These drugs include ure.60,69 It is now recognized that beta blockers are
agents such as candesartan, losartan and valsartan. As actually beneficial in people with heart failure because
indicated in Chapter 21, these drugs prevent angio- these drugs attenuate the excessive sympathetic activi-
tensin II from binding to receptors on vascular tissues, ty associated with this disease.56,64 As indicated earlier,
24Ciccone(p)-24 2/2/07 6:58 PM Page 341
increased sympathetic activity and other neurohumor- so that sympathetic activity is normalized rather than
al changes often contribute to the vicious cycle associ- reduced to unacceptably low levels.
ated with heart failure, and excessive sympathetic
stimulation can accelerate the pathologic changes in
the failing heart.7,62,65 Beta blockers reduce the harm-
Diuretics
ful effects of excessive sympathetic stimulation, and Diuretics increase the excretion of sodium and water
use of these drugs has been shown to reduce the mor- (see Chapter 21). These agents are useful in conges-
bidity and mortality associated with heart failure.3,38,65 tive heart failure primarily because of their ability to
Hence, beta blockers are now considered one of the reduce congestion in the lungs and peripheral tissues
principal treatments of this disease, and use of these by excreting excess fluid retained in these tissues.32,60
drugs along with ACE inhibitors and traditional Diuretics also decrease the amount of fluid the heart
agents (digitalis, diuretics, and so forth) is advocated as must pump (cardiac preload), thereby reducing the
state-of-the-art therapy for providing optimal treat- workload on the failing heart.60 Diuretics help
ment in heart failure.27,53 improve the symptoms of heart failure, and they are
often used with other agents (ACE inhibitors, beta
Effects and Mechanism of Action blockers, digitalis) to provide optimal treatment of this
disease.14,32 Diuretic drugs, which are also used to
Beta blockers bind to beta-1 receptors on the myo- treat hypertension, are discussed in more detail in
cardium and block the effects of norepinephrine and Chapter 21. Diuretics that can be used in the treat-
epinephrine (see Chapter 20). These drugs therefore ment of congestive heart failure and hypertension are
normalize sympathetic stimulation of the heart and listed in Chapter 21, Table 21–3.
help reduce heart rate (negative chronotropic effect)
and myocardial contraction force (negative inotropic
effect). Beta blockers may also prevent angina by sta- Effects and Mechanism of Action
bilizing cardiac workload, and they may prevent cer- Diuretics work by inhibiting the reabsorption of sodi-
tain arrhythmias by stabilizing heart rate.40 These um from the nephron, which, in turn, decreases the
additional properties can be useful to patients with amount of water that is normally reabsorbed with
heart failure who also have other cardiac symptoms. sodium, thus increasing water excretion. This effect
Finally, it has been suggested that some of the reduces congestion caused by fluids retained in the
newer “third-generation” beta blockers such as body and decreases cardiac preload by excreting excess
carvedilol (Coreg) may be especially useful in heart fluid in the vascular system. Chapter 21 provides a
failure because these drugs block beta-1 receptors on more detailed discussion on the mechanism of action
the heart while also blocking alpha-1 receptors on the of diuretic drugs.
vasculature, thus causing peripheral vasodilation.30,55 It has also been suggested that certain diuretics
Vasodilation of peripheral vessels could further reduce such as spironolactone (Aldactone) might be especial-
myocardial stress by decreasing the pressure that ly helpful in heart failure.14,42 Spironolactone blocks
the heart must work against in the peripheral vessels aldosterone receptors in the kidneys and other tissues,
(cardiac afterload). thereby producing a diuretic effect as well as prevent-
ing adverse cardiovascular changes associated with
excess aldosterone production. Future studies will
Adverse Side Effects
help clarify whether spironolactone should be used
The side effects and problems associated with beta preferentially in heart failure because of its ability to
blockers were addressed in Chapter 20. The primary reduce fluid volume and protect against aldosterone-
problem associated with these drugs is that they may induced damage.53
cause excessive inhibition of the heart, resulting in an
abnormally slow heart rate and reduced contraction
Adverse Side Effects
force. This effect is especially problematic in heart
failure because the heart is already losing its ability to By the very nature of their action, diuretics are often
pump blood. Nonetheless, the risk of this and other associated with disturbances in fluid and electrolyte
side effects is acceptable in most people with heart fail- balance. Volume depletion, hyponatremia, hypokale-
ure, and this risk is minimized by adjusting the dosage mia, and altered pH balance are among the most fre-
24Ciccone(p)-24 2/2/07 6:58 PM Page 342
quent problems.68 These electrolyte and pH changes hydralazine, organic nitrates, and BNP produce vaso-
can produce serious consequences by affecting cardiac dilation by a direct inhibitory effect on the vascular
excitability and precipitating arrhythmias. Patients on smooth-muscle cells (see Chapters 21 and 22).
diuretics should be monitored closely for symptoms Although these vasodilators work by different mecha-
such as fatigue, confusion, and nausea, which may nisms, they all can decrease cardiac workload by
indicate the presence of drug-induced disturbances in decreasing peripheral vascular resistance. These drugs
fluid-electrolyte balance. Some patients may also may be combined with other agents (digoxin, ACE
become resistant to diuretic drugs; the effectiveness of inhibitors, beta blockers) to provide optimal benefits
the diuretic is diminished primarily because the kid- in patients with varying degrees of congestive heart
neys adapt to the drug-induced sodium excretion.23,44 failure.53,60
Resistance can often be prevented, however, by alter-
ing the dose and type of diuretic or by adding a second Adverse Side Effects
diuretic.23,39
The primary side effects associated with vasodilators
include headache, dizziness, hypotension, and ortho-
Vasodilators static hypotension. These effects are all related to the
tendency of these drugs to increase peripheral blood
Various drugs that vasodilate peripheral vessels have
flow and decrease peripheral vascular resistance. Vaso-
been successful in treating patients with cases of severe
dilators may also cause reflex tachycardia in certain
congestive heart failure.22,60 By reducing peripheral
patients if the baroreceptor reflex increases heart rate
vascular resistance, these agents decrease the amount
in an attempt to maintain adequate blood pressure.
of blood returning to the heart (cardiac preload) and
reduce the pressure that the heart must pump against
(cardiac afterload). Reduced cardiac preload and after-
load helps alleviate some of the stress on the failing
Summary of Drug Therapy
heart, thus slowing the disease progression. Vasodila- The treatment of heart failure has undergone substan-
tors commonly used in heart failure include prazosin, tial changes over the past few years. Digitalis, once the
hydralazine, and organic nitrates (e.g., nitroglycerin, cornerstone of treatment, is associated with a number
isosorbide dinitrate, sodium nitroprusside; see Table of serious side effects, and there is considerable doubt
24–1). In particular, a combination of hydralazine and as to whether digitalis actually increases the rate of sur-
isosorbide dinitrate has been found to be helpful in vival of patients with congestive heart failure.36,53 Stan-
reducing symptoms and improving survival in patients dard treatment is now centered on using drugs that
with advance heart failure.22,53 decrease cardiac workload, such as ACE inhibitors and
In addition to these traditional vasodilators, nesir- beta blockers.53 These drugs not only help resolve the
itide (Natrecor) was developed as a newer method for symptoms of heart failure, but can also slow the pro-
producing arterial and venous dilation in people with gression of this disease and help prolong life expectan-
heart failure.58 This substance was derived from cy. Other drugs such as digitalis, diuretics, and
human B-type natriuretic peptide (BNP) using recom- vasodilators can be added to the ACE inhibitor/beta
binant DNA techniques. BNP is a naturally occurring blocker regimen as needed to help resolve symptoms,
substance that is released from the ventricles when the or as heart failure becomes more pronounced. Regard-
heart is subjected to increased blood volume and pres- less of which drugs are used, there is consensus that
sure.12 This substance dilates peripheral arteries and early intervention in the treatment of congestive heart
veins, thus reducing cardiac afterload and preload, failure is crucial in providing the best outcome.60
respectively. Hence, nesiritide can be administered
intravenously to reduce cardiac workload in certain SUMMARY
patients with severe or acute heart failure.12,58
Congestive heart failure is a serious cardiac condition
in which the ability of the heart to pump blood be-
Effects and Mechanism of Action
comes progressively worse. Decreased myocardial per-
Prazosin produces vasodilation by blocking alpha-1 formance leads to a number of deleterious changes,
receptors on vascular smooth muscle (see Chapter 20); including peripheral edema (i.e., congestion) and in-
24Ciccone(p)-24 2/2/07 6:58 PM Page 343
CA S E ST U DY
Congestive Heart Failure By the end of the first week, however, the therapist noted a
distinct change in the patient’s demeanor. She was confused
Brief History. D.S. is a 67-year-old woman with a and quite lethargic. The therapist initially suspected that she
long history of congestive heart failure caused by myocarditis. might have had another stroke. However, physical examina-
She has been treated successfully with digitalis glycosides tion did not reveal any dramatic decrease in strength or coor-
(digoxin [Zanoxin], 0.5 mg/d) for several years. Despite some dination. Realizing that the patient was still taking digitalis for
swelling in her ankles and feet and a tendency to become the treatment of heart failure, the therapist began to suspect
winded, she has maintained a fairly active lifestyle and enjoys the possibility of digitalis toxicity.
gardening and other hobbies. Recently, she developed some Decision/Solution. The therapist immediately notified
weakness and incoordination that primarily affected her right the physician about the change in the patient’s status. The
side. Subsequent testing revealed that she had suffered a patient was admitted to the hospital, where a blood test con-
cerebral vascular accident (stroke). She was not admitted to firmed the presence of digitalis toxicity (i.e., blood levels of
the hospital but remained living at home with her husband. digitalis were well above the therapeutic range). Apparently,
Physical therapy, however, was provided in the home to facil- the stroke had sufficiently altered the metabolism and excre-
itate optimal recovery from her stroke. The therapist began tion of the digitalis so that the therapeutic dosage was now
seeing her three times each week for a program of therapeu- accumulating in the patient’s body. The altered pharmacoki-
tic exercise and functional training. netic profile was probably caused in part by the decrease in
Problem/Influence of Medication. The therapist the patient’s mobility and level of activity that occurred after
initially found D.S. to be alert, coherent, and eager to begin the stroke. The digitalis dosage was reduced, and a diuretic
therapy. Although there was some residual weakness and was added to provide management of the congestive heart
decreased motor skills, the prognosis for a full recovery failure. The patient was soon discharged from the hospital and
appeared good. The therapist was impressed by the patient’s resumed physical therapy at home. Her rehabilitation pro-
enthusiasm and pleasant nature during the first two sessions. gressed without further incident.
24Ciccone(p)-24 2/2/07 6:58 PM Page 344
creased fatigue during physical activity. Treatment of system, and beta blockers prevent excessive cardiovas-
congestive heart failure consists primarily of drug ther- cular stimulation from the sympathetic nervous sys-
apy. Certain drugs such as digitalis and other positive tem. These effects help prevent abnormal stimulation
inotropic agents attempt to directly increase cardiac of the heart and vasculature, and early treatment with
pumping ability. Other drugs such as diuretics and ACE inhibitors and beta blockers is now recognized as
vasodilators decrease cardiac workload by decreasing critical in delaying the progression of this disease and
vascular fluid volume or dilating peripheral blood ves- decreasing mortality in people with heart failure. Even
sels, respectively. with optimal treatment, however, the prognosis for
ACE inhibitors and beta blockers have gained patients with congestive heart failure is often poor.
widespread acceptance in treating heart failure because Therapists should be aware of the drugs used to treat
these drugs decrease the abnormal neurohumoral this disorder and that certain side effects may adverse-
changes associated with this disease. Specifically, ACE ly affect rehabilitation or signal a problem with drug
inhibitors decrease activity in the renin-angiotensin treatment.
24. Erhardt LR. A review of the current evidence for the 43. Kivikko M, Lehtonen L. Levosimendan: a new inodila-
use of angiotensin-receptor blockers in chronic heart tory drug for the treatment of decompensated heart
failure. Int J Clin Pract. 2005;59:571–578. failure. Curr Pharm Des. 2005;11:435–455.
25. Fedak PW, Verma S, Weisel RD, Li RK. Cardiac 44. Kramer BK, Schweda F, Riegger GA. Diuretic treat-
remodeling and failure: from molecules to man ment and diuretic resistance in heart failure. Am J
(part I). Cardiovasc Pathol. 2005;14:1–11. Med. 1999;106:90–96.
26. Felker GM, O’Connor CM. Inotropic therapy for 45. Lehtonen LA, Antila S, Pentikainen PJ. Pharmacoki-
heart failure: an evidence-based approach. Am Heart netics and pharmacodynamics of intravenous inotropic
J. 2001;142:393–401. agents. Clin Pharmacokinet. 2004;43:187–203.
27. Fonarow GC. When to initiate beta-blockers in heart 46. Levine TB, Levine AB. Rationale for the use of
failure: is it ever too early? Curr Heart Fail Rep. 2005; angiotensin II receptor blockers in patients with left
2:94–99. ventricular dysfunction (part I of II). Clin Cardiol.
28. Francis GS. Pathophysiology of chronic heart failure. 2005;28:215–218.
Am J Med. 2001;110(suppl 7A):37S–46S. 47. Levine TB, Levine AB. Clinical update: the role of
29. Gheorghiade M, De Luca L, Fonarow GC, et al. angiotensin II receptor blockers in patients with left
Pathophysiologic targets in the early phase of acute ventricular dysfunction (part II of II). Clin Cardiol.
heart failure syndromes. Am J Cardiol. 2005;96: 2005;28:277–280.
11G–17G. 48. Luzier AB, DiTusa L. Underutilization of ACE
30. Greenberg B. Nonselective versus selective beta-block- inhibitors in heart failure. Pharmacotherapy. 1999;
ers in the management of chronic heart failure: clinical 19:1296–1307.
implications of the carvedilol or Metoprolol European 49. Mahmud A, Feely J. Arterial stiffness and the renin-
Trial. Rev Cardiovasc Med. 2004;5(suppl 1):S10–S17. angiotensin-aldosterone system. J Renin Angiotensin
31. Gutierrez C, Blanchard DG. Diastolic heart failure: Aldosterone Syst. 2004;5:102–108.
challenges of diagnosis and treatment. Am Fam Physi- 50. Mann DL. Basic mechanisms of left ventricular
cian. 2004;69:2609–2616. remodeling: the contribution of wall stress. J Card
32. Guyatt GH, Devereaux PJ. A review of heart failure Fail. 2004;10(suppl 6):S202–S206.
treatment. Mt Sinai J Med. 2004;71:47–54. 51. McDonough AA, Velotta JB, Schwinger RH, et al. The
33. Hebert PR, Foody JM, Hennekens CH. The renin- cardiac sodium pump: structure and function. Basic Res
angiotensin system: the role of inhibitors, blockers, Cardiol. 2002;97(suppl 1):I19–I24.
and genetic polymorphisms in the treatment and pre- 52. McMurray JJ. Angiotensin inhibition in heart failure.
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34. Hobbs RE. Guidelines for the diagnosis and manage- 53. McMurray JJ, Pfeffer MA. Heart failure. Lancet. 2005;
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Cardiol. 2004;43:317–327. 55. Metra M, Cas LD, di Lenarda A, Poole-Wilson P.
36. Hood WB, Jr, Dans AL, Guyatt GH, et al. Digitalis Beta-blockers in heart failure: are pharmacological
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38. Jafri SM. The effects of beta blockers on morbidity 57. Pickett JR, Dickinson ET. Dealing with DIG. A com-
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9:115–121. toxic effects. JEMS. 2005;30:70–78, 82, 84.
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63. Sanderson JE. Diastolic heart failure or heart failure 69. Sorrentino MJ. Beta-blockers for congestive heart
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25Ciccone(p)-25 1/30/07 2:53 PM Page 347
Chapter 25
Treatment of Coagulation
Disorders and Hyperlipidemia
Blood coagulation, or hemostasis, is necessary to pre- other lipids are progressively deposited onto arterial
vent excessive hemorrhage from damaged blood ves- walls, forming plaquelike lesions indicative of athero-
sels. Under normal conditions, clotting factors in the sclerosis. These atherosclerotic lesions progressively
bloodstream spontaneously interact with damaged ves- occlude the arterial lumen, and atherosclerotic plaques
sels to create a blood clot that plugs the leaking vessel. can suddenly rupture, thus leading to thrombosis and
Obviously, inadequate blood clotting is harmful in that infarction. Atherosclerotic heart disease is one of the
even minor vessel damage can lead to excessive blood leading causes of morbidity and mortality in the Unit-
loss. Overactive clotting is also detrimental because it ed States, and pharmacologic methods to lower plasma
will lead to thrombogenesis (i.e., the abnormal formation lipids are often used in conjunction with dietary and
of blood clots, or thrombi).92,108 Thrombus formation lifestyle modifications to treat hyperlipidemia and pre-
may lead directly to vessel occlusion and tissue infarc- vent atherosclerosis.
tion. Also, a piece of a thrombus may dislodge, creat- Drugs used to normalize blood clotting or reduce
ing an embolism that causes infarction elsewhere in hyperlipidemia are among the most common medica-
the body, for example, in the lungs or brain. tions used clinically, and rehabilitation specialists will
Consequently, normal hemostasis can be regard- deal with many patients taking these agents. Many
ed as a balance between too much and too little blood patients, in fact, will be treated in therapy for problems
coagulation.133,140 This balance is often disrupted by a relating directly to thrombus formation (e.g., ischemic
number of factors. Insufficient levels of blood clott- stroke, myocardial infarction, pulmonary embolism).
ing factors typically cause inadequate clotting, as in Individuals with inadequate clotting, such as patients
patients with hemophilia. Excessive clotting often with hemophilia, are also seen routinely in rehabilita-
occurs during prolonged bed rest or when blood flow tion because of the intrajoint hemorrhaging and other
through vessels is partially obstructed, as in coronary problems associated with this disease. Consequently,
atherosclerosis. the purpose of this chapter is to acquaint therapists
Restoration of normal hemostasis is accomplished with several common and important groups of drugs
through pharmacologic methods. Excessive clotting used to treat coagulation disorders and hyperlipidemia.
and thrombus formation are rectified by drugs that
prevent clot formation (anticoagulants, antithrom-
botics) or facilitate the removal of previously formed Normal Mechanism
clots (thrombolytics). Inadequate clotting is resolved by
replacing the missing clotting factors or by drugs that
of Blood Coagulation
facilitate the synthesis of specific clotting factors. To understand how various drugs affect hemostasis, it
Hemostasis can also be influenced by hyperlipi- is necessary to review the normal way in which blood
demia, which is a chronic and excessive increase in clots are formed. The physiologic mechanisms in-
plasma lipids. With hyperlipidemia, cholesterol and volved in hemostasis are outlined in Figure 25–1, with
347
25Ciccone(p)-25 1/30/07 2:53 PM Page 348
INTRINSIC SYSTEM
Tissue Contact
IX VII
IXa VIIa
X X
Xa
VIII
V
Ca++
platelets
Prothrombin Thrombin
Fibrinogen Fibrin
CLOT
Tissue Plasminogen
Activator
FIGURE 25–1 ▼ Mechanism of blood coagulation. Factors involved in clot formation are shown
above the dashed line; factors involved in clot breakdown are shown below the dashed line. See text
for further discussion.
clot formation and breakdown illustrated in the upper forth.128,135 As shown in Figure 25–1, clot formation
and lower parts of the figure, respectively. occurs through two systems: an intrinsic and an extrin-
sic system. In the intrinsic system, the direct contact of
the first clotting factor (factor XII) with the damaged
Clot Formation vessel wall activates the clotting factor and initiates the
Clot formation involves the activation of various clot- cascade. In the extrinsic system, a substance known as
ting factors circulating in the bloodstream.108,135 The tissue factor (known also as thromboplastin) is released
clotting factors are proteolytic enzymes synthesized in from the damaged vascular cell. Tissue factor directly
the liver that remain inactive until there is some injury activates clotting factor VII, which then activates sub-
to a blood vessel. Blood vessel damage begins a cascade sequent factors in the clotting mechanism. For optimal
effect, whereby one of the clotting factors is activated, coagulation to occur in vivo, both the intrinsic and
which leads to the next factor’s activation, and so extrinsic systems must be present.
25Ciccone(p)-25 1/30/07 2:53 PM Page 349
Heparin
Drugs Used to
Heparin is the primary drug used in the initial treat-
Treat Overactive Clotting ment of venous thrombosis.100,103 The anticoagulant
Drugs used to treat excessive clot formation can be effects of heparin are seen almost instantly after
grouped into three primary categories: anticoagulant, administration. Heparin works by potentiating the
antithrombotic, and thrombolytic agents (Table 25–1). activity of a circulating protein known as antithrombin
Anticoagulants exert their effect by controlling the III.24,76 Antithrombin III binds to several of the active
function and synthesis of clotting factors; these drugs clotting factors (including thrombin) and renders the
are used primarily to prevent clot formation in the clotting factors inactive. Heparin accelerates the anti-
venous system—that is, venous thrombosis. Anti- thrombin III–induced inactivation of these clotting
thrombotic drugs act primarily by inhibiting platelet factors, thus reducing the tendency for clotting and
function, and primarily prevent thrombus formation thrombogenesis.
in arteries. Thrombolytic drugs facilitate the destruc- Heparin is a large, sugarlike molecule that is
tion of blood clots, and are used to reestablish blood poorly absorbed from the gastrointestinal tract. Con-
flow through vessels that have been occluded by sequently, heparin must be administered parenterally.
thrombi. Specific agents discussed below are listed in The agent was traditionally administered through
Table 25–1. intravenous (IV) infusion or repeated IV injection
25Ciccone(p)-25 1/30/07 2:53 PM Page 350
through a rubber-capped indwelling needle called a The LMWHs appear to be as effective as unfrac-
heparin lock. In the past, heparin preparations were also tionated (mixed) heparins, but they offer certain
somewhat heterogeneous and contained various forms advantages. For example, LMWHs can be adminis-
of compounds with heparinlike activity. In recent tered by subcutaneous injection into fat tissues, there-
years, efforts have been made to chemically extract cer- by decreasing the need for repeated intravenous
tain types of heparin from the more general (unfrac- administration. Subcutaneous administration offers an
tionated) forms of this compound.76,103 These efforts easier and more convenient route, especially for peo-
have led to the extraction and clinical use of specific ple who are being treated at home or as outpa-
forms of heparin known as low-molecular-weight hepa- tients.98,118 Dosing schedules of LMWHs are typically
rins (LMWHs). These agents are enoxaparin, easier (once per day), compared to 2 or more daily
(Lovenox), dalteparin (Fragmin), tinzaparin (Innohep), injections of unfractioned heparin.132 The anticoagu-
and other drugs identified by the “-parin” suffix. lant effects of LMWHs are also more predictable, and
25Ciccone(p)-25 1/30/07 2:53 PM Page 351
these agents tend to normalize clotting with less risk Clotting factor
Clotting factor
of adverse effects such as hemorrhage and death.142 (incomplete)
The more predictable response to LMWHs also
decreases or eliminates the need for repeated labora-
tory monitoring of partial thromboplastin time, inter-
national normalized ratio (INR), or other indicators of
clotting time.98,103
Vitamin K Vitamin K-
The use of traditional (unfractionated) heparin epoxide
has therefore been replaced by LMWHs to a large
extent.18,100 LMWHs are clearly safer and more con- Vitamin K-
venient to their unfractionated counterparts, and these epoxide reductase
drugs have become the primary method of treating
acute venous thrombosis.47,100 LMWHs are now used
routinely to prevent or treat deep vein thrombosis
(DVT) following various types of surgery or medical
conditions (ischemic stroke, cancer).70,127 It has also Oral Anticoagulants
been suggested that LMWHs will produce optimal (warfarin)
effects if they are administered for more than a few
days, and some patients who are at high risk for throm- FIGURE 25–2 ▼ Role of vitamin K in the synthesis of vitamin K–
bosis may receive LMWHs via subcutaneous injection dependent clotting factors (II, VII, IX, and X). Vitamin K catalyzes the
reaction necessary for completion of clotting factor synthesis, but it is
for several weeks or months.80 Future research will oxidized in the process to vitamin K epoxide. Regeneration of vitamin
help determine the best way to use LMWHs to pre- K occurs via vitamin K epoxide reductase. Oral anticoagulants such
vent or treat venous thrombosis in specific clinical sit- as warfarin (Coumadin) block the regeneration of the vitamin K, thus
uations. halting the further synthesis of the vitamin K–dependent factors.
anticoagulants that inhibit thrombin activity, fonda- body.101,119 Development of type II HIT is therefore
parinux inhibits clotting factor Xa (see Fig. 25–1). an emergency situation typically resolved by discon-
Moreover, preliminary studies suggest that fonda- tinuing heparin and substituting an alternative type of
parinux may be more effective in preventing DVT anticoagulant (e.g., lepirudin).101
than heparin (including LMWHs).5,70 In addition, Finally, oral anticoagulants may produce some
fondaparinux may be safer because it does not appear gastrointestinal distress (nausea, stomach cramps, diar-
to cause heparin-induced thrombocytopenia.76 Hence, rhea); these side effects are more common with
fondaparinux will probably continue to gain accept- dicumarol than with the other oral anticoagulants.
ance as a primary way to prevent DVT in many clini-
cal situations.
Finally, ximelagatran is new drug that is current-
Antithrombotic Drugs
ly being developed to prevent or treat DVT.109 Xime- Whereas anticoagulants affect the synthesis and func-
lagatran directly inhibits thrombin, but has the tion of clotting factors, antithrombotics primarily
advantage of oral administration. If approved, this inhibit the function of platelets.117,152 In the blood
drug could offer a convenient alternative to other oral stream, platelets respond to vascular injury by chang-
coagulants such as warfarin in the long-term manage- ing their shape and adhering to one another (aggrega-
ment of DVT and pulmonary embolism (PE).2,5 tion) at the site of clot formation. Platelets may
Future research should determine the optimal use of sometimes aggregate inappropriately, however, thus
this agent—either alone or in combination with exist- forming a thrombus and occluding certain blood ves-
ing anticoagulants. sels. In particular, arterial thrombi are often formed by
abnormal platelet aggregation, especially in arteries
with atherosclerotic plaques that rupture suddenly and
Adverse Effects of Anticoagulant Drugs
initiate platelet clotting at the site of the rupture.97
Predictably, hemorrhage is the primary and most seri- Hence, antithrombotic drugs are primarily used to
ous problem with drugs used to decrease blood clot- prevent the formation of arterial clots, such as those
ting.58,75,90 Increased bleeding may occur with heparin, that cause coronary artery occlusion or cerebral
warfarin, and other anticoagulants; this bleeding may infarction.
be quite severe in some patients. Any unusual bleed-
ing, such as blood in the urine or stools, unexplained
nosebleeds, or an unusually heavy menstrual flow, may
Aspirin
indicate a problem. Also, back pain or joint pain may Aspirin suppresses platelet aggregation by inhibiting
be an indication of abdominal or intrajoint hemor- the synthesis of prostaglandins and thromboxanes.94,151
rhage, respectively. To prevent excessive bleeding, lab- As discussed in Chapter 15, aspirin exerts virtually all
oratory tests that measure hemostasis are sometimes of its effects by inhibiting the cyclooxygenase enzyme
used to monitor patients taking anticoagulants. Tests that initiates the synthesis of lipidlike hormones known
such as partial thromboplastin time and prothrombin as prostaglandins and thromboxanes. Certain prosta-
time can indicate the effectiveness of drugs that alter glandins and thromboxanes, especially thromboxane
blood coagulation, and adjustments in drug dosage are A2, have a potent ability to induce platelet aggregation.
based on whether coagulation time falls within an By inhibiting the synthesis of these proaggregation
acceptable range.47,75 substances, aspirin prevents platelet-induced thrombus
Heparin may also produce a decrease in platelets formation.
(thrombocytopenia) in some patients.13,84 This condi- Although the exact dose may vary in specific
tion, known commonly as heparin-induced thrombo- clinical situations, patients typically experience a
cytopenia (HIT), is less common with LMWHs versus meaningful antithrombotic effect at very low aspirin
unfractionated heparin, but HIT can occur with any doses. For example, many antithrombotic regimens
type of heparin treatment.101,145 suggest a daily dosage between 75 and 325 mg/d.81,123
Heparin-induced thrombocytopenia (HIT) can Considering that an adult aspirin tablet typically con-
likewise be asymptomatic and resolve spontaneously tains 325 mg of drug, these antithrombotic dosages
(type I HIT), or it can be severe (type II HIT). Type represent taking the equivalent of one tablet or
II HIT is mediated by an immune reaction, which can less each day. A pediatric (baby) aspirin tablet typical-
lead to serious complications including increased ly contains 160 mg of drug, and many patients achieve
thrombosis in vascular tissues throughout the adequate antithrombotic effects with one baby aspirin
25Ciccone(p)-25 1/30/07 2:53 PM Page 353
tablet each day. Antithrombotic effects can be ity and mortality associated with these types of infarc-
achieved at these remarkably low doses because tion. Nonetheless, the long-term effects of aspirin on
aspirin inhibits platelet function irreversibly.94 That is, other organs such as the liver, kidneys, and gastroin-
when aspirin reaches a given platelet, that platelet testinal tract must be considered. In addition, the
is inhibited for the remainder of its lifespan (about 7–8 therapeutic effects of low-dose aspirin therapy vary
days). substantially from person to person, and some people
Because of its antithrombotic effects, aspirin has may appear resistant to aspirin’s antithrombotic
received a great deal of attention regarding its use in effects.48,138 Although the reasons are not clear, the
treating and preventing myocardial infarction. During antithrombotic effects of low-dose aspirin therapy
the acute phase of an infarction, aspirin is critical in may also differ between men and women—men expe-
helping to limit the progression of platelet-induced rience greater protection against heart attack and
occlusion, thereby reducing the extent of damage to women experience greater protection against ischemic
the myocardium.55 Following the acute phase, aspirin stroke.17 Hence, continued analysis of this topic prom-
is often administered for prolonged periods to main- ises to be an exciting and productive area of pharma-
tain coronary artery patency and prevent reinfarc- cologic research.
tion.65,94 Also, low doses of aspirin may decrease the Finally, aspirin has also been used to prevent
incidence of an initial infarction in susceptible indi- thrombus formation in peripheral veins (deep vein
viduals—that is, people who have not yet sustained an thrombosis [DVT]), and aspirin is sometimes used as
infarction but have one or more risk factors for coro- an adjunct or alternative to anticoagulants (heparin,
nary artery disease.94 warfarin) that are routinely used to treat DVTs.8 As-
These rather remarkable findings have prompted pirin can likewise be administered to prevent throm-
a great deal of debate about the chronic use of aspirin boembolism following surgical procedures such as
and possible side effects such as increased hemor- coronary artery bypass, arterial grafts, endarterecto-
rhage. In particular, the incidence of intracranial hem- my, and valve replacement.45,78 By preventing platelet-
orrhage (hemorrhagic stroke) may be increased when induced thrombogenesis, aspirin helps maintain
aspirin is administered to decrease thrombosis.62 patency and prevent reocclusion of vessels following
Nonetheless, aspirin is considered standard therapy these procedures.
during the acute phase of myocardial infarction, and
prolonged use of aspirin is one of the primary phar-
Other Antithrombotic Drugs
macologic methods used to prevent reinfarction.
Although increasing the risk of hemorrhagic Although aspirin remains the primary antithrombotic
stroke, aspirin may help prevent the type of stroke agent, this drug is a relatively weak inhibitor of platelet
caused by cerebral ischemia and infarction.3,59,107 The activity.48 As indicated, aspirin may also increase the
rationale is that aspirin will prevent infarction in cere- risk of intracranial hemorrhage, and may be poorly
bral vessels in the same manner that it prevents coro- tolerated in some patients due to gastric irritation, an
nary infarction in heart attacks. Clearly, the use of allergic response, and so forth.48,123 Efforts have there-
aspirin must be limited to the types of stroke that fore been made to develop stronger and safer anti-
result from insufficient blood flow, as opposed to platelet drugs.
hemorrhagic stroke. In particular, aspirin seems espe- One antiplatelet strategy that has shown consider-
cially helpful in reducing the risk of ischemic stroke able promise is the use of drugs that inhibit the ability
in people with atrial fibrillation.3,107 Even so, the anti- of fibrinogen and other chemical mediators to activate
thrombotic benefits of aspirin in some cerebral vessels platelets.63,40 These drugs are known as glycoprotein
must be weighed against the possible side effects such (GP) IIb-IIIa inhibitors because they block (antago-
as increased bleeding in other vessels. Long-term nize) the GP receptor on the platelet membrane that is
aspirin therapy is probably beneficial to a certain per- stimulated by fibrinogen and other chemical media-
centage of stroke patients, but should be used selec- tors.7,35 Fibrinogen is unable to bind to the platelet,
tively.59,107 thereby decreasing platelet activation and reducing
Consequently, the role of chronic aspirin admin- platelet-induced clotting.64 Agents that are currently
istration in helping to prevent myocardial and cerebral available include abciximab (ReoPro), eptifibatide
infarction remains an area of intense investigation. (Integrilin), and tirofiban (Aggrastat) (see Table
There seems to be little doubt that aspirin can be a 25–1).21 GP IIb-IIIa inhibitors are the post powerful
very cost-effective method for decreasing the morbid- inhibitors of platelet activity,129 and these drugs are
25Ciccone(p)-25 1/30/07 2:53 PM Page 354
used primarily during balloon angioplasty and other venting reinfarction after a heart attack, especially in
percutaneous coronary interventions that help reestab- patients who are not able to tolerate aspirin or other
lish coronary artery blood flow.23,35 Administering antithrombotic drugs.
these drugs intravenously during such procedures can
help maintain coronary flow and decrease mortality, Adverse Effects of Antithrombotic Drugs
especially in people at high risk for reinfarction.7,22 GP
The primary concern with aspirin and other anti-
IIb-IIIa inhibitors, however, are not typically adminis-
thrombotic drugs is an increased risk of bleeding.
tered orally for the long-term prevention of myocar-
Patients taking these agents should be especially alert
dial infarction and similar thrombotic events.123
for any unexplained or heavy bleeding or any other
Another antiplatelet strategy involves drugs that
symptoms that might indicate hemorrhage (sudden
inhibit the adenosine diphosphate (ADP) receptor on
increases in joint or back pain, severe headaches, and
the platelet membrane.63,104 ADP is another compound
so forth). Aspirin can likewise cause gastric irritation,
that increases platelet activity, and platelet-induced
and high doses of aspirin may be toxic to the liver and
clotting is reduced by drugs that inhibit the receptor
kidneys (see Chapter 15). However, the likelihood of
for this compound.93,104 Such drugs include clopido-
severe gastric disturbances and liver or renal toxicity is
grel (Plavix) and ticlopidine (Ticlid); these drugs are
relatively low at the doses needed to create an anti-
used primarily to prevent myocardial infarction and
thrombotic effect. Other potential side effects of non-
ischemic stroke (see Table 25–1). They produce mod-
aspirin antithrombotics include hypotension for the
erate inhibition of platelet activity, making them some-
GP IIb-IIIa inhibitors (abciximab, eptifibatide), gas-
what more effective than aspirin but not as strong as
trointestinal distress for clopidogrel and dipyridamole,
the GP IIb-IIIa inhibitors.129 Likewise, these ADP
blood dyscrasias (neutropenia, agranulocytosis, throm-
receptor inhibitors seem to be well-tolerated, and they
bocytopenia) for ticlopidine, and formation of kidney
therefore provide an option for decreasing platelet-
stones for sulfinpyrazone.
induced clotting in patients who cannot tolerate other
antiplatelet drugs such as aspirin.48 ADP inhibitors
such as clopidogrel (Plavix) can also be added to low-
Thrombolytic Drugs
dose aspirin therapy in cases where aspirin alone does Thrombolytics facilitate the breakdown and dissolu-
not provide adequate antithrombotic effects.31,93,124 tion of clots that have already formed. These drugs
Dipyridamole (Persantine, other names) has been work by converting plasminogen (profibrinolysin) to
used alone or in combination with aspirin to decrease plasmin (fibrinolysin).34 As shown in Figure 25–1, plas-
platelet-induced clotting. This drug may affect platelet min is the active form of an endogenous enzyme that
function by impairing adenosine metabolism and/or breaks down fibrin clots. Thrombolytic drugs activate
by increasing the concentration of cyclic adenosine this enzyme by various mechanisms and can be used to
monophosphate within the platelet.1 The exact mech- dissolve clots that have already formed, thus reopening
anism of dipyridamole, however, is poorly understood. occluded blood vessels.
Although it is not used as commonly as other anti- Thrombolytic drugs are extremely valuable in
platelet drugs, dipyridamole has shown benefits in pre- treating acute myocardial infarction.14,102 When ad-
venting ischemic stroke and myocardial infarction.85,87 ministered at infarction onset, these drugs can rees-
It has also been suggested that dipyridamole can be tablish blood flow through occluded coronary vessels,
combined with aspirin to provide greater benefits often preventing or reversing myocardial damage,
compared to using either drug alone.85 Hence, dipyri- which decreases the morbidity and mortality normally
damole is a potential alternative or adjunct to other associated with a heart attack.39 These drugs can help
antiplatelet agents (aspirin, ADP receptor inhibitors) reopen occluded coronary vessels when administered
in treating arterial thrombosis. within 12 hours after symptom onset.102 Thrombolyt-
Finally, sulfinpyrazone (Anturane) is usually ad- ics seem to produce the best results, however, when
ministered to treat gouty arthritis, but has also shown they are administered soon after the symptom onset.
some antithrombotic properties because of an ability Administration within 1 hour after symptom onset, for
to decrease platelet function. Sulfinpyrazone decreas- example, can result in a 50 percent reduction in mor-
es platelet aggregation by inhibiting prostaglandin tality in patients with acute myocardial infarction.105
synthesis in a manner similar to aspirin. Sulfinpyra- Consequently, thrombolytic agents are adminis-
zone can be used as an alternative to aspirin in pre- tered whenever possible during the first few hours after
25Ciccone(p)-25 1/30/07 2:53 PM Page 355
an acute myocardial infarction. It was originally is especially helpful during severe, limb-threatening
believed that these drugs had to be administered occlusion, or when surgical removal of the thrombus is
directly into the coronary arteries to reopen occluded not possible.68,113
coronary vessels.6 However, it is now realized that To minimize the risk of side effects, thrombolyt-
these drugs will produce beneficial effects when inject- ic drugs can be administered directly to the site of the
ed intravenously into the systemic circulation; that is, clot through an intravascular catheter.68,112 Throm-
the drug can be injected into any accessible vein and bolytics may also play a role in treating acute, massive
eventually reach the coronary clot through the general pulmonary embolism (PE).60,82 Use of these drugs in
circulation.137 The intravenous route is a much more PE is typically reserved for life-threatening situations,
practical method of administration because it is easier, especially when the PE is so severe that function of the
faster, and safer than the intracoronary route. right ventricle is compromised.82 Bypass grafts and
Thrombolytic drugs offer an attractive method of shunts that have become occluded because of clot for-
preventing—or even reversing—myocardial damage mation may also be cleaned out with thrombotic drug
during acute myocardial infarction. Intracranial hem- use.21
orrhage and other bleeding problems are the primary The most common thrombolytic agents are listed
drawbacks to thrombolytic treatment because these below. Although these drugs differ chemically, they all
drugs can also stimulate clot breakdown in other ves- ultimately activate fibrinolysis in some way. There has
sels, including the cerebral vasculature.16,116 Throm- likewise been considerable debate about which agent
bolytics are therefore contraindicated in certain provides optimal long-term benefits following myo-
situations, including in patients with a history of hem- cardial infarction. With regard to myocardial infarc-
orrhagic stroke, intracranial neoplasm, active internal tion, these agents are fairly similar in terms of efficacy
bleeding, possible aortic dissection, and several other and safety profile.116 Selecting a specific agent seems
factors representing the increased risk of hemor- less important than simply making sure that the agent
rhage.102,137 Also, thrombolytic therapy may not be is used in a timely fashion; that is, the time elapsed
curative, and reocclusion occurs in certain patients. before beginning treatment is probably more impor-
Thrombolytic agents may also be used to treat tant than the actual type of thrombolytic agent admin-
specific cases of ischemic stroke.4,74 It was originally istered to treat myocardial infarction.137 Some of the
thought that these drugs should not be used to treat newer agents, however, can be administered by rapid
ischemic stroke because of the risk of intracranial hem- (bolus) infusion, and may therefore help decrease the
orrhage.111 It appears, however, that thrombolytic time between when a patient arrives at the hospital and
treatment can be used carefully in selected patients to when meaningful amounts of the drug are able to
dissolve clots within cerebral vessels and allow reper- reach the clot.14,50 The relative benefits and unique
fusion of the brain, thus limiting the amount of dam- aspects of each agent are presented here.
age from the infarction.146 The window of opportunity
for administration, however, is smaller when treating
Streptokinase and Urokinase
ischemic stroke compared to myocardial infarction,
and thrombolytic agents must typically be adminis- Streptokinase and urokinase both bring about the
tered within 3 hours after cerebral infarction.4 Also, activation of plasmin. Streptokinase indirectly acti-
certain thrombolytics, such as recombinant tissue plas- vates plasmin (fibrinolysin) by binding to the precur-
minogen activator (see below), may be better than sor molecule plasminogen (profibrinolysin) and
other thrombolytics when treating ischemic stroke.4,146 facilitating activation by endogenous mechanisms.
Nonetheless, thrombolytic treatment is regarded as an Urokinase directly converts plasminogen to plasmin
important option for patients who are experiencing an by enzymatically cleaving a peptide bond within the
ischemic stroke, and who have minimal risk factors for plasminogen molecule. Both agents have been used
intracranial or systemic hemorrhage. successfully to resolve acute clot formation in coronary
Finally, thrombolytic drugs are gaining accept- arteries and peripheral vessels. Streptokinase, however,
ance in treating other types of arterial and venous tends to be the most commonly used type of throm-
occlusion. For example, thrombolytic therapy can help bolytic because it is relatively inexpensive and because
dissolve clots in peripheral arteries (femoral, popliteal, the incidence of intracranial hemorrhage may be
and so forth)56; these drugs can help resolve thrombus somewhat lower with streptokinase than with other
formation in the large veins (DVT).68 This treatment thrombolytics.116
25Ciccone(p)-25 1/30/07 2:53 PM Page 356
relatively straightforward, obtaining sufficient amounts days following birth, newborns lack the intestinal bac-
of the missing factor is a very costly procedure. At teria necessary to help synthesize vitamin K. Vitamin K
present, the primary source of clotting factors VIII and is administered to facilitate clotting factor synthesis
IX is human blood extract. Obtaining an adequate sup- until the newborn is able to produce sufficient endoge-
ply can cost more than $30,000 per patient per year. nous vitamin K. Finally, vitamin K can be administered
A more serious problem is the potential for clot- to accelerate clotting factor production when clotting
ting factor extract to contain viruses such as hepatitis time is excessively long (e.g., INR between 4.5 and
B, or HIV, which causes AIDS. The lack of proper 10.0).69,148 Specifically, patients with delayed blood
blood screening has resulted in tragic consequences; clotting due to excess warfarin levels can be adminis-
for example, clotting factors extracted from patients tered vitamin K either orally or by parenteral routes to
infected with HIV have served as a vehicle for viral help reestablish normal clotting time.69
transmission to patients with hemophilia. More strin-
gent screening procedures and other techniques such
as heat treatment of clotting factor extracts have Antifibrinolytics
decreased the risk of transmission, but patients with The excessive bleeding that sometimes occurs follow-
hemophilia receiving exogenous factors remain at risk ing surgery, trauma, or advanced cancer may be caused
for viral infection. New methods of drug production, by an overactive fibrinolytic system—that is, hyperfibri-
such as genetic engineering and recombinant DNA nolysis.27,115,130 Hyperfibrinolysis results in excessive
techniques, are currently being used to manufacture clot destruction and ineffective hemostasis. Likewise,
specific clotting factors such as factor VIII.21 It is patients with hemophilia who undergo surgery, includ-
hoped that these techniques will provide a safer, ing dental procedures (tooth extractions, restorations,
cheaper source of missing clotting factors for patients etc.), will benefit if clot breakdown is inhibited because
with hemophilia. hemorrhage and the need for additional clotting fac-
tors are reduced. Antifibrinolytic agents such as
Deficiencies of Vitamin K– aminocaproic acid (Amicar) and tranexamic acid (Cyk-
Dependent Clotting Factors lokapron) are often used in these situations.27,106,130,115
These drugs appear to inhibit activation of plasmino-
As indicated earlier in this chapter, the liver needs ade- gen (profibrinolysin) to plasmin (fibrinolysin). Plasmin
quate amounts of vitamin K to synthesize clotting fac- is the enzyme responsible for breaking down fibrin
tors II, VII, IX, and X. As shown in Figure 25–2, clots (see Fig. 25–1). Antifibrinolytics prevent the acti-
vitamin K catalyzes the final steps in the synthesis of vation of this enzyme, thus preserving clot formation.
these factors. Normally, vitamin K is supplied through Aminocaproic acid and tranexamic acid are ad-
the diet or synthesized by intestinal bacteria and sub- ministered either orally or intravenously for the acute
sequently absorbed from the gastrointestinal tract into treatment of hyperfibrinolysis or to prevent clot break-
the body. However, any defect in vitamin K ingestion, down in patients with hemophilia who are undergoing
synthesis, or absorption may result in vitamin K defi- surgery. Some adverse effects such as nausea, diarrhea,
ciency. Insufficient vitamin K in the body results in an dizziness, and headache may occur when these drugs
inadequate hepatic synthesis of the clotting factors are administered, but these problems are relatively
listed previously, thus resulting in poor hemostasis and minor and usually disappear when the drug is discon-
excessive bleeding. tinued.
Deficiencies in vitamin K and the related synthe-
sis of the vitamin K–dependent clotting factors are
treated by administering exogenous vitamin K.20 Agents Used to
Various commercial forms of this vitamin are available
for oral or parenteral (intramuscular or subcutaneous)
Treat Hyperlipidemia
administration. Specifically, individuals with a poor Hyperlipidemia, an abnormally high concentration of
diet, intestinal disease, or impaired intestinal absorp- lipids in the bloodstream, is one of the primary causes
tion may require vitamin K to maintain proper hemo- of cardiovascular disease in industrialized nations.
stasis. This condition typically causes deposition of fatty
Vitamin K is routinely administered to newborn plaquelike lesions on the walls of large and medium-
infants to prevent hemorrhage.10,121 For the first 5 to 8 sized arteries (atherosclerosis), which can lead to throm-
25Ciccone(p)-25 1/30/07 2:53 PM Page 358
bosis and infarction. Hence, elevated plasma lipids are tion, especially in liver cells. Decreased hepatic choles-
related to some of the events discussed previously in terol biosynthesis also causes more surface receptors
this chapter because atherosclerosis can precipitate for LDL cholesterol to be synthesized; this increase in
increased clotting and thromboembolic disease. surface receptors triggers an increase in the breakdown
Hyperlipidemia is often caused by poor diet and of LDL cholesterol and a decrease in the synthesis of
lifestyle, as well as by several genetic conditions that VLDL, which serves as a precursor for LDL synthe-
cause disorders in lipid metabolism.83,89 It is not possi- sis.57 HMG-CoA reductase inhibitors can also decrease
ble to review the endogenous control of lipid metabo- triglyceride levels,57 and produce a modest increase in
lism or the various pathologic processes involved in HDL levels.89 However, the exact reasons for the ben-
hyperlipidemia here—these topics are addressed in eficial effects on triglycerides and HDL levels are not
other sources.89,139 It should be realized, however, that entirely clear.
lipids such as cholesterol are transported in the blood- The HMG-CoA reductase inhibitors therefore
stream as part of a lipid-protein complex known as a improve several aspects of the plasma lipid profile.
lipoprotein. Certain lipoproteins are considered benefi- These agents may produce several favorable effects
cial because they may decrease the formation of ather- that are independent of their ability to affect plasma
osclerotic plaques by removing cholesterol from the lipid levels.9,96 It appears that certain by-products of
arterial wall. These beneficial complexes are known as cholesterol metabolism act directly or influence the
high-density lipoproteins (HDLs) because of the rela- production of other chemical signals that adversely
tively large amount of protein in the complex. Other affect cellular function in various tissues.9 Increased
lipoproteins are considered harmful because they production of these by-products could therefore influ-
transport and deposit cholesterol on the arterial wall. ence a variety of pathological conditions. By control-
These atherogenic lipoproteins include intermediate- ling the production of these by-products, statins may
density lipoproteins (IDLs), low-density lipoproteins produce a wide range of beneficial effects in addition
(LDLs), and very-low-density lipoproteins (VLDLs). to their ability to improve plasma lipids.
Pharmacologic and nonpharmacologic strategies to Statins, for example, might produce direct bene-
reduce hyperlipidemia typically focus on reducing ficial effects on the vascular endothelium by increasing
these atherogenic lipoproteins and increasing the ben- the production and vasodilating effects of nitric oxide,
eficial HDLs. and they may help stabilize atherosclerotic plaques on
Drugs that can be used to treat hyperlipidemia are the arterial wall.37,51,150 These drugs may likewise have
summarized in Table 25–2 and are discussed briefly anti-inflammatory and antioxidant effects that con-
below. These agents are typically used when plasma tribute to their ability to improve the vascular wall’s
lipid levels are unsuccessfully controlled by nonphar- function.37,96 Statins may even have anticancer effects,
macologic methods such as low-fat diets, weight reduc- and investigators continue to explore their potential in
tion, regular exercise, and smoking cessation.41,136,143 preventing and treating certain malignancies.40,54
However, these drugs can be used in conjunction with Statins therefore seem to exert several complex effects,
nonpharmacologic methods, and optimal results are and their ability to reduce the risk of cardiovas-
often realized through a combination of drug therapy cular disease is probably the result of a combination of
and various dietary and lifestyle modifications.136 their favorable effects on plasma lipids combined with
their ability to improve the function of the vascular
HMG-CoA Reductase endothelium.
Statins are helpful in decreasing morbidity and
Inhibitors (Statins) mortality in people with high cholesterol, as well as
This category includes atorvastatin (Lipitor), fluvas- individuals who have normal cholesterol but other risk
tatin (Lescol), lovastatin (Mevacor), pravastatin (Prava- factors for cardiovascular disease.66 It is estimated that
chol), and simvastatin (Zocor) (Table 25–2). These these drugs decrease the risk of a major cardiac event
drugs, known commonly as statins, are characterized by approximately 30 to 35 percent, although the ben-
by their ability to inhibit an enzyme known as 3- efits depend on the extent that cholesterol is reduced
hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) and the influence of other risk factors.91,95,126 None-
reductase.96 This enzyme catalyzes one of the early theless, statins are now regarded as a mainstay in treat-
steps of cholesterol synthesis, and drugs that inhibit ing cardiovascular disease, and efforts are underway to
HMG-CoA reductase decrease cholesterol produc- expand the use of these medications and to explore the
25Ciccone(p)-25 1/30/07 2:53 PM Page 359
Cholestyramine Questran 4 g 2–6 times each day before meals Decreases total cholesterol and
and at bedtime LDL-C
Clofibrate Abitrate, Atromid-S 1.5–2.0 g each day in 2–4 divided Lowers triglycerides and VLDL-C;
doses may also increase HDL-C levels
Niacin Niaspan, others 1–2 g 3 times each day Lowers total cholesterol, triglyc-
erides, LDL-C, and VLDL-C;
increases HDL-C
optimal use of these drugs with other pharmacologic marily decrease triglyceride levels, and are therefore
and nonpharmacologic interventions in cardiovascular most helpful in hyperlipidemias that are characterized
disease.66,91 by increased triglycerides.49,147 Fibrates also produce
beneficial increases in HDL production, and can help
lower LDL levels.42,147 Fibrates are therefore helpful
in treating a combination of lipid abnormalities (i.e.,
Fibric Acids mixed hyperlipidemias) that include increased triglyc-
Fibric acids or “fibrates” include clofibrate (Abitrate, erides and LDL levels along with low HDL lev-
Atromid) and gemfibrozil (Lopid). These drugs pri- els.43,49,52
25Ciccone(p)-25 1/30/07 2:53 PM Page 360
The exact mechanism of these drugs is unclear, Finally, ezetimibe (Zetia) is a relatively new agent
but they probably work by binding to a specific that inhibits cholesterol absorption from the gastroin-
nuclear receptor known as the peroxisome proliferator testinal (GI) tract.33,110 This action produces many
activated receptor.52,141 This receptor, found primarily beneficial effects including reduced LDL and triglyc-
in the liver and adipose tissues, affects the transcrip- eride levels, and increased HDL levels.12 Ezetimibe
tion of genes that affect lipid metabolism.89 Fibrates seems especially useful in complimenting the effects
activate this receptor, thereby mediating several of the statin drugs, and it can be combined safely
changes at the nuclear level that ultimately cause a with a statin to produce optimal benefits in many
decrease in triglycerides and other beneficial changes patients.114,131 Additional drugs limiting cholesterol
in plasma lipid metabolism.30,52 In a manner similar to absorption may ultimately be developed as part of the
the statins, fibrates may also exert anti-inflammatory, treatment against hyperlipidemia.
antioxidant, and other beneficial effects in addition to
their positive effects on plasma lipids.42,49 Adverse Effects of
Although it is not exactly clear how much these
agents can reduce the risk of a major cardiac event
Antihyperlipidemia Agents
(e.g., infarction, stroke), these drugs will probably Most of the drugs used to treat hyperlipidemia are
remain the first choice for people with certain hyper- well tolerated. Some gastrointestinal distress (nausea,
lipidemias (e.g., increased triglycerides). These drugs diarrhea) is common with most of the drugs, but these
are likewise advocated for mixed hyperlipidemias that problems are usually minor and do not require the dis-
are common in metabolic disorders such as type 2 dia- continuation of drug therapy.
betes mellitus (see Chapter 32).32,141 Certain fibrates Other bothersome side effects are related to spe-
can be used with other drugs, such as statins, to pro- cific agents. Niacin, for instance, is often associated
vide more comprehensive pharmacologic control of with cutaneous vasodilation and a sensation of warmth
certain lipid disorders.30,147 when doses are administered, but administering an
extended-release form of this drug can reduce these
sensations.71,99 Some fairly serious problems, includ-
Other Lipid-Lowering Agents ing liver dysfunction, gallstones, and pancreatitis, can
Several other agents have beneficial effects on plasma occur with many antihyperlipidemia drugs, but the
lipid profiles occurring through various cellular mech- incidence of these side effects is rare. Cardiovascular
anisms.89 Cholestyramine (Questran), for example, problems such as arrhythmias, blood dyscrasias, and
attaches to bile acids within the gastrointestinal lumen angioneurotic syndrome may also occur with fibric
and increases the fecal excretion of these acids. This acids.
action leads to decreased plasma cholesterol concen- Neuromuscular problems have been noted with
trations because cholesterol breakdown is accelerated certain agents. In particular, myopathy (muscular pain,
to replace the bile acids that are lost in the feces. inflammation, weakness) is a rare, but potentially seri-
Niacin (nicotinic acid, vitamin B3, Niaspan, other ous side effect of statin drugs. The reasons for these
names) has received considerable attention as a “broad effects are unclear, but statin-induced myopathy is
spectrum” antilipidemic because this drug produces associated with several risk factors such as high statin
beneficial effects on virtually all aspects of the lipid doses, advanced age, multiple diseases, frail stature,
profile.28,99 That is, high doses of niacin (several grams and immunosuppressant drugs.125,144 Combining a
each day) help decrease LDL and triglyceride levels statin with certain fibric acids (gemfibrozil) may also
while raising HDL levels.71,99 This drug apparently increase the risk of myopathy. Although statin-induced
binds to a specific nicotinic acid receptor in fat cells myopathy is usually reversible, this syndrome should
and initiates a number of metabolic effects, which be recognized early before it can progress to more
leads to decreased lipid synthesis and increased lipoly- severe forms of muscle disease and muscle damage
sis.29 Likewise, niacin may be used in combination (rhabdomyolysis).11,77 Treatment typically consists of
with statins to produce optimal benefits in certain discontinuing the statin, and allowing an adequate
patients without increasing the risk of stain-induced period of rest and recovery—4 to 6 weeks in most
myopathy (see next section, “Adverse Effects of Anti- cases. Preliminary studies suggest that statins may also
hyperlipidemia Agents”).71 Hence, niacin continues to affect nervous tissue, and that sensory and motor neu-
gain acceptance as an important drug in treating hy- ropathies may occur in certain patients.11 Future stud-
perlipidemia. ies are needed to clarify the effects of these drugs on
25Ciccone(p)-25 1/30/07 2:53 PM Page 361
CA S E ST U DY
Clotting Disorders To prevent further thromboembolism, streptokinase infu-
sion was followed by heparin. A low-molecular weight
Brief History. C.W. is an obese, 47-year-old woman heparin (enoxaparin [Lovenox], 1.5 mg/kg body weight) was
who sustained a compression fracture of the L-1 and L-2 ver- administered subcutaneously once each day. Clotting time
tebrae during a fall from a second-story window. (There was was monitored by periodic blood tests during the heparin
some suggestion that she may have been pushed during an treatment. After 7 days of heparin therapy, C.W. was switched
argument with her husband, but the details remain unclear.) to warfarin. Warfarin (Coumadin) was administered orally, and
She was admitted to the hospital, where her medical condition the dosage was adjusted until she was receiving 5 mg/d. Oral
was stabilized, and surgical procedures were performed to warfarin was continued throughout the remainder of the
treat her vertebral fracture. Her injuries ultimately resulted in a patient’s hospital stay, as well as after discharge.
partial transection of the spinal cord, with diminished motor Impact on Rehabilitation. The drugs used to resolve
and sensory function in both lower extremities. She began an the thromboembolic episode greatly facilitated the patient’s
extensive rehabilitation program, including physical therapy recovery. The use of a thrombolytic agent (streptokinase)
and occupational therapy. She was progressing well when she enabled the patient to resume her normal course of rehabili-
developed shortness of breath and an acute pain in her right tation within 2 days of the pulmonary embolism. Thus, the use
thorax. A diagnosis of massive pulmonary embolism was made. of these drugs directly facilitated physical therapy and occu-
Evidently she had developed deep vein thrombosis in both pational therapy by allowing the patient to resume therapy
lower extremities, and a large embolism from the venous clots much sooner than if the embolism had been treated more
had lodged in her lungs, producing a pulmonary infarction. conservatively (i.e., rest and anticoagulants) or more radically
Drug Treatment. Because of the extensive nature of (i.e., surgery). Because the patient remained on anticoagulant
the pulmonary infarction, a thrombolytic agent was used to drugs for an extended period of time, the therapists dealing
attempt to resolve the clot. An initial dosage of 250,000 units with the patient routinely looked for signs of excessive bleed-
of streptokinase (Streptase) was administered intravenously ing such as skin bruising and hematuria. The patient remained
within 2 hours after the onset of symptoms. Streptokinase free from any further thromboembolic episodes, however, and
was continued via intravenous infusion at a rate of 100,000 was eventually discharged to an extended-care rehabilitation
units/hr for 24 hours after the initial dose. facility to continue her progress.
nervous tissue, and to lend more insight to the preven- vessels that have suddenly become occluded because
tion and treatment of statin-induced neuromuscular of acute thrombus formation.
toxicity. The inadequate blood clotting and excessive
bleeding that occur in patients with hemophilia are
treated by replacing the missing clotting factor. Other
SUMMARY conditions associated with inadequate coagulation
Normal hemostasis is a balance between excessive and may be treated by administering either vitamin K,
inadequate blood clotting. Overactive blood clotting is which helps improve the synthesis of certain clotting
harmful because of the tendency for thrombus forma- factors, or antifibrinolytic agents (aminocaproic acid,
tion and occlusion of arteries and veins. Vessels may tranexamic acid), which inhibit clot breakdown.
become directly blocked by the thrombus, or a portion Hyperlipidemia can lead to atherosclerosis and
of the thrombus may break off and create an embolism subsequent cardiovascular incidents such as thrombo-
that lodges elsewhere in the vascular system. The ten- sis and infarction. This condition is often treated by a
dency for excessive thrombus formation in the venous combination of drug therapy and diet and life-style
system is usually treated with anticoagulant drugs such modifications. Pharmacologic interventions are typi-
as heparin and warfarin. Platelet inhibitors such as cally targeted toward decreasing the synthesis of harm-
aspirin help prevent arterial thrombogenesis. Throm- ful (atherogenic) plasma components, including
bolytic drugs (streptokinase, t-PA) that facilitate the certain lipoproteins (IDL, LDL, VLDL) that are asso-
dissolution of harmful clots may successfully reopen ciated with atherosclerotic plaque formation.
25Ciccone(p)-25 1/30/07 2:53 PM Page 363
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characteristics of thrombolytic agents. Rev Cardiovasc in pulmonary embolism. Semin Vasc Med. 2001;1:
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SECTION
Respiratory and
Gastrointestinal
Pharmacology
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Chapter 26
Respiratory Drugs
The respiratory system is responsible for mediating respiratory tract infections. Many of these drugs are
gas exchange between the external environment and found in over-the-counter preparations. Often, sever-
the bloodstream. The upper respiratory tract conducts al different agents are combined in the same commer-
air to the lower respiratory passages and ultimately to cial preparation; for example, a decongestant, an
the lungs. It also humidifies and conditions inspired antitussive, and an expectorant may be combined and
air and serves to protect the lungs from harmful sub- identified by a specific trade name. Also, agents within
stances. In the lungs, gas exchange takes place a specific category may have properties that overlap
between the alveoli and the pulmonary circulation. into other drug categories. Certain antihistamines, for
The drugs discussed in this chapter are directed instance, may also have antitussive properties.
primarily at maintaining proper airflow through the
respiratory passages. Agents that treat specific prob-
lems in the lungs themselves are not discussed here but Antitussives
are covered in other areas of this text. For instance, Antitussive drugs are used to suppress coughing asso-
drugs used to treat infectious diseases of the lower res- ciated with the common cold and other minor throat
piratory tract and lungs are presented in Section 8 irritations. When used to treat cold and flu symptoms,
(Chapters 33 to 35). these drugs are often combined with aspirin or aceta-
The respiratory agents presented here are divided minophen, as well as with other respiratory tract
into two primary categories. The first group includes agents.93 Antitussives are usually recommended for
drugs that treat acute and relatively minor problems, short-term use in relieving symptomatic coughing.13
such as nasal congestion, coughing, and seasonal aller- Nonetheless, the extensive use of antitussives has been
gies. The second category includes drugs that treat questioned in our society. Coughing is a type of
more chronic and serious airway obstructions, such as defense mechanism that can help expel mucus and for-
bronchial asthma, chronic bronchitis, and emphysema. eign material from the upper respiratory tract.83 By
Physical therapists and occupational therapists will inhibiting this mechanism, antitussives may reduce the
frequently treat patients with both acute and chronic ability of coughing to raise secretions. Hence, antitus-
respiratory conditions. Consequently, the overview of sives may be helpful in treating an annoying dry
the drugs presented in this chapter is of interest. cough, but use of these drugs to treat an active and
productive cough may not be justified.47
There is also concern that many antitussives are
Drugs Used to Treat not really effective in treating cough. In particular,
Respiratory Tract Irritation and over-the-counter products may not contain an ade-
quate amount of the active medication, and it appears
Control Respiratory Secretions that these products may be no more effective than
The drugs presented below are used to treat sympto- placebo in treating cough.92,93 Doses that are effective
matic coughing and irritation resulting from problems in treating cough may also produce serious side
such as the common cold, seasonal allergies, and upper effects.20,83 Hence, mechanisms underlying the cough
369
26Ciccone(p)-26 1/30/07 2:53 PM Page 370
reflex continue to be studied so that safer and more agents may be taken systemically or applied locally to
effective antitiussives can be developed.26,59 the nasal mucosa via aerosol sprays. It appears that
Some of the commonly used antitussives are list- occasional use of these drugs can help the symptoms
ed in Table 26–1. As shown in the table, codeine and related to nasal congestion.35,108 These drugs, howev-
similar opiate derivatives suppress the cough reflex er, can mimic the effects of increased sympathetic
by a central inhibitory effect.21,124 Other nonopioid nervous system activity, and can cause serious cardio-
antitussives work by inhibiting the irritant effects of vascular and central nervous system (CNS) excitation.
histamine on the respiratory mucosa or by a local anes- Excessive use or abuse should therefore be avoided.
thetic action on the respiratory epithelium. The pri- The primary adverse effects associated with de-
mary adverse effect associated with most antitussives is congestants are headache, dizziness, nervousness, nau-
sedation. Dizziness and gastrointestinal upset may also sea, and cardiovascular irregularities (increased blood
occur. pressure, palpitations). As indicated, these effects be-
come more apparent at higher doses and during pro-
longed or excessive drug use.90
Decongestants
Congestion within and mucous discharge from the
upper respiratory tract are familiar symptoms of many
Antihistamines
conditions. Allergies, the common cold, and various Antihistamines are used for reasons ranging from
respiratory infections often produce a runny nose and sedation to the treatment of parkinsonism. One of
a stuffy head sensation. Decongestants used to treat the most common applications of antihistamines,
these symptoms are usually alpha-1–adrenergic ago- however, is the treatment of the respiratory allergic
nists (see Chapter 20).36 These agents bind to alpha-1 response to seasonal allergies (hay fever, and so forth)
receptors located on the blood vessels of the nasal and other allergens (hence their inclusion in this
mucosa and stimulate vasoconstriction, thus effective- chapter).44,46,64
ly drying up the mucosal vasculature and decreasing Histamine is an endogenous chemical that is
local congestion in the nasal passages.35 involved in the normal regulation of certain physio-
Alpha-1 agonists used as decongestants are listed logic functions (gastric secretion, CNS neural modu-
in Table 26–2. Depending on the preparation, these lation), as well as various hypersensitivity (allergic)
Codeine Many trade names Inhibits cough reflex by direct effect on brainstem
cough center
Dextromethorphan Many trade names Inhibits cough reflex (similar to codeine), but is
non-narcotic
*Trade names often reflect combination of the antitussive with other agents (i.e., expectorants, decongestants).
26Ciccone(p)-26 1/30/07 2:53 PM Page 371
*Trade names often reflect combination of the decongestant with other ingredients.
reactions.50,96 Histamine exerts its effects on various help control rhinitis and sinusitis (see “Treatment of
cells through four primary receptor subtypes: the H1, Bronchial Asthma”).61,130
H2, H3, and H4 receptors.97 By definition, antihista- The primary adverse effects associated with
mines are drugs that specifically block the H1 subtype antihistamines are sedation, fatigue, dizziness, blurred
of histamine receptors; that is, the effects of histamine vision, and incoordination. Gastrointestinal distress
during allergic reactions, respiratory infections, and so (nausea, vomiting) is also quite common. Certain side
forth are mediated primarily through the H1 receptor effects, however, are related directly to each drug’s
located on vascular, respiratory, and other tissues.39 ability to cross the blood-brain barrier (see Chapter 5
H2 receptors are involved primarily in the regula- for a description of the blood-brain barrier). The orig-
tion of gastric acid secretion. Drugs that selectively inal or “first-generation” antihistamines readily cross
block the H2 receptor (referred to simply as H2 antag- the blood-brain barrier and enter the brain, thus caus-
onists) may help control gastric secretion in condi- ing CNS-related side effects such as sedation and psy-
tions such as peptic ulcer; these drugs are discussed in chomotor slowing.39,110 Newer “second-generation”
Chapter 27. antihistamines, however, do not easily cross the blood-
A third receptor subtype, the H3 receptor, has brain barrier, and the risk of sedation and other CNS
been identified, and this subtype may be involved in side effects is reduced substantially.110,119 These newer
the local regulation of histamine release from CNS agents, also known as nonsedating antihistamines, in-
nerve terminals.109 Likewise, a new H4 receptor has clude cetirizine (Zyrtec), loratadine (Claritin), deslora-
been identified on blood cells or cells derived from tidine (Clarinex), and fexofenadine (Allegra) (see Table
blood cells.97 The clinical and pharmacologic signifi- 26–3). Newer antihistamines also seem to be more
cance of H3 and H4 receptors remains to be deter- selective for the H1 receptor subtype, and produce
mined.97 fewer side effects related to other histamine receptors
Antihistamines used in the symptomatic treat- and receptors for other neurotransmitters (e.g., acetyl-
ment of hay fever and similar allergies are listed in choline, serotonin, and norepinephrine).38,119
Table 26–3. By blocking the effects of histamine on the The newer drugs therefore represent a substantial
upper respiratory tissues, these drugs help decrease improvement over original antihistamines. They are
nasal congestion, mucosal irritation and discharge not, however, devoid of side effects. For example, cer-
(rhinitis, sinusitis), and conjunctivitis that are caused tain nonsedating antihistamines such as astemizole and
by inhaled allergens.96,97 Similarly, antihistamines may terfenadine may be cardiotoxic, and problems such as
decrease the coughing and sneezing associated with severe ventricular arrhythmias (torsades de pointes)
the common cold. Although these drugs do not reverse have occurred when these drugs are taken in high
bronchospasm associated with asthma, antihistamines doses or taken by individuals with preexisting cardiac
may be used as an adjunct in patients with asthma to and liver problems.70,71 These cardiac effects, however,
26Ciccone(p)-26 1/30/07 2:53 PM Page 372
person.
26Ciccone(p)-26 1/30/07 2:53 PM Page 373
do not seem to occur with other nonsedating antihist- Several expectorant agents have been used in the
amines, and drugs other than astemizole and terfena- past, but guaifenesin is the only drug currently
dine can be used in patients at risk for cardioxicity.71,127 acknowledged by the FDA to have evidence of thera-
Likewise, the nonsedating effects of the newer agents peutic effects.27,128 This drug is administered to
vary according to the drug and the patient, and efforts increase the production of respiratory secretions, thus
should be made to find the drug and dose that pro- encouraging ejection of phlegm and sputum. Exactly
duces antihistamine effects with the fewest side effects how guaifenesin exerts this effect, however, is not fully
for each patient.12,38 Nonetheless, several newer understood. Guaifenesin, which is usually adminis-
nonsedating agents are currently available, and these tered orally in some form of syrup or elixir, is often
drugs have become the agents of choice for many peo- combined with other agents in over-the-counter pre-
ple because they decrease histamine-related symptoms parations, which are known by many different trade
without producing excessive sedation and other neu- names. The primary adverse effect associated with
ropsychiatric effects. guaifenesin is gastrointestinal upset, which is exacer-
bated if excessive doses are taken or if this drug is taken
on an empty stomach.
Mucolytics and Expectorants
Mucolytic drugs attempt to decrease the viscosity of
respiratory secretions. Expectorant drugs facilitate the Drugs Used to Maintain
production and ejection of mucus. These drugs are Airway Patency in Obstructive
used to prevent the accumulation of thick, viscous Pulmonary Disease
secretions that can clog respiratory passages and lead
to pulmonary problems. Expectorants and mucolytics Airway obstruction is a major problem in respiratory
are used in acute disorders ranging from the common disorders such as bronchial asthma, chronic bronchitis,
cold to pneumonia, as well as in chronic disorders such and emphysema. The latter two disorders are usually
as emphysema and chronic bronchitis.74,85 These grouped under the heading of chronic obstructive pul-
drugs are often used in combination with other agents monary disease (COPD).55 Asthma and COPD are char-
(e.g., antitussives, decongestants, bronchodilators). acterized by bronchospasm, airway inflammation, and
Although mucolytics and expectorants are widely used, mucous plugging of the airways.55,121 One of the pri-
there is some question about whether these drugs mary goals of drug treatment is to prevent or reverse
actually produce beneficial effects in various types of the bronchial constriction and subsequent obstruction
respiratory disease.85,93 Some studies have documented of the airways in these disorders by using bronchodila-
that these drugs can improve the ability to expel mucus tors (beta-adrenergic agonists, xanthine derivatives,
and increase pulmonary function, but the extent of anticholinergics) and anti-inflammatory agents (gluco-
these benefits may vary widely according to the specif- corticoids, others). These agents are discussed in the
ic patient and type of respiratory illness.53,74 next section.
The primary mucolytic drug currently in use is
acetylcysteine (Mucomyst, Mucosil).128 This drug is Beta-Adrenergic Agonists
thought to work by splitting the disulfide bonds of res-
Rationale for Use and Mechanism of Action
piratory mucoproteins, thus forming a less viscous
secretion. There is, however, some evidence that this Respiratory smooth-muscle cells contain the beta-2
drug also has antioxidant effects, and some of acetyl- subtype of adrenergic receptors.76 (See Chapter 18 for
cysteine’s benefits may be due to its ability to decrease a discussion of adrenergic receptor classifications.)
free-radical damage in the respiratory tissues.129 Stimulation of these beta-2 receptors results in relax-
Acetylcysteine is usually administered directly to the ation of bronchiole smooth muscle. Hence, drugs that
respiratory mucosa by inhalation or intratracheal stimulate these beta-2 adrenergic receptors (i.e., beta-
instillation (through a tracheostomy). The primary adrenergic agonists) produce bronchodilation and can
adverse effects associated with this drug include nau- be used to prevent or inhibit airway obstruction in
sea, vomiting, inflammation of the oral mucosa (stom- bronchospastic diseases.22,99
atitis), and rhinorrhea. However, serious adverse Beta-adrenergic agonists are believed to induce
effects are relatively rare. smooth-muscle relaxation by the mechanism illustrat-
26Ciccone(p)-26 1/30/07 2:53 PM Page 374
beta-2 beta
respiratory smooth
receptor agonist
muscle cell
adenyl
cyclase
ATP
cyclic AMP
protein phosphorylation
bronchodilation
FIGURE 26–1 ▼ Mechanism of action of beta agonists on respiratory smooth muscle. Beta ago-
nists facilitate bronchodilation by stimulating adenyl cyclase activity, which in turn increases intracel-
lular cyclic AMP production. Cyclic AMP activates protein kinase, which appears to add an inhibitory
phosphate group to contractile proteins, thus causing muscle relaxation and bronchodilation.
ed in Figure 26–1. As shown in the figure, stimulation is less chance of side effects caused by stimulation of
of the beta-2 receptor increases activity of the adenyl other adrenergic receptors located on other tissues
cyclase enzyme. This enzyme increases the production (e.g., beta-1 receptors on the myocardium).94 When
of intracellular cyclic adenosine monophosphate administered via inhalation, however, the issue of
(cAMP). The cAMP acts as an intracellular second adrenergic receptor selectivity becomes less important
messenger, which then increases the activity of other because the drug is applied directly to the respiratory
enzymes such as protein kinase. The increased protein tissues that primarily contain the beta-2 subtype.76
kinase activity ultimately inhibits smooth-muscle con- These agents also have different durations of action;
traction, probably by adding a phosphate group to some of the newer drugs (formoterol, salmeterol) are
specific contractile proteins. considered to be long-acting beta-adrenergic ago-
nists.94,99 These long-acting agents may provide more
stable and sustained bronchodilation in conditions
Specific Agents and Method of Administration such as asthma.22,99
Beta-adrenergic agonists used to induce bronchodila- Beta-adrenergic drugs can be administered
tion are listed in Table 26–4. As shown in the table, orally, subcutaneously, or by inhalation. Inhalation of
some drugs are nonselective and stimulate alpha and these drugs is often the preferred method of adminis-
beta receptors fairly equally. Other agonists are more tration in treating respiratory disorders. Inhalation
selective and preferentially stimulate the beta-adrener- allows the drug to be delivered directly to the respira-
gic receptors. Finally, the beta-2–specific agents are tory tissues with a minimum of systemic side effects
the most selective and tend to bind preferentially to because of its absorption into the systemic circula-
beta-2 receptors. Beta-2–selective agonists offer an ad- tion.4 The onset of action is also more rapid with
vantage when administered systemically because there inhalation.
26Ciccone(p)-26 1/30/07 2:53 PM Page 375
Oral or subcutaneous administration is usually tated by using a spacer or reservoirlike attachment that
associated with more side effects. However, when ad- sequesters the drug between the MDI and the patient’s
ministered orally or subcutaneously, beta agonists may mouth.17 The patient can first dispense the drug into
reach the more distal branches of the airway to a the reservoir and then take a deep breath, thus improv-
greater extent. The bronchioles are usually constrict- ing delivery to the respiratory tissues.
ed during an asthmatic attack, and the drug may not Another method of inhaling beta agonists is
reach the distal respiratory passages when adminis- through a nebulizer.33,81 These devices mix the drug
tered by inhalation. with air to form a fine mist that is inhaled through a
Several beta agonists are available in metered- mask, thus reaching the lungs over a more prolonged
dose inhalers (MDIs) for inhalation administration. period (10 minutes). Nebulizers originally needed to
MDIs contain the drug in a small aerosol canister, and be used in the home because they were large and
a specific amount is dispensed each time the patient needed an electrical outlet. Newer devices, however,
depresses the canister.33,81 Although MDIs are conven- are portable and use batteries. It was thought that neb-
ient because of their small size and portability, there is ulizers would provide a more effective treatment than
a certain amount of coordination required on the part MDIs because the nebulizer provides a fine mist and
of the patient to ensure adequate delivery of the drug. longer time for administration, which would enable
Some patients (e.g., young children) may have trouble better delivery of the drug to the more distal bronchi-
timing the inhaled dose with a proper inspiratory oles. This fact, however, has not been proven conclu-
effort.37 In these patients, drug delivery can be facili- sively, and the therapeutic benefits from nebulizers
26Ciccone(p)-26 1/30/07 2:53 PM Page 376
O O CH3 O CH3
H
H3C C N H3C C N C N
N C N C HN C
CH CH CH
C C C C C C
O N N O N N O N N
*Dosage forms that use the inhalation route are often preferred in asthma and other obstructive pulmonary
diseases. Systemic administration by the oral route or by injection is typically reserved for acute or severe bron-
choconstrictive disease (see text for details).
systemic administration.14,125 Other possible systemic eral loss and other side effects when these drugs are
effects include retardation of growth in children, used for prolonged periods.14 Nonetheless, these drugs
cataracts, glaucoma, hyperglycemia, aggravation of are extremely effective in treating various types of
diabetes mellitus, and hypertension.69,125 Patients may bronchoconstriction, and they should be used judi-
also become resistant to anti-inflammatory effects ciously whenever possible.49,68
during repeated exposure to these drugs, especially
when they are used to treat COPD.5 Prolonged or Cromones
excessive use can have a negative feedback effect on
Rationale for Use and Mechanism of Action
the adrenal gland, resulting in loss of adrenal function
(adrenal suppression) while these drugs are being Cromones such as cromolyn sodium (Intal, Nasal-
administered.30 crom) and nedocromil sodium (Tilade) can help pre-
Fortunately, the risk of these adverse effects is vent bronchospasm in people with asthma. These
minimal when these drugs are administered by inhala- drugs are not bronchodilators and will not reverse
tion. Inhalation provides a more direct and topical bronchoconstriction during an asthmatic attack.
application of the glucocorticoid to the respiratory tis- Hence, these agents must be taken prior to the onset of
sues, with fairly limited absorption of the drug into the bronchoconstriction, and they must typically be
systemic circulation. The risk of adverse effects is also administered prophylactically to prevent asthma
minimized when the total dose of the glucocorticoid attacks that are initiated by specific, well-defined activ-
is kept below certain levels.69,113 Consequently, pro- ities (e.g., exercise, exposure to a friend’s pet, pollen).107
longed systemic drug administration should be avoid- Likewise, the regular use of these drugs several times
ed, and glucocorticoids should be administered by each day for several months may decrease airway hy-
inhalation using the lowest effective dose. It is also perresponsiveness so that the incidence of asthmatic
prudent to periodically examine patients for bone min- attacks decreases.102,113
26Ciccone(p)-26 1/30/07 2:53 PM Page 380
Cromolyn and nedocromil are believed to prevent lower dose of glucocorticoid (glucocorticoid sparing
bronchoconstriction by inhibiting the release of in- effect).52,123 Hence, the combination of a glucocorti-
flammatory mediators such as histamine and leukotri- coid and antileukotriene drug has become a popular
enes from pulmonary mast cells.56,102 Both agents can option for many patients with bronchoconstrictive
be administered by MDI; cromolyn can also be admin- disease.52
istered through a nebulizer. In addition, cromolyn is
available in a nonprescription nasal spray (Nasalcrom)
Adverse Side Effects
that can be helpful in preventing allergic rhinitis asso-
ciated with seasonal allergies such as hay fever.80 Leukotriene inhibitors are safer than other anti-
inflammatory agents such as the glucocorticoids. Some
hepatic impairment has been reported with these
Adverse Side Effects drugs, but cases of severe toxicity are relatively rare.
Some irritation of the nasal and upper respiratory pas-
sages may occur following inhalation, but these drugs
are remarkably free of serious adverse reactions.
Hence, cromolyn and nedocromil are often used pref-
Treatment of
erentially to treat mild persistent asthma, especially in Bronchial Asthma
children or in individuals who are unable to tolerate
Pathophysiology of Bronchial Asthma
the side effects of other antiasthma drugs.102,113
Asthma is a disease of the respiratory system charac-
terized by bronchial smooth-muscle spasm, airway
Leukotriene Inhibitors inflammation, and mucous plugging of the air-
ways.111,116 Patients with asthma have an exaggerated
Rationale for Use and Mechanism of Action
bronchoconstrictor response of the airways to various
Leukotrienes are inflammatory compounds that are stimuli.23,111 In some patients, the stimuli that trigger
especially important in mediating the airway inflam- an asthmatic attack are well-defined (e.g., allergens
mation that underlies bronchoconstrictive disease.3,45 like dust, pollen, chemicals, or certain drugs). Other
As indicated in Chapter 15, leukotrienes are 20-carbon factors such as exercise, cold, psychologic stress, and
fatty acids (eicosanoids) that are similar in structure viral infections may trigger an asthmatic attack in
and function to prostaglandins. Leukotrienes are actu- some individuals. In other patients, the initiating fac-
ally derived from the same precursor as prostaglandins tor may be unknown.
(arachidonic acid), but leukotrienes are synthesized by Although the exact cause of asthma remains to be
the lipoxygenase enzyme rather than by the cyclooxy- determined, the basis for the increased airway reactiv-
genase enzyme (see Chapter 15, Fig. 15–2). Recently, ity has been elucidated somewhat. Airway inflamma-
strategies have been developed to selectively decrease tion is the critical factor in initiating the exaggerated
the effects or synthesis of leukotrienes. For example, bronchial reactions associated with this disease.116,117
zileuton (Zyflo) inhibits the lipoxygenase enzyme, In asthmatic airways, there seems to be a complex
thereby reducing the production of leukotrienes.63 interaction between several different cells including
Other drugs such as montelukast (Singulair) and zafir- macrophages, neutrophils, eosinophils, platelets, and
lukast (Accolate) block the receptor for leukotrienes on the airway epithelial cells themselves.10,32 These cells
respiratory tissues.11,67 These drugs offer a fairly selec- release proinflammatory chemical mediators such as
tive method for controlling a specific aspect of inflam- prostaglandins, leukotrienes, bradykinin, histamine,
mation in bronchoconstrictive disease.42,100 and platelet activating factor.10 The chemicals irritate
Evidence also suggests that leukotriene inhibitors the respiratory epithelium and stimulate the con-
can be combined with other drugs (glucocorticoids, traction of bronchiole smooth muscle. Thus, the
beta agonists) to provide optimal management in spe- localized inflammation appears to sensitize airway
cific patients with asthma and COPD.11,60 In particu- structures to asthmatic triggers, and the bronchocon-
lar, it appears that these drugs may enhance the striction and other features of asthma seem to be
anti-inflammatory effects of glucocorticoids, and may related directly to the inflammatory response underly-
therefore provide therapeutic effects at a relatively ing this disease.
26Ciccone(p)-26 1/30/07 2:53 PM Page 381
Long-Term Management of Asthma therapy for asthma has been questioned. Prolonged
and excessive use of beta-2 agonists may actually
The primary focus of treating asthma has undergone a increase airway hyperresponsiveness, thus increasing
shift within the past few years. In the past, treatment the risk of bronchoconstrictive attacks.2,22
consisted primarily of bronchodilators such as the The current philosophy is that beta-2 agonists
beta-adrenergic agonists and the xanthine derivatives, still serve an important role in the treatment of peri-
with systemic anti-inflammatory steroids (glucocorti- odic or acute bronchospasm22; that is, the intermittent
coids) added only in more advanced and severe cases. use of a short-acting beta-2 agonist can help decrease
The use of glucocorticoids has increased, however, the severity of an acute asthma attack. The role of
and these drugs are now used as first-line agents in beta-2 agonists in the long-term treatment of asthma
most patients, including cases of newly detected, mild is less obvious. These drugs are clearly not the pri-
asthma.68,87 The increased use of glucocorticoids is mary form of treatment, but long-acting beta-2 ago-
largely due to the fact that certain types of glucocorti- nists such as salmeterol and formoterol can be
coids can now be administered by inhalation. As indi- combined with glucocorticoids to provide optimal
cated previously, inhaled glucocorticoids are not results in certain patients.25,82 Long-acting beta-2 ago-
absorbed readily into the systemic circulation, and the nists are therefore considered supplemental to gluco-
risk of systemic side effects is therefore substantially corticoid therapy, and the addition of these beta
reduced. Another reason for the shift toward increased agonists should be considered if glucocorticoid treat-
glucocorticoid use is the recognition that these drugs ment alone is not successful in the long-term manage-
directly reduce the inflammation that underlies asth- ment of asthma.25,82 Combining a long-acting beta-2
matic disease, whereas bronchodilators merely treat drug with a glucocorticoid can also reduce the dosage
the secondary manifestations of this disease.68 Put of the glucocorticoid, thus reducing the risk of side
more simply, glucocorticoids directly affect the under- effects associated with high doses of glucocorticoids.25
lying disease process by decreasing the inflammation The role of theophylline in treating asthma has
causing airway hyperresponsiveness. been reexamined. Once considered the foundation for
Glucocorticoids have assumed the leading role in drug therapy, theophylline is now used sparingly com-
treating asthma. In addition, the role of leukotriene in- pared to glucocorticoids and other antiasthmatic drugs
hibitors has recently expanded to help control inflam- (beta-2 agonists, antileukotriene drugs). Theophylline
mation in asthma.11,52 As indicated earlier, leukotrienes is a powerful bronchodilator, but problems with toxic-
play a key role in mediating airway inflammation, and ity often limit its use in the long-term management of
drugs that block leukotriene receptors (montelukast, asthma.43,103 Currently, low doses of theophylline are
zafirlukast), or inhibit the formation of leukotri- sometimes added to the drug regimen of patients who
enes (zileuton) can be extremely helpful in the long are resistant to treatment using glucocorticoids and
term control of asthma. These leukotriene inhibitors beta agonists.43 The combination of theophylline with
are nonsteroidal, and they can be especially helpful a glucocorticoid may likewise provide optimal effects
when combined with an anti-inflammatory steroid at lower doses.43 As indicated earlier, it is also recog-
(glucocorticoid). The combination can provide opti- nized that theophylline may have anti-inflammatory
mal anti-inflammatory effects using lower doses of the effects, and some of the renewed interest in using low-
glucocorticoid, thus preventing the systemic adverse dose theophylline therapy is based on this drug’s abili-
effects associated with higher doses of steroids.52,123 ty to control airway inflammation rather than actually
Hence, guidelines now advocate dual therapy using a produce bronchodilation.24 Hence, theophylline
glucocorticoid and leukotriene inhibitor for the long- remains an important adjunct in treating certain
term management of many patients with asthma.52,114 patients with asthma, and this drug may be used more
Beta-2 agonists are still used frequently as the extensively as more is learned about the synergistic
primary method of symptomatically treating asthma effects of theophylline and glucocorticoids.
attacks. Many patients, for example, inhale beta-2 ago- Inhaled glucocorticoids are therefore the corner-
nists through MDIs as “rescue” therapy at the onset of stone of drug therapy for patients with asthma.
a bronchospastic attack; this technique is a mainstay in Leukotriene inhibitors, beta agonists, and theo-
managing acute episodes of asthma.22,49 Nonetheless, phylline can be used to supplement glucocorticoids as
the use of beta-2 agonists as long-term maintenance needed, with the specific drug regimen determined on
26Ciccone(p)-26 1/30/07 2:53 PM Page 382
a patient-by-patient basis. In addition, other drugs situation remains controversial. In contrast to their
such as the cromones (cromolyn sodium, nedocromil) beneficial effects in asthma, glucocorticoids have not
and antihistamines can be used to prevent the release always produced clear therapeutic benefits in the long-
or block the irritant effects of histamine in people with term treatment of COPD.10,14 Hence, these drugs are
asthma.102,130 Efforts should be made to find the opti- not typically prescribed on a routine basis but are usu-
mal combination of agents for each patient, and the ally reserved for the more severe cases or acute exacer-
drug regimen must be reviewed constantly and adjust- bations of COPD-related bronchospasm.32,58
ed in response to the patient’s needs and the clinical
course of the asthmatic disease.
Along with drug therapy, several nonpharmaco- Treatment of Respiratory
logic interventions should be employed. Efforts
should be made to determine the initiating factors of
Problems in Cystic Fibrosis
an asthmatic attack, and patients should be taught how Cystic fibrosis is one of the most common hereditary
to avoid these factors whenever possible. Also, consid- diseases in Caucasian populations—the autosomal-
erable evidence exists that aerobic conditioning can recessive trait is found in approximately 1 of every
improve the overall health and well-being of people 2000 Caucasian births.15 Cystic fibrosis essentially
with asthma.62,122 Of course, exercise itself may be an affects all the major exocrine glands, resulting in very
asthmatic trigger in some individuals.73 However, cer- thick, viscous secretions. These thickened secretions
tain forms of aerobic exercise such as swimming may often form mucous plugs, which obstruct major ducts
be an excellent way to improve the cardiorespiratory in various glands and organs.15,66 For instance, the
status of patients with asthma without causing exces- pancreatic and bile ducts are often obstructed, result-
sive risk of bronchospastic attacks.62 ing in problems with nutrient digestion and absorp-
tion. Mucous plugging of the bronchioles occurs quite
frequently, leading to pulmonary problems such as
Treatment of Reversible pneumonia, bronchiectasis, pulmonary fibrosis, and
various pulmonary infections (especially Staphylococ-
Bronchospasm in COPD cus). These respiratory problems are usually the pri-
As indicated previously, bronchospasm is often present mary health threat to individuals with cystic fibrosis.15
in COPD—that is, in chronic bronchitis and emphy- Pharmacologic management of respiratory prob-
sema.121 Chronic bronchitis is a clinical diagnosis applied lems in cystic fibrosis is focused on maintaining airway
to a long-standing inflammation of the bronchial tree. patency as much as possible. Bronchodilators and
Emphysema is a pathologic condition marked by the mucolytic and/or expectorant drugs may help limit the
destruction of alveolar walls and enlargement of the formation of mucous plugs. Systemic glucocorticoids
terminal air spaces. (e.g., prednisone) may also be beneficial in some
Drug therapy for COPD is directed primarily patients in limiting airway inflammation and improv-
toward maintaining airway patency and preventing ing pulmonary function.28 The side effects and risks of
airflow restriction.7,55 Thus, anticholinergics (iprat- systemic glucocorticoids, however, may outweigh any
ropium, tiotropium) are typically the first drugs used, benefits, especially in children.19,28 Inhaled glucocorti-
followed by other bronchodilators such as long-acting coids could reduce the likelihood of severe adverse
beta-2 agonists.29,106 Theophylline can also be used as effects, but their beneficial effects are limited because
a bronchodilator in COPD, but it is usually reserved inhaled forms of these drugs cannot penetrate through
for acute exacerbations or for patients who have not the thick mucus secretions in the airways of people
responded adequately to other bronchodilators.9,79 It with cystic fibrosis.28 Other nonsteroidal anti-inflam-
has been suggested that at relatively low doses, theo- matory interventions, including high doses of NSAIDs
phylline may also produce beneficial effects in COPD (e.g., ibuprofen), might also be helpful, but additional
because of its anti-inflammatory effects rather than its studies will be needed to clarify the role of these inter-
bronchodilating properties.6,54 Hence, there has been ventions in people with cystic fibrosis.19,75
renewed interest in using theophylline as a part of Anti-infectious agents also play a key role in the
COPD treatment.54 treatment of cystic fibrosis, and respiratory infections
Glucocorticoids have also been used to treat are treated with appropriate antibiotic agents.16,89 In
airway inflammation in COPD, but their use in this particular, azithromycin has shown considerable
26Ciccone(p)-26 1/30/07 2:53 PM Page 383
promise because it is an antibacterial drug with anti- flammatory cells is deposited into the airway lumen
inflammatory properties.75,89 In addition to drug ther- when these cells are destroyed. DNA increases the vis-
apy, daily maintenance of respiratory hygiene (postural cosity and thickness of the respiratory secretions, and
drainage, breathing exercises, etc.) is a key component preparations that contain recombinant human deoxyri-
in the management of cystic fibrosis. Evidence for the bonuclease (rhDNAse, dornase alfa, Pulmozyme) can
beneficial effects of chest physical therapy has been lyse this DNA, thus decreasing the viscosity of these
questioned somewhat, but there seems little doubt that secretions, thereby improving pulmonary function
a regular exercise program can help improve cardio- and reducing the chance of lung collapse (atelectasis)
vascular health and musculoskeletal function in people and infection.48,104 This treatment is typically adminis-
with cystic fibrosis.31 With recent advances in medical tered by inhalation via a nebulizer, with the dose and
treatment, many people with cystic fibrosis are living frequency adjusted according to the needs of each
into their third or fourth decade, and an exercise pro- patient. Researchers continue to investigate the opti-
gram seems especially important in helping maintain mal and most cost effective way to incorporate deoxy-
quality-of-life for these individuals.31 ribonuclease therapy into a drug for people with cystic
Although there is still no cure for cystic fibrosis, fibrosis.104,105
several pharmacologic techniques have been recently Many other drug and nutritional interventions
developed that may help decrease the viscosity of res- have also been attempted as part of the treatment for
piratory secretions in patients with this disease. One cystic fibrosis, but most of these interventions lack
technique uses aerosol preparations that contain conclusive evidence of beneficial effects.75 On the
enzymes known as deoxyribonucleases. These enzymes other hand, considerable progress has been made to
can be inhaled to break down the large quantities of develop strategies to correct the defective gene caus-
DNA that are present in respiratory secretions of ing cystic fibrosis.72,107 This gene therapy may some-
patients with cystic fibrosis.48,104 Respiratory secretions day provide an effective long-term treatment by
in these patients often contain large amounts of DNA replacing the defective gene with a functionally cor-
because the genetic material contained in airway in- rect gene.40,107 These strategies and other new tech-
Therapists should also be aware of the potential side effects of bronchodilator drugs. In
particular, the cardiac side effects of the beta-adrenergic agonists and xanthine derivatives
(theophylline, others) should be considered. Therapists may notice cardiac arrhythmias while
monitoring the electrocardiogram (ECG) or while taking the patient’s pulse; these cardiac
abnormalities may indicate a problem with bronchodilator medications. Noncardiac symptoms
such as nervousness, confusion, and tremors may also indicate bronchodilator toxicity and
should be brought to the physician’s attention. Early recognition of toxicity may be lifesaving,
especially when xanthine derivatives such as theophylline are used. Finally, patients receiving
systemic glucocorticoid treatment may be prone to the well-known catabolic effects of these
drugs. Therapists should be especially alert for skin breakdown, and care should be taken not to
overstress the bones and musculotendinous structures that may be weakened by the prolonged
use of glucocorticoids.
CA S E ST U DY
Respiratory Drugs by a respiratory therapist. The respiratory therapy treat-
ments included administration of the mucolytic drug acetyl-
Brief History. V.C., a 63-year-old man, has a long his- cysteine via a nebulizer three times daily. The patient
tory of COPD and hypertension. Twelve years ago, he continued to self-administer the beta-2 agonist at the onset of
was diagnosed with emphysema. During the past 5 years, his bronchospasms.
symptoms of shortness of breath, wheezing, and bron- Problem/Influence of Medication. Despite the
chospasm have become progressively worse. He is also a program of respiratory therapy, bronchial secretions began to
chronic cigarette smoker and has had a cough for many accumulate in the patient’s airways. The patient had also been
years, which produces large amounts of sputum daily. instructed in deep-breathing and coughing exercises, and
Although his physician advised him repeatedly to quit he was told by the respiratory therapist to perform these
smoking, the patient was unable to kick the habit. To control exercises periodically throughout the day. However, no pos-
his bronchospasm, the patient self-administers an inhaled tural drainage was being performed to encourage ejection of
anticholinergic agent (tiotropium) once each day. To help sputum.
resolve acute bronchospasm, he also uses an inhaled Decision/Solution. In addition to the neuromuscular
beta-2 agonist (albuterol) via an MDI at the onset of an facilitation activities, the physical therapist initiated a program
attack. He is also taking a diuretic and beta-1 blocker to con- of chest physical therapy including postural drainage and
trol his hypertension. Two days ago, he was admitted to the deep-breathing exercises. The physical therapist coordinated
hospital with weakness and incoordination in his left arm and these activities with the respiratory therapist so that the
leg. Subsequent medical tests indicated that he had patient first received a treatment of the mucolytic agent. Also,
suffered a cerebral vascular accident. Physical therapy was the physical therapist had the patient self-administer a dose
ordered to begin at the patient’s bedside to facilitate optimal of the inhaled beta-2 bronchodilator approximately 1 hour
recovery from the stroke. The physical therapist began prior to the chest therapy session, thus allowing the bron-
treating the patient with passive and active exercises to chodilator to produce maximal airway dilation and permit
encourage motor return. The patient was also being seen optimal clearance of bronchial secretions.
31. Dodd ME, Prasad SA. Physiotherapy management of 49. Joos GF, Brusselle GG, Van Hoecke H, et al. Position-
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Chapter 27
Gastrointestinal Drugs
This chapter discusses drugs that are used to treat spe- these drugs are used will help therapists recognize their
cific problems in the gastrointestinal (GI) system. The role in the patient’s pharmacotherapeutic regimen.
GI tract is responsible for food digestion and the
absorption of nutrients and water. Dietary constituents
normally undergo a series of digestive processes as Drugs Used to Control
they progress through the GI system. Under normal Gastric Acidity and Secretion
conditions, the transit time of food and water is ade-
quate to allow the processes of digestion and absorp- The acidic nature of the gastric juices is essential for
tion to take place. Indigestible and nonabsorbable activating digestive protease activity and controlling
products are eliminated by defecation. intestinal bacteria. The gastric acids, however, can
The primary disorders that occur in the GI tract cause severe ulceration and hemorrhage of the stom-
are related to damage from gastric acid secretion and ach lining if excessive amounts of acid are produced or
abnormal food movement through the GI tract. Prob- if the normal protection of the stomach mucosa is dis-
lems may develop if digestive secretions in the stom- turbed by irritants, drugs, or bacterial infection.54,56
ach begin to damage the upper GI mucosa and cause a Consequently, several different types of drugs are
peptic ulcer. Certain drugs attempt to prevent or heal available that attempt to control or prevent the detri-
peptic ulcers by controlling gastric acid secretion and mental effects of gastric acid. These agents are used to
protecting the mucosal lining. Problems with gas- treat peptic ulcers—that is, ulcerations of the mucosal
trointestinal motility may also respond to pharmaco- lining of the esophagus, stomach, and duodenum.37,51
logic management. Excessive motility (diarrhea) and These drugs may also be helpful in treating general
inadequate bowel evacuation (constipation) are treated problems related to indigestion and epigastric pain
with various agents that normalize peristalsis and facil- (dyspepsia) and to heartburn sensations caused by the
itate normal bowel movements. Drugs are also avail- leakage of gastric acid into the distal esophagus, called
able to treat other problems with digestion and gastroesophageal reflux.1 Agents used to control gastric
vomiting (emesis). The GI system is susceptible to var- acidity and secretion are presented below.
ious infectious and parasitic invasions. The drugs used
to treat these disorders are presented in Chapters 33 Antacids
through 35, which deal with the chemotherapy of
Rationale for Use and Mechanism of Action
infectious diseases.
Rehabilitation specialists will often treat patients Antacids attempt to chemically neutralize stomach
taking some form of GI agent. These medications are acids. These drugs typically contain a base such as car-
commonly used by the general public, as well as by bonate or hydroxide combined with aluminum, mag-
hospitalized individuals and outpatients receiving nesium, or calcium.34 The base combines with excess
physical therapy and occupational therapy. Although hydrogen ions (H⫹) in the stomach to increase intra-
the direct impact of most GI drugs on physical reha- gastric pH. The basic strategy of this chemical neu-
bilitation is relatively small, an understanding of how tralization is illustrated in Figure 27–1.
389
27Ciccone(p)-27 1/30/07 2:35 PM Page 390
acid under basal conditions and during stimulation by macokinetics (absorption, metabolism, and so forth)
food and other factors.31,53 and their potential for interacting with other drugs.21
The H2 blockers are therefore used for both Hence, all H2 blockers seem to be essentially similar
acute and long-term management of peptic ulcer and when used at moderate doses to control excess gastric
other problems such as dyspepsia and gastroe- acid secretion.
sophageal reflux disease (GERD).59 These drugs have
a good safety profile, and many of the H2 blockers
originally introduced as prescription agents are now Adverse Side Effects
available as over-the-counter preparations. Nonethe- These drugs are generally well-tolerated in most
less, the use of H2 blockers have diminished somewhat patients, and adverse effects are rare during short-
because of the superior effects achieved with proton term or periodic use. Problems that may occur include
pump inhibitors (see below).23 H2 blockers remain an headache and dizziness. Mild, transient GI problems
option for treating mild or occasional gastric irrita- (nausea, diarrhea, constipation) may also occur with
tion, but the routine use of these drugs in serious gas- the H2 blockers, and arthralgia and myalgia have been
tric disease has been largely replaced by more effective reported with cimetidine use. Tolerance may occur
drugs such as proton pump inhibitors. during long-term use, and acid rebound can occur
after discontinuation from prolonged use.23
Specific Agents
The primary H2 blockers used to control gastric secre- Proton Pump Inhibitors
tions are listed in Table 27–1. Cimetidine was the first Rationale for Use and Mechanism of Action
H2 blocker to be widely used as an antiulcer agent.
Newer drugs such as famotidine, nizatidine, and rani- These drugs inhibit the H⫹, K⫹ -ATPase enzyme that
tidine appear to be at least as effective as cimetidine; is ultimately responsible for secreting acid from gastric
they differ from one another primarily in their phar- parietal cells into the lumen of the stomach.21 This
enzyme is also known as the “proton pump”; hence
these drugs are often referred to as proton pump
inhibitors (PPIs). PPIs are extremely effective at in-
Table 27–1 H2 RECEPTOR BLOCKERS
hibiting the proton pump, and therapeutic doses can
Generic Trade Adult Oral virtually eliminate gastric acid secretion.6,14 There is
Name Name Dosage* some evidence that PPIs also have antibacterial effects
against Helicobacter pylori infection and that these drugs
Cimetidine Tagamet 300 mg 4 times each may have some anti-inflammatory properties that help
day with meals and at decrease gastric irritation.10 Evidence indicates that
bedtime, 400 or 600 mg PPIs are more effective than H2 blockers and antacids
in the morning and at in controlling acid secretion and promoting the heal-
bedtime, or 800 mg at ing of ulcers.8,47,55 PPIs have therefore gained promi-
bedtime nence in treating gastric problems, and are now the
Famotidine Pepcid 40 mg once daily at drug of choice in the long-term treatment of patients
bedtime or 20 mg BID with gastric and duodenal ulcers and GERD.12,47
Rabeprazole AcipHex 20 mg 20 mg 20 mg 20 mg
*Doses are usually administered once each day. Time of administration (morning, bedtime, and so forth) is
determined according to each patient’s symptoms and disease characteristics.
effective, and remarkably safe option for patients who gested that this bacterium may cause or potentiate
need to suppress gastric irritation and treat GERD.24 gastroduodenal ulcers, and that the treatment of an H.
pylori infection is essential in order to treat these types
Adverse Side Effects of ulcers.7,54 Use of antibiotics results in an increased
healing rate and a decreased recurrence of gastric
PPIs are usually well-tolerated. As with antacids and ulcers in many people who test positive for H. pylori
H2 blockers, increased secretion of gastric acid (acid infection.16,42 The fact that H. pylori is present in
rebound) can occur when PPIs are discontinued after certain patients should not eliminate the possibility
prolonged use.21 It has also been suggested that long- that other factors (stress, diet, and so forth) may also
term use is associated with gastric polyps and gas- be contributing to gastric ulcer disease.41 There are
trointestinal tumors.46 This suggestion, however, patients who are infected with H. pylori who do not
arises from studies on animals, and no causative link develop gastric ulcers.2 Hence, the exact role of this
between PPIs and gastrointestinal hyperplasia has bacterium as a causative factor in gastric ulcers
been established in humans.21 On the other hand, remains uncertain. Nonetheless, H. pylori may con-
there is substantial evidence that PPIs can decrease the tribute to the development of gastric ulcers in suscep-
morbidity associated with increased gastric acid secre- tible individuals, and antibacterial drugs should be
tion, and PPIs can decrease the risk of esophageal considered in patients with ulcers who are infected
damage and carcinoma associated with GERD.30 with this bacterium.
Hence, the benefits of these drugs seem to outweigh Treatment of H. pylori infection typically consists
the risks, and PPIs do not usually produce any adverse of a combination therapy, using several drugs simulta-
effects during the long-term treatment of peptic ulcer neously.42 For example, one common form of “triple
and gastrointestinal reflux disease.3 therapy” consists of two antibacterials (amoxicillin and
clarithromycin) and one of the PPIs described earlier
Treatment of H. Pylori Infection in this chapter.17,36 Alternatively, various “quadruple
therapies” have been used combining bismuth com-
in Gastric Ulcer Disease pound (described later in the section on “Treatment of
Helicobacter pylori (H. pylori) is a gram-negative bac- Diarrhea”) with a PPI and two antibacterials (e.g.,
terium that is often present in the upper GI tract in tetracycline and metronidazole).5,36 These drug regi-
people with gastric ulcer disease.42 It has been sug- mens are typically administered for 1 to 2 weeks; and
27Ciccone(p)-27 1/30/07 2:35 PM Page 393
antibacterial drugs are discontinued after this period. into the esophagus. This drug may therefore be help-
Some patients, however, may need to remain on main- ful in treating gastroesophageal reflux disease.44 The
tenance doses of the PPI or other antiulcer drugs to primary side effects associated with metoclopramide
facilitate ulcer healing and prevent recurrence.18 are related to its antagonistic effects on central nerv-
Consequently, treatment of H. pylori infection ous system (CNS) dopamine receptors. Restlessness,
may improve the prognosis of people with gastric drowsiness, and fatigue are fairly common. Some ex-
ulcers and other forms of upper GI distress (dyspepsia, trapyramidal symptoms (i.e., parkinsonismlike tremor
gastroesophageal reflux disease). Patients with clinical and rigidity) may also occur because of the central
signs of ulcers who also test positive for this infection antidopamine effects.
should receive a treatment regimen attempting to Prostaglandins. There is little doubt that certain
eradicate the infection. Successful treatment of an H. prostaglandins such as PGE2 and PGI2 inhibit gastric
pylori infection may reduce or eliminate the need for secretion and help protect the stomach mucosa by
subsequent antiulcer medications in patients with gas- stimulating gastric mucus secretion.4,29 The problem
tric ulcer disease.42 has been determining exactly how the prostaglandins
are involved and whether exogenous prostaglandin
Other Agents Used to Control analogs can be used to help treat peptic ulcer. Two
prostaglandin analogs, enprostil and misoprostol, have
and Treat Gastric Ulcers been studied as possible treatments for peptic ulcer.11,39
Several other agents besides the antacids, H2 blockers, The general consensus from clinical trials has been
and PPIs have proved successful in preventing or that these drugs are successful in treating ulcers, but
treating problems associated with gastric acidity and they do not seem to offer any advantages over more
mucosal breakdown. Some of the more frequently traditional antiulcer drugs such as PPIs.21 Also, prosta-
used agents are discussed below. glandin analogs may be effective only at doses that also
Anticholinergics. The role of muscarinic cholin- cause other GI effects, such as diarrhea.21
ergic antagonists in treating peptic ulcers was dis- Consequently, prostaglandin analogs have not
cussed in Chapter 19. Cholinergic stimulation of the gained overwhelming acceptance as antiulcer drugs.
gut via vagal efferent fibers produces a general Currently, only misoprostol (Cytotec) is available for
increase in GI motility and secretion. Drugs that block clinical use, and this drug is typically reserved for the
the effects of acetylcholine on stomach parietal cells treatment of gastric damage caused by aspirin and sim-
will decrease the release of gastric acid. Nonetheless, ilar nonsteroidal anti-inflammatory drugs (NSAIDs).21
atropine and similar anticholinergics are rarely used to The use of misoprostol to reduce or prevent NSAID-
control gastric acid secretion because most cholinergic induced gastropathy is discussed in more detail in
muscarinic inhibitors cause many side effects, such as Chapter 15.
dry mouth, constipation, urinary retention, and confu- Sucralfate (Carafate, Sulcrate). Sucralfate is a di-
sion.21 One possible exception is the antimuscarinic saccharide that exerts a cytoprotective effect on the
drug pirenzepine (Gastrozepin), which is fairly selec- stomach mucosa.26,37 Although the exact mechanism is
tive for muscarinic receptors located on the stomach unclear, sucralfate may form a protective gel within
mucosa, and effectively decreases gastric secretion at a the stomach that adheres to ulcers and shields them
dose that does not cause excessive side effects.21 from the contents of the stomach. The protective bar-
Although this drug is not as effective as newer agents rier formed by the drug prevents further erosion and
(PPIs, H2 blockers), it can be used when treatment permits healing of duodenal and gastric ulcers. Sucral-
with other agents is not possible. fate is well tolerated, although constipation may occur
Metoclopramide (Reglan). This drug is officially in some patients.
classified as a dopamine receptor antagonist but also
appears to enhance the peripheral effects of acetyl-
choline. Primarily because of this latter effect, meto-
clopramide stimulates motility in the upper GI tract
Antidiarrheal Agents
(prokinetic effect), which may be useful in moving the Normal propulsion of food through the GI tract is
stomach contents toward the small intestine, thus crucial for proper absorption of nutrients and water. If
decreasing the risk of gastric acid moving backward transit time is too fast, diarrhea occurs, resulting in
27Ciccone(p)-27 1/30/07 2:35 PM Page 394
poor food absorption and dehydration. Diarrhea is ter 14, opioids bind to CNS receptors and mediate
often a temporary symptom of many relatively minor analgesic effects, which may help decrease symptoms
GI disorders, but it may also occur with more serious of cramping and abdominal discomfort. The primary
conditions such as dysentery, ulcerative colitis, and effects of opioids on GI motility (antiperistalsis), how-
cholera. If diarrhea is sustained for even a few days, ever, seem to occur because opioids bind to neuronal
the resulting dehydration can be a serious problem, receptors on the enteric nerve plexus within the gut
especially in infants or debilitated patients. Conse- wall or by a direct effect of opioids on GI epithelial
quently, efforts should be made to control diarrhea as and smooth muscle cells.13,19 In particular, the mu sub-
soon as possible. Antidiarrheal agents are listed in type of the opioid receptor seems to be important in
Table 27–3, and their pharmacology is discussed in the mediating the GI effects of opioid drugs; stimulation
following sections. of these receptors is the primary method for reducing
GI motility and treating diarrhea.13
Opioid Derivatives Specific Agents
Rationale for Use and Mechanism of Action
Opioid derivatives used to treat diarrhea are listed in
The constipating effects of morphine and certain Table 27–3. Opium tincture (laudanum) and camphor-
other opioid derivatives have been recognized for ated opium tincture (paregoric) are naturally occur-
some time. These drugs produce a general decrease in ring opiates that are very potent inhibitors of
GI motility, and they may also reduce fluid loss by peristalsis. These natural agents are still available for
increasing the absorption of salt and water or by treating diarrhea, but they have essentially been
decreasing fluid and electrolyte excretion from the GI replaced by newer opioids such as diphenoxylate and
tract.44 The exact manner in which opioids exert these loperamide. These newer opioids are somewhat less
effects, however, is not known. As indicated in Chap- potent but may produce fewer side effects.
Kaolin, Pectin Kao-Spen, Kapectolin* 60–120 mL regular-strength suspension after each loose,
bowel movement
Bismuth salicylate Pepto-Bismol, others 525 mg every half hour to 1 hour or 1050 mg every hour
if needed
Opioid derivatives
Difenoxine Motofen† 2 mg initially, 1 mg after each loose stool or every 3–4 hrs
the fecal mass, thus softening the stool and permitting constituents is impaired. In particular, digestants are
easier defecation. These agents may also exert a laxa- often administered to individuals with cystic fibrosis.49
tive effect because of the increased pressure in the As discussed in Chapter 26, cystic fibrosis is a heredi-
bowel secondary to the increased stool size. tary disease that affects all the major exocrine glands,
resulting in thick, viscous secretions. These thickened
secretions may form mucous plugs that obstruct cer-
Adverse Effects tain ducts such as the pancreatic and bile ducts. This
Disturbances in the GI system, such as nausea and condition leads to a chronic deficiency of pancreatic
cramps, may occur with laxative use. With prolonged enzymes and bile salts; as a result, patients cannot
use, serious lower GI irritation, including spastic coli- digest and absorb nutrients from the GI tract. Prepa-
tis, may occur. Fluid and electrolyte abnormalities are rations containing these digestants may be adminis-
also a potential problem. Excessive loss of water and tered orally to replace the missing compounds, thus
the concomitant loss of electrolytes may transpire, improving digestion and nutrient absorption.
resulting in dehydration and possible acid-base imbal-
ances.44 These abnormalities are especially significant
in older or debilitated patients. Finally, chronic ad- Emetics
ministration may result in a laxative dependence when Emetics are used to induce vomiting and are frequent-
bowel evacuation has become so subservient to laxa- ly administered to help empty the stomach of poisons
tive use that the normal mechanisms governing evac- or ingested toxins. The two primary emetics are apo-
uation and defecation are impaired. morphine and ipecac. Both agents seem to work by
stimulating the medullary emetic center, and ipecac
also exerts a direct emetic effect on the stomach.
Miscellaneous
Gastrointestinal Drugs
Antiemetics
Several other types of drugs are administered for spe-
cific purposes in controlling GI function. These other Antiemetics are used to decrease the nausea and vom-
drugs are introduced here only to alert the reader to iting that are associated with motion sickness and
their existence. For a more detailed description of the recovery from surgery or that develop in response to
use of any of these agents, one of the drug indexes other medical treatments, such as cancer chemothera-
such as the Physician’s Desk Reference (PDR) should be py and radiation treatment.33,40,43 Antiemetic agents
consulted. include antihistamines (dimenhydrinate, meclizine,
others), anticholinergics (scopolamine), drugs that
block specific CNS dopamine (D2) and serotonin (5-
Digestants HT3) receptors, cannabinoids, and several other drugs
that act at various sites in the CNS to suppress nausea
These agents are administered to aid in the digestion
and vomiting.44 Other antiemetic drugs such as
of food. The primary digestant preparations contain
antacids and adsorbents act locally to soothe the gas-
pancreatic enzymes or bile salts. Pancreatic enzymes
tric mucosa and decrease the irritation that may cause
such as amylase, trypsin, and lipase are responsible for
vomiting.
digestion of carbohydrates, proteins, and lipids,
respectively. These enzymes are normally synthesized
in the pancreas and secreted into the duodenum via the
pancreatic duct. Bile salts are synthesized in the liver,
Cholelitholytic Agents
stored in the gallbladder, and released into the duode- Drugs like chenodeoxycholic acid (chenodiol) and
num via the common bile duct. Bile salts serve to ursodeoxycholic acid (ursodiol) can dissolve certain
emulsify lipids in the intestinal tract and are important types of gallstones.28,45 These drugs decrease the cho-
in lipid digestion and absorption. lesterol content of bile and may help dissolve gall-
Digestant preparations are used to replace diges- stones that are supersaturated with cholesterol; these
tive constituents in the stomach and upper small intes- drugs do not appear effective in the treatment of cal-
tine whenever the endogenous production of these cified gallstones.28
27Ciccone(p)-27 1/30/07 2:35 PM Page 398
CA S E ST U DY
Gastrointestinal Drugs Decision/Solution. The physical therapist con-
sulted with the ‘patient’s physician and recommended that
Brief History. M.B. is a 48-year-old insurance sales a brief trial with a bulk-forming laxative might be helpful
representative with a long history of back pain. He has had during the acute episode of back pain in this patient. The
recurrent episodes of sciatica because of a herniated disk at therapist also explained to the patient that straining during
the L5-S1 interspace. Currently, he is being seen as an out- defecation exacerbated his back problems. To prevent the
patient in a private physical therapy practice. Despite several recurrence of this problem, the patient was encouraged
treatments, his back pain did not improve. In fact, his pain was to ingest a high-fiber diet and adequate amounts of water
recently exacerbated when he was straining to pass a stool to prevent constipation. M.B. was also informed that the
during a period of constipation. Evidently, this occurrence had short-term use of a laxative might be necessary to avoid con-
been repeated often, and the patient’s back problems were stipation and straining. The therapist warned the patient,
increased by the bowel-related problems causing straining however, about the laxative dependence that can occur dur-
during defecation. ing chronic use.
bents, and bismuth salicylate. Decreased motility are used frequently in rehabilitation patients and, it is
(constipation) is usually treated with various laxatives. hoped, will produce beneficial effects that will allow
Other GI agents attempt to treat specific problems the patient to participate more actively in the rehabil-
such as poor digestion, emesis, or gallstones. GI drugs itation program.
References 20. Hade JE, Spiro HM. Calcium and acid rebound: a
reappraisal. J Clin Gastroenterol. 1992;15:37–44.
21. Hoogerwerf WA, Pasricha PJ. Pharmacotherapy of
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Opin Pharmacol. 2005;5:589–595. reflux disease. In: Brunton LL, et al, eds. The Pharma-
2. Berardi RR. Peptic ulcer disease. In: DiPiro JT, et al, cological Basis of Therapeutics. 11th ed. New York:
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4. Brzozowski T, Konturek PC, Konturek SJ, et al. Role dynamic essentials of H(2)-receptor antagonists and
of prostaglandins in gastroprotection and gastric adap- proton pump inhibitors for the practising physician.
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8. Carballo F. Efficiency of potent gastric acid inhibition. gastric ulcer: evaluation of aluminum adherence. J Int
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chronic gastritis, and proton pump inhibitors. J Clin 28. Konikoff FM. Gallstones—approach to medical man-
Gastroenterol. 1998;27(suppl 1):S163–S169. agement. Med Gen Med. 2003;5:8.
11. Davies NM, Longstreth J, Jamali F. Misoprostol thera- 29. Konturek SJ, Konturek PC, Brzozowski T. Prosta-
peutics revisited. Pharmacotherapy. 2001;21:60–73. glandins and ulcer healing. J Physiol Pharmacol. 2005;
12. Dekel R, Morse C, Fass R. The role of proton pump 56(suppl 5):5–31.
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2004;64:277–295. ment of Barrett’s esophagus. Drugs. 2005;65(suppl 1):
13. De Schepper HU, Cremonini F, Park MI, Camilleri 75–82.
M. Opioids and the gut: pharmacology and current 31. Lazzaroni M, Bianchi Porro G. Non-steroidal
clinical experience. Neurogastroenterol Motil. 2004; anti-inflammatory drug gastropathy: clinical
16:383–394. results with H2 antagonists and proton pump
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gastro-esophageal reflux disease. Drugs. 2005;65 32. Lehmann F, Hildebrand P, Beglinger C. New
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16. Fennerty MB. Helicobacter pylori: why it still matters in Evidence-based recommendations for the use of
2005. Cleve Clin J Med. 2005;72(suppl 2):S1–S7. antiemetics in radiotherapy. Radiother Oncol. 2005;
17. Gisbert JP. Potent gastric acid inhibition in Heli- 76:227–233.
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al. Preclinical studies of opioids and opioid antagonists ication of Helicobacter pylori: recent advances
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37. Metz DC. Preventing the gastrointestinal conse- oesophageal acidity in patients with a history of
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38. Mossner J, Caca K. Developments in the inhibition 49. Schibli S, Durie PR, Tullis ED. Proper usage of pan-
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47. Robinson M. Proton pump inhibitors: update on their review: the efficacy of intermittent and on-demand
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SECTION
Endocrine
Pharmacology
28Ciccone(p)-28 1/30/07 3:52 PM Page 402
Chapter 28
Introduction to Endocrine
Pharmacology
The endocrine system helps to maintain internal ed to provide rehabilitation specialists with a general
homeostasis through the use of endogenous chemicals review of endocrine and hormone activity; subsequent
known as hormones. A hormone is typically regarded as chapters deal with specific endocrine drugs and the
a chemical messenger that is released into the blood- problems they are used to treat.
stream to exert an effect on target cells located some
distance from the hormonal release site.2 Various
endocrine glands manufacture and release specific hor- Primary Endocrine Glands
mones that help regulate physiologic processes such as and Their Hormones
reproduction, growth and development, energy meta-
bolism, fluid and electrolyte balance, and response to The primary endocrine glands and the hormones they
stress and injury.2,20 produce are briefly discussed here. These glands and
The use of drugs to help regulate and control the physiologic effects of their hormones are also sum-
endocrine function is an important area of pharmacol- marized in Tables 28–1 and 28–2. For the purpose of
ogy. In one sense, hormones can be considered drugs this chapter, only the primary endocrine glands and
that are manufactured by the patient’s body. This situ- their respective hormones are discussed. Substances
ation presents an obvious opportunity to use exoge- such as prostaglandins and kinins, which are produced
nous chemicals to either mimic or attenuate the effects locally by a variety of different cells, are not discussed
of specific hormones during endocrine dysfunction. here, but are referred to elsewhere in this text (e.g., see
Drugs can be used as replacement therapy during Chapter 15). Also, chemicals such as norepinephrine,
hormonal deficiency—for example, insulin administra- which serve a dual purpose as hormones and neuro-
tion in diabetes mellitus. Likewise, exogenous hor- transmitters, are discussed in this chapter only with
mone analogs can be administered to accentuate the regard to their endocrine function.
effects of their endogenous counterparts, such as using
glucocorticoids to help treat inflammation. Converse-
ly, drugs can be administered to treat endocrine hyper-
Hypothalamus and Pituitary Gland
activity—for example, the use of antithyroid drugs in The pituitary gland is a small, pea-shaped structure
treating hyperthyroidism. Finally, drugs can be used to located within the sella turcica at the base of the brain.
regulate normal endocrine function to achieve a The pituitary lies inferior to the hypothalamus and is
desired effect, as is done through the inhibition of ovu- attached to the hypothalamus by a thin stalk of tissue
lation by oral contraceptives. known as the infundibulum. The structural and func-
The purpose of this chapter is to review the basic tional relationships between the hypothalamus and
aspects of endocrine function, including the primary pituitary gland are briefly discussed later in this sec-
hormones and their effects. The factors regulating tion. A more detailed presentation of the anatomic
hormonal release and the cellular mechanisms of hor- and physiologic functions of the hypothalamus and
mone action are also briefly discussed. Finally, the pituitary gland can be found in several sources.8,14,32
basic ways in which drugs can be used to alter endo- The pituitary can be subdivided into an anterior,
crine function are presented. This overview is intend- an intermediate, and a posterior lobe. These subdivi-
403
28Ciccone(p)-28 1/30/07 3:52 PM Page 404
Posterior lobe
Antidiuretic hormone (ADH) ↑ renal reabsorption of water
Oxytocin ↑ uterine contraction; ↑ milk ejection during lactation
Adrenal medulla Epinephrine, Norepinephrine Vascular and metabolic effects that facilitate
increased physical activity
sions and their respective hormones are listed in Table primarily on the kidneys, where it increases the
28–1 and briefly discussed below. reabsorption of water from the distal renal tubules.
Anterior Lobe. The anterior pituitary, or adeno- Oxytocin is important in parturition and stimulates
hypophysis, secretes six important peptide hormones. the uterus to contract. It also promotes lactation by
The anterior pituitary releases: growth hormone stimulating the ejection of milk from the mammary
(GH), luteinizing hormone (LH), follicle-stimulating glands.
hormone (FSH), thyroid-stimulating hormone (TSH), The hypothalamic control of the posterior pitu-
adrenocorticotropic hormone (ACTH), and prolactin itary is quite different than that of the anterior and
(Pr). The physiologic effects of these hormones are intermediate lobes. Specific neurons have their cell
listed in Table 28–1. bodies in certain hypothalamic nuclei. Cell bodies in
Hormonal release from the anterior pituitary is the paraventricular nuclei manufacture oxytocin,
controlled by specific hormones or releasing factors whereas the supraoptic nuclei contain cell bodies that
from the hypothalamus.2,15 Basically, a releasing factor synthesize ADH. The axons from these cells extend
is sent from the hypothalamus to the anterior pituitary downward through the infundibulum to terminate
via local vascular structures known as the hypothalam- in the posterior pituitary. Hormones synthesized in
ic-hypophysial portal vessels. For example, to increase the hypothalamic cell bodies are transported down
the secretion of growth hormone, the hypothalamus the axon to be stored in neurosecretory granules in
first secretes growth hormone–releasing hormone their respective nerve terminals (located in the poste-
(GHRH) into the portal vessels. The GHRH travels a rior pituitary). When an appropriate stimulus is pres-
short distance to the anterior pituitary via the hypo- ent, these neurons fire an action potential, which
thalamic-hypophysial portal system. Upon arriving at causes the hormones to release from their pituitary
the pituitary, the GHRH causes the anterior pituitary nerve terminals. The hormones are ultimately picked
to release growth hormone into the systemic circula- up by the systemic circulation and transported to their
tion, where it can then travel to various target tissues target tissues.
in the periphery. Other hypothalamic-releasing fac-
tors that have been identified are listed in Table 28–1.
Specific releasing factors are still being investigated,
Thyroid Gland
and the identification of additional factors (including The thyroid gland is located in the anterior neck
those that inhibit anterior pituitary hormone release) region, approximately at the level of the fifth cervical
will undoubtedly be forthcoming. to first thoracic vertebrae.22 This gland consists of
Intermediate Lobe. In mammals, there is a small bilateral lobes that lie on either side of the trachea and
intermediate lobe of the pituitary (pars intermedia) are connected by a thin piece of the gland known as the
that may secrete melanocyte-stimulating hormone isthmus. The thyroid synthesizes and secretes two
(MSH). Although it can influence skin pigmentation hormones: thyroxine (T4) and triiodothyronine (T3).
in lower vertebrates, the intermediate lobe does not The synthesis of these hormones is controlled by
produce MSH in meaningful amounts in humans. the hypothalamic-pituitary system via thyroid-releas-
Humans can, however, produce MSH from a precur- ing hormone from the hypothalamus, which causes
sor protein (proopiomelacortin) that is synthesized in thyroid-stimulating hormone release from the anterior
central tissues (anterior pituitary, hypothalamus) and pituitary. Thyroid-stimulating hormone increases T3
the periphery (skin, lymphoid tissues).32 MSH may and T4 synthesis and release from the thyroid gland.
play a role in controlling several diverse functions The primary effect of the thyroid hormones is to
such as appetite, energy homeostasis, and inflamma- increase cellular metabolism in most body tissues.24,39
tion.5,21,38 MSH and similar hormones such as ACTH These hormones stimulate virtually all aspects of cel-
are key components of a neuroendocrine arrangement lular function, including protein, fat, and carbohy-
known as the melanocortin system; investigators con- drate metabolism. By exerting a stimulatory effect on
tinue to determine if this system can be manipulated the cellular level, thyroid hormones play a crucial role
pharmacologically to help control various physiologi- in helping maintain and regulate body heat (thermoge-
cal systems. nesis) in the whole organism. T3 and T4 also play an
Posterior Lobe. The posterior pituitary, or neuro- important role in growth and development, especially
hypophysis, secretes two hormones: antidiuretic hor- in the growth and maturation of normal bone. Finally,
mone (ADH) and oxytocin.2,12 ADH exerts its effect thyroid hormones play a permissive role in allowing
28Ciccone(p)-28 1/30/07 3:52 PM Page 406
other hormones, such as steroids, to exert their effects. the bloodstream and returning blood glucose to nor-
The physiology and pharmacology of thyroid hor- mal levels. Insulin also exerts a number of other effects
mones are further discussed in Chapter 31. on protein and lipid metabolism. The effects of insulin
and its pharmacologic replacement in diabetes melli-
tus are discussed in more detail in Chapter 32
Parathyroid Gland
Parathyroid glands are small, egg-shaped structures
Adrenal Gland
embedded in the posterior surface of the thyroid
gland. There are usually four parathyroid glands, with Adrenal glands are located at the superior poles of
two glands located on each half of the thyroid gland. each kidney. Each adrenal gland is composed of an
The parathyroids synthesize and release parathyroid outer cortex and an inner medulla. The hormones
hormone (PTH). PTH is essential in maintaining nor- associated with the adrenal cortex and adrenal medul-
mal calcium homeostasis in the body; the primary la are described in the following sections.
effect of PTH is to increase the concentration of calci- Hormones of the Adrenal Cortex. The adrenal
um in the bloodstream.33,34 PTH increases circulating cortex synthesizes and secretes two primary groups of
calcium levels primarily by mobilizing calcium from steroidal hormones: the glucocorticoids and the min-
storage sites in bone. eralocorticoids.41 Small amounts of sex steroids (estro-
The primary factor regulating PTH release is the gens, androgens, progesterone) are also produced, but
level of calcium in the bloodstream.42 Parathyroid these amounts are essentially insignificant during nor-
gland cells appear to act as calcium sensors that mon- mal adrenal function.
itor circulating calcium levels. As circulating calcium Glucocorticoids such as cortisol have a number of
levels fall below a certain point, PTH secretion is physiologic effects.1 Glucocorticoids are involved in
increased. Conversely, elevated plasma calcium titers the regulation of glucose metabolism and are impor-
inhibit PTH secretion. The ability of PTH to control tant in enhancing the body’s ability to handle stress.
plasma calcium levels and regulate bone mineral They also have significant anti-inflammatory and
metabolism is discussed in more detail in Chapter 31 immunosuppressive properties and are often used ther-
apeutically to control inflammation or suppress the
immune response in various clinical situations. Gluco-
Pancreas corticoid synthesis is controlled by the hypothalamic-
The pancreas is located behind the stomach in the pituitary system. Corticotropin-releasing hormone
lower left area of the abdomen. This gland is unique in (CRH) from the hypothalamus stimulates ACTH
that it serves both endocrine and exocrine functions.4,19 release from the anterior pituitary, which in turn stim-
The exocrine aspect of this gland involves digestive ulates the synthesis of glucocorticoids.
enzymes that are excreted into the duodenum. As an Mineralocorticoids are involved in controlling
endocrine gland, the pancreas primarily secretes two electrolyte and fluid levels.9,44 The primary mineralo-
peptide hormones: insulin and glucagon. These hor- corticoid produced by the adrenal cortex is aldosterone.
mones are synthesized and secreted by cells located in Aldosterone increases the reabsorption of sodium
specialized clusters known as the islets of Langerhans. In from the renal tubules. By increasing sodium reab-
the islets of Langerhans, glucagon and insulin are syn- sorption, aldosterone facilitates the reabsorption of
thesized by alpha and beta cells, respectively. water. Aldosterone also inhibits the renal reabsorption
Pancreatic hormones are involved in the regula- of potassium, thus increasing potassium excretion.
tion of blood glucose, and the glucose concentration Mineralocorticoid release is regulated by fluid and
in the blood serves as the primary stimulus for hor- electrolyte levels in the body and by other hormones,
mone release. For example, following a fast, glucagon such as the renin-angiotensin system.
is released from pancreatic alpha cells as blood glucose The pharmacologic aspects of the glucocorticoids
levels fall. Glucagon mobilizes the release of glucose and mineralocorticoids are discussed in more detail in
from storage sites in the liver, thus bringing blood glu- Chapter 29
cose levels back to normal. An increase in blood glu- Hormones of the Adrenal Medulla. The adrenal
cose after eating a meal stimulates insulin release from medulla synthesizes and secretes epinephrine and nor-
the beta cells. Insulin facilitates the storage of glucose epinephrine.11,37 These hormones have a number of
in the liver and muscle, thus removing glucose from physiologic effects, which are discussed in Chapters 18
28Ciccone(p)-28 1/30/07 3:52 PM Page 407
and 20. Small amounts of epinephrine and norepi- are the hypothalamic releasing factors and the pitu-
nephrine are released under resting, basal conditions. itary hormones. Finally, several hormones are modi-
The primary significance of these hormones, however, fied from a single amino acid. For instance, the
seems to be in helping to prepare the body for sudden thyroid hormones (T3 and T4) are manufactured from
physical activity. The classic function of the adrenal the amino acid tyrosine. In addition, hormones from
medulla can be illustrated by the fight-or-flight reac- the adrenal medulla (epinephrine, norepinephrine) are
tion, in which a stressful challenge is presented to the synthesized from either phenylalanine or tyrosine.
individual and interpreted as requiring either a The basic chemical structure of various hormones
defense or a need to flee. is significant in determining how the hormone will
The release of epinephrine and norepinephrine exert its effects on target tissues (see “Hormone
from the adrenal medulla is controlled by the sympa- Effects on the Target Cell,” later). Different hormones
thetic division of the autonomic nervous system. As that are fairly similar in structure can often have simi-
discussed in Chapter 18, sympathetic cholinergic pre- lar physiologic and pharmacologic effects. This is es-
ganglionic neurons directly innervate this gland. An pecially true for the steroids, in which one category of
increase in sympathetic activity causes increased firing steroidal agents may have some of the same properties
in these neurons, which in turn stimulates the release of a different category.36 For instance, the endogenous
of epinephrine and norepinephrine from the adrenal glucocorticoids (e.g., cortisol) also exert some mineral-
medulla. ocorticoid effects, presumably because of their similar
chemical structure. The overlapping effects and their
consequences are discussed in more detail in Chapters
Gonads 29 through 32, which deal with specific endocrine
Reproductive organs are the primary source of the systems.
steroid hormones that influence sexual and reproduc-
tive functions. In men, the testes produce testosterone Synthesis and Release of Hormones
and similar androgens that are responsible for sper-
matogenesis and the secondary sexual characteristics Hormones are typically synthesized within the cells of
of adult males.7,26 In women, sexual maturation and their respective endocrine glands. Most hormones are
reproductive function are governed by the production synthesized and packaged in storage granules within
of estrogens and progestins from the ovaries.27 The the gland. When the gland is stimulated, the storage
release of male and female sex steroids is controlled by granule fuses with the cell membrane, and the hor-
hormones from the hypothalamus and anterior pitu- mone is released by exocytosis. Notable exceptions to
itary.32 The control of male and female hormone this are the steroid hormones, which are not stored to
activity and the pharmacologic implications of these any great extent but are synthesized on demand when
hormones are discussed in Chapter 30. an appropriate stimulus is present.2
Hormone synthesis and release can be initiated
by both extrinsic and intrinsic factors.2 Extrinsic fac-
tors include various environmental stimuli such as
Endocrine Physiology pain, temperature, light, and smell. Intrinsic stimuli
and Pharmacology include various humoral and neural factors. For
instance, release of a hormone can be initiated by
Hormone Chemistry other hormones. These occurrences are particularly
Hormones can be divided into several primary cate- typical of the anterior pituitary hormones, which are
gories according to their basic chemical structure. controlled by releasing hormones from the hypothal-
Steroid hormones share a common chemical framework amus. Hormonal release can be influenced by neural
that is derived from lipids such as cholesterol.28 Exam- input; a primary example is the sympathetic neural
ples of steroids include the sex hormones (androgens, control of epinephrine and norepinephrine release
estrogens, progesterone), the glucocorticoids, and the from the adrenal medulla. Other intrinsic factors that
mineralocorticoids. Peptide hormones consist of amino affect hormone release are the levels of ions and
acids linked together in a specific sequence. These metabolites within the body. For instance, parathyroid
peptide chains can range in length from 3 to 180 hormone release is governed directly by the calcium
amino acids. Primary examples of peptide hormones concentration in the bloodstream, and the release of
28Ciccone(p)-28 1/30/07 3:52 PM Page 408
transport in the bloodstream, certain hormones such as the receptor initiates some change in the enzymatic
steroids are bound to specific plasma proteins. These machinery located within the cell. This event usually
protein carriers appear to help prolong the half-life of results in a change in the production of some intracel-
the hormone and prevent premature degradation. lular chemical second messenger such as cyclic adeno-
Other protein carriers may be important in the local sine monophosphate (cAMP).6
effects of hormone function. For instance, the testes An example of a hormone that exerts its effects
produce androgen-binding protein, which helps trans- through a surface receptor–second messenger system
port and concentrate testosterone within the seminif- is ACTH.36 ACTH is a polypeptide that binds to a
erous tubules of the testes (see Chapter 30). surface receptor on adrenal cortex cells. The surface
receptor then stimulates the adenylate cyclase enzyme
to increase production of cAMP, which acts as a sec-
Hormone Effects on the Target Cell ond messenger (the hormone was the first messenger),
Most hormones affect their target cell by interacting and increases the activity of other enzymes within
with a specific receptor. Hormone receptors are locat- the cell to synthesize adrenal steroids such as cortisol.
ed at three locations, shown in Figure 28–2. These For a more detailed description of surface receptor–
primary locations are on the surface membrane of the second messenger systems, see Chapter 4.
cell, within the cytosol of the cell, or within the cell’s Cytosolic Hormone Receptors. Steroid hormones
nucleus.2 Receptors at each location tend to be specif- typically bind to protein receptors, which are located
ic for different types of hormones and also tend to directly within the cytosol (see Fig. 28–2).17 Of course,
affect cell function in a specific manner. Each type of this means that the hormone must first enter the cell,
receptor is briefly discussed below. which is easily accomplished by the steroid hormones
Surface Membrane Receptors. These receptors because they are highly lipid soluble. After entering
are located on the outer surface of the plasma mem- the cell, the hormone initiates a series of events that
brane (see Fig. 28–2).6 Surface receptors tend to rec- are depicted in Figure 28–3. Basically, the hormone
ognize the peptide hormones and some amino acid and receptor form a large activated steroid-receptor
derivatives (e.g., pituitary hormones, catecholamines). complex.17 This complex travels to the cell’s nucleus,
They are typically linked to specific intracellular where it binds to specific genes located within the
enzymes. When stimulated by a peptidelike hormone, DNA sequence.31,40 This process initiates gene expres-
Target Cell
Peptide
I II
Hormones
Steroid nucleus
Hormones
III
Thyroid
Hormones
FIGURE 28–2 ▼ Primary cellular locations of hormone receptors. Peptide hormones tend to bind
to surface membrane receptors (site I); steroid hormones bind to cytosolic receptors (site II); and
thyroid hormones bind to receptors in the cell nucleus (site III).
28Ciccone(p)-28 1/30/07 3:52 PM Page 410
Steroid-responsive Cell
S S R
1.
nucleus
S-R* 2.
S-R*
DNA
chromatin
3.
mRNA
4.
protein
synthesis
FIGURE 28–3 ▼ Sequence of events of steroid hormone action. (1) Steroid hormone enters the
cell, binds to a cytosolic receptor, and creates an activated steroid-receptor complex (S-R). (2) S-R
complex travels to the cell’s nucleus, where it binds to specific gene segments on nuclear chromatin.
(3) DNA undergoes transcription into messenger RNA (mRNA) units. (4) mRNA undergoes trans-
lation in the cytosol into specific proteins that alter cell function.
sion and transcription of messenger RNA units, which Nuclear Hormone Receptors. Certain hormones
go back to the cytosol and are translated into specific interact directly with hormonal receptors that are
proteins by the endoplasmic reticulum.40 These newly located on the chromatin within the cell nucleus (see
manufactured proteins are usually enzymes or struc- Fig. 28–2).3 Thyroid hormones (T3 and T4) are a pri-
tural proteins that change cell function in a specific mary example of hormones that bind directly to
manner. For instance, anabolic steroids increase mus- nuclear receptors.29 After binding, thyroid hormones
cle size by facilitating the production of more contrac- invoke a series of changes similar to those caused by
tile proteins. Thus, steroids tend to exert their effects the steroid–cytosolic receptor complex; that is, the
on target cells by directly affecting the cell’s nucleus nucleus begins to transcribe messenger RNA, which is
and subsequently altering the production of certain ultimately translated into specific proteins. In the case
cellular proteins. of the thyroid hormones, these new proteins usually
Hence, steroids exert their primary effects by act- alter the cell’s metabolism. Thyroid hormones are dis-
ing on receptors located within the cell. As discussed cussed in more detail in Chapter 31.
in Chapter 4, it is apparent that these substances exert Hormone receptors have some obvious and
some of their effects by binding to a second set of important pharmacologic distinctions. Drugs that can
receptors located on the cell surface.13,18 Studies con- bind to and activate specific hormonal receptors (ago-
tinue to define the exact role of steroidal surface nists) will mimic the effects of the endogenous com-
receptors and their contribution to the effects of each pounds. Drugs that block the receptors (antagonists)
type of steroid will attenuate any unwanted hormonal effects. In fact,
28Ciccone(p)-28 1/30/07 3:52 PM Page 411
drugs may be produced that are even more specific for treated pharmacologically. Inhibition of hormone
hormonal receptors than their endogenous counter- function can occur at several levels. For instance, drugs
parts. For instance, synthetic glucocorticoids, such as that directly inhibit the synthesis of the hormone or
dexamethasone, exert anti-inflammatory effects in a inhibit its release through various negative feedback
manner similar to that of endogenous glucocorticoids, mechanisms (see previous section, “Feedback Control
but with diminished mineralocorticoid-like side effects Mechanisms in Endocrine Function”) may be admin-
such as water and sodium retention. This increased istered. Also, hormone antagonists (drugs that block
specificity is presumably brought about by a more pre- hormone receptors) may be used for prolonged peri-
cise action of the synthetic compound on the gluco- ods to attenuate the effects of excessive hormone pro-
corticoid receptors rather than the mineralocorticoid duction.
receptors. Exploitation of Beneficial Hormone Effects. Hor-
mones and their synthetic analogs are often adminis-
tered to exaggerate the beneficial effects of their
Clinical Use of endogenous counterparts. The classic example is the
use of glucocorticoids to treat inflammation. Doses of
Endocrine Drugs glucocorticoids that are much higher than the physio-
The general ways in which pharmacologic agents can logic levels produced by the body can be very effective
be used to alter endocrine activity are as follows. in decreasing inflammation in a variety of clinical con-
Replacement Therapy. If the endogenous produc- ditions (e.g., rheumatoid arthritis, allergic reactions).
tion of a hormone is deficient or absent, therapeutic Of course, the use of high doses of hormones to accen-
administration of the hormone can be used to restore tuate beneficial effects may also cause some side effects
normal endocrine function.30,35 The exogenous hor- and impair various aspects of endocrine function.
mone can be obtained from natural sources, such as However, short-term use of hormones in this capacity
extracts from animal tissues, or from chemical synthe- is often a useful therapeutic intervention.
sis. In addition, new recombinant DNA techniques are Use of Hormones to Alter Normal Endocrine Func-
being used to produce hormones from cell cultures, tion. Because of the intrinsic control mechanisms in
and these techniques have shown great promise in the endocrine system, administration of exogenous
being able to generate hormones like human insulin. hormones can often affect the normal release of hor-
Hormone substitution is sometimes referred to as mones. This fact can be exploited in certain situations
simple replacement therapy. However, the use of to cause a desired change in normal endocrine func-
exogenous hormones to replace normal endocrine tion. For instance, oral contraceptives containing estro-
function can be a complicated task. Problems such as gen and progesterone inhibit ovulation by inhibiting
regulation of optimal dosage, the interaction of the the release of LH and FSH from the anterior pituitary.
exogenous drug with other endogenous hormone sys- Use of Hormones in Nonendocrine Disease. There
tems, and drug-induced side effects are frequently are many examples of how various hormones and
encountered. hormone-related drugs can be used to treat conditions
Diagnosis of Endocrine Disorders. Hormones or that are not directly related to the endocrine system.
their antagonists can be administered to determine the For instance, certain forms of cancer respond to treat-
presence of excess endocrine function or endocrine ment with glucocorticoids (see Chapter 36). Drugs
hypofunction. For example, hormones or their syn- that block the cardiac beta-1 receptors may help con-
thetic analogs can be administered that either increase trol angina and hypertension by preventing excessive
or decrease pituitary secretion to determine if pitu- stimulation from adrenal medulla hormones (epineph-
itary function is normal. Likewise, antagonists to spe- rine, norepinephrine; see Chapters 21 and 22).
cific hormones can be administered to see if symptoms
are caused by excessive hormone production. Specific
examples of how hormones are used to diagnose
SUMMARY
endocrine abnormalities are presented in subsequent The endocrine glands regulate a variety of physiolog-
chapters. ic processes through the release of specific hormones.
Treatment of Excessive Endocrine Function. Hy- Hormones are the equivalent of endogenously pro-
peractive or inappropriate endocrine function is often duced drugs that usually travel through the blood-
28Ciccone(p)-28 1/30/07 3:52 PM Page 412
stream to exert an effect on specific target tissues. sive hormonal activity, and produce other desirable
Hormones typically alter cell function by binding to changes in endocrine activity. The use of hormones
receptors located at specific sites on or within the tar- and hormone-related substances in the pharmacolog-
get cell. Pharmacologic agents can be administered to ic management of specific disorders is discussed in
mimic or exaggerate hormonal effects, inhibit exces- Chapters 29 through 32.
28. Miller WL. Disorders of androgen synthesis—from The Pharmacological Basis of Therapeutics. 11th ed. New
cholesterol to dehydroepiandrosterone. Med Princ York: McGraw-Hill 2006.
Pract. 2005;14(suppl 1):58–68. 37. Schinner S, Bornstein SR. Cortical-chromaffin cell
29. Moore JM, Guy RK. Coregulator interactions with the interactions in the adrenal gland. Endocr Pathol.
thyroid hormone receptor. Mol Cell Proteomics. 2005; 2005;16:91–98.
4:475–482. 38. Seeley RJ, Drazen DL, Clegg DJ. The critical role of
30. Morley JE, Haren MT, Kim MJ, et al. Testosterone, the melanocortin system in the control of energy bal-
aging and quality of life. J Endocrinol Invest. 2005; ance. Annu Rev Nutr. 2004;24:133–149.
28(suppl):76–80. 39. Silvestri E, Schiavo L, Lombardi A, Goglia F. Thyroid
31. Ozawa H. Steroid hormones, their receptors and hormones as molecular determinants of thermogenesis.
neuroendocrine system. J Nippon Med Sch. 2005;72: Acta Physiol Scand. 2005;184:265–283.
316–325. 40. Smoak KA, Cidlowski JA. Mechanisms of glucocorti-
32. Parker KL, Schimmer BO. Pituitary hormones and coid receptor signaling during inflammation. Mech
their hypothalamic releasing factors. In: Brunton LL, Ageing Dev. 2004;125:697–706.
et al, eds. The Pharmacological Basis of Therapeutics. 11th 41. Stewart PM. The adrenal cortex. In: Larsen PR, et al,
ed. New York: McGraw-Hill; 2006. eds. Williams Textbook of Endocrinology. 10th ed.
33. Poole KE, Reeve J. Parathyroid hormone—a bone Philadelphia: WB Saunders; 2003.
anabolic and catabolic agent. Curr Opin Pharmacol. 42. Tfelt-Hansen J, Brown EM. The calcium-sensing
2005;5:612–617. receptor in normal physiology and pathophysiology: a
34. Potts JT. Parathyroid hormone: past and present. J review. Crit Rev Clin Lab Sci. 2005;42:35–70.
Endocrinol. 2005;187:311–325. 43. Unsworth WP, Taylor JA, Robinson JE. Prenatal pro-
35. Prelevic GM, Kocjan T, Markou A. Hormone replace- gramming of reproductive neuroendocrine function:
ment therapy in postmenopausal women. Minerva the effect of prenatal androgens on the development
Endocrinol. 2005;30:27–36. of estrogen positive feedback and ovarian cycles in the
36. Schimmer BP, Parker KL. Adrenocorticotropic hor- ewe. Biol Reprod. 2005;72:619–627.
mone; adrenocortical steroids and their synthetic 44. Wehling M. Effects of aldosterone and mineralocorti-
analogs; inhibitors of the synthesis and actions of coid receptor blockade on intracellular electrolytes.
adrenocortical hormones. In: Brunton LL, et al, eds. Heart Fail Rev. 2005;10:39–46.
28Ciccone(p)-28 1/30/07 3:52 PM Page 414
Chapter 29
Adrenocorticosteroids
This chapter discusses the pharmacology of the steroid steroid groups. The basic physiologic and pharmaco-
hormones that are produced by the adrenal cortex. logic properties of the glucocorticoids are then
The two primary types of adrenal steroids are the glu- addressed, followed by a description of mineralocorti-
cocorticoids and mineralocorticoids. Small amounts coid function. This chapter should provide therapists
of other steroids such as the sex hormones (andro- with a better understanding of the pharmacotherapeu-
gens, estrogens, and progestins) are also produced by tic and toxic characteristics of these compounds.
the adrenal cortex. These steroids are discussed in
Chapter 30.
The adrenocorticosteroids have several impor-
tant physiologic and pharmacologic functions. The
Steroid Synthesis
glucocorticoids (cortisol, corticosterone) are prima- The primary pathways involved in steroid biosynthesis
rily involved in the control of glucose metabolism and are shown in Figure 29–1. These hormones are manu-
the body’s ability to deal with stress. Glucocorticoids factured by enzymes located in the cytosol of adreno-
have other attributes, such as their ability to decrease cortical cells. As shown in Figure 29–1, there are three
inflammation and suppress the immune system. Min- primary pathways, each leading to one of the major
eralocorticoids, such as aldosterone, are involved in types of steroid hormone.16,62 The mineralocorticoid
maintaining fluid and electrolyte balance in the body. pathway synthesizes aldosterone, the glucocorticoid
Adrenal steroids and their synthetic analogs can pathway synthesizes cortisol, and the androgen/estro-
be administered pharmacologically to mimic the gen pathway leads to the synthesis of sex hormones.
effects of their endogenous counterparts. This ap- Although all three pathways are present in the adrenal
proach is frequently used as replacement therapy in cortex, the mineralocorticoid and glucocorticoid path-
various hormonal deficiencies. The quantity adminis- ways predominate. The appropriate enzymes for sex
tered during hormonal replacement is roughly equiva- hormone are biosynthesis are also present in the
lent to the normal endogenous production and is often gonads, where hormones are synthesized in the testes
referred to as a physiologic dose. In higher doses, (men) or ovaries (women).
adrenal steroids can be used to capitalize on a particu- Steroid hormones bear a remarkable structural
lar beneficial effect, such as using glucocorticoids as similarity to one another (see Fig. 29–1). The precur-
anti-inflammatory agents. These larger doses are typi- sor for steroid biosynthesis is cholesterol. Conse-
cally referred to as pharmacologic doses in order to quently, all of the steroid hormones share the same
differentiate them from the amount used to maintain basic chemical configuration as their parent com-
normal endocrine function. pound. This fact has several important physiologic
Physical and occupational therapists will encoun- and pharmacologic implications. First, even relatively
ter many patients who are receiving adrenal steroids minor changes in the side chains of the parent com-
for hormone replacement or for various other thera- pound create steroids with dramatically different
peutic reasons. This chapter discusses the biosynthesis physiologic effects. For instance, the addition of only
of the adrenal steroids in an effort to show some of the one hydrogen atom in the sex steroid pathway changes
structural and functional similarities between various testosterone (the primary male hormone) to estradiol
415
29Ciccone(p)-29 1/30/07 2:29 PM Page 416
C
C C C C C
C
C
HO
Cholesterol
11-Deoxycorticosterone 11-Deoxycortisol
OH
Corticosterone
CH2OH
O
C O
HO OH
Testosterone
CH2OH
O
C O
CH
HO OH
O
Cortisol
O
Aldosterone HO
Estradiol
FIGURE 29–1 ▼ Pathways of adrenal steroid biosynthesis. Cholesterol is the precursor for the three steroid hor-
mone pathways. Note the similarity between the structures of the primary mineralocorticoid (aldosterone), the primary
glucocorticoid (cortisol), and the sex hormones (testosterone, estradiol). See text for further discussion.
(one of the primary female hormones). Second, the ticosterone (a glucocorticoid) is even the precursor to
structural similarity between different types of aldosterone (a mineralocorticoid).
steroids helps explain why there is often some Steroid structure and biosynthesis have been used
crossover in the physiologic effects of each major cat- from a pharmacologic standpoint. Pharmacologists
egory. One can readily understand how aldosterone have tried to develop more effective and less toxic syn-
has some glucocorticoidlike activity and cortisol has thetic steroids by manipulating the chemical side
some mineralocorticoidlike effects when one consid- groups of these compounds. An example is the syn-
ers the similarity in their organic configuration. Cor- thetic glucocorticoid dexamethasone, which is 25 times
29Ciccone(p)-29 1/30/07 2:29 PM Page 417
Glucocorticoids
Role of Glucocorticoids ACTH
in Normal Function
The primary glucocorticoid released in humans is cor-
Adrenal Cortex
tisol (also known as hydrocortisone). Cortisol synthesis
and secretion are under the control of specific hypo-
thalamic and pituitary hormones.7,24,31 Corticotropin-
releasing hormone (CRH) from the hypothalamus Cortisol
stimulates the release of adrenocorticotropic hormone
(ACTH) from the anterior pituitary. ACTH travels in
the systemic circulation to reach the adrenal cortex, Target Tissues
where it stimulates cortisol synthesis. Cortisol then
travels in the bloodstream to various target tissues to FIGURE 29–2 ▼ Negative feedback control of glucocorticoid
synthesis. Cortisol limits its own synthesis by inhibiting the release
exert a number of physiologic effects (see “Physiolog- of corticotropin-releasing hormone (CRH) from the hypothalamus
ic Effects of Glucocorticoids,” later). and adrenocorticotropic hormone (ACTH) from the anterior pituitary.
Cortisol also plays a role in controlling the
release of CRH and ACTH from the hypothalamus
and pituitary, respectively. As illustrated in Figure hemorrhage, temperature extremes, food and water
29–2, the relationship between plasma cortisol and deprivation, and any perceived psychologic stress can
CRH and ACTH release is a classic example of a neg- increase cortisol release.8,55,71,80 Various stressful events
ative feedback control system. Increased plasma corti- generate afferent input to the hypothalamus, thus
sol levels serve to inhibit subsequent release of CRH evoking CRH and ACTH release from the hypothala-
and ACTH, thus helping to maintain homeostasis by mus and anterior pituitary, respectively.
moderating glucocorticoid activity.
Under normal conditions, cortisol release occurs Mechanism of Action
on a cyclic basis, as shown in Figure 29–3. In an
unstressed human, plasma cortisol levels rise slowly
of Glucocorticoids
throughout the early morning hours and peak at Glucocorticoids affect various cells in a manner that is
approximately 8 AM.16 This type of physiologic event characteristic of steroid hormones (see Chapter 28,
is often referred to as a circadian rhythm, indicating Fig. 28–3). In general, steroids alter protein synthesis
that the cycle is repeated over a 24-hour period. The in responsive cells through a direct effect on the cell’s
fact that plasma cortisol levels progressively increase nucleus. These hormones alter the transcription of
as the individual is preparing to arise suggests that specific DNA genes, which results in subsequent
cortisol helps prepare the organism for increased changes in RNA synthesis and the translation of RNA
activity. Indeed, this belief is supported by the obser- into cellular proteins.6,73
vation that in a rat, plasma glucocorticoid levels peak Specifically, glucocorticoids exert their classic
at around midnight, which corresponds to the time cellular effects first by entering the target cell and
when nocturnal animals become active. binding to a receptor located in the cytosol.19,33 Bind-
In addition to their normal circadian release, glu- ing the glucocorticoid to the receptor creates an acti-
cocorticoids are also released in response to virtually vated hormone-receptor complex. This activated
any stressful stimulus. For instance, trauma, infection, complex then travels (translocates) to the nucleus of
29Ciccone(p)-29 1/30/07 2:29 PM Page 418
Sleep
20 often takes several hours or days to occur because of
Plasma cortisol (mg/dL)
Cortisol
gluconeogenesis
glucose
glycogen
Liver Cell
FIGURE 29–4 ▼ Effects of cortisol on muscle, fat, and liver cells. Cortisol causes the breakdown
of muscle and fat into amino acids and free fatty acids, which can be used by the liver to produce
glucose.
glucose (gluconeogenesis). Glucose that is synthesized the expense of muscle breakdown. This muscle catab-
in the liver can either be stored as glycogen or released olism is one of the primary problems that occurs when
back into the bloodstream to increase blood glucose glucocorticoids are administered for long periods as a
levels. Cortisol also inhibits the uptake of glucose into therapeutic agent (see “Adverse Effects of Glucocorti-
muscle and fat cells, thus allowing more glucose to coids,” later).
remain available in the bloodstream.
Consequently, one of the primary effects of glu-
Anti-Inflammatory Effects
cocorticoids is to maintain blood glucose and liver
glycogen levels to enable a supply of this energy sub- Glucocorticoids are effective and potent anti-inflam-
strate to be readily available for increased activity. matory agents. Regardless of the cause of the inflam-
This effect occurs during the daily basal release of cor- mation, glucocorticoids attenuate the heat, erythema,
tisol and to an even greater extent when high levels of swelling, and tenderness of the affected area. The
cortisol are released in response to stress. However, exact way that these agents intervene in the inflamma-
the beneficial effects on glucose titers occur largely at tory process is complex and not completely under-
29Ciccone(p)-29 1/30/07 2:29 PM Page 420
stood. Some of the primary anti-inflammatory mech- dative enzymes. When lysosomes are ruptured, these
anisms are addressed here. enzymes begin to digest cellular components, thus
As indicated earlier, glucocorticoids often inhibit contributing to the local damage present at a site of in-
transcription factors that normally stimulate genes flammation. Glucocorticoids may help prevent lysoso-
within specific cells to express inflammatory compo- mal rupture and subsequent damage contributing to
nents.1,33 Glucocorticoids—for example—act on mac- the inflammatory response. Glucocorticoids also
rophages, lymphocytes, and endothelial cells to inhibit decrease vascular permeability by either increasing the
the expression of inflammatory proteins (cytokines) reactivity of the vasculature to other vasoconstrictors
such as interleukin-1, interleukin-6, tissue necrosis (epinephrine, norepinephrine) or by suppressing the
factor alpha, interferon gamma, and similar inflamma- local release of vasoactive substances such as histamine,
tory cytokines.62 These cytokines are the primary kinins, and other chemicals that cause increased capil-
chemical signal for activating various inflammatory lary permeability.16,85 This reduction in vascular per-
cells such as T lymphocytes, fibroblasts, and natural meability helps control swelling and erythema at the
killer cells.62 By inhibiting the production and release site of inflammation.
of these inflammatory cytokines, glucocorticoids
inhibit the function of key cells comprising the inflam-
Immunosuppression
matory response.
Glucocorticoids also inhibit the transcription and Glucocorticoids have long been recognized for their
expression of adhesion molecules such as endothelial ability to inhibit hypersensitivity reactions, especially
leukocyte adhesion molecule-1 and intracellular adhe- delayed or cell-mediated allergic reactions. The exact
sion molecule-1.64,72 These adhesion molecules are way in which this immunosuppression occurs is
responsible for attracting leukocytes in the blood- unclear, but many immunosuppressive effects are
stream to endothelial cells at the site of inflamma- mediated by the same actions that explain the anti-
tion.13,62 Glucocorticoids inhibit the production of inflammatory effects of these drugs. As indicated pre-
adhesion molecules, thereby diminishing the ability of viously, glucocorticoids inhibit the transcription of
leukocytes to find and enter inflamed tissues. Like- various factors that signal and direct other cells in the
wise, glucocorticoids inhibit the production of other inflammatory and immune responses. Loss of these
chemoattractive chemicals, such as platelet-activating key signals results in decreased migration of leukocytes
factor and interleukin-1.13 By limiting the production and macrophages to the location of a foreign tissue or
of factors attracting leukocytes to the site of inflam- antigen.62 These drugs also suppress the ability of
mation, glucocorticoids inhibit a critical step in the immune cells to synthesize or respond to chemical
initiation of the inflammatory process.62 mediators such as interleukins and interferons.26,62
Glucocorticoids inhibit the production of other Chemicals such as interleukin-1, gamma interferon,
pro-inflammatory substances such as prostaglandins and related substances normally mediate the commu-
and leukotrienes.15,74 The role of these substances in nication between immune system cells such as T cells,
mediating the inflammatory response was discussed in B cells, and other lymphocytes.56,62 By suppressing the
Chapter 15. Glucocorticoids activate specific genes synthesis and effects of these mediators, glucocorti-
that promote the synthesis of a family of proteins coids interrupt cellular interaction and inhibit activa-
known as annexins.51,74 Annexins (known previously as tion of key cellular components that cause the immune
lipocortins) inhibit the phospholipase A2 enzyme, response. The effects of glucocorticoids on the
which is responsible for liberating phospholipids from immune response and the clinical applications of glu-
cell membranes so that they can be transformed into cocorticoid-induced immunosuppression are discussed
prostaglandins and leukotrienes (see Chapter 15, Fig. further in Chapter 37.
15–1). By inhibiting this enzyme, glucocorticoids elim-
inate the precursor for prostaglandin and leukotriene
Other Effects of Glucocorticoids
biosynthesis, thus preventing the production of these
pro-inflammatory substances. Cortisol and similar glucocorticoids affect a variety of
Finally, high doses of glucocorticoids appear to other tissues.62 These hormones affect renal function
stabilize lysosomal membranes, thereby making them by enhancing sodium and water reabsorption and by
less fragile and susceptible to rupture.35 Lysosomes are impairing the ability of the kidneys to excrete a water
subcellular organelles that contain a variety of degra- load. They alter central nervous system (CNS) func-
29Ciccone(p)-29 1/30/07 2:29 PM Page 421
Amcinonide Cyclocort X
Clocortolone Cloderm X
Cortisone Cortone X
Desoximetasone Topicort X
Flurandrenolide Cordran X
Halcinonide Halog X
Halobetasol Ultravate X
a long and diverse list of nonendocrine conditions. the serious side effects these agents produce. Some of
Some of the approved indications for glucocorticoid the more common problems associated with glucocor-
administration are listed in Table 29–2. Of particular ticoid use are described below.
interest to rehabilitation specialists is the use of these
agents in treating collagen diseases and rheumatic dis- Adrenocortical Suppression
orders, including rheumatoid arthritis.
As indicated in Table 29–2, these drugs are gen- Adrenocortical suppression occurs because of the neg-
erally used to control inflammation or suppress the ative feedback effect of the administered glucocorti-
immune system for relatively short periods of time, coids on the hypothalamic–anterior pituitary system
regardless of the underlying pathology. The very fact and the adrenal glands.20,32 Basically, the patient’s nor-
that these drugs are successful in such a wide range of mal production of glucocorticoids is shut down by the
disorders illustrates that glucocorticoids do not cure exogenous hormones. The magnitude and duration of
the underlying problem. In a sense, they only treat a this suppression are related to the dosage, route of
symptom of the original disease—that is, inflamma- administration, and duration of glucocorticoid thera-
tion. This fact is important because the patient may py.4,62 Some degree of adrenocortical suppression can
appear to be improving, with decreased symptoms of even occur after a single large dose.45 This suppression
inflammation, while the disease continues to worsen. will become more pronounced as systemic administra-
Also, glucocorticoids are often administered in fairly tion is continued for longer periods. Also, topical glu-
high dosages to capitalize on their anti-inflammatory cocorticoid administration over an extensive area of
and immunosuppressive effects. These high dosages the body (especially in infants) may provide enough
may create serious adverse effects when given for pro- systemic absorption to suppress adrenocortical func-
longed periods (see the next section, “Adverse Effects tion.69 Adrenocortical suppression can be a serious
of Glucocorticoids”). Despite these limitations, gluco- problem when glucocorticoid therapy is terminated.
corticoids can be extremely helpful and even lifesaving Patients who have experienced complete suppression
in the short-term control of severe inflammation and will not be able to immediately resume production of
various allergic responses. glucocorticoids. Because abrupt withdrawal can be
life-threatening, glucocorticoids must be withdrawn
slowly by tapering the dose.36,62
Adverse Effects
of Glucocorticoids Drug-Induced Cushing Syndrome
The effectiveness and extensive clinical use of natural In drug-induced Cushing syndrome, patients begin to
and synthetic glucocorticoids must be tempered by exhibit many of the symptoms associated with the
29Ciccone(p)-29 1/30/07 2:29 PM Page 424
Principal Desired of
General Indication Glucocorticoids Examples of Specific Disorders
Allergic disorders Decreased inflammation Anaphylactic reactions, drug-induced aller-
gic reactions, severe hay fever, serum
sickness
Neurotrauma Decreased edema;* inhibit free radi- Brain surgery, closed head injury, certain
cal-induced neuronal damage brain tumors, spinal cord injury
*Efficacy of glucocorticoid use in decreasing cerebral edema has not been conclusively proved.
29Ciccone(p)-29 1/30/07 2:29 PM Page 425
adrenocortical hypersecretion typical of naturally The magnitude of the wasting effect caused by
occurring Cushing syndrome.36 These patients com- systemic glucocorticoids is dependent on many factors,
monly exhibit symptoms of roundness and puffiness in including the patient’s overall health and the duration
the face, fat deposition and obesity in the trunk region, and dosage of drug therapy. Nonetheless, it is apparent
muscle wasting in the extremities, hypertension, osteo- that significant bone and muscle loss can occur even
porosis, increased body hair (hirsutism), and glucose when these drugs are given in low doses.67 Likewise,
intolerance. These changes are all caused by the meta- moderate to high doses will almost certainly cause
bolic effects of the glucocorticoids. The adverse effects some degree of muscle and bone loss when glucocorti-
can be alleviated somewhat by reducing the glucocor- coids are administered continuously for more than a
ticoid dosage. Some of the Cushing syndrome effects few weeks.77,79
must often be tolerated, however, to allow the gluco- The potential for tissue breakdown must always
corticoids to maintain a therapeutic effect (decreased be considered during the rehabilitation of patients tak-
inflammation or immunosuppression). ing these drugs, and therapists must be especially care-
ful to avoid overstressing tissues that are weakened by
the prolonged use of systemic glucocorticoids. Like-
Breakdown of Supporting Tissues wise, bone loss and risk of osteoporosis should be eval-
Glucocorticoids exert a general catabolic effect not uated periodically in patients receiving long-term
only on muscle (as described previously) but also on systemic glucocorticoids.38,67 Patients with evidence of
other tissues. Bone, ligaments, tendons, and skin are excessive bone loss can be treated with drugs such as
also subject to a wasting effect from prolonged gluco- the bisphosphonates (etidronate, pamidronate).61,77
corticoid use. Although the exact mechanisms are Estrogen replacement may also be helpful in minimiz-
complex and not well understood, glucocorticoids ing bone loss in women receiving glucocorticoids,
appear to weaken these supporting tissues by inhibit- although the beneficial effects on bone mineral con-
ing the genes responsible for production of collagen tent must be balanced against the risks of estrogen
and other tissue components, and by increasing the replacement (cancer, cardiovascular disease; see Chap-
expression of substances that promote breakdown of ter 30).86 Other interventions such as calcium supple-
bone, muscle, and so forth.22,44 Glucocorticoids, for ments, vitamin D supplements, and calcitonin may
example, probably interfere with muscle protein syn- help prevent bone loss in people receiving long-term
thesis by altering the muscle’s ability to retain and use glucocorticoid therapy.61,86 The ability of various
amino acids.14,57 Thus, these drugs cause atrophy of drugs to stabilize bone and prevent osteoporosis is
skeletal muscle by increasing the rate of protein break- addressed in Chapter 31.
down and decreasing the rate of protein synthesis.60,68
In severe cases, glucocorticoids can induce a steroid
myopathy that is characterized by proximal muscle
Other Adverse Effects
weakness, which can affect ambulation and functional Several other problems can occur during prolonged
ability.53,62 This type of myopathy is typically resolved glucocorticoid use. Peptic ulcer may develop because
by discontinuing the glucocorticoid, but symptoms of the breakdown of supporting proteins in the stom-
may persist long after the drug has been withdrawn.62 ach wall or direct mucosal irritation by the drugs. An
Glucocorticoids also have negative effects on increased susceptibility to infection often occurs be-
bone; loss of bone strength is considered one of the cause of the immunosuppressive effect of glucocorti-
most common side effects of prolonged, systemic glu- coids. These drugs may retard growth in children
cocorticoid administration.3,46 Again, the exact reasons because of their inhibitory effect on bone and muscle
for these effects are unclear, but glucocorticoids prob- growth and because they inhibit growth hormone.11,29
ably suppress the production of substances that stimu- Glucocorticoids may cause glaucoma by impairing the
late bone formation (e.g., insulin-like growth factor-I), normal drainage of aqueous fluid from the eye, and
and increase the expression of substances that promote cataract formation is also associated with prolonged
bone loss (e.g., colony-stimulating factor-1, nuclear use.39,41 Mood changes and even psychoses have been
factor k-B ligand).12 The result is a loss of bone miner- reported, but the reasons for these occurrences are not
al content that can lead to osteoporosis and fractures, clear.59,84 Glucocorticoids with some mineralocorti-
particularly in the ribs and vertebral bodies.62 coidlike activity may cause hypertension because of
29Ciccone(p)-29 1/30/07 2:29 PM Page 426
affinity for the newer synthetic glucocorticoids, such as occur because the hormone binds to a different set of
dexamethasone. This accounts for the finding that cer- receptors on the epithelial cell membrane that increas-
tain glucocorticoids exert some mineralocorticoidlike es the activity of existing sodium channels and pumps
effects, whereas others have relatively minor effects on such as the Na⫹-K⫹ ATPase.63 At this point, however,
electrolyte and fluid balance.10,54 efforts to identify a specific mineralocorticoid receptor
Mineralocorticoids are believed to increase sodi- on the cell membrane have been unsuccessful, and
um reabsorption by affecting sodium channels and there is still debate about how mineralocorticoids exert
sodium pumps on the epithelial cells lining the renal their rapid, nonnuclear effects.28,49 Nonetheless, the
tubules.18,58 Mineralocorticoids’ ability to increase the effects of mineralocorticoids (like the glucocorticoids
expression of sodium channels is illustrated in Figure discussed earlier) seem to occur in two phases: a rapid
29–5. These hormones enter the tubular epithelial cell, phase that is mediated by nonnuclear mechanisms and
bind to receptors in the cell, and create an activated a delayed, but prolonged phase that is mediated by
hormone-receptor complex.18 This complex then trav- intracellular receptors binding to the cell’s nucleus and
els to the nucleus to initiate transcription of messenger increasing the transcription of specific proteins.18,49
RNA units, which are translated into specific mem- The two phases of mineralocorticoid action both play
brane-related proteins.27,58 These proteins in some way a role in the physiologic action of these hormones, and
either create or help open sodium pores on the cell future research should help to define how these actions
membrane, thus allowing sodium to leave the tubule can be affected by various drugs and diseases.
and enter the epithelial cell by passive diffusion.27,83 In addition to its normal role in controlling fluid
Sodium is then actively transported out of the cell and and electrolyte balance, aldosterone can have detri-
reabsorbed into the bloodstream. Water reabsorption mental effects on the heart and vasculature. Excess or
is increased as water follows the sodium movement prolonged aldosterone production can cause hyper-
back into the bloodstream. As sodium is reabsorbed, trophy and fibrosis of cardiac and vascular tissues and
potassium is secreted by a sodium-potassium exchange, lead to detrimental changes in these tissues.30,78 More-
thus increasing potassium excretion (see Fig. 29–5). over, it is now apparent that aldosterone can be pro-
In addition to their effects on the synthesis of duced locally within certain tissues including the heart
membrane sodium channels, mineralocorticoids also and vascular endothelium.78,83 That is, these tissues
have a more rapid and immediate effect on sodium may produce their own supply of aldosterone as well
reabsorption.28,43 This effect was originally thought to as receive circulating levels of aldosterone from the
Na+
NEPHRON LUMEN
5.
4.
protein
3. synthesis
mRNA
nucleus
2.
A-R*
R Na+
1.
6.
A BLOOD STREAM
K+
FIGURE 29–5 ▼ Effect of aldosterone on renal tubule cells. (1) Aldosterone (A) enters the
cell and binds to a cytosolic receptor (R), creating an activated hormone-receptor complex (A–R).
(2) A–R complex travels to the cell’s nucleus, where it induces mRNA synthesis. (3) mRNA units
undergo translation in the cytosol. (4) Specific proteins are synthesized that increase membrane
permeability to sodium (Na⫹). (5) Na⫹ leaves the nephron lumen and enters the cell down an elec-
trochemical gradient. (6) Na⫹ is actively reabsorbed into the body, and potassium (K⫹) is actively
secreted from the bloodstream by the cellular Na⫹-K⫹ pump.
29Ciccone(p)-29 1/30/07 2:29 PM Page 428
adrenal cortex. It therefore appears that high levels of receptor, these drugs block the effects of endogenous
aldosterone may adversely affect cardiovascular tissues mineralocorticoids (aldosterone) by preventing the
and contribute to cardiovascular disease. Hence, cer- aldosterone from binding to renal cells and other tis-
tain drugs such as the aldosterone antagonists (see sues. Consequently, spironolactone and eplerenone
below) may help control the detrimental effects of antagonize the normal physiologic effects of aldos-
aldosterone on cardiovascular tissues, and these drugs terone, resulting in increased sodium and water excre-
are gaining acceptance in the treatment of certain car- tion and decreased potassium excretion.
diovascular diseases such as hypertension and heart Spironolactone and eplerenone are used primari-
failure.27,40 ly as diuretics in treating hypertension and heart fail-
ure. These drugs are classified as potassium-sparing
diuretics because they help increase sodium and water
Therapeutic Use of excretion without increasing the excretion of potassi-
Mineralocorticoid Drugs um (see Chapter 21). Spironolactone is also used to
Drugs with mineralocorticoidlike activity (aldosterone help diagnose hyperaldosteronism. The drug is given
agonists) are frequently administered as replacement for several days to antagonize the effects of excessive
therapy whenever the natural production of mineralo- aldosterone production. When the drug is discontin-
corticoids is impaired. Mineralocorticoid replacement ued, serum potassium levels will decrease sharply if
is usually required in patients with chronic adrenocor- hyperaldosteronism is present; that is, plasma potassi-
tical insufficiency (Addison disease), following adrena- um levels will fall when aldosterone is again permitted
lectomy, and in other forms of adrenal cortex to increase potassium excretion.
hypofunction. These conditions usually require both As indicated above, mineralocorticoid antago-
mineralocorticoid and glucocorticoid replacement. nists, such as spironolactone and eplerenone, can help
Fludrocortisone (Florinef) is the primary aldos- decrease the detrimental effects of aldosterone on the
teronelike agent that is used in replacement therapy. heart and vasculature. By blocking aldosterone recep-
This compound is chemically classified as a gluco- tors in cardiac and vascular cells, these drugs prevent
corticoid, but it has high levels of mineralocorticoid adverse cellular changes (fibrosis, hypertrophy) that
activity and is used exclusively as a mineralocorticoid. can contribute to hypertension, heart failure, and
Fludrocortisone is administered orally. other cardiovascular diseases.27,40 Preliminary evidence
suggests that mineralocorticoid receptor antagonists
may help reduce the progression of these diseases, and
Adverse Effects of future studies will help clarify how these drugs can be
Mineralocorticoid Agonists best used as part of the pharmacological regimen for
patients with cardiovascular dysfunction.82
The primary problem associated with mineralocorti- Mineralocorticoid antagonists may cause an
coid agonists is hypertension. Because these drugs increase in plasma potassium levels (hyperkalemia),
increase sodium and water retention, blood pressure which could be life-threatening if prolonged or
may increase if the dosage is too high. Other adverse severe.70 Spironolactone can also interfere with the
effects may include peripheral edema, weight gain, function of the endogenous sex hormones, thereby
and hypokalemia. These problems are also caused by producing side effects such as increased body hair,
the effects of these drugs on electrolyte and fluid bal- deepening of the voice, decreased libido, menstrual
ance, and are usually resolved by adjusting the dosage. irregularities, and breast enlargement in men. It
appears, however, that eplerenone has a lower inci-
dence of these sexual side effects, and this drug may
Mineralocorticoid Antagonists preferentially suppress mineralocorticoid function
The mineralocorticoid antagonists used clinically without also affecting the sex hormones.81 Finally,
include spironolactone (Aldactone) and eplerenone mineralocorticoid antagonists can cause gastrointesti-
(Inspra). These drugs are competitive antagonists nal disturbances (diarrhea, stomach pain, gastric
of the aldosterone receptor; that is, they bind to the ulcers), and spironolactone can also cause CNS effects
receptor but do not activate it. When bound to the (drowsiness, lethargy, confusion, headache).
29Ciccone(p)-29 1/30/07 2:29 PM Page 429
CA S E ST U DY
Adrenocorticosteroids Problem/Influence of Medication. Glucocorticoid
administration produced a dramatic decrease in the swelling
Brief History. E.M. is a 58-year-old woman with and inflammation in both knees. The therapist was tempted to
a history of rheumatoid arthritis. She has involvement of begin aggressive stretching activities to resolve the knee flex-
many joints in her body, but her knees are especially ion contractures and restore normal range of motion. The
affected by this disease. Her symptoms of pain, swelling, and therapist was aware, however, that glucocorticoids may
inflammation are fairly well controlled by nonsteroidal weaken ligaments, tendons, and other supporting structures
anti-inflammatory drugs. She does experience periods of because of an inhibitory effect on collagen formation. The
exacerbation and remission, however. During periods of exac- therapist also realized that this effect may be present for some
erbation, she receives physical therapy as an outpatient time after glucocorticoid administration. Even though only a
at a private practice. The therapy typically consists of heat, single intra-articular injection was used, the drug may be
ultrasound, range of motion, and strengthening activities retained locally within fat and other tissues because of the
to both knees. During a recent exacerbation, her symp- high degree of lipid solubility of steroid agents. Consequent-
toms were more severe than usual, and the patient ly, the injected glucocorticoid may continue to exert a cata-
began to develop flexion contractures in both knees. The bolic effect on knee joint structures for some time.
therapist suggested that she consult her physician. Upon Decision/Solution. The therapist was especially care-
noting the severe inflammation, the physician elected ful to use low-intensity, prolonged-duration stretching forces
to inject both knees with a glucocorticoid agent. Methyl- when trying to resolve the knee flexion contractures. Gentle
prednisolone (Depo-Medrol) was injected into the knee stretching, massage, and other manual techniques were con-
joints. The patient was advised to continue physical therapy tinued until full active and passive knee extension was
on a daily basis. achieved.
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Chapter 30
Male and Female Hormones
In this chapter, the pharmacology of male and female used for illicit reasons, such as the use of male hor-
hormones is discussed. Male hormones, such as testos- mones to enhance athletic performance. Hence, reha-
terone, are usually referred to collectively as andro- bilitation specialists should be aware of the therapeutic
gens. The female hormones consist of two principal and potential toxic effects of these drugs.
groups: the estrogens (e.g., estradiol) and the prog-
estins (e.g., progesterone). Androgens, estrogens, and
progestins are classified as steroid hormones; their
chemical structure is similar to those of the other Androgens
primary steroid groups, the glucocorticoids and miner- Source and Regulation
alocorticoids (see Chapter 29). The principal func-
tions, however, of male and female hormones are to
of Androgen Synthesis
control reproductive function and secondary sexual In adult males, testosterone is the principal androgen
characteristics in their respective gender groups. produced by the testes.39,40,144 Testosterone is synthe-
Male and female hormones are produced prima- sized by Leydig cells located in the interstitial space
rily in the gonads. Androgens are synthesized in the between the seminiferous tubules (Fig. 30–1). The
testes in the male. In the female, the ovaries are the seminiferous tubules are the convoluted ducts within the
principal sites of estrogen and progestin production. testes in which sperm production (spermatogenesis)
As discussed in Chapter 29, small amounts of sex- takes place. Testosterone produced by the Leydig cells
related hormones are also produced in the adrenal exerts a direct effect on the seminiferous tubules, as
cortex in both sexes, which accounts for the fact that well as systemic effects on other physiologic systems
small amounts of hormones of the opposite sex are (see “Physiologic Effects of Androgens”).
seen in females and males; that is, low testosterone Production of testosterone by the Leydig cells
levels are seen in females, and males produce small is regulated by the pituitary gonadotropins luteiniz-
quantities of estrogen. However, under normal condi- ing hormone (LH) and follicle-stimulating hormone
tions, the amounts of sex-related hormones produced (FSH).71,159 LH and FSH appear to control spermato-
by the adrenal cortex are usually too small to produce genesis, as shown in Figure 30–1. LH is the primary
significant physiologic effects. hormone that stimulates testosterone production. LH
This chapter first discusses the physiologic role of released from the anterior pituitary binds to receptors
the male hormones and the pharmacologic use of nat- on the surface of Leydig cells and directly stimulates
ural and synthetic androgens. The physiologic and testosterone synthesis.61,144 FSH is also released from
pharmacologic characteristics of the female hormones the anterior pituitary; this hormone primarily affects
are then addressed. As these discussions indicate, there the Sertoli cells that line the seminiferous tubules and
are several aspects of male and female hormones that are responsible for the development and maturation of
should concern physical therapists and occupational normal sperm (see Fig. 30–1).1,159 FSH stimulates the
therapists. Rehabilitation patients may use these growth and function of Sertoli cells, and this hormone
agents for approved purposes, for example, female induces Sertoli cells to produce several products that
hormones as contraceptives. These agents may also be influence spermatogenesis and androgen function.
435
30Ciccone(p)-30 1/30/07 2:54 PM Page 436
anterior
pituitary
LH FSH
ABP
T
Leydig T
ABP
cells
Sertoli
cells
Seminiferous
Tubules
(x-section)
FSH, for example, increases the expression of a poly- whereas FSH acts on the Sertoli cells to stimulate
peptide known as androgen-binding protein (ABP). their function and help testosterone reach target tis-
ABP helps concentrate testosterone within the semi- sues within the seminiferous tissues. Other hormones
niferous tubules and helps transport testosterone to may also play a synergistic role in steroidogenesis in
the epididymis.39 FSH may also affect Leydig cell the male. For instance, growth hormone, thyroid hor-
function indirectly by increasing the production of mones, insulin-like growth factor 1, and prolactin may
other chemical messengers from the Sertoli cells that also affect the functions of Leydig and Sertoli cells,
enhance differentiation and function of Leydig thereby influencing the production and effects of
cells.146,147 testosterone.21,98
Therefore, both pituitary gonadotropins are Release of the pituitary gonadotropins (LH,
required for optimal androgen function. LH acts on FSH) is regulated by gonadotropin-releasing hor-
the Leydig cells to stimulate testosterone synthesis, mone (GnRH) from the hypothalamus.21,144 A classic
30Ciccone(p)-30 1/30/07 2:54 PM Page 437
negative feedback system exists between the GnRH/ tein synthesis in skeletal muscle, thus increasing mus-
pituitary gonadotropins and testosterone synthesis. cle mass in certain situations, such as at the onset of
Increased plasma levels of testosterone inhibit the puberty. This particular androgenic effect (increased
release of GnRH, LH, and FSH, thus maintaining muscle mass) as it relates to androgen abuse in athletes
testosterone levels within a relatively finite range. In is discussed in more detail under “Androgen Abuse”
addition, testosterone production is fairly tonic in later in this chapter.
normal men. Fluctuations may occur in the amount of
testosterone produced over a given period, and andro-
gen production tends to diminish slowly as part of Role in Spermatogenesis
normal aging.108 Androgen production, however, does As discussed previously, androgens are essential for
not correspond to a regular monthly cycle similar to the production and development of normal sperm.39,69
hormonal production in women; that is, testosterone Testosterone is produced by the Leydig cells located
is produced more or less constantly, whereas female in the interstitial space between the seminiferous
hormones are typically produced according to the tubules. LH serves as the primary stimulus to increase
stages of the menstrual cycle (see “Estrogen and Prog- androgen production from Leydig cells. Testosterone
esterone,” later). enters the tubules to directly stimulate the production
of sperm through an effect on protein synthesis with-
Physiologic Effects of Androgens in the tubule cells. FSH must also be present in the
testes to facilitate testosterone transport into the Ser-
Testosterone and other androgens are involved in the toli cells and to work synergistically with testosterone
development of the sexual characteristics in males and to allow full growth and maturation of developing
in the stimulation of spermatogenesis. These two pri- sperm.100,159
mary effects are described below.
haps increase the risk of prostate cancer in susceptible role of various hormones in the treatment of cancer is
older men.106,152 Hence, androgen replacement con- discussed in more detail in Chapter 36.
tinues to be evaluated as a therapeutic option in cer- Anemia. Testosterone and similar compounds are
tain men who are experiencing an excessive decline in potent stimulators of erythropoietin synthesis from
androgen production during aging.85,108 Future stud- the kidneys and other tissues.109 Erythropoietin, in
ies should help clarify how these hormones might be turn, stimulates production of red blood cell synthesis
used to promote optimal health in older men.105 in bone marrow. Human erythropoietin, however, can
Catabolic States. Androgens can be administered now be synthesized using recombinant DNA tech-
for their anabolic properties in conditions where there niques. Hence, various types of anemia that occur sec-
is substantial muscle catabolism and protein loss.101 ondary to renal disease, cancer chemotherapy, and so
Such conditions include chronic infections, severe forth are usually treated directly with recombinant
traumas, severe burns, and recovery from extensive erythropoietin.109 Nonetheless, androgens may be
surgeries.35,115 However, the use of androgens in these used as an adjunct to erythropoietin and other drugs to
situations is somewhat controversial. These agents are stimulate red blood cell production in certain patients
not typically used as a primary treatment, but as with severe or recalcitrant anemia.10
adjuncts to more conventional treatments such as Hereditary Angioedema. This hereditary disorder
dietary supplementation and exercise. is characterized by a defect in the control of clotting
Androgens can also be used to increase lean body factors that ultimately leads to increased vascular per-
mass in men who are infected with human immunod- meability.114 Loss of vascular fluid from specific capil-
eficiency virus (HIV). Men with HIV infection may lary beds causes localized edema in various tissues
have muscle wasting because of low testosterone pro- such as the skin, upper respiratory tract, and gastroin-
duction combined with the catabolic effects of this testinal tract. Certain androgens act on the liver to
infection and subsequent anti-HIV therapies (see restore production of several clotting factors and to
Chapter 34).38,150 Physiologic dosages of androgens increase production of a glycoprotein inhibiting the
have therefore been used to maintain or increase mus- initial stages of the clotting sequence that leads to
cle mass and bone density in these individuals. The increased vascular permeability.114 Hence, androgens
effects of this treatment, however, have not been over- are typically given prophylactically to decrease the
whelmingly successful; only modest increases in lean frequency and severity of angioedema attacks.
body mass were seen in some studies.83 Larger (supra-
physiologic) dosages of androgens, such as oxan-
drolone, have been reported to produce beneficial
Specific Agents
effects on muscle mass and strength in men with HIV Androgens that are used clinically are listed in Table
infection, especially if drug therapy is combined with 30–1. Specific agents are usually administered orally or
resistance training.149 Hence, androgens may be a pos- intramuscularly, as indicated, to replace endogenous
sible option to help reduce muscle wasting and main- androgen production, or to treat various medical prob-
tain muscle strength and function in men who lems. Androgens can also be classified according to
experience severe muscle loss during HIV infection their relative androgenic and anabolic properties; that
and AIDS.83,150 is, certain androgens are given primarily to mimic
Delayed Puberty. In males, androgens may be male sexual characteristics (androgenic effects), where-
administered on a limited basis to accelerate the nor- as other androgens are given primarily to enhance tis-
mal onset of puberty.124,125 These drugs are typically sue metabolism (anabolic effects; see Table 30–1). This
used when puberty is anticipated to occur sponta- distinction is not absolute, however, because all com-
neously but at a relatively late date—that is, when pounds given to produce anabolism will also produce
puberty is not delayed because of some pathologic some androgenic effects. Many other androgenic and
condition. anabolic steroids exist and can be acquired relatively
Breast Cancer. Androgens have been used to treat easily on the black market by individuals engaging in
a limited number of hormone-sensitive tumors, such androgen abuse (see “Androgen Abuse”). Nonetheless,
as certain cases of breast cancer in women. Other the agents listed in Table 30–1 are the principal andro-
drugs such as the antiestrogens, however, have largely gens approved for clinical use; these drugs are used to
replaced the use of androgens in such cancers. The treat catabolic states, anemias, and similar conditions.
30Ciccone(p)-30 1/30/07 2:54 PM Page 439
Routes of
Generic Name Trade Name(s) Primary Indication(s) Administration
Fluoxymesterone Android-F, Halotestin Androgen deficiency; breast cancer Oral
in women; delayed puberty in
boys; anemia
development due to premature closure of epiphyseal GnRH. GnRH analogs include buserelin (Suprefact),
plates. Consequently, these drugs are used very cau- goserelin (Zoladex), leuprolide (Lupron), and nafare-
tiously in children. lin (Synarel). When first administered, these agents
The described adverse effects are related to the cause an increase in pituitary LH release, which—in
dose and duration of androgen use; problems are seen turn—stimulates testicular androgen production.
more frequently during prolonged androgen adminis- However, continued administration of GnRH analogs
tration at relatively high doses. In adults, most of desensitizes pituitary GnRH receptors, thus decreas-
these adverse effects are reversible, and symptoms ing LH and testosterone production from the pitu-
will diminish once the agent is discontinued. A few itary and testes, respectively.89 A newer agent, abarelix
effects, however—such as vocal changes in females— (Plenaxis), directly antagonizes (blocks) the GnRH
may persist even after the drugs are withdrawn. Skele- receptor on the pituitary.144 This drug is especially
tal changes are irreversible, and permanent growth helpful in certain patients because it will cause a more
impairment may occur if these drugs are used in direct and immediate decrease in LH production
children. compared to the GnRH analogs.
As indicated earlier, androgens may increase the
risk of prostate cancer, especially in older men who are
susceptible to this disease.106 Other side effects of long- Androgen Abuse
term, high-dose androgen use include liver damage
and hepatic carcinoma. Hypertension may occur
Nature of Androgen Abuse
because of the salt-retaining and water-retaining The use of androgens or anabolic steroids to increase
effects of these drugs, and androgens can adversely athletic performance is an issue of controversy and
affect plasma lipids (increased total cholesterol, de- concern. The fact that certain athletes self-administer
creased levels of high density lipoproteins). Although large doses of androgens in an effort to increase mus-
these hepatic and cardiovascular problems may occur cle size and strength has been known for some time.
during therapeutic androgen use, their incidence is Typically, androgen use is associated with athletes
even more prevalent when extremely large doses of involved in strength and power activities such as
androgens are used to enhance athletic performance. weight lifting, bodybuilding, shot put, and the like.
The use and abuse of androgens in athletes are dis- Androgen abuse, however, has infiltrated many aspects
cussed later in “Androgen Abuse.” of athletic competition at both the amateur and pro-
fessional levels. There also appears to be a contingent
of men, women, and adolescents who are not athletes,
Antiandrogens but take anabolic steroids to increase lean body mass
Antiandrogens are drugs that inhibit the synthesis or for cosmetic purposes; that is, these individuals take
effects of endogenous androgen production.144 These these drugs to simply appear more muscular.37,47
agents can be helpful in conditions such as prostate Individuals who admit to using anabolic steroids
cancer and other conditions aggravated by excessive or who test positive for androgen abuse represent
androgen production.31,112 Specific antiandrogens some of the top performers in their respective
affect endogenous male hormones in several different sports.103 Also, the use of anabolic steroids among the
ways. Finasteride (Proscar) and dutasteride (Avodart) general athletic population may be reaching alarming
inhibit the conversion of testosterone to dihydrotes- proportions, including younger athletes.19 A compre-
tosterone. Dihydrotestosterone accelerates the growth hensive survey of male high school students indicated
and development of the prostate gland; these antian- that over 6 percent had taken anabolic steroids at least
drogens may be helpful in attenuating this effect in once in their lifetime.126 Clearly, androgen abuse is one
conditions such as benign prostate hypertrophy. Flu- of the major problems affecting the health and welfare
tamide (Eulexin), bicalutamide (Casodex), and nilu- of athletes of various ages and athletic pursuits.
tamide (Nilandron) act as antagonists (blockers) of the Athletes engaging in androgen abuse usually
cellular androgen receptor; these drugs are used to obtain these drugs from various illicit but readily avail-
decrease hirsutism in women or to help treat prostate able sources.155 Some examples of anabolic steroids
cancer. that are used by athletes are listed in Table 30–2. These
Advanced prostate cancer is also treated with a agents include testosterone, synthetic analogs of
number of drugs that mimic or block the effects of testosterone, and precursors that are converted to ana-
30Ciccone(p)-30 1/30/07 2:54 PM Page 441
Table 30–3 EXAMPLE OF A STEROID DOSING CYCLE USED DURING ANDROGEN ABUSE*
Dosage (mg)
Week
Drug Name 1 2 3 4 5 6 7 8
Testosterone cypionate 200 400 600 1200 2400 4200 4200 4200
Nandrolone (Deca-Durabolin) 100 100 100 200 400 600 600 600
Oxymetholone (Anadrol) 100 150 200 250 300 500 750 1000
Methandrostenolone 25 30 35 50 60 75 100 125
(Dianabol)
Methandrostenolone 25 25 50 50 100 100 100 100
(Dianabol injectable)
Oxandrolone (Anavar) 25 30 35 50 50 50 50 50
*This regimen was used by a bodybuilder who went through three cycles each year for 8 years.The subject also
reported taking 600 mg of testosterone per week between cycles. This subject ultimately developed avascular
necrosis in both femoral heads.
Source: From Pettine, p 96, with permission.118
30Ciccone(p)-30 1/30/07 2:54 PM Page 442
letes as part of controlled research studies. The effects determine the precise incidence and type of adverse
of androgens on athletic performance and the potential effects.64 Also, the long-term effects of androgen
adverse effects of these drugs are discussed briefly here. abuse may not be known for some time; that is,
pathologies may not be fully realized until several
Effects of Androgens on years after the drugs are discontinued.50,117 Nonethe-
less, there is considerable evidence, often in the form
Athletic Performance of individual reports and case studies, that androgen
There is little doubt that androgens can promote abuse can have severe and possibly fatal consequences.
skeletal muscle growth and increase strength in people Some of the more common adverse effects associated
who do not synthesize meaningful amounts of endoge- with androgen administration are presented below.
nous androgens (women, prepubescent males). The Further discussion of the potential adverse effects in
question has often been whether large amounts of athletes can be found in several reviews listed at the
exogenous androgens can increase muscle size, end of this chapter.50,64,99,117
strength, and athletic performance in healthy men. In High doses of androgens can produce liver dam-
general, it appears that athletic men taking androgens age, including the formation of hepatic tumors and
during strength training may experience greater incre- peliosis hepatis (blood-filled cysts within the
ments in lean body mass and muscle strength than ath- liver).17,99,145 In some individuals, these liver abnormal-
letes training without androgens.47,50,64 The extent of ities have proved fatal. Androgens can also produce
the increase, however, will vary considerably depend- detrimental changes in cardiac structure and function
ing on the dosage and type of androgens used.6,64 that result in cardiomyopathy, ischemic heart disease,
It also remains unclear what magnitude of any arrhythmias, and heart failure.48,157 Furthermore,
strength gains can be directly attributed to anabolic these hormones pose additional cardiovascular risks by
steroids. For instance, the anabolic effects of steroids producing unfavorable changes in blood lipid profiles,
cannot be isolated easily from the other factors that such as decreased high-density lipoprotein cholesterol
produce increments in strength and muscle size (e.g., levels.6,99 These effects on plasma lipids predispose the
weight training). In particular, androgens appear to athlete to atherosclerotic lesions and subsequent vessel
increase aggressiveness, and individuals taking these occlusion, and specific cases of stroke and myocardial
drugs may train longer and more intensely than ath- infarction in athletes using androgens have been
letes who are not taking them.63 Consequently, attributed to the atherogenic effects of these drugs.48,64
strength increments in the athlete taking androgens Androgens also cause hypertension because of direct
may be brought about by the enhanced quality and effects on the myocardium and because of the salt- and
quantity of training rather than as a direct effect of water-retaining properties of these drugs.99 Problems
anabolic steroids on muscle protein synthesis. with glucose metabolism brought about by insulin
Thus, the effects of androgens on athletic per- resistance have also been reported.24
formance in men remain unclear. It seems probable Androgens can affect bone metabolism, and avas-
that high dosages of androgens would increase muscle cular necrosis of the femoral heads has been docu-
size and strength, which might ultimately translate to mented in a weight lifter using these drugs.118
improved athletic performance.64 Nonetheless, we Androgens also accelerate closure of epiphyseal plates
may never know the exact ergogenic effects of these and can lead to impaired skeletal growth in young chil-
drugs in men because of the illicit nature of androgen dren. This effect on skeletal development is important
abuse and the ethical problems involved in performing because athletes may begin to self-administer anabolic
clinical studies of these drugs in humans.64,87 steroids at a relatively young age (i.e., prior to age
16).19 As previously mentioned, androgens may pro-
duce behavioral changes, including increased aggres-
Adverse Effects of Androgen Abuse sion, leading to radical mood swings and violent
Virtually any drugs that are taken at extremely high episodes in some individuals.99,103,116
dosages can be expected to produce serious side Androgens can produce changes in reproductive
effects. Exactly how harmful androgen abuse is in an function and secondary sexual characteristics. In males,
athletic population remains somewhat uncertain, high levels of androgens act as negative feedback and
however.64 The illicit nature of androgen abuse and lead to testicular atrophy and impaired sperm produc-
the various dosage regimens have made it difficult to tion. Infertility in males may result because of an
30Ciccone(p)-30 1/30/07 2:54 PM Page 443
inability to form sperm (azoospermia).75,93 In females, the onset of puberty, a complex series of hormonal
androgens produce certain masculinizing effects, such events stimulates the ovaries to begin producing estro-
as an increase in body hair, a deepening of the voice, gen and progesterone. Ovarian production of these
and changes in the external genitalia. Androgens may hormones initiates the maturation of reproductive
also impair the normal female reproductive (menstru- function and development of secondary sexual charac-
al) cycle. Some changes in male and female sexual and teristics in the female.
reproductive function appear to be reversible, but Estrogen is the primary hormone that initiates the
changes such as male infertility and azoospermia may growth and development of the female reproductive
take 4 months or longer to return to normal.75 Other system during puberty. Changes in the external geni-
effects, such as vocal changes in females, may be per- talia and maturation of the internal reproductive
manent. organs (e.g., uterus, oviducts, vagina) are primarily
In summary, anabolic steroids may produce some brought about by the influence of estrogen. Estrogen
ergogenic benefits in a limited subset of athletes, but also produces several other characteristic changes in
rather serious consequences may occur. Nonetheless, females, such as breast development, deposition of sub-
athletes may be so driven to succeed that the adverse cutaneous fat stores, and changes in the skeletal system
effects are disregarded. Also, athletes may suspect that (for example, closure of epiphyseal plates, widening of
their competitors are using steroids and feel that they the pelvic girdle). Progesterone is less important in
must also take these drugs to remain competitive. sexual maturation and is involved to a greater extent in
Clearly, there is a need for governing agencies to try facilitating and maintaining pregnancy.
to eliminate the illicit use of these substances from
athletic competition. Health care professionals can Regulation and Effects of Hormonal
also discourage androgen abuse by informing athletes
that the risks of androgen abuse exceed any potential
Synthesis During the Menstrual Cycle
benefits.154 In the nonpregnant, postpubescent female, production
of estrogen and progesterone is not tonic in nature but
follows a pattern or cycle of events commonly referred
Estrogen and Progesterone to as the menstrual cycle. The menstrual cycle usually
occurs over a 28-day period. The primary function of
In women, the ovaries produce two major categories this cycle is to stimulate the ovaries to produce an
of steroid hormones: estrogens and progestins. The ovum that is available for fertilization, while simulta-
primary estrogen produced in humans is estradiol, and neously preparing the endometrium of the uterus for
the primary progestin is progesterone. For simplicity, implantation of the ovum, should fertilization occur.
the terms estrogen and progesterone will be used to indi- These events are illustrated in Figure 30–2. The cycle
cate these two primary forms of female hormones. is characterized by several specific phases and events
Small amounts of male hormones (androgens) are also that are briefly outlined below. A more detailed de-
produced by the ovaries, and these androgens may scription of the regulation of female reproduction can
play a role in the development of some secondary sex- be found in several sources listed at the end of this
ual characteristics in the female during puberty, for chapter.33,88,94,113
example, increased body hair and growth spurts. Follicular Phase. The first half of the menstrual
Nonetheless, the hormones exerting the major influ- cycle is influenced by hormonal release from a devel-
ence on sexual development and reproduction in the oping ovarian follicle, hence the term “follicular
female are estrogen and progesterone. The physiolog- phase.” In the follicular phase, the anterior pituitary
ic effects of these hormones are presented here. releases FSH. As its name implies, FSH stimulates the
maturation of several follicles within the ovary. Usual-
Effects of Estrogen and Progesterone ly, one such follicle undergoes full maturation and
ultimately yields an ovum. Because of the effect of
on Sexual Maturation FSH, the developing follicle also begins to secrete in-
Estrogen and progesterone play a primary role in pro- creasing amounts of estrogen. Estrogen produced by
moting sexual differentiation in the developing female the ovarian follicle causes proliferation and thickening
fetus. These hormones also become important in com- of the endometrial lining of the uterus. The follicular
pleting female sexual maturation during puberty. At phase is also referred to as the proliferative phase.
30Ciccone(p)-30 1/30/07 2:54 PM Page 444
phase stimulates the LH surge that evokes ovulation. ment of the maternal mammary glands in prepara-
This event is considered an example of positive feed- tion for lactation. Although the role of estrogen is
back because low estrogen levels increase LH release, less clear, increased estrogen production may play
which further increases estrogen secretion, thus fur- a pivotal part in setting the stage for parturition.
ther increasing LH release, and so on. Conversely, Clearly, both steroids are needed for normal birth and
secretion of the pituitary gonadotropins (LH, FSH) is delivery.
inhibited toward the latter part of the luteal phase,
presumably because of the negative feedback influence
of high levels of estrogen and progesterone.
Pharmacologic intervention can take advantage Pharmacologic Use of
of these complex feedback systems in certain situa- Estrogen and Progesterone
tions. Most notable is the use of estrogen and proges- The most frequent and prevalent use of the female
terone as hormonal contraceptives. By altering the hormones is in contraceptive preparations (see “Hor-
normal control between pituitary and ovarian hor- monal Contraceptives”). The other primary indica-
mones and uterine function, preparations containing tions for estrogen and progesterone are replacement of
these two steroids are an effective means of birth con- endogenous hormone production and subsequent res-
trol. The pharmacologic use of female hormones is
olution of symptoms related to hormonal deficiencies.
discussed in more detail in “Pharmacologic Use of
This replacement can be especially important follow-
Estrogen and Progesterone.”
ing menopause—that is, when the female reproductive
cycle ceases and the associated cyclic production of the
Female Hormones in ovarian hormones ends. Specific clinical conditions
Pregnancy and Parturition that may be resolved by estrogen and progesterone are
listed below.
Estrogen and progesterone also play a significant role
in pregnancy and childbirth. For successful implanta-
tion and gestation of the fertilized egg to occur, Conditions Treated with
synthesis of these two steroids must be maintained
to prevent the onset of menstruation. As just men-
Estrogen and Progesterone
tioned, menstruation begins when the corpus luteum Replacement Therapy. Estrogen and progesterone
is no longer able to produce sufficient estrogen and are often used to replace the endogenous production
progesterone to sustain the endometrium. When of hormones following menopause or in women who
fertilization does occur, however, some hormonal have had an ovariectomy. Hormone replacement ther-
response must transpire to maintain steroid produc- apy—that is, the replacement of both estrogen and
tion from the corpus luteum and to ensure that progesterone, or the replacement of only estrogen—
the endometrium remains ready for implantation. has been used in certain women to control peri-
This response is caused by the release of human chori- menopausal and postmenopausal symptoms such as
onic gonadotropin (HCG) from the fertilized ovum. atrophic vaginitis, atrophic dystrophy of the vulva, and
HCG takes over the role of LH and rescues the vasomotor effects such as hot flashes.46,90,151 Likewise,
corpus luteum from destruction.82,133 The corpus there is little doubt that estrogens are essential in pre-
luteum then continues to produce steroids (especially venting and treating postmenopausal osteoporo-
progesterone), which maintain the uterine lining in a sis.28,92,148 Women receiving hormone replacements
suitable state for implantation and gestation of the fer- with estrogen are able to maintain or increase bone
tilized egg. mineral density, and estrogen replacement is often
Eventually, the corpus luteum does begin to associated with a decreased incidence of vertebral frac-
degenerate between the 9th and 14th week of gesta- tures and other osteoporosis-related problems.25,53,92
tion. By that point, the placenta has assumed estrogen Estrogen can also be combined with other interven-
and progesterone production. Generally speaking, tions such as calcium supplements, physical activity,
maternal progesterone helps to maintain the uterus and other medications (see Chapter 31) to provide
and placenta throughout the rest of the pregnancy. optimal protection against osteoporosis following
Progesterone also increases the growth and develop- menopause.28,78
30Ciccone(p)-30 1/30/07 2:54 PM Page 446
Nonetheless, the benefits of estrogen or hormone for Alzheimer disease, and additional studies are need-
replacement therapy must be balanced against the po- ed to determine the exact relationship between hor-
tential risks of these interventions (see “Adverse mone replacement therapy and dementia in older
Effects of Estrogen and Progesterone,” later). Certain women.
benefits that previously were reported from observa- Hypogonadism. Estrogens, or a combination of
tional studies have been challenged recently by ran- estrogen and progesterone, may be used to treat
domized controlled trials carefully investigating the abnormally low ovarian function. Appropriate use of
effects of hormonal replacement.11,127 For example, these hormones induces the uterine changes and cyclic
low doses of estrogen cause favorable changes in plas- bleeding associated with the normal female reproduc-
ma lipid profiles (decreased levels of low-density tive cycle.
lipoproteins and increased levels of high-density lipo- Failure of Ovarian Development. Occasionally, the
proteins), and it was thought that the beneficial effects ovaries fail to undergo normal development because
on plasma lipoproteins might decrease the risk of ath- of hypopituitarism or other disorders. Estrogens may
erosclerotic lesions and reduce the incidence of coro- be given at the time of puberty to encourage develop-
nary heart disease in postmenopausal women.121,134,160 ment of secondary sexual characteristics (e.g., breast
The idea that estrogen replacement offers protection development).
against coronary heart disease was challenged some- Menstrual Irregularities. Various problems with
what by a study known as the Heart and Estrogen/ normal menstruation are treated by estrogen and
Progesterone Replacement Study (HERS).74 Accord- progesterone. These hormones are used either sepa-
ing to the HERS findings, estrogen combined with rately or are combined to resolve amenorrhea, dys-
progesterone did not decrease the incidence of infarc- menorrhea, and other types of functional uterine
tion and death in postmenopausal women with a his- bleeding that are caused by a hormonal imbalance.
tory of coronary heart disease.74 In addition, the Endometriosis. Endometriosis is a condition char-
Women’s Health Initiative (WHI)—a large, random- acterized by growths of uterinelike tissue that occur at
ized controlled trial—failed to find a beneficial effect various locations within the pelvic cavity. Progesterone
on the incidence of coronary heart disease in postmen- and estrogen-progesterone combinations help sup-
opausal women receiving estrogen replacement.3,134 press bleeding from these tissues and may help shrink
Hence, it appears that hormone replacement the size of these growths.
can play a role in modifying certain risk factors associ- Carcinoma. Estrogen has been used to treat
ated with coronary heart disease in postmenopausal metastatic breast cancer in men and postmenopausal
women, but the actual outcomes (heart attack, death) women. Advanced prostate cancer in men may also
do not seem to be affected significantly by these hor- respond to estrogen treatment. Progesterone is help-
monal interventions. Clearly, continued research in ful in treating uterine cancer and several other types of
this area is needed to clarify if hormone replacement metastases, such as breast, renal, and endometrial car-
therapy can help decrease cardiac morbidity and mor- cinoma.
tality in certain postmenopausal women.60,121
Finally, it has been suggested that estrogen
Specific Agents
replacement may offer some protection against cogni-
tive decline in conditions such as Alzheimer disease Therapeutically used types of estrogens and prog-
and other forms of dementia.65,96 Estrogen may, for estins are listed in Tables 30–4 and 30–5. Both types of
example, have several neuroprotective effects, includ- hormones can be administered in their natural form
ing the ability to decrease free radical–induced dam- (estradiol and progesterone), and several synthetic
age, sustain cholinergic function in the brain, and derivatives of each type are also available. Most of the
inhibit the neuronal degeneration associated with drugs listed in Tables 30–4 and 30–5 are available as
Alzheimer disease.73 Conclusive evidence of the bene- oral preparations, and many conditions can be conve-
ficial effects, however, is lacking.11,65 On the contrary, niently treated by oral administration. These hor-
there is some evidence that estrogen replacement may mones may also be administered transdermally via
increase the incidence of dementia in older post- patches, creams, or gels; the transdermal route may
menopausal women.65,138 Estrogen replacement is offer certain advantages, such as decreased side effects
therefore not currently accepted as standard treatment and liver problems.86,130 Certain preparations can be
30Ciccone(p)-30 1/30/07 2:54 PM Page 447
such as chest pain, flulike syndrome, leg cramping, clinical application of these drugs is the termination of
venous thromboembolism, skin rash, and cystitis or pregnancy; that is, these drugs can be used to induce
urinary tract infections. abortion during the early stages of gestation. Because
Efforts continue to develop other SERMs that progesterone is largely responsible for sustaining the
will capitalize on the beneficial effects of estrogen placenta and fetus, the blockade of progesterone
while minimizing or even reducing the carcinogenic receptors in the uterus negates the effects of this hor-
effects of estrogen on other tissues. As newer agents mone, with subsequent detachment of the placenta
are developed, SERMs may have an expanded role in and loss of placental hormones such as human chori-
the treatment of various diseases and perhaps provide onic gonadotropin. Detachment of the placenta from
a safer and more effective method of estrogen replace- the uterine lining results in loss of the fetus and ter-
ment.54,59 mination of the pregnancy.
The primary antiprogestin is mifepristone,
known also as RU486. This drug can be administered
Antiestrogens orally during the first 7 weeks of pregnancy, with abor-
In addition to the SERMs, a limited number of drugs tion typically occurring within the next 2 to 3 days. To
directly antagonize all the effects of estrogen and are stimulate uterine contraction and ensure complete
considered to be true antiestrogens. These antiestro- expulsion of the detached embryo, a prostaglandin
gens appear to bind to estrogen receptors in the analog such as misoprostol or prostaglandin E1 is typ-
cytosol but do not cause any subsequent changes in ically administered orally or intravaginally 48 hours
cellular function. Hence, these drugs block the effects after mifepristone administration.135 This regimen of
of estrogen by occupying the estrogen receptor and mifepristone followed by a prostaglandin agent is suc-
preventing estrogen from exerting a response. Clomi- cessful in terminating pregnancy in approximately 95
phene (Clomid, Serophene) is an antiestrogen that is percent of cases.135
sometimes administered to women to treat infertili- Mifepristone has been used as an abortive agent
ty.8,72 The mechanism of clomiphene as a fertility drug in China and parts of Europe for some time, and this
is somewhat complex. Relatively high levels of estro- drug recently received FDA approval for use in the
gen normally produce an inhibitory or negative feed- United States. This drug is marketed in the United
back effect on the release of pituitary gonadotropins States under the trade name Mifeprex. When used to
(LH and FSH). As an antiestrogen, clomiphene blocks induce abortion, the primary physical side effects of
this inhibitory effect, thus facilitating gonadotropin mifepristone are excessive uterine bleeding and
release.72 Increased gonadotropins (especially LH) cramping, although these side effects may be related
promote ovulation, thus improving the chance of fer- more to the use of prostaglandins following mifepris-
tilization. The primary adverse effects associated with tone treatment.94 The chance of incomplete abortion
clomiphene are vascular hot flashes. Enlarged ovaries must also be considered, and a follow-up physician
may also occur because of the stimulatory effect of visit approximately 2 weeks after administration is
increased gonadotropin release. needed to ensure that the pregnancy was terminated.
More recently, fulvestrant (Faslodex) was intro- Consequently, the major focus on this drug at
duced as an antiestrogen. This drug binds to and present is its potential for use in terminating pregnan-
blocks estrogen receptors, and may also result in the cy. In the future, mifepristone may also be used for
receptors’ degradation.42,58 Hence, fulvestrant is used other reasons. This drug could, for example, have con-
to treat estrogen-sensitive breast cancers.27,58 This traceptive potential because it prevents ovulation and
drug is administered monthly by intramuscular injec- blocks the effects of progesterone on endometrial pro-
tion, and some redness and irritation can occur at the liferation and vascularization, thus rendering the
injection site. Other common side effects include gas- endometrium less favorable for implantation of the
trointestinal symptoms (nausea, vomiting, loss of fertilized egg. Mifepristone may likewise be useful as a
appetite) and vasomotor symptoms (hot flashes). “morning after” pill to prevent conception after
unprotected sex (see “Types of Contraceptive Prepara-
tions,” later).55,132 In addition to its effects on proges-
Antiprogestins terone receptors, mifepristone can also block cellular
Agents that specifically block progesterone receptors glucocorticoid receptors; the clinical significance of
were first developed in the early 1980s.94 The primary this effect remains to be explored.18 Finally, mifepris-
30Ciccone(p)-30 1/30/07 2:54 PM Page 450
tone may be useful in treating certain growths and more traditional (monthly) cycle regimens, although
tumors that are exacerbated by progesterone, includ- the longer cycles may cause more unscheduled bleed-
ing endometriosis, leiomyoma, meningioma, and ing or “spotting,” especially during the first few
breast cancer.94 It will be interesting to see how this cycles.2,66,110 Still, long cycle regimens may be pre-
drug is ultimately used to prevent or terminate preg- ferred by some women because they offer the conven-
nancy and perhaps manage progesterone-related dis- ience of fewer periods and menstrual symptoms
eases as well. (cramps, etc.).43,161
Contraceptive hormones can also be administered
via nonoral routes. A contraceptive patch containing
Hormonal Contraceptives ethinyl estradiol (an estrogen) and norelgestromin
(a progestin) can be applied to the skin once a week, to
During the 1960s, oral contraceptives containing allow the slow, transdermal administration of these
estrogens and progestins were approved for use in pre- hormones.49,79 A vaginal ring is also available as an
venting pregnancy. The introduction of these birth alternative to the oral contraceptive pill.131 This ring
control pills provided a relatively easy and effective typically contains estrogen and progesterone, and
method of contraception. Today, oral contraceptives these hormones are released slowly into the vagina
are taken routinely by many women of child-bearing and local tissues following insertion. The ring is insert-
age, and these drugs are among the most commonly ed vaginally for 3 weeks, and then removed for one
prescribed medications in the United States and week to allow menstruation (i.e., mimic the normal
throughout the world.94 Hormonal alternatives to oral uterine cycle).67 Transdermal patches and vaginal
contraceptives are also gaining popularity, and admin- rings are similar to oral contraceptives in terms of
istration of various compounds by injection, transder- effectiveness and side effects.119 The primary advan-
mal patch, subcutaneous implants, vaginal inserts, and tages of the nonoral routes are increased convenience
intrauterine devices are now available. These agents and adherence to the contraceptive regimen; that is,
are addressed below. the use of patches or a vaginal ring can be very help-
ful in women who sometimes forget to take a pill
every day.49,76
Types of Contraceptive Preparations
Other versions of oral contraceptives are available
The most common form of hormonal preparation is that contain only a progestin (norethindrone,
the oral contraceptive or “birth control pill,” which norgestrel; see Table 30–6). These “minipills” were
typically contains a fixed amount of estrogen and developed to avoid the adverse effects normally attrib-
progesterone in the same pill. Examples of some com- uted to estrogen. Progestin-only minipills are some-
mon estrogen-progestin contraceptives are listed in what less attractive as an oral contraceptive because
Table 30–6. When taken appropriately, these prepara- these preparations are only about 97 to 98 percent
tions appear to be 99 to 100 percent effective in pre- effective and because they tend to cause irregular
venting pregnancy.94 Typically, the contraceptive pill and unpredictable menstrual cycles. An implantable
is taken each day for 3 weeks, beginning at the onset form of a progestin-only preparation (Norplant) has
of menstruation. This intake is followed by 1 week in also been developed, whereby small, semipermeable
which either no pill or a “blank” pill that lacks the hor- tubes containing levonorgestrel are inserted subcuta-
mones is taken. For convenience and improved adher- neously in the arm.56,143 The progestin is delivered in
ence, these preparations are usually packaged in some a slow, continuous fashion, allowing effective contra-
form of dispenser that encourages the user to remem- ception for up to 5 years. These implants appear to
ber to take one pill each day. have contraceptive efficacy that is better than prog-
More recently, a variation on the length of the estin-only pills and is only slightly less effective than
oral contraceptive cycle was introduced in which combined estrogen-progestin oral contraceptives.
women take the active form of the pill for 84 days, and Progestin-only implants can be replaced at the end of
then take a 7-day placebo.66,70 This provides a 3- 5 years to continue this method of contraception, or
month cycle before menstruation, thus reducing the they can be removed at any time because of side effects
number of menstrual periods to only 4 per year. These or other reasons. There is likewise a form of proges-
long cycle regimens seem to be as effective as the terone (Depo Provera) that can be administered by
30Ciccone(p)-30 1/30/07 2:54 PM Page 451
Nonoral contraceptives
Ethinyl estradiol Norelgestromin Ortho Evra (transdermal patch)
deep intramuscular injection every 12 weeks.137 Also, coital interventions, or “morning-after pills,” typically
an intrauterine device has been developed that consist of a high dose of a natural or synthetic estro-
slowly releases a progestin within the uterus.79,137 gen, a progestin such as levonorgestrel, or estrogen
These implantable and injectable forms of proges- combined with a progestin (e.g., ethinyl estradiol
terone therefore offer alternatives to women who combined with norgestrel). The exact mechanism of
cannot tolerate estrogen-progesterone pills or who these morning-after pills is not known, but they
have difficulty adhering to traditional oral contracep- appear to somehow interfere with ovulation or make
tive regimens. the endometrium less favorable to implantation.122 As
Oral contraceptives that contain various hor- indicated earlier, mifepristone can be used as a morn-
mones are sometimes used to prevent conception fol- ing-after pill because this drug inhibits ovulation and
lowing sexual intercourse, especially in specific blocks progesterone receptors in the uterus, thereby
situations such as rape or unprotected sex. These post- negating the effects of progesterone on the endo-
30Ciccone(p)-30 1/30/07 2:54 PM Page 452
metrium and developing placenta.55 Hence, several activity, with the exception that chances of conception
options exist for preventing pregnancy after a specific are dramatically reduced.
incidence of sexual intercourse. Although these pills
can be helpful in emergency situations, they are not
meant to be an alternative to traditional birth control Adverse Effects of
methods. Hormonal Contraceptives
Although hormonal contraceptives provide an easy
Mechanism of Contraceptive Action and effective means of birth control, their use has been
Hormonal contraceptives exert their effects prima- limited somewhat by potentially serious side effects. In
rily by inhibiting ovulation and impairing the normal particular, contraceptive medications have been asso-
development of the uterine endometrium.94,122 As ciated with cardiovascular problems such as throm-
discussed previously, the normal menstrual cycle is bophlebitis, stroke, and myocardial infarction.153 The
governed by the complex interaction between endoge- incidence of these adverse effects, however, seems to
nous ovarian hormones and the pituitary gonado- depend to a large extent on whether the user has other
tropins. High levels of estrogen and progesterone in risk factors associated with cardiovascular disease
the bloodstream act as negative feedback and inhib- (smoking cigarettes, hyperlipidemia, hypertension,
it the release of LH and FSH from the anterior and so forth).84,120,162 Likewise, cardiovascular risks
pituitary. Hormonal contraceptives maintain fairly may be diminished with the newer forms of hormonal
high plasma levels of estrogen and progestin, thus contraceptives, which contain relatively less estrogen
limiting the release of LH and FSH through this than their predecessors.
negative feedback system. Because ovulation is nor- Over the years, the amount of estrogen contained
mally caused by the midcycle LH surge (see Fig. in the combined estrogen-progesterone preparations
30–2), inhibition of LH release prevents ovulation. has been reduced without sacrificing the contraceptive
This event prevents an ovum from being made avail- efficacy of these drugs.164 The lower estrogen content
able for fertilization. theoretically reduces the risk of cardiovascular prob-
The estrogen and progestin supplied by the con- lems, although scientific studies have not been able
traceptive also affect the development of the uterine to conclusively link the decreased risk of cardiovascu-
lining. These hormones promote a certain amount of lar incidents with a decrease in estrogen content in
growth and proliferation of the uterine endometrium. contraceptive products.52,153 Likewise, the newer hor-
The endometrium, however, does not develop to quite monal contraceptives tend to contain progestins that
the same extent or in quite the same manner as it have less androgenic properties; these newer prog-
would if it were controlled by normal endogenous estins may help reduce the risk of cardiovascular com-
hormonal release. Consequently, the endometrial en- plications.9,14 This does not mean that hormonal
vironment is less than optimal for implantation, even contraceptives are devoid of cardiovascular side effects.
if ovulation and fertilization should take place. Also, These agents clearly have the potential to impair
there is an increase in the thickness and viscosity of normal hemostasis and lead to venous thromboem-
the mucous secretions in the uterine cervix, thus bolism, myocardial infarction, and stroke.80,120 This
impeding the passage of sperm through the cervical risk is relatively modest, however, if modern estrogen-
region, which adds to these preparations’ contracep- progesterone preparations are taken by relatively
tive efficacy. healthy young women.120 Still, hormonal contracep-
Through the effects on the endometrium, tradi- tives should probably not be used by women with any
tional contraceptive regimens can be used to mimic a preexisting cardiovascular problems (hypertension,
normal menstrual flow. When the contraceptive hor- recurrent thrombosis) or any conditions or situations
mones are withdrawn, the endometrium undergoes a that may lead to cardiovascular disease (e.g., cigarette
sloughing similar to that in the normal cycle. Of smoking).80,120,153
course, the endometrium is being regulated by the There has been some indication that hormonal
exogenous hormones rather than the estrogen and contraceptives may lead to certain forms of cancer.
progesterone normally produced by the ovaries. Still, Some early versions of the pill were believed to cause
this method of administration and withdrawal can tumors of the endometrium of the uterus. Early
produce a more or less normal pattern of uterine forms that were sequential in nature may have caused
30Ciccone(p)-30 1/30/07 2:54 PM Page 453
this effect; that is, they provided only estrogen for There are a number of other less serious but
the first half of the menstrual cycle and estrogen bothersome side effects associated with hormonal
combined with progesterone for the second half. contraceptives. Problems such as nausea, loss of
However, the newer combined forms that supply appetite, abdominal cramping, headache, dizziness,
both hormones throughout the cycle do not appear to weight gain, and fatigue are fairly common. These
increase the risk of uterine cancer. In fact, it appears symptoms are often transient and may diminish fol-
that the form of oral contraceptive commonly used lowing continued use.
may actually decrease the risk of endometrial cancer, as Consequently, the serious risks associated with
well as prevent other forms of cancer, including hormonal contraceptives have diminished somewhat
ovarian cancer.12,13,45 The carcinogenic properties of since their initial appearance on the market. These
hormonal contraceptives have not been totally drugs are not without some hazards, however. In
ruled out, however. The effects on breast cancer general, it is a good policy to reserve this form of birth
remain controversial, and the possibility exists that control for relatively young, healthy women who do
certain subgroups of women may have an increased not smoke. Avoiding continuous, prolonged adminis-
risk of breast cancer, depending on factors such tration to diminish the risk of liver cancer may also
as how long they used the pill, their age, genetic be prudent. Finally, any increase in the other side
predisposition, and so forth.13,34,44 There is also con- effects associated with hormonal contraceptives, such
siderable evidence that prolonged use of oral contra- as headache and abdominal discomfort, should be care-
ceptives (more than 8 years) may increase the risk of fully evaluated to rule out a more serious underlying
liver cancer.91,163 problem.
CA S E ST U DY
Male and Female Hormones ing. Upon further examination, the patient also reported a dull
ache and tightness in the right calf, which was exacerbated by
Brief History. S.K. is a 32-year-old woman who sus- active and passive ankle dorsiflexion. Because the patient was
tained a whiplash injury during a motor vehicle accident. She taking an oral contraceptive and was also a cigarette smoker,
was being seen as an outpatient for physical therapy man- the therapist was concerned that this patient might have a
agement of neck pain, decreased cervical range-of-motion, deep vein thrombosis (DVT). The therapist called the patient’s
and cervicogenic headaches. The patient’s neck pain was physician, and the patient was referred immediately to the
being managed pharmacologically by an oral muscle relaxant local hospital for further evaluation. Venous plethysmography
(carisoprodol), and she also took an over-the-counter aceta- revealed a large DVT that began in the calf but extended prox-
minophen product as needed. During the initial examina- imally into the popliteal vein. The patient was admitted to the
tion/evaluation, the therapist queried the patient about other hospital to begin anticoagulant therapy.
medications, and the patient reported taking an oral contra- Decision/Solution. The patient was placed immedi-
ceptive product containing an estrogen (ethinyl estradiol, 0.05 ately on a low molecular weight heparin (enoxaparin), which
mg) and a progestin (norgestrel, 0.5 mg). This contraceptive was administered by subcutaneous injection (see Chapter
facilitated traditional monthly cycles (3 weeks of the active pill, 25). She also wore graduated compression stockings to
one week of placebo); she had been taking this product con- reduce the risk of further thromboembolic disease. The oral
tinuously for the past 11 years. The patient also smoked ciga- contraceptive medication was discontinued, and she was
rettes, and she had recently increased cigarette use following counseled on strategies to quit smoking. The patient was
the neck injury. eventually discharged to her home with instructions for con-
Problem/Influence of Medication. Approximately 2 tinuing the subcutaneous heparin. After approximately 10
weeks after beginning treatment, (i.e., during the fourth ther- days, an oral anticoagulant (warfarin) was substituted for the
apy session), the patient reported an increase in headache heparin. She resumed physical therapy as an out-patient,
pain. This finding surprised the therapist because the patient’s where her neck problem was ultimately resolved without fur-
neck pain and cervical function had had been steadily improv- ther incident.
30Ciccone(p)-30 1/30/07 2:54 PM Page 454
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Chapter 31
Thyroid and Parathyroid
Drugs: Agents Affecting
Bone Mineralization
This chapter discusses the function and pharmaco- rich vascular supply as well as extensive innervation
logic aspects of two important endocrine structures: from the sympathetic nervous system.55
the thyroid and parathyroid glands. Hormones secret- The thyroid gland synthesizes two primary hor-
ed from the thyroid gland are involved in controlling mones: thyroxine and triiodothyronine. A discussion of
metabolism; they also work synergistically with other the synthesis and function of these hormones follows.
hormones to promote normal growth and develop-
ment. The parathyroid glands are essential in regu- Synthesis of Thyroid Hormones
lating calcium homeostasis and are important in
maintaining proper bone mineralization. The chemical structures of thyroxine and triiodothy-
Problems in the function of the thyroid or para- ronine are shown in Figure 31–1. As shown in the fig-
thyroid glands are often treated by pharmacologic ure, thyroid hormones are synthesized first by adding
methods. Pharmacologic management of thyroid and iodine to residues of the amino acid tyrosine. Addition
parathyroid function should be of interest to rehabili- of one iodine atom creates monoiodotyrosine, and the
tation specialists because physical therapists and occu- addition of a second iodine creates diiodotyrosine.
pational therapists treat patients with bone healing Two of these iodinated tyrosines are then combined to
disorders and other endocrine problems related to complete the thyroid hormone. The combination of a
these glands. This chapter first discusses normal phys- monoiodotyrosine and a diiodotyrosine yields tri-
iologic function of the thyroid gland, followed by the iodothyronine, and the combination of two diiodoty-
types of drugs used to treat hyperthyroidism and hy- rosines yields thyroxine.55
pothyroidism. The function of the parathyroid glands Because thyroxine contains four iodine residues,
is covered next, discussing the role of the parathyroid this compound is also referred to by the abbreviation
glands and other hormones in maintaining bone min- T4. Likewise, triiodothyronine contains three iodine
eral homeostasis. Finally, drugs used to regulate bone residues, hence the abbreviation T3. There has been
calcification are presented. considerable discussion about which hormone exerts
the primary physiologic effects. Plasma levels of T4
are much higher than T3 levels, but T3 may exert most
of the physiologic effects on various tissues, which
Function of the Thyroid Gland suggests that T4 is a precursor to T3 and that the con-
The thyroid gland lies on either side of the trachea in version of T4 to T3 occurs in peripheral tissues.23
the anterior neck region and consists of bilateral lobes Regardless of which hormone ultimately affects cellu-
that are connected by a central isthmus. The entire lar metabolism, both T4 and T3 are needed for normal
gland weighs approximately 15 to 20 g and receives a thyroid function.
459
31Ciccone(p)-31 1/30/07 2:28 PM Page 460
I I NH2 I I NH2
The primary steps in thyroid hormone biosynthe- roglobulin (TGB), which contains tyrosine residues.
sis are shown schematically in Figure 31–2. Thyroid The TGB molecule is manufactured within the follicle
follicle cells take up and concentrate iodide from the cell and stored in the central lumen of the thyroid fol-
bloodstream—this is significant because there must be licle (see Fig. 31–2). During hormone synthesis, iodide
a sufficient amount of iodine in the diet to provide is oxidized and covalently bonded to the tyrosine
what is needed for thyroid hormone production.55 residues of the TGB molecule.35 Two iodinated tyro-
Thyroid cells also manufacture a protein known as thy- sine residues combine within the TGB molecule to
Blood Stream
Iodide
T4 T3
thyroid
peroxidase T4 T3
I– lysis
Thyroid
Follicle
Cell
I– iodinated TGB
G1
Thyroglobulin (TGB) (pre-DNA
synthesis)
Follicle Lumen
FIGURE 31–2 ▼ Thyroid hormone biosynthesis. Iodide is taken into the follicle cell, where it is
converted by thyroid peroxidase to an oxidized form of iodine (I–). I– is transported to the follicle
lumen, where it is bonded to tyrosine residues of the thyroglobulin (TGB) molecule. Iodinated TGB
is incorporated back into the cell, where it undergoes lysis to yield the thyroid hormones T3 and T4.
See text for further discussion.
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Chapter 31 Thyroid and Parathyroid Drugs: Agents Affecting Bone Mineralization 461
form T4 (primarily), and smaller amounts of T3 are various tissues, such as skeletal muscle, cardiac muscle,
also produced. At this point, the hormones are still and liver and kidney cells.
incorporated within the large TGB molecule. The iod- Growth and Development. Thyroid hormones
inated TGB molecule (TGB containing the iodinated facilitate normal growth and development by stimu-
tyrosines) is absorbed back into the follicle cell, where lating the release of growth hormone and by enhanc-
the large molecule is lysed to yield thyroid hormones. ing the effects of growth hormone on peripheral
The hormones are then secreted into the systemic cir- tissues. Thyroid hormones also directly enhance the
culation, where they can reach various target tissues. development of many physiologic systems, especially
the skeletal system and central nervous system (CNS).
If thyroid hormones are not present, severe growth
Regulation of Thyroid restriction and mental retardation (cretinism) ensue.
Hormone Release Cardiovascular Effects. Thyroid hormones appear
to increase heart rate and myocardial contractility,
Thyroid hormone production is controlled by the
thus leading to an increase in cardiac output. It is
hypothalamic-pituitary system (see Chapter 28). Thy-
unclear, however, if this occurrence is a direct effect of
rotropin-releasing hormone (TRH) from the hypo-
these hormones or if the thyroid hormones increase
thalamus stimulates the release of thyroid-stimulating
myocardial sensitivity to other hormones (norepi-
hormone (TSH) from the anterior pituitary.17,63 TSH
nephrine and epinephrine).
then travels via the systemic circulation to the thyroid
Metabolic Effects. Thyroid hormones affect
gland to stimulate the production of thyroxine and tri-
energy substrate utilization in a number of ways. For
iodothyronine.
instance, these hormones increase intestinal glucose
Thyroid hormone release is subject to the nega-
absorption and increase the activity of several enzymes
tive feedback strategy that is typical of endocrine sys-
involved in carbohydrate metabolism. Thyroid hor-
tems controlled by the hypothalamic-pituitary axis.
mones enhance lipolysis by increasing the response of
Increased circulating levels of the thyroid hormones
fat cells to other lipolytic hormones. In general, these
(T4, T3) serve to limit their own production by
and other metabolic effects help to increase the avail-
inhibiting TRH release from the hypothalamus and
ability of glucose and lipids for increased cellular
TSH release from the anterior pituitary.30,35 This neg-
activity.
ative feedback control prevents peripheral levels of
thyroid hormones from becoming excessively high.
Mechanism of Action
of Thyroid Hormones
Physiologic Effects of
The preponderance of evidence indicates that the thy-
Thyroid Hormones roid hormones enter the cell and bind to specific
Thyroid hormones affect a wide variety of peripheral receptors located within the cell’s nucleus.35,61 These
tissues throughout the individual’s life.8,55 In some sit- thyroid hormone receptors act as DNA transcription
uations, these hormones exert a direct effect on cellu- factors that bind to specific DNA sequences regulat-
lar function (e.g., T4 and T3 appear to increase cellular ing gene expression. When activated by the thyroid
metabolism by directly increasing oxidative enzyme hormone, thyroid receptors induce transcription of
activity). In other instances, thyroid hormones appear specific DNA gene segments, which ultimately results
to play a permissive role in facilitating the function of in altered protein synthesis within the cell.24,94 Most, if
other hormones. For instance, thyroid hormones must not all, of the physiologic effects of the thyroid hor-
be present for growth hormone to function properly. mones are related to this alteration in cellular protein
The principal effects of the thyroid hormones are production. For instance, thyroid hormones may act
listed below. through nuclear DNA transcription to stimulate the
Thermogenesis. T4 and T3 increase the basal synthesis of a particular enzymatic protein. Such a
metabolic rate and subsequent heat production from protein may increase the transport of specific sub-
the body, which are important in maintaining ade- stances (e.g., amino acids, glucose, sodium) across the
quate body temperature during exposure to cold envi- cell membrane, or the newly synthesized protein may
ronments. Increased thermogenesis is achieved by be directly involved in a metabolic pathway (e.g., gly-
thyroid hormone stimulation of cellular metabolism in colysis or lipid oxidation).
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Chapter 31 Thyroid and Parathyroid Drugs: Agents Affecting Bone Mineralization 463
gerated thyroid hormone production.3,79 There are tissues in certain forms of hyperthyroidism, such as
several other types of hyperthyroidism based on dif- in Graves disease.67,74 A specific dose of radioactive
ferent causes and clinical features (see Table 31–1).25,74 iodine is administered orally and rapidly sequestered
The principal manifestations of hyperthyroidism within the thyroid gland. The isotope then begins
are listed in Table 31–2. The treatment of this condi- to emit beta radiation, which selectively destroys the
tion often consists of ablation of the thyroid gland, thyroid follicle cells. Essentially no damage occurs
accomplished by surgically removing thyroid or by to surrounding tissues because the radioactivity is
administering radioactive iodine. Several pharmaco- contained within the thyroid gland. Thus, adminis-
logic agents may also be used in the management of tration of radioactive iodine is a simple, relatively
hyperthyroidism in various situations.1,74 These drugs safe method of permanently ablating the thyroid gland
and their clinical applications are discussed in the fol- and reducing excess thyroid hormone function.35 Of
lowing sections. course, patients who undergo radioactive destruction
Antithyroid Agents. Antithyroid drugs directly of the thyroid gland (or surgical thyroidectomy) must
inhibit thyroid hormone synthesis. The agents cur- typically be given thyroid hormones as replacement
rently in use are propylthiouracil (Propyl-Thyracil) therapy.67
and methimazole (Tapazole).19,45 These drugs inhibit Beta-Adrenergic Blockers. Beta-adrenergic block-
the thyroid peroxidase enzyme necessary for prepar- ers are usually associated with the treatment of cardio-
ing iodide for addition to tyrosine residues (see Fig. vascular problems such as hypertension and angina
31–2).5 These agents also prevent the coupling of pectoris. Beta blockers may also be helpful as an
tyrosine residues within the thyroglobulin molecule.19 adjunct in thyrotoxicosis.65,84 Although these drugs do
Propylthiouracil also inhibits the effects of the thyroid not directly lower plasma levels of thyroid hormones,
hormones by blocking the conversion of T4 to T3 in they may help suppress symptoms such as tachycardia,
peripheral tissues.19 The most common adverse effects palpitations, fever, and restlessness. Consequently,
of antithyroid drugs are skin rash and itching, beta blockers are usually not the only drugs used in
although this is usually mild and transient. Although the long-term control of hyperthyroidism but serve
serious problems involving formed blood elements as adjuncts to other medications such as antithy-
(agranulocytosis and aplastic anemia) may occur, the roid drugs. Beta blockers may be especially helpful in
incidence of such problems is relatively small. Finally, severe, acute exacerbations of thyrotoxicosis (thyroid
excessive inhibition of thyroid hormone synthesis storm). These drugs are also administered preopera-
from drug overdose may cause symptoms resembling tively to control symptoms until a more permanent
hypothyroidism, such as coldness and lethargy. means of treating thyrotoxicosis (thyroidectomy) can
Iodide. Relatively large dosages of iodide (exceed- be implemented.65 Some beta blockers that have been
ing 6 mg/d) cause a rapid and dramatic decrease in thy- used effectively in thyrotoxicosis are acebutolol,
roid function.35 In sufficient amounts, iodide inhibits atenolol, metoprolol, nadolol, oxprenolol, propra-
virtually all the steps involved in thyroid hormone nolol, sotalol, and timolol. The pharmacology and
biosynthesis. For instance, high iodide levels limit the adverse effects of these compounds are described in
uptake of iodide into thyroid follicle cells, inhibit the Chapter 20.
formation of T4 and T3, and decrease the secretion of
the completed hormones from the thyroid cell.
Although iodide is effective in treating hyperthy-
Hypothyroidism
roidism for short periods, the effects of this drug begin There are many forms of hypothyroidism, differing in
to diminish after about 2 weeks of administration.35 their cause and age of onset (see Table 31–1). Severe
Consequently, iodide is used in limited situations, adult hypothyroidism (myxedema) may occur idio-
such as temporary control of hyperthyroidism prior to pathically or may be caused by specific factors such as
thyroidectomy. In addition, iodide may cause a severe autoimmune lymphocytic destruction (Hashimoto
hypersensitive reaction in susceptible individuals. disease). In the child, thyroid function may be con-
Therefore, the use of iodide has been replaced some- genitally impaired, and cretinism will result if this
what by other agents such as antithyroid drugs and condition is untreated. Hypothyroidism may result at
beta blockers. any age if the dietary intake of iodine is extremely low.
Radioactive Iodine. A radioactive isotope of io- Several other forms of hypothyroidism that have a
dine(131I) is often used to selectively destroy thyroid genetic or familial basis also exist.54
31Ciccone(p)-31 1/30/07 2:28 PM Page 464
The primary physiologic effects of decreased thy- perceived quality-of-life.23,91 Hence, the ideal replace-
roid function are listed in Table 31–2. Although ment regimen may vary depending on each patient’s
enlargement of the thyroid gland (goiter) is usually needs, and efforts should be made to find the opti-
associated with hyperthyroidism, goiter may also be mal type and dose of thyroid hormones for each
present in some forms of hypothyroidism (although patient.
for different reasons). For instance, thyroid enlarge- Regardless of the exact regimen, thyroid hor-
ment occurs during hypothyroidism when there is a mone replacement is essential for maintaining optimal
lack of dietary iodine (endemic goiter). Under the health in adults with various forms of hypothy-
influence of TSH, the thyroid manufactures large roidism. Administration of thyroid hormones is
quantities of thyroglobulin. Thyroid hormone synthe- likewise important in infants and children with
sis is incomplete, however, because no iodine is avail- hypothyroidism because adequate amounts of these
able to add to the tyrosine residues. If no thyroid hormones are needed for normal physical and
hormones are produced, there is no negative feedback mental development.52 Thyroid hormone replacement
to limit the secretion of TSH. Consequently, the thy- is also necessary following thyroidectomy or pharma-
roid gland increases in size because of the unabated cologic ablation of the thyroid gland with radioac-
production of thyroglobulin. tive iodine. Thyroid hormones may be used to prevent
The primary method of treating hypothyroidism and treat cancer of the thyroid gland and to prevent
is to administer thyroid hormones as replacement enlargement of the thyroid gland (goiter) caused
therapy. Long-term administration of thyroid hor- by other drugs such as lithium. Thyroid hormone
mones is usually a safe, effective means of maintaining maintenance may be beneficial in patients who
optimal patient health in hypothyroidism. Replace- are in the preliminary or sub- clinical phase of
ment therapy using thyroid hormone preparations is hypothyroidism. Some clinicians feel that administer-
described below. ing these hormones in the early stages may prevent the
Thyroid Hormones. Replacement of deficient thy- disease from fully developing.7
roid hormones with natural and synthetic analogs is Thyroid hormone preparations used clinically are
necessary in most forms of hypothyroidism.14,91 listed in Table 31–3. The primary problems associated
Preparations containing T4 (levothyroxine), T3 (lio- with these agents occur with overdosage. Symptoms
thyronine), or both hormones can be administered to of excess drug levels are similar to the symptoms of
mimic normal thyroid function whenever the endoge- hyperthyroidism (see Table 31–2). Presence of these
nous production of these hormones is impaired. symptoms is resolved by decreasing the dosage or
There has, however, been considerable debate about changing the medication.
whether a replacement regimen should consist of T4
only, or a combination of T4 and T3. It appears that
combining both hormones does not provide addi- Function of the
tional benefits in certain physiologic responses (body
weight, lipid metabolism) compared to replacement
Parathyroid Glands
using only T4.15,33 Combining both hormones, how- In humans, there are usually four parathyroid glands
ever, may result in greater improvements in other that are embedded on the posterior surface of the
responses, including mood, psychometric skills, and thyroid gland. Each parathyroid gland is a pea-sized
T3 ⫽ triiodothyronine; T4 ⫽ thyroxine.
31Ciccone(p)-31 1/30/07 2:28 PM Page 465
Chapter 31 Thyroid and Parathyroid Drugs: Agents Affecting Bone Mineralization 465
structure weighing about 50 mg. Despite their PTH works with two other primary hormones—
diminutive size, parathyroids serve a vital role in calcitonin and vitamin D—in regulating calcium
controlling calcium homeostasis.36,70 Because calcium homeostasis. These three hormones, as well as several
is crucial in many physiologic processes—includ- other endocrine factors, are all involved in controlling
ing synaptic transmission, muscle contraction, and calcium levels for various physiologic needs. How
bone mineralization—the importance of parathy- these hormones interact in controlling normal bone
roid function is obvious. In fact, removal of the formation and resorption is of particular interest to
parathyroid glands results in convulsions and death rehabilitation specialists. Regulation of bone mineral
because of inadequate plasma calcium levels. The homeostasis and the principal hormones involved in
parathyroids control calcium homeostasis through the this process are presented in the following section.
synthesis and secretion of parathyroid hormone
(PTH), and the regulation and function of PTH is
discussed below. Regulation of Bone
Mineral Homeostasis
Parathyroid Hormone Bone serves two primary functions: to provide a rigid
PTH is a polypeptide hormone that is synthesized framework for the body and to provide a readily avail-
within the cells of the parathyroid glands. The pri- able and easily interchangeable calcium pool.83 To
mary factor controlling the release of PTH is the serve both functions simultaneously, an appropriate
amount of calcium in the bloodstream.36 A calcium- balance must exist between bone formation and bone
sensing receptor is located on the outer surface of the resorption.72 As already discussed, bone resorption
parathyroid cell membrane, and this receptor moni- (breakdown) can supply calcium for various physio-
tors plasma calcium levels.11,88 A decrease in plasma logic processes. Mineral resorption, however, occurs
calcium activates this receptor and causes increased at the expense of bone formation. The primary miner-
release of PTH. As blood calcium levels increase, the als that enable bone to maintain its rigidity are calci-
receptor is inhibited, and PTH release is reduced. um and phosphate. Excessive resorption of these
The primary physiologic effect of PTH is to in- minerals will result in bone demineralization, and the
crease blood calcium levels by altering calcium metab- skeletal system will undergo failure (fracture). In addi-
olism in three primary tissues: bone, kidney, and the tion, bone is continually undergoing specific changes
gastrointestinal tract.47,88 PTH directly affects skeletal in its internal architecture. This process of remodel-
tissues by increasing bone turnover, thus liberating cal- ing allows bone to adapt to changing stresses and opti-
cium from skeletal stores.70 High levels of PTH appear mally resist applied loads.72
to enhance the development and action of cells (osteo- Consequently, bone is a rather dynamic tissue
clasts) that break down skeletal tissues.86 Increased that is constantly undergoing changes in mineral con-
osteoclast activity degrades the collagen matrix within tent and internal structure. The balance between bone
the bone, thus releasing calcium into the bloodstream. resorption and formation is controlled by the complex
PTH also increases plasma calcium levels by increas- interaction of local and systemic factors. In particular,
ing renal reabsorption of calcium. As renal calcium several hormones regulate bone formation and help
reabsorption increases, PTH produces a simultaneous maintain adequate plasma calcium levels. The primary
increase in phosphate excretion. Thus, PTH produces hormones involved in regulating bone mineral home-
a rise in plasma calcium that is accompanied by a ostasis are described below.
decrease in plasma phosphate levels.36 Parathyroid Hormone. The role of the parathyroid
Finally, PTH helps increase the absorption of gland and PTH in controlling calcium metabolism
calcium from the gastrointestinal tract. This effect was previously discussed. A prolonged or continuous
appears to be caused by the interaction between PTH increase in the secretion of PTH increases blood calci-
and vitamin D metabolism. PTH increases the con- um levels by several methods, including increased
version of vitamin D to 1,25-dihydroxycholecalciferol resorption of calcium from bone. High levels of PTH
(calcitriol).36 Calcitriol directly stimulates calcium accelerate bone breakdown (catabolic effect) to mobi-
absorption from the intestine. lize calcium for other physiologic needs.
Consequently, PTH is crucial to maintaining However, normal or intermittent PTH release
adequate levels of calcium in the body. In addition, may actually enhance bone formation.70,77 That is, in-
31Ciccone(p)-31 1/30/07 2:28 PM Page 466
termittent release of moderate amounts of PTH can effects of calcitonin on bone mineral metabolism,
stimulate osteoblast activity and promote bone forma- however, are relatively minor compared with PTH,
tion (anabolic effect). The anabolic effects of low or and endogenous production of calcitonin is not
normal PTH levels seem limited to trabecular or can- essential for normal bone mineral homeostasis.41 In
cellous bone; PTH does not seem to enhance forma- contrast, PTH is a much more dominant hormone,
tion of solid or cortical bone.60 Nonetheless, the and the absence of PTH produces acute disturbances
possibility that small intermittent doses of PTH may in calcium metabolism that result in death. Calcitonin
increase certain types of bone formation has sparked does have an important therapeutic function, and
interest in using this hormone to prevent or reverse pharmacologic doses of calcitonin may be helpful
bone demineralization in certain conditions, includ- in preventing bone loss in certain conditions (see
ing osteoporosis (see later).71,77 Therefore, PTH plays “Pharmacologic Control of Bone Mineral Homeosta-
an important and complex role in regulating bone sis,” later).
metabolism. A prolonged, continuous increase in PTH Other Hormones. A number of other hormones
secretion favors bone breakdown, whereas normal influence bone mineral content.10 Glucocorticoids
(intermittent) PTH release encourages bone synthesis produce a general catabolic effect on bone and other
and remodeling. supporting tissues (see Chapter 29). Certain prosta-
Vitamin D. Vitamin D is a steroidlike hormone glandins are also potent stimulators of bone resorption.
that can be obtained from dietary sources or synthe- A number of hormones, such as estrogens, androgens,
sized in the skin from cholesterol derivatives in the growth hormone, insulin, and the thyroid hormones,
presence of ultraviolet light. Vitamin D produces sev- generally enhance bone formation. In general, the
eral metabolites that are important in bone mineral effects of these other hormones are secondary to the
homeostasis.27,31 In general, vitamin D derivatives more direct effects of PTH, vitamin D, and calcitonin.
such as 1,25 dihydroxyvitamin D3 increase serum cal- Nonetheless, all of the hormones that influence bone
cium and phosphate levels by increasing intestinal cal- metabolism interact to some extent in the regulation of
cium and phosphate absorption and by decreasing bone formation and breakdown. In addition, distur-
renal calcium and phosphate excretion.27,46 bances in any of these secondary endocrine systems
The effects of vitamin D metabolites on bone may produce problems that are manifested in abnor-
itself are somewhat unclear. Some metabolites seem to mal bone formation, including excess glucocorticoid
promote bone resorption and others seem to favor activity and growth hormone deficiency.
bone formation.10 The overall influence of vitamin D,
however, is to enhance bone formation by increasing
the supply of the two primary minerals needed for Pharmacologic Control
bone formation (calcium and phosphate). Vitamin D
also directly suppresses the synthesis and release of
of Bone Mineral Homeostasis
PTH from the parathyroid glands, an effect that tends Satisfactory control of the primary bone minerals is
to promote bone mineralization by limiting the cata- important in both acute and long-term situations.
bolic effects of PTH.46,92 Blood calcium levels must be maintained within a lim-
Calcitonin. Calcitonin is a hormone secreted by ited range to ensure an adequate supply of free calci-
cells located in the thyroid gland. These calcitonin- um for various physiologic purposes. The normal
secreting cells (also known as parafollicular or C cells) range of total calcium in the plasma is 8.6 to 10.6
are interspersed between follicles that produce thyroid mg/100 mL.41 If plasma calcium levels fall to below 6
hormones. Calcitonin can be considered the physio- mg/100 mL, tetanic muscle convulsions quickly ensue.
logic antagonist of PTH.36 Calcitonin lowers blood Excess plasma calcium (blood levels greater than 12
calcium by stimulating bone formation and increas- mg/100 mL) depresses nervous function, leading to
ing the incorporation of calcium into skeletal storage. sluggishness, lethargy, and possibly coma.
The action of calcitonin also enhances the incorpora- Chronic disturbances in calcium homeostasis can
tion of phosphate into bone. Renal excretion of cal- also produce problems in bone calcification. Likewise,
cium and phosphate is increased by a direct effect of various metabolic bone diseases can alter blood cal-
calcitonin on the kidneys, which further reduces the cium levels, leading to hypocalcemia or hypercal-
levels of these minerals in the bloodstream. The cemia. Some of the more common metabolic diseases
31Ciccone(p)-31 1/30/07 2:28 PM Page 467
Chapter 31 Thyroid and Parathyroid Drugs: Agents Affecting Bone Mineralization 467
Renal osteodystrophy Chronic renal failure; induces complex Vitamin D, calcium supplements
metabolic changes resulting in exces-
sive bone resorption
Gaucher disease Excessive lipid storage in bone leads to No drugs are effective
impaired remodeling and excessive
bone loss
women,9 but these supplements are certainly helpful Types of calcium supplements used clinically are
when combined with other treatments such as bisphos- listed in Table 31–5. The dose of a calcium supple-
phonates (see “Bisphosphonates,” later).85 The use of ment should make up the difference between dietary
oral calcium supplements appears to be especially calcium intake and established daily guidelines for
important in individuals who do not receive sufficient each patient. The exact dose for a patient therefore
amounts of calcium in their diet.12,85 depends on factors such as the amount of dietary
Calcium supplements Calcium carbonate (BioCal, Os-Cal Provide an additional source of calcium to pre-
500, Tums, others) vent calcium depletion and encourage bone
Calcium citrate (Citracal) formation in conditions such as osteoporo-
Calcium glubionate (Calcionate, Neo- sis, osteomalacia, rickets, and hypoparathy-
Calglucon) roidism
Calcium gluconate
Calcium lactate
Dibasic calcium phosphate
Tribasic calcium phosphate (Posture)
Estrogens Conjugated estrogens (Premarin) Stabilize bone turnover and promote bone
Esterified estrogen (Menest) mineralization in women that lack endoge-
Estradiol (Estrace, Climara, Estraderm, nous estrogen production (e.g., following
others) menopause or ovariectomy)
Estropipate (Ogen, Ortho-Est)
Raloxifene** (Evista)
Chapter 31 Thyroid and Parathyroid Drugs: Agents Affecting Bone Mineralization 469
calcium, age, gender, and hormonal and reproductive similar agents (see Table 31–5). Although their exact
status (e.g., women who are pregnant, premenopausal, mechanism is unclear, these compounds appear to
or postmenopausal).40,64 A woman, for example, who is adsorb directly into calcium crystals in the bone and to
postmenopausal and ingests 500 to 600 mg of dietary reduce bone resorption by inhibiting osteoclast activ-
calcium per day would need a supplemental dosage of ity.73,75 Thus, bisphosphonates are often used in Paget
approximately 800 mg/d because the recommended disease to help prevent exaggerated bone turnover and
dietary allowance (RDA) guideline for women after promote adequate mineralization.53 These agents can
menopause is 1200 to 1500 mg/d.13 also be used to inhibit abnormal bone formation in
Clearly, the dosage of a calcium supplement must conditions such as heterotopic ossification and to pre-
be determined by the specific needs of each individual. vent hypercalcemia resulting from increased bone
Excessive doses must also be avoided because they resorption in neoplastic disease.50,66 Bisphosphonates
may produce symptoms of hypercalcemia, including can also help prevent and treat bone loss during pro-
constipation, drowsiness, fatigue, and headache. As longed administration of anti-inflammatory steroids
hypercalcemia becomes more pronounced, confusion, (glucocorticoids).87
irritability, cardiac arrhythmias, hypertension, nausea Bisphosphonates have emerged as one of the pri-
and vomiting, skin rashes, and pain in bones and mus- mary treatments for osteoporosis, including osteo-
cle may occur. Hypercalcemia is a cause for concern porosis associated with estrogen loss in women after
because severe cardiac irregularities may prove fatal. menopause.26,90 Use of these drugs can increase bone
mineral density and reduce the risk of vertebral and
Vitamin D nonvertebral fractures (e.g., hip fractures) in men and
women with osteoporosis.26,69,73 Bisphosphonates have
Vitamin D is a precursor for a number of compounds
become especially attractive in treating post-
that increase intestinal absorption and decrease renal
menopausal osteoporosis because they improve bone
excretion of calcium and phosphate. Metabolites of
health in women without the risks associated with
vitamin D and their pharmacologic analogs are typical-
estrogen replacement (see “Estrogen Therapy,” later).
ly used to increase blood calcium and phosphate levels
Hence, bisphosphonates have become a mainstay in
and to enhance bone mineralization in conditions such
treatment of osteoporosis, and researchers continue to
as osteodystrophy, rickets, or other situations where
investigate optimal dosing regimens that take advan-
people lack adequate amounts of vitamin D. Vitamin D
tage of the beneficial effects of these drugs.22,32
analogs such as calcitriol have also been combined with
Bisphosphonates may produce some relatively
calcium supplements to help treat postmenopausal
minor side effects, including gastrointestinal distur-
osteoporosis,4,9 and to treat bone loss caused by anti-
bances such as nausea and diarrhea. In addition,
inflammatory steroids (glucocorticoids; see Chapter
patients should remain upright after taking a bisphos-
29).28,76 Specific vitamin D–related compounds and
phonate so that the drug does not reflux into the
their clinical applications are listed in Table 31–5.
esophagus and cause irritation (esophagitis). Specific
Vitamin D is a fat-soluble vitamin, and excessive
agents may also be associated with certain side effects.
doses can accumulate in the body, leading to toxicity.
Etidronate (Didronel), for example, can cause tender-
Some early signs of vitamin D toxicity include
ness and pain over bony lesion sites in Paget disease,
headache, increased thirst, decreased appetite, metallic
leading to fractures if excessive doses are taken for
taste, fatigue, and gastrointestinal disturbances (nau-
prolonged periods. Pamidronate (Aredia) may cause
sea, vomiting, constipation, or diarrhea). Increased
fever and localized pain and redness at the injection
vitamin D toxicity is associated with hypercalcemia,
site, but these effects usually last for only a day or two.
high blood pressure, cardiac arrhythmias, renal failure,
mood changes, and seizures. Vitamin D toxicity is a
serious problem that can cause death because of car- Calcitonin
diac and renal failure.
Calcitonin derived from synthetic sources can be
administered to mimic the effects of the endogenous
Bisphosphonates hormone. As described previously, endogenous calci-
The bisphosphonates (also called diphosphonates) are a tonin decreases blood calcium levels and promotes
group of inorganic compounds that include alen- bone mineralization. Consequently, synthetically
dronate (Fosamax), pamidronate (Aredia), and several derived calcitonin is used to treat hypercalcemia and to
31Ciccone(p)-31 1/30/07 2:28 PM Page 470
decrease bone resorption in Paget disease.53 Calcitonin Recent studies, however, indicated that estrogen
has also been used to help prevent bone loss in a replacement is associated with substantial risks, includ-
variety of other conditions, including rheumatoid ing an increased incidence of cardiovascular disease
arthritis,81 postmenopausal osteoporosis,44 and gluco- and certain cancers (see Chapter 30).2,89 Hence, estro-
corticoid-induced osteoporosis.62 Administration of gen replacement is no longer considered the corner-
calcitonin can reduce the risk of vertebral fractures, but stone for the long-term management of women with
does not seem to be as effective as the bisphosphonates postmenopausal osteoporosis.34 Estrogen can be used
in reducing this risk.82 On the other hand, calcitonin on a limited basis to prevent osteoporosis in certain
may have an analgesic effect on bone pain that compli- postmenopausal women with persistent vasomotor
ments the drug’s ability to promote bone healing.59,81 symptoms (i.e., hot flashes); that is, estrogen is used to
Hence, calcitonin may be a suitable alternative for peo- improve bone health while simultaneously treating the
ple with painful vertebral fractures who cannot tolerate vasomotor symptoms.18 Candidates for this treatment,
other drugs such as bisphosphonates.82,93 however, must be considered on a case-by-case basis to
In the past, calcitonin was administered by injec- make sure they do not have an increased risk for car-
tion (intramuscular or subcutaneous), but aerosolized diovascular disease or breast and uterine cancers.43
versions of calcitonin are now available that allow Estrogen can also be combined with other treatments
delivery in the form of nasal sprays.51,68 Oral delivery (calcium supplements, calcitonin, calcitriol, bisphos-
of calcitonin is difficult because this hormone is phonates) to promote optimal bone mineralization in
absorbed poorly from the gastrointestinal (GI) tract suitable candidates.
and because calcitonin is degraded by proteolytic Fortunately, concerns about estrogen led to the
enzymes in the stomach.57 Nonetheless, efforts are development of estrogenlike compounds that acti-
being made to overcome these limitations, and an oral vate estrogen receptors on certain tissues such as
form of calcitonin may be available someday.62 bone while blocking the effects of estrogen on breast
Hence, calcitonin has emerged as an effective and and uterine tissues. These agents are known as selec-
easy way to treat a variety of conditions that are char- tive estrogen receptor modulators (SERMs) because
acterized by increased bone resorption.59,82 Calcitonin of their ability to activate certain estrogen receptors
preparations used clinically are either identical to the on certain types of tissue preferentially.20,78 The phar-
human form of this hormone (Cibacalcin) or chemi- macology of SERMs is addressed in more detail in
cally identical to salmon calcitonin (Calcimar, Miacal- Chapter 30
cin). Redness and swelling may occur locally when The primary SERM used to prevent osteoporosis
these agents are administered by injection. Other side is raloxifene (Evista).21,42,48 This drug binds to and acti-
effects include gastrointestinal disturbances (stomach vates estrogen receptors in bone, thus preventing bone
pain, nausea, vomiting, and diarrhea), loss of appetite, loss and demineralization. At the same time, raloxifene
and flushing or redness in the head, hands, and feet. blocks estrogen receptors on breast and uterine tissues,
thereby preventing the excessive stimulation of recep-
tors that might lead to the development of cancer.
Estrogen Therapy Raloxifene also promotes positive effects on the car-
The benefits and risks of estrogen replacement ther- diovascular system, including improvements in plasma
apy were addressed in Chapter 30. There is little lipid profiles. Hence, SERMs such as raloxifene pro-
doubt that providing estrogen to women who lack vide an alternative to traditional estrogen therapy, and
endogenous estrogen production—that is, following may be especially useful to women who are at risk for
menopause or ovariectomy—can help increase bone cardiovascular disease or have a history of breast or
mineral content and reduce the risk of frac- uterine cancer.39 Efforts continue to develop other
tures.16,18,38,58 Estrogen is critical in maintaining ade- SERMs that will be effective in preventing osteoporo-
quate bone mineralization in women, and low doses of sis while minimizing the risks associated with tradi-
estrogen alone or estrogen combined with a progestin tional estrogen replacement therapy.
can be administered in certain women when endoge-
nous estrogen production is lost. Replacement of Other Agents That Promote
estrogen following menopause has been shown to be
especially effective—this treatment can return the rate
Bone Mineral Content
of bone formation and bone resorption to pre- Several other innovative strategies have been devel-
menopausal levels.38 oped recently to improve bone mineralization. Teri-
31Ciccone(p)-31 1/30/07 2:28 PM Page 471
Chapter 31 Thyroid and Parathyroid Drugs: Agents Affecting Bone Mineralization 471
paratide (Forteo), for example, is a synthetic form of earlier, plasma calcium ions regulate the release of
human parathyroid hormone (PTH) that was devel- PTH by affecting calcium receptors on the parathyroid
oped to treat severe cases of osteoporosis.77,80 As indi- gland. An increase in plasma calcium inhibits release of
cated earlier, prolonged or continuous release of PTH PTH, and a decrease in plasma calcium stimulates
increases bone resorption and breakdown, whereas PTH release. Drugs mimicking the effects of endoge-
intermittent doses of PTH may increase bone mineral nous calcium (i.e., calcimimetics) can therefore be used
density. Hence, small dosages of teriparatide (20 g) can to reduce PTH release in people with parathyroid
be administered daily by subcutaneous injection to tumors or other conditions that cause prolonged, con-
provide a burst of PTH activity.37,71 This treatment can tinuous release of PTH.29,49 This effect will help pre-
increase bone mineral density throughout the body, vent bone breakdown and the resulting increase in
resulting in a reduced risk of vertebral and nonverte- plasma calcium levels (hypercalcemia) that are associat-
bral fractures. ed with excessive PTH release. Cinacalcet (Sensipar) is
Another new strategy involves drugs that stim- the primary calcimimetic agent that is clinically used;
ulate calcium receptors on the parathyroid gland, other calcimimetics and strategies for controlling bone
thereby inhibiting the release of PTH.49 As indicated mineral content may be forthcoming.
CA S E ST U DY
Agents Affecting Bone total caloric intake and dietary levels of calcium and vitamin D
Mineral Metabolism have been very low. The patient is also rather reclusive,
spending most of her time indoors. Consequently, she virtu-
Brief History. R.D. is a 74-year-old woman with a his- ally lacks any exposure to natural sunlight. To treat her osteo-
tory of generalized bone demineralization caused by osteo- malacia, she was placed on a regimen of oral calcium
malacia that was primarily brought on by poor diet; that is, her supplements and vitamin D. However, she has been reluctant
31Ciccone(p)-31 1/30/07 2:28 PM Page 472
to take these supplements because when she did, she occa- to tolerate vitamin D (or its analogs), possibly because of
sionally experienced problems with diarrhea. Recently, she hypersensitivity to these compounds.
sustained a fracture of the femoral neck during a fall. She was Decision/Solution. The physical therapist working
admitted to the hospital, and the fracture was stabilized by with this patient realized that ultraviolet radiation stimulates
open reduction and internal fixation. The patient was referred the production of endogenous vitamin D. Ultraviolet light cat-
to physical therapy for strengthening and pre–weight-bearing alyzes the conversion of a cholesterollike precursor (7-dehy-
activities. drocholesterol) to vitamin D3 within the skin. Vitamin D3 then
Problem/Influence of Medication. During the undergoes conversions in the liver and kidneys to form spe-
postoperative period, calcium and vitamin D supplements cific vitamin D metabolites (i.e., 1,25-dihydroxyvitamin D),
were reinstituted to facilitate bone formation. The patient, which enhance intestinal calcium absorption. After conferring
however, soon began to experience bouts of diarrhea, appar- with the physician, the therapist incorporated a program of
ently as a side effect of the vitamin D supplements. Conse- therapeutic ultraviolet radiation into the treatment regimen.
quently, the vitamin D supplements were withdrawn, and only The appropriate dose of ultraviolet exposure was first deter-
the calcium supplement was continued. Because metabolic mined, followed by daily application of whole-body irradiation.
by-products of vitamin D accelerate the absorption of calcium Ultraviolet therapy was continued throughout the remainder
from the gastrointestinal tract, both agents should be admin- of the patient’s hospitalization, and callus formation at the
istered together. This patient, however, was apparently unable fracture site was progressing well at the time of discharge.
Chapter 31 Thyroid and Parathyroid Drugs: Agents Affecting Bone Mineralization 473
13. Celotti F, Bignamini A. Dietary calcium and 32. Epstein S, Zaidi M. Biological properties and mecha-
mineral/vitamin supplementation: a controversial nism of action of ibandronate: application to the treat-
problem. J Int Med Res. 1999;27:1. ment of osteoporosis. Bone. 2005;37:433–440.
14. Clarke N, Kabadi UM. Optimizing treatment of 33. Escobar-Morreale HF, Botella-Carretero JI, Gomez-
hypothyroidism. Treat Endocrinol. 2004;3:217–221. Bueno M, et al. Thyroid hormone replacement
15. Clyde PW, Harari AE, Getka EJ, Shakir KM. therapy in primary hypothyroidism: a randomized trial
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with levothyroxine alone in primary hypothyroidism: thyroxine alone. Ann Intern Med. 2005;142:412–424.
a randomized controlled trial. JAMA. 2003;290: 34. Farquhar CM, Marjoribanks J, Lethaby A, et al. Long
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60. Miyakoshi N. Effects of parathyroid hormone on can- Trends Endocrinol Metab. 2005;16:243–248.
cellous bone mass and structure in osteoporosis. Curr 80. Silver J, Bushinsky D. Harnessing the parathyroids to
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62. Munoz-Torres M, Alonso G, Raya MP. Calcitonin ther- 82. Silverman SL. Calcitonin. Endocrinol Metab Clin North
apy in osteoporosis. Treat Endocrinol. 2004;3:117–132. Am. 2003;32:273–284.
63. Nikrodhanond AA, Ortiga-Carvalho TM, Shibusawa 83. Simon LS. Osteoporosis. Clin Geriatr Med. 2005;21:
N, et al. Dominant role of thyrotropin-releasing hor- 603–629.
mone in the hypothalamic-pituitary-thyroid axis. J Biol 84. Streetman DD, Khanderia U. Diagnosis and treat-
Chem. 2006;281:5000–5007. ment of Graves disease. Ann Pharmacother. 2003;37:
64. North American Menopause Society. The role of calci- 1100–1109.
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opinion of The North American Menopause Society. osteoporosis drug therapy. J Womens Health. 2005;
Menopause. 2001;8:84–95. 14:180–192.
65. Panzer C, Beazley R, Braverman L. Rapid preoperative 86. Swarthout JT, D’Alonzo RC, Selvamurugan N, Par-
preparation for severe hyperthyroid Graves’ disease. J tridge NC. Parathyroid hormone-dependent signaling
Clin Endocrinol Metab. 2004;89:2142–2144. pathways regulating genes in bone cells. Gene. 2002;
66. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates 282:1–17.
for breast cancer. Cochrane Database Syst Rev. 2005; 87. Tamura Y, Okinaga H, Takami H. Glucocorticoid-
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postmenopausal women after total hip arthroplasty. py: controversies, pros and cons. Best Pract Res Clin
Gerontology. 2005;51:242–252. Endocrinol Metab. 2004;18:317–332.
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Chapter 31 Thyroid and Parathyroid Drugs: Agents Affecting Bone Mineralization 475
90. Watts NB. Bisphosphonate treatment of osteoporosis. 93. Woo T, Adachi JD. Role of bisphosphonates and calci-
Clin Geriatr Med. 2003;19:395–414. tonin in the prevention and treatment of osteoporosis.
91. Wiersinga WM. Thyroid hormone replacement thera- Best Pract Res Clin Rheumatol. 2001;15:469–481.
py. Horm Res. 2001;56(suppl 1):74–81. 94. Yen PM, Chin WW. Genomic and nongenomic
92. Willett AM. Vitamin D status and its relationship with actions of thyroid hormone. In: Braverman LE, Utiger
parathyroid hormone and bone mineral status in older RD, eds. Werner and Ingbar’s The Thyroid. 9th ed. New
adolescents. Proc Nutr Soc. 2005;64:193–203. York: Lippincott Williams and Wilkins; 2005.
31Ciccone(p)-31 1/30/07 2:28 PM Page 476
Chapter 32
Pancreatic Hormones and the
Treatment of Diabetes Mellitus
The pancreas functions uniquely as both an endocrine Langerhans. These islets contain cells that synthesize
and an exocrine gland. The gland’s exocrine role con- and secrete pancreatic hormones, thus constituting
sists of excretion of digestive enzymes into the duode- the endocrine portion of the gland.
num via the pancreatic duct. Pancreatic endocrine The pancreatic islets consist of four primary cell
function consists of the secretion of two principal hor- types: alpha (A) cells, which produce glucagon; beta (B)
mones—insulin and glucagon—into the bloodstream. cells, which produce insulin; delta (D) cells, which
Insulin and glucagon are primarily involved with the produce somatostatin; and (F) cells, which produce
regulation of blood glucose. Insulin also plays a role in pancreatic polypeptide. As previously mentioned, this
protein and lipid metabolism and is important in sev- chapter focuses on the functions of insulin and glu-
eral aspects of growth and development. Problems cagon. The exact physiologic roles of the other pan-
with the production and function of insulin cause a creatic hormones are not entirely clear. For example,
fairly common and clinically significant disease known the function of the pancreatic polypeptide released
as diabetes mellitus. from pancreatic F cells remains to be determined.
The purpose of this chapter is to review the nor- Somatostatin, however, is a polypeptide hormone
mal physiologic roles of the pancreatic hormones and that appears to affect several physiologic systems,
to describe the pathogenesis and treatment of diabetes including the regulation of gastrointestinal (GI)
mellitus. Diabetes mellitus has many sequelae that absorption and motility. Although the exact role of
influence patients’ neuromuscular and cardiovascular pancreatic somatostatin is still somewhat unclear, this
functioning. Patients with diabetes mellitus often hormone may inhibit the release of glucagon and
undergo physical rehabilitation for problems related insulin.93 Somatostatin is also produced in other tissues
to the condition. Consequently, the nature of diabetes including the brain and GI tract, and this hormone
mellitus and the pharmacotherapeutic treatment of may affect many other neuroendocrine responses.92
this disease are important to physical therapists and Future studies may clarify the physiological effects of
occupational therapists. somatostatin and pancreatic polypeptide.
Insulin
␣␣ Target cell
  ATP
ADP
PO4
insulin receptor
substrates
Glu Glu
glucose glucose
uptake storage
sequent postreceptor events may be responsible for duces a rapid increase in glycogen breakdown (gly-
some of the changes seen in certain forms of diabetes cogenolysis) in the liver, thus liberating glucose in the
mellitus. The possible role of these receptor-mediated bloodstream from hepatic glycogen stores. Glucagon
problems in diabetes is discussed later in “Type 2 then stimulates a more prolonged increase in hepatic
Diabetes.” glucose production (gluconeogenesis). This gluconeo-
genesis sustains blood glucose levels even after hepatic
glycogen has been depleted.93
Glucagon appears to exert its effects on liver cells
Glucagon by a classic adenyl cyclase–cyclic adenosine monophos-
Glucagon is considered to be the hormonal antagonist phate (cAMP) second messenger system (see Chapter
of insulin.29,35 The primary effect of glucagon is to in- 4).93 Glucagon binds to a specific receptor located on
crease blood glucose to maintain normal blood glucose the hepatic cell membrane. This stimulates the activi-
levels and to prevent hypoglycemia.35,93 Glucagon pro- ty of the adenyl cyclase enzyme that transforms adeno-
32Ciccone(p)-32 1/30/07 2:30 PM Page 480
sine triphosphate (ATP) into cAMP. Then, cAMP acts cells. When insulin release diminishes, the inhibition
as an intracellular second messenger that activates spe- of glucagon production is removed, and glucagon se-
cific enzymes to increase glycogen breakdown and cretion is free to increase. This intraislet regulation
stimulate gluconeogenesis. between insulin and glucagon is important during nor-
mal physiologic function as well as in pathologic con-
ditions, such as diabetes mellitus.53 A deficiency of
Control of Insulin insulin production permits an increase in glucagon
release, and the effects of increased glucagon may con-
and Glucagon Release tribute to some of the metabolic changes in diabetes
An adequate level of glucose in the bloodstream is mellitus (although the exact role of increased glucagon
necessary to provide a steady supply of energy for cer- in diabetes mellitus remains controversial).35
tain tissues, especially the brain. Normally, blood glu- Consequently, insulin and glucagon serve to
cose is maintained between 80 and 90 mg of glucose maintain blood glucose within a finite range. If the
per 100 mL of blood.29 A severe drop in blood glucose endocrine portion of the pancreas is functioning nor-
(hypoglycemia) is a potentially serious problem that can mally, blood glucose levels remain remarkably con-
result in coma and death. Chronic elevations in blood stant, even in situations such as exercise and prolonged
glucose (hyperglycemia) have been implicated in pro- fasting. However, any abnormalities in pancreatic
ducing pathologic changes in neural and vascular endocrine function can alter the regulation of blood
structures. Consequently, insulin and glucagon play glucose. In particular, problems associated with the
vital roles in controlling glucose levels, and the release production and effects of insulin can produce serious
of these hormones must be closely regulated. disturbances in glucose metabolism, as well as a num-
The level of glucose in the bloodstream is the pri- ber of other metabolic problems. Problems in insulin
mary factor affecting pancreatic hormone release.29 As production and function are characteristic of a disease
blood glucose rises (e.g., following a meal), insulin known as diabetes mellitus. The pathogenesis and
secretion from pancreatic beta cells is increased. treatment of this disease is presented in the following
Insulin then promotes the movement of glucose out of section.
the bloodstream and into various tissues, thus reducing
plasma glucose back to normal levels. As blood glucose
levels fall (e.g., during a sustained fast), glucagon is
released from the alpha cells in the pancreas. Glucagon
Diabetes Mellitus
resolves this hypoglycemia by stimulating the synthe- Diabetes mellitus is a disease caused by insufficient
sis and release of glucose from the liver. insulin secretion or a decrease in the peripheral effects
The release of insulin and glucagon may also be of insulin. This disease is characterized by a primary
governed by other energy substrates (lipids and amino defect in the metabolism of carbohydrates and other
acids), other hormones (thyroxine, cortisol), and auto- energy substrates. These metabolic defects can lead to
nomic neural control.29,46 Nonetheless, the major fac- serious acute and chronic pathologic changes. The
tor influencing pancreatic hormone release is blood term diabetes mellitus differentiates this disease from an
glucose. Cells located in the pancreatic islets are unrelated disorder known as diabetes insipidus. Dia-
bathed directly by the blood supply reaching the pan- betes insipidus is caused by a lack of antidiuretic hor-
creas. These cells act as glucose sensors, directly mon- mone (ADH) production or insensitivity to ADH.
itoring plasma glucose levels. In particular, the beta Consequently, the full terminology of “diabetes melli-
cells or insulin-secreting cells act as the primary glu- tus” should be used when referring to the insulin-relat-
cose sensors, and adequate control of insulin release ed disease. Most clinicians, however, refer to diabetes
seems to be a somewhat higher priority than the con- mellitus as simply “diabetes.”
trol of glucagon function.29 Diabetes mellitus is a common disease that affects
An important interaction between insulin and approximately 16 million people in the United States.90
glucagon may also take place directly within the pan- This disease is a serious problem in terms of increased
creas, and insulin appears to be the dominant hormone morbidity and mortality. Diabetes mellitus is the lead-
controlling this interaction.29,53 When the beta cells ing cause of blindness in adults and is the primary fac-
sense an increase in blood glucose, they release insulin, tor responsible for 30 percent of the cases of end-stage
which in turn inhibits glucagon release from the alpha renal failure.90 It is also estimated that 67,000 lower-
32Ciccone(p)-32 1/30/07 2:30 PM Page 481
extremity amputations are performed annually because cell destruction characteristic of this disease may be
of complications related to diabetes mellitus.90 Conse- caused in many patients by an autoimmune reac-
quently, this disease is a serious problem affecting the tion.40,126 Specifically, a virus or some other antigen
lives of many individuals. may trigger an autoimmune reaction that selectively
Diabetes mellitus is apparently not a single, destroys the insulin-secreting beta cells in susceptible
homogeneous disease but rather a disease existing in at individuals.71,126 Certain patients’ susceptibility to
least two primary forms.35,90 Patients with diabetes such viral-initiated immunodestruction may be due to
mellitus are usually classified as having either type 1 or genetic predisposition, environmental factors, or
type 2 diabetes, depending on the disease pathogene- other factors that remain to be determined.31,71,80 The
sis. The primary characteristics of type 1 and type 2 idea that type 1 diabetes may have an autoimmune
diabetes mellitus are summarized in Table 32–1. Spe- basis has led to the use of immunosuppressant agents
cific aspects of these two primary forms of diabetes in the early stages of this disease (see “Immunosup-
mellitus are discussed in more detail below. pressants,” later in this chapter).
to as insulin resistance.19,105 For instance, tissues such as obesity, and hyperlipidemia occur simultaneously in
the liver and skeletal muscle fail to respond adequate- the patient.61 Although the causes of insulin resistance
ly to insulin in the bloodstream.12 Thus, peripheral in this syndrome are not completely understood, they
uptake and use of glucose are blunted, even when probably involve a complex series of changes at the
insulin is present. systemic, cellular, and subcellular levels.19 There is
The exact cellular mechanisms responsible for consensus, however, that therapeutic strategies for
insulin resistance are unknown. The resistance may be resolving insulin resistance should be considered an
caused by a primary (intrinsic) defect at the target cell important part of the management of various condi-
that results in a decreased response of the cell to tions that exhibit this phenomenon.61,127
insulin. The decreased insulin response most likely
occurs because of changes in the way the cell responds Effects and Complications
after insulin binds to the surface receptor. Problems in
of Diabetes Mellitus
postreceptor signaling, such as decreased protein phos-
phorylation, impaired production of chemical media- The most common symptom associated with diabetes
tors, and a lack of glucose transporters, have all been mellitus is a chronic elevation of blood glucose (hyper-
suggested as intracellular events that could help explain glycemia). Hyperglycemia results from a relative lack
insulin resistance.12,19 Therefore, even though insulin of insulin-mediated glucose uptake and use by periph-
binds to the receptor, the cellular response is inade- eral tissues. Hyperglycemia initiates a number of com-
quate. Thus, insulin resistance appears to be a complex plex and potentially serious acute metabolic changes.
phenomenon that may involve a number of changes at For example, hyperglycemia is usually accompanied by
the cellular level. The exact changes in receptor signal- increased glucose excretion by the kidneys (glyco-
ing or postreceptor function that cause this problem suria). Glycosuria is caused by an inability of the kid-
remain to be determined. neys to adequately reabsorb the excess amount of
A defect in pancreatic beta cell function may also glucose reaching the nephron. Increased glucose ex-
contribute to the manifestations of type 2 diabetes. As cretion causes an osmotic force that promotes fluid
indicated, type 2 diabetes is often associated with plas- and electrolyte excretion, thus leading to dehydration
ma insulin levels that are normal or even slightly ele- and electrolyte imbalance.93 Also, the loss of glucose
vated. Insulin release, however, does not follow a in the urine causes a metabolic shift toward the mobi-
normal pattern in people with type 2 diabetes. Nor- lization of fat and protein as an energy source.
mally, insulin is released from the beta cells following Increased use of fats and protein leads to the formation
a meal, and release decreases substantially during fast- of acidic ketone bodies in the bloodstream. Excessive
ing. In most people with type 2 diabetes, insulin is accumulation of ketones lowers plasma pH, produc-
released continuously, even during fasting.35 Follow- ing acidosis (ketoacidosis), which can lead to coma
ing a meal, beta cells also fail to adequately increase and death.24
insulin release in proportion to the increased glucose Diabetes mellitus is associated with several other
levels in the bloodstream. This abnormal pattern of long-term complications involving vascular and neural
insulin release suggests that beta cell function has structures. Perhaps the most devastating complications
been impaired in people with type 2 diabetes. Hence, associated with this disease result from the develop-
the combination of peripheral tissue resistance and ment of abnormalities in small blood vessels (microan-
inappropriate beta cell response creates the funda- giopathy).35,103 Small vessels may undergo a thickening
mental metabolic abnormalities that underlie type 2 of the basement membrane, which can progress to the
diabetes. point of vessel occlusion.125 The progressive ischemia
Finally, insulin resistance is present in disease caused by small-vessel disease is particularly damaging
states other than type 2 diabetes mellitus. Patients to certain structures such as the retina (leading to
with conditions such as hypertension, obesity, and cer- blindness) and the kidneys (leading to nephropathy
tain hyperlipidemias are also found to have decreased and renal failure).7,57,125 Damage to cutaneous vessels
tissue sensitivity to circulating insulin.19,72 As dis- results in poor wound healing that can lead to ulcer
cussed in Chapter 21, a combination of these abnor- formation.85 Problems with large blood vessels (macro-
malities is often described as metabolic syndrome, or angiopathy) can also occur in diabetes because of defects
syndrome X.127,128 Metabolic syndrome occurs when in lipid metabolism that lead to atherosclerosis.35,110
insulin resistance, high blood pressure, abdominal Macroangiopathy is a principal contributing factor in
32Ciccone(p)-32 1/30/07 2:30 PM Page 483
Intermediate-acting
Long-acting
*
Human forms are derived from recombinant or biosynthetic human insulin.
**
Animal sources are derived from purified pork insulin.
or long-acting forms provide a sustained background For instance, a long-acting preparation may be supple-
level of insulin effects throughout the day or night. mented by occasional administration of a rapid-acting
Intermediate- and long-acting preparations can be cre- agent to provide optimal glycemic control.
ated by adding acetate buffers and zinc (Lente insulins) Finally, several commercial preparations are now
or protamine and zinc (NPH insulins) to the insulin available that combine two forms of insulin in the
molecule.35 These additions delay the absorption of same product. Some common examples include
the insulin molecule, thereby prolonging the effects preparations that contain a mixture of intermediate-
and decreasing the need for frequent administration. acting insulin (e.g., isophane human insulin) and
In addition, insulin glargine is a long-acting insulin rapid-acting insulin (e.g., regular human insulin,
that has been produced biosynthetically.120 Intermedi- aspart, or lispro). These insulins can be combined in
ate- and long-acting preparations are usually reserved specific amounts such as 50:50, 70:30, or 75:25 ratio of
for individuals who require less stringent control of intermediate- to rapid-acting form, depending on the
blood glucose levels—for example, those who are help- preparation. Products that combine two different
ing to manage their condition through diet and weight forms of insulin can help provide optimal control of
control. Also, combinations of different preparations blood glucose levels while minimizing the number of
may be used to manage diabetes in specific situations. injections needed to achieve this control.
32Ciccone(p)-32 1/30/07 2:30 PM Page 485
Administration of Insulin injections each day. These pumps may also provide
better control over blood glucose levels while reduc-
Insulin, a large polypeptide, is not suitable for oral ing the risk of side effects such as severe hypo-
administration. Even if the insulin molecule survived glycemia.95 The major drawback at present is that
digestion by proteases in the stomach and small intes- insulin pumps can malfunction, primarily because the
tine, this compound is much too large to be absorbed catheter delivering insulin becomes occluded or
through the gastrointestinal wall. Consequently, obstructed.42 Patients using insulin pumps must also
insulin is usually administered through subcutaneous monitor their glucose levels several times each day,
injection. Insulin may also be administered by the and they must understand how to correctly use the
intravenous route in emergency situations (e.g., dia- pump to deliver the appropriate amount of insulin.
betic coma). Nonetheless, insulin pumps currently offer a conven-
Patients on long-term insulin therapy are usually ient way to administer insulin, and technologic
trained to administer their own medication. In order to improvements in these devices may result in more
safely use insulin, it is important to provide adequate extensive use in the future.95
(refrigerated) storage of the preparation, to maintain Alternative routes for administering insulin are
sterile syringes, to accurately measure the dose and fill also being considered.51 In particular, a form of insulin
the syringe, and to use a proper injection technique. (Exubera) has been developed that can be administered
Patients should rotate the sites of administration by inhalation or nasal spray, thus precluding the need
(abdomen, upper thighs, upper arms, back, and but- for subcutaneous injection.88,104 Other modifications
tocks) to avoid local damage from repeated injection. of the insulin molecule or use of chemical enhancers
The optimal dosage of insulin varies greatly from can increase the permeability of this hormone so that
patient to patient, as well as within each patient. Fac- insulin can be administered through the skin (transcu-
tors such as exercise and dietary modification can taneously) or even via oral or buccal routes.2,35 Tech-
change the insulin requirements for each individual. nologic and practical advancements in insulin delivery
Consequently, the dosage of insulin is often adjusted continue to be explored, and methods for administer-
periodically by monitoring the patient’s blood glucose ing insulin may be safer and more convenient in the
level. Adjustment of insulin dosage in poorly con- future.
trolled diabetes mellitus is usually done under the
close supervision of a physician. Advancements in
glucose-monitoring devices that can be used in the
Intensive Insulin Therapy
home, however, now permit patients to routinely As indicated previously, the ultimate goal in the treat-
check their own blood glucose levels. Many patients ment of diabetes mellitus is to maintain blood glucose
can make their own insulin adjustments based on peri- in the normal physiologic range as much as possible.
odic blood glucose measurement. This process of glu- To achieve this goal, an administration strategy known
cose self-monitoring and insulin dosage adjustment as intensive insulin therapy has been developed for
permits optimal management of blood glucose levels persons who require exogenous insulin.17 The idea of
on a day-to-day basis. intensive insulin therapy is that the patient frequently
To avoid some of the problems of repeated sub- monitors his or her blood glucose level and self-
cutaneous injection, several alternative ways to admin- administers several (three or more) dosages of insulin
ister insulin have been explored. Insulin pumps, for per day, with each dose adjusted carefully to meet
example, can be used to deliver a continuous (back- the patient’s needs.33 Basically, several relatively small
ground) infusion of insulin that can also be supple- doses of insulin are able to maintain blood glucose in
mented at mealtime by manually activating the pump. the appropriate range much better than one or two rel-
These pumps can be worn outside the body, with atively large doses. Likewise, different types of insulin
insulin administered subcutaneously through a small can be combined to provide optimal results. For exam-
catheter and needle that is held in place by skin tape.42 ple, daily regimens can be designed that provide sever-
Alternatively, small implantable pumps are being al doses of short-acting insulin (including the newer
developed that can be placed surgically under the skin insulin analogs like insulin lispro, aspart, and glulisine),
and programmed to release insulin as needed.22 along with one or more doses of intermediate-acting
Insulin pumps are obviously much more convenient insulin.79,97 The short-acting doses can be adminis-
than using a hypodermic syringe to make multiple tered at mealtimes or whenever immediate control of
32Ciccone(p)-32 1/30/07 2:30 PM Page 486
glucose levels is needed, and the intermediate-acting Initial symptoms of hypoglycemia include
form can be administered once or twice a day to pro- headache, fatigue, hunger, tachycardia, sweating, anx-
vide lower, background levels of insulin throughout iety, and confusion. Symptoms progressively worsen
the day or night.34,79 as blood glucose continues to decrease, and severe
Of course, intensive insulin therapy requires hypoglycemia may lead to loss of consciousness, con-
more motivation and compliance on the part of the vulsions, and death. Consequently, early detection and
patient. Intensive therapy may also be associated resolution of hypoglycemia are imperative.13,121 In the
with a somewhat greater risk of severe hypoglycemia early stages, hypoglycemia can usually be reversed if
if the insulin dosage does not carefully match the the patient ingests foods containing glucose (soft
patient’s needs throughout the day.67 There is, drinks, fruit juice, glucose tablets, etc.). Typically,
nonetheless, considerable evidence that this strategy administration of the equivalent of 10 to 15 g of D-
reduces the long-term complications associated glucose is recommended to restore blood glucose in
with diabetes, including a lower incidence of neu- the early stages of hypoglycemia.90
ropathies, renal disease, and other complications relat- Other problems that may be encountered are
ed to microangiopathy.17,34,99 Hence, intensive insulin related to the immunologic effects of insulin use. Cer-
therapy may be worth the extra effort because this tain forms of insulin may evoke an immune reaction
strategy can help prevent devastating complications and stimulate antibody production. These anti-insulin
that are typically associated with poorly controlled antibodies may cause an allergic reaction in some indi-
diabetes mellitus. viduals, as well as a resistance to the exogenous insulin
molecule. As discussed previously, the incidence of
these immunologic reactions seems to be greater
Adverse Effects of Insulin Therapy when animal (i.e., pork) forms of insulin are used.
The primary problem associated with insulin adminis- Consequently, these problems are often resolved by
tration is hypoglycemia.90,121 Exogenous insulin may switching the patient to another type of preparation,
produce a dramatic fall in blood glucose levels because preferably biosynthetic human insulin.
insulin lowers blood glucose. Hypoglycemia may
occur during insulin therapy if the dose of insulin is
higher than the patient’s needs. Missing a meal or
receiving a delayed meal may also precipitate hypo-
Oral Antidiabetic Drugs
glycemia. During insulin treatment, insulin is not Several agents are now available that can be adminis-
released exclusively after a meal, as it would be during tered by mouth to help control blood glucose levels
normal function. Insulin administered from an exoge- in people with type 2 (NIDDM) diabetes mellitus.
nous source may be present in the bloodstream even if These drugs tend to be most effective if some endoge-
the patient fails to provide glucose by eating. Hence, nous insulin production is present, but insulin
insulin may reduce blood glucose below normal levels secretion is relatively inadequate and the peripheral
because of the lack of a periodic replenishment of tissues are resistant to the effects of the endogenous
blood glucose from dietary sources. insulin. These agents are therefore not effective for
Strenuous physical activity may promote hypo- treating type 1 diabetes, but they can be used along
glycemia during insulin therapy. Exercise generally with diet and exercise for the long-term management
produces an insulinlike effect, meaning that exercise of type 2 diabetes.
accelerates the movement of glucose out of the blood- Oral antidiabetic drugs do not offer a cure for
stream and into the peripheral tissues (skeletal muscle) type 2 diabetes, and their effectiveness varies consid-
where it is needed. The combined effects of exercise erably from patient to patient. Still, it appears that
and insulin may produce an exaggerated decrease in early and aggressive use of one or more of these
blood glucose, thus leading to hypoglycemia. To avoid agents can substantially reduce any complications
exercise-induced hypoglycemia, the insulin dose associated with this disease. A brief description of cur-
should be decreased by 30 to 35 percent.16 Careful rently available oral antidiabetic agents follows; agents
measurement of blood glucose before and after exer- that are categorized as sulfonylureas will be addressed
cise can help predict how much the insulin should be first, followed by a diverse group of newer orally act-
adjusted in each patient. ing agents.
32Ciccone(p)-32 1/30/07 2:30 PM Page 487
Classification and Examples* Mechanism of Action and Effects Primary Adverse Effects
Sulfonylureas Increase insulin secretion from pancre- Hypoglycemia is the most common
Acetohexamide (Dymelor) atic beta cells; increased insulin and potentially serious side
Chlorpropamide (Diabinese) release helps reduce blood glucose effect of the sulfonylureas; other
Glimepiride (Amaryl) by increasing glucose storage in bothersome effects (gastroin-
Glipizide (Glucotrol) muscle and by inhibiting hepatic glu- testinal disturbances, headache,
Glyburide (DiaBeta, Micronase) cose production etc.) may occur depending on
Tolazamide (Tolinase) the specific agent
Tolbutamide (Orinase)
(e.g., leukopenia, agranulocytosis). These side effects ue to improve as more is learned about the best way to
are usually mild and transient, but may require atten- use existing oral drugs, and as other new oral antidia-
tion if they are severe or prolonged. betic agents become available.32
quite prevalent in patients with type 2 diabetes, weight tissues and surgically transplanted into the pancreas
loss seems to be especially effective in reducing drug of patients with type 1 diabetes who lack adequate
requirements in these individuals.44 insulin production. Other strategies induce stem cells
to develop into insulin-producing cells that can be
transplanted into the pancreas.91,98,111 Agents that
Exercise induce differentiation and growth of endogenous beta
Exercise appears to be beneficial in diabetes melli- cells may likewise help sustain or increase beta cell
tus for several reasons. First, physical training may mass in certain patients with diabetes.15,86,124 Alterna-
help facilitate weight loss, thus helping to decrease tively, the entire pancreas can be transplanted from
body mass and drug requirements.6,107 Secondly, reg- organ donors into patients with type 1 diabetes; this
ular exercise appears to increase the sensitivity of procedure may be done simultaneously with a kidney
peripheral tissues to insulin; that is, training helps transplant in patients with diabetic nephropathy.65,113 If
overcome insulin resistance.63,77 The exact reason for successful, these tissue transplants can provide the
this effect is not clear. Finally, a program of physical patient with an endogenous source of insulin that will
training will improve general health and well being, decrease or eliminate the need for insulin therapy. The
making patients with diabetes less susceptible to vari- success rates of these transplants are likewise improv-
ous problems such as cardiovascular disease.6,87 Of ing steadily, primarily because newer immunosuppres-
course, patients beginning a program of regular exer- sant agents and gene-based strategies are available to
cise should undergo a complete physical examination, prevent tissue rejection.20,119
and the frequency and intensity of the exercise should New molecular strategies are also being investi-
be closely monitored. gated that could reestablish insulin production and
insulin sensitivity by transplanting insulin-related
genes into the cells of patients with diabetes melli-
Tissue Transplants and Gene Therapy tus.47,68 These techniques basically attempt to either
A relatively new approach in treating diabetes mellitus deliver insulin genes directly into patients’ cells or
is the transplantation of tissues containing pancreatic focus on transplanting genetically altered cells that
beta cells into patients with this disease.73,109 For exam- will produce or respond to insulin.68 Although tech-
ple, islet tissues containing functioning beta cells can niques such as tissue transplants and gene therapy are
be harvested from adult, neonatal, or fetal pancreatic still relatively experimental, they may eventually be
precipitated if the patient has not eaten or is engaging in relatively strenuous physical activity.
Therapists must ensure that patients are maintaining a regular dietary schedule and have not
skipped a meal prior to the therapy session. Likewise, therapists should be especially alert for
any signs of hypoglycemia during and after exercise.
Therapists should note any changes (confusion, fatigue, sweating, nausea) in the patient
that may signal the onset of hypoglycemia. If these symptoms are observed, administration of a
high-glucose snack is typically recommended. Therapists working with diabetic patients should
have sources of glucose on hand to reverse these hypoglycemic symptoms. Some sources of glu-
cose include soft drinks, fruit juices, and tablets containing D-glucose.29
Physical therapists and occupational therapists may help reinforce the importance of
patient compliance during pharmacologic management of diabetes mellitus. Therapists can
question whether patients have been taking their medications on a routine basis. Regular admin-
istration of insulin is essential in preventing a metabolic shift toward ketone body production
and subsequent ketoacidosis, especially in patients with type 1 diabetes. In addition, therapists
can help explain that adequate control of blood glucose not only prevents acute metabolic prob-
lems but also seems to decrease the incidence of the neurovascular complications.
Finally, rehabilitation specialists can encourage patient compliance in the nonpharmaco-
logic management of their disease. Therapists can emphasize the importance of an appropriate
diet and adequate physical activity in both type 1 and type 2 diabetes. Therapists may also play
an important role in preventing the onset of diabetic foot ulcers and infection by educating the
patient in proper skin care and footwear.
CA S E ST U DY
Diabetes Mellitus ity. The physical therapist was aware of this and other poten-
tial problems that could arise.
Brief History. W.S. is an 18-year-old woman who Decision/Solution. The therapist reminded the ath-
began experiencing problems with glucose metabolism fol- lete to monitor her blood glucose levels before and after each
lowing a viral infection when she was 12. She was subse- practice session and to adjust her insulin dosage accordingly.
quently diagnosed as having type 1 diabetes mellitus. Since During some of the initial practice sessions, blood glucose
then, her condition has been successfully managed by insulin was also monitored during practice to ensure that insulin
administration combined with dietary control. Once-daily dosages were adequate. On practice days, insulin was
administration of intermediate-acting insulin combined with injected into abdominal sites rather than around exercising
periodic administration of short-acting insulin usually provides muscles (thighs), in order to prevent the insulin from being
optimal therapeutic effects. She is also very active athletically absorbed too rapidly from the injection site. The therapist also
and was a member of her high school soccer team. She is reminded the athlete to eat a light meal before each practice
entering her first year of college and is beginning preseason and to be sure to eat again afterward. The therapist main-
practice with the college’s soccer team. The physical therapist tained a supply of glucose tablets and fruit juice on the prac-
that serves as the team’s athletic trainer was apprised of her tice field. The athlete was questioned periodically to look for
condition. early signs of hypoglycemia (confusion, nausea, etc.), and
Problem/Influence of Medication. Exercise pro- ingestion of carbohydrates was encouraged whenever appro-
duces an insulinlike effect; that is, it lowers blood glucose by priate. Finally, the therapist assigned a teammate to check on
facilitating the movement of glucose out of the bloodstream the athlete within an hour after practice ended to ensure that
and into peripheral tissues. Because insulin also lowers blood no delayed effects of hypoglycemia were apparent. With these
glucose, the additive effects of insulin and exercise may pro- precautions, the athlete successfully completed preseason
duce profound hypoglycemia. As a result, a lower dosage of training, as well as the entire soccer season without any seri-
insulin is usually required on days that involve strenuous activ- ous incident.
32Ciccone(p)-32 1/30/07 2:30 PM Page 492
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SECTION
Chemotherapy
of Infectious and
Neoplastic Diseases
33Ciccone(p)-33 1/30/07 4:10 PM Page 498
Chapter 33
Treatment of Infections I:
Antibacterial Drugs
This chapter and the next two chapters in this text Agents used specifically against small, unicellular orga-
address drugs used to treat infections caused by patho- nisms (e.g., bacteria, viruses) are often referred to as
genic microorganisms and parasites. Microorganisms antimicrobial drugs. Antimicrobial agents are also com-
such as bacteria, viruses, and protozoa, as well as larg- monly referred to as antibiotics, indicating that these
er multicellular parasites, frequently invade human tis- substances are used to kill other living organisms (i.e.,
sues and are responsible for various afflictions ranging anti-”bios,” or life). To avoid confusion, drugs in this
from mild and annoying symptoms to life-threatening text are classified and identified according to the pri-
diseases. Often, the body’s natural defense mechanisms mary type of infectious organism they are used to
are unable to deal with these pathogenic invaders, and treat––that is, whether they are antibacterial, antiviral,
pharmacologic treatment is essential in resolving infec- antifungal, and so on.
tions and promoting recovery. Drugs used to treat in- This chapter discusses drugs used to treat bacter-
fection represent one of the most significant advances ial infections. Drugs used to treat and prevent viral
in medical history, and these agents are among the infections are presented in Chapter 34, followed by
most important and widely used pharmacologic agents the pharmacologic management of other parasitic
throughout the world. infections (antifungal, antiprotozoal, and anthelmintic
Drugs used to treat infectious diseases share a drugs) in Chapter 35. Because infectious disease rep-
common goal of selective toxicity, meaning they resents one of the most common forms of illness,
must selectively kill or attenuate the growth of the many patients undergoing therapists physical rehabil-
pathogenic organism without causing excessive dam- itation take one or more of these drugs. Physical ther-
age to the host (human) cells. In some cases, the path- apists and occupational therapists will undoubtedly
ogenic organism may have some distinctive structural deal with patients undergoing chemotherapy for
or biochemical feature that allows the drug to selec- infectious disease on a routine basis. The pharma-
tively attack the invading cell. For instance, drugs that cotherapeutic management of infectious disease that is
capitalize on certain differences in membrane struc- presented in Chapters 33 through 35 should be of
ture, protein synthesis, or other unique aspects of cel- interest to all rehabilitation specialists.
lular metabolism in the pathogenic organism will be
effective and safe anti-infectious agents. Of course,
selective toxicity is a relative term, because all of the Bacteria: Basic Concepts
drugs discussed in the following chapters exert some
adverse effects on human tissues. However, drugs used
Bacterial Structure and Function
to treat various infections generally impair function Bacteria are unicellular microorganisms, ranging in
much more in the pathogenic organism than in human size from 0.8 to 15.0 m in diameter.45 Bacteria are
tissues. distinguished from other microorganisms by several
Several other general terms are also used to features, including a rigid cell wall that surrounds the
describe the drugs used to treat infectious disease. bacterial cell and the lack of a true nuclear membrane
499
33Ciccone(p)-33 1/30/07 4:10 PM Page 500
(i.e., the genetic material within the bacterial cell is Streptococcus genus, which are commonly associated
not confined by a distinct membrane).50 Bacteria usu- with pyogenic or pus-producing characteristics.
ally contain the basic subcellular organelles needed to Because of diverse bacterial genera, bacteria are
synthesize proteins and maintain cellular metabolism, often categorized according to common characteris-
including ribosomes, enzymes, and cytoplasmic stor- tics, such as the shape and histologic staining of the
age granules. Bacteria, however, must depend on some bacterial cell.50 For example, gram-positive cocci refers
kind of nourishing medium to provide metabolic sub- to spherical bacteria (cocci) that retain the discol-
strates to maintain function. Hence, these microor- oration of a particular staining technique (Gram’s
ganisms often invade human tissues to gain access to a method of staining). However, development of a com-
supply of amino acids, sugars, and other substances. prehensive taxonomy that neatly categorizes all bacte-
ria is difficult because of the diverse morphologic and
biochemical characteristics of the various bacterial
Pathogenic Effects of Bacteria families and genera.
Bacterial infections can be harmful to host organisms For the purpose of this chapter, bacteria are cate-
in several ways.32,45 First, bacteria multiply, competing gorized according to the criteria outlined in Table
with host (human) cells for essential nutrients. Bacteria 33–1. This classification scheme does not fully identi-
also may directly harm human cells by releasing toxic fy all of the various characteristics of the many bacter-
substances. Moreover, bacteria may cause an immune ial families. The classifications listed in Table 33–1 are
response that will ultimately damage human tissues used here only to categorize bacteria according to the
and the invading bacteria. Of course, not all bacteria in use of antibacterial agents, which are discussed later in
the human body are harmful. For example, certain bac- this chapter under “Specific Antibacterial Agents.”
teria in the gastrointestinal system inhibit the growth
of other microorganisms and assist in the digestion of
food and synthesis of certain nutrients. In addition,
many bacteria that enter the body are adequately dealt
Treatment of Bacterial
with by normal immunologic responses. However, the Infections: Basic Principles
invasion of pathogenic bacteria can lead to severe Spectrum of Antibacterial Activity
infections and death, especially if the patient’s immune
system is compromised or the body’s endogenous Some drugs are effective against a variety of bacteria;
defense mechanisms are unable to combat the infec- these are usually referred to as broad-spectrum agents.
tion. In some cases, bacteria may establish growth For example, a drug such as tetracycline is considered
areas or colonies that remain innocuous for extended to have a broad spectrum of activity because this drug
periods. However, this colonization may begin to pro- is effective against many gram-negative, gram-positive,
liferate and become a health threat when the patient and other types of bacteria. In contrast, a drug such as
succumbs to some other disorder or illness. Conse- isoniazid is specific for the bacillus that causes tuber-
quently, the chance of severe, life-threatening infec- culosis (i.e., Mycobacterium tuberculosis), and its spec-
tions is especially high in individuals who are trum of activity is relatively narrow. Hence, the
debilitated or have some immune system defect. antibacterial spectrum is one property of an antibac-
terial drug that determines the clinical applications of
that agent. Other factors, including patient tolerance,
Bacterial Nomenclature bacterial resistance, and physician preference, also
and Classification influence the selection of a particular drug for a partic-
Bacteria are usually named according to their genus ular condition. The clinical use of antibacterial drugs
and species; these names are identified in italic type- relative to specific bacterial pathogens is discussed in
face.45 For instance, Escherichia coli refers to bacteria “Clinical Use of Antibacterial Drugs: Relationship to
from the Escherichia genus, coli species. According to Specific Bacterial Infections.”
this nomenclature, the genus is capitalized and refers
to bacteria with common genetic, morphologic, and Bactericidal Versus
biochemical characteristics. The species name is not
capitalized and often refers to some physical, patho-
Bacteriostatic Activity
genic, or other characteristic of the species. For exam- The term bactericidal refers to drugs that typically kill
ple, Streptococcus pyogenes refers to bacteria from the or destroy bacteria. In contrast, drugs that do not actu-
33Ciccone(p)-33 1/30/07 4:10 PM Page 501
Gram-negative bacilli Rod-shaped; do not retain color by Gram’s Escherichia coli, Klebsiella pneumoni-
method ae, Pseudomonas aeruginosa
Gram-positive cocci Generally spherical or ovoid in shape; retain Staphylococcus aureus, Streptococcus
color by Gram’s method pneumoniae
Gram-negative cocci Spherical or ovoid; do not retain color by Neisseria gonorrhoeae (gonococcus),
Gram’s method Neisseria meningitidis (meningo-
coccus)
Acid-fast bacilli Rod-shaped; retains color of certain stains Mycobacterium leprae, Mycobacteri-
even when treated with acid um tuberculosis
Spirochetes Slender; spiral shape; able to move about Lyme disease agent; Treponema pal-
without flagella (intrinsic locomotor ability) lidum (syphilis)
Actinomycetes Thin filaments that stain positively by Gram’s Actinomyces israelii; Nocardia
method
Others:
Mycoplasmas Spherical; lack the rigid, highly structured cell Mycoplasma pneumoniae
wall found in most bacteria
ally kill bacteria but limit the growth and proliferation nisms include (1) inhibition of bacterial cell wall syn-
of bacterial invaders are referred to as bacteriosta- thesis and function, (2) inhibition of bacterial protein
tic. Antibacterial drugs are usually classified as either synthesis, and (3) inhibition of bacterial DNA/RNA
bactericidal or bacteriostatic, depending on their function. The details of these mechanisms, along with
mechanism of action. In addition, the classification of the reasons why each mechanism is specific for bacte-
whether a drug is bactericidal or bacteriostatic may rial (versus human) cells, are discussed next.
depend on the drug dosage. For instance, drugs such as
erythromycin exhibit bacteriostatic activity at lower
doses but are bactericidal at higher doses.
Inhibition of Bacterial Cell
Wall Synthesis and Function
Penicillin, cephalosporins, and several other common-
Basic Mechanisms ly used drugs exert antibacterial effects by inhibiting
the synthesis of bacterial cell walls.56 These drugs are
of Antibacterial Drugs selectively toxic because the bacterial cell walls differ
As mentioned previously, antibacterial and other considerably from those of their mammalian counter-
antimicrobial drugs must be selectively toxic to the parts. The membrane surrounding most bacterial cells
infectious microorganism, without causing excessive (with the exception of the Mycoplasma genus) is a rela-
damage to human cells. Drugs that exert selective tox- tively rigid, firm structure.74 This rigidity appears to
icity against bacteria generally employ one of the be essential in constraining the high osmotic pressure
mechanisms shown in Figure 33–1. These mecha- within the bacterial cell.88 This behavior contrasts
33Ciccone(p)-33 1/30/07 4:10 PM Page 502
*
(polymyxin B, colistin). These drugs are cationic com-
1. Inhibition of cell wall pounds that are attracted to negatively charged phos-
synthesis/function pholipids in the bacterial cell membrane. The
e.g. penicillins selectivity of these agents for bacterial cell membranes
cephalosporins
polymixins
may be due to a greater attraction to certain bacterial
phospholipids, as opposed to human cell membrane
phospholipids. In any event, these drugs penetrate and
disrupt the architecture and integrity of the surface
*
e.g. metronidazole
rifampin
sulfonamides Bacteria, like most living organisms, must continually
trimethoprim synthesize specific proteins to carry out various cellu-
lar functions, including enzymatic reactions and mem-
brane transport. A fairly large and well-known group
of antibacterial agents works by inhibiting or impair-
FIGURE 33–1 ▼ Primary sites of antibacterial drug action on bacte- ing the synthesis of these bacterial proteins. Drugs
rial cells. See text for discussion. that exert their antibacterial effects in this manner
include the aminoglycosides (e.g., gentamicin, strep-
tomycin), erythromycin, the tetracyclines, and several
with the relatively supple, flexible membrane encom-
other agents.34,79 Generally, drugs that inhibit bacteri-
passing the mammalian cell.
al protein synthesis enter the bacterial cell and bind to
The increased rigidity of bacterial cell walls is
specific ribosomal subunits.5,59 Antibacterial drugs
caused by the presence of protein-polysaccharide
that work by this mechanism have a much greater
structures known as peptidoglycans.74,88 Peptidoglycan
affinity for bacterial ribosomes than for human ribo-
units (also known as mureins) are cross-linked to one
somes, hence their relative specificity in treating bac-
another within the cell wall in such a way as to provide
terial infections. Binding of the drug to the ribosome
a remarkable amount of rigidity and firmness to the
either blocks protein synthesis or causes the ribosome
cell. If these peptidoglycans are not present, the bac-
to misread the messenger RNA (mRNA) code, result-
terial membrane will lack integrity and will cause
ing in the production of meaningless or nonsense pro-
altered function and impaired homeostasis within the
teins.34,87 The lack of appropriate protein production
bacterial cell. Also, the lack of adequate membrane
impairs bacterial cell membrane transport and meta-
cytoarchitecture appears to initiate a suicidal autolysis,
bolic function, resulting in retarded growth or death
whereby bacterial hydrolases released from lysosomes
of the bacteria.
begin to break down the cell wall, thus further con-
tributing to destruction of the microorganism.50
Consequently, drugs that cause inadequate pro- Inhibition of Bacterial DNA/RNA
duction of peptidoglycans or other structural compo-
nents within the cell wall may produce a selective
Synthesis and Function
bactericidal effect. Also, a limited number of antibac- As in any cell, bacteria must be able to replicate their
terial agents directly punch holes in the bacterial cell genetic material to reproduce and function normally.
membrane, destroying the selective permeability and An inability to produce normal DNA and RNA will
separation of internal from external environment, prohibit the bacteria from mediating continued growth
33Ciccone(p)-33 1/30/07 4:10 PM Page 503
and reproduction. Drugs that exert their antibacterial other essential metabolites. Examples of drugs that
activity by directly or indirectly interfering with the exert antibacterial effects by this mechanism are
structure, synthesis, and function of DNA and RNA trimethoprim and the sulfonamide drugs (e.g., sulfadi-
in susceptible bacteria include the fluoroquinolones, azine, sulfamethoxazole).33,82
sulfonamides, and several other agents.57 Apparently,
these drugs are able to selectively impair bacterial
DNA/RNA function because they have a greater affin-
ity for bacterial genetic material and enzymes related Specific Antibacterial Agents
to bacterial DNA/RNA synthesis. Considering the vast number of antibacterial drugs, we
Several antibacterial drugs inhibit bacterial nucle- cannot explore the pharmacokinetic and pharmacolog-
ic acid synthesis by inhibiting the production of folic ic details of each individual agent. For the purposes of
acid.17 Folic acid serves as an enzymatic cofactor in a this chapter, the major groups of antibacterial drugs
number of reactions, including synthesis of bacterial are categorized according to the basic modes of anti-
nucleic acids and certain essential amino acids. The bacterial action that were previously discussed (inhibi-
pathway for synthesis of these folic acid cofactors is tion of cell wall synthesis, etc.). Pertinent aspects of
illustrated in Figure 33–2. Certain antibacterial drugs each group’s actions, uses, and potential side effects are
block specific steps in the folate pathway, thus impair- briefly discussed. For a more detailed description of
ing the production of this enzymatic cofactor and ulti- any specific agent, the reader is referred to one of the
mately impairing the production of nucleic acids and current drug indexes, such as the Physician’s Desk Refer-
ence (PDR).
Para-aminobenzoic Acid
Antibacterial Drugs That
Dihydrofolate
Inhibit Bacterial Cell Wall
synthetase Synthesis and Function
Table 33–2 lists drugs that exert their primary anti-
Dihydrofolic Acid bacterial effects by impairing bacterial cell membrane
synthesis and function. Clinical use and specific
aspects of these drugs are presented below.
Dihydrofolate
reductase
Penicillins
Folic Acid Cofactors Penicillin, the first antibiotic, was originally derived
from mold colonies of the Penicillium fungus during
the early 1940s. Currently, there are several forms of
natural and semisynthetic penicillins (see Table 33–2).
These agents have a chemical structure and mode of
action similar to the cephalosporin drugs and several
Nucleic Acid Precursor Synthesis other agents. Collectively, the penicillins and these
other drugs are known as beta-lactam antibiotics
because they share a common structure known as a
beta-lactam ring.56
Penicillin and other beta-lactam agents exert their
effects by binding to specific enzymatic proteins with-
DNA Synthesis in the bacterial cell wall. These enzymatic proteins,
known as penicillin-binding proteins (PBPs), are
FIGURE 33–2 ▼ Folic acid metabolism in bacterial cells. Certain
antibacterial drugs (e.g., sulfonamides and trimethoprim) inhibit the responsible for the normal synthesis and organization
dihydrofolate synthetase and reductase enzymes, thus interfering of the bacterial cell wall. In particular, PBPs help man-
with DNA biosynthesis. ufacture the peptidoglycans, which are essential for
33Ciccone(p)-33 1/30/07 4:10 PM Page 504
normal membrane structure and function.47,78 Peni- V) can be administered orally but have a relatively
cillins and other beta-lactam drugs attach to the PBPs narrow antibacterial spectrum. Some semisynthetic
and inhibit their function.56,78 Thus, construction of penicillins (amoxicillin, ampicillin) have a broader
the bacterial cell wall is impaired, and the cell dies antibacterial spectrum and may be administered either
from the membrane’s inability to serve as a selective orally or parenterally, depending on the specific agent.
barrier and to contain the high internal osmotic pres- Penicillinase-resistant forms of penicillin were
sure of the bacterial cell. developed to overcome strains of bacteria that contain
an enzyme known as a penicillinase or beta-lactamase.
This enzyme destroys natural and some semisynthetic
Classification and Use of Penicillins
penicillins, rendering these drugs ineffective in bacte-
As indicated in Table 33–2, penicillins can be classified ria containing this enzyme. For penicillinase-contain-
according to their chemical background, spectrum of ing bacteria, the semisynthetic forms of penicillin that
antibacterial activity, or pharmacokinetic features.56 are resistant to destruction by the penicillinase must
The naturally occurring penicillins (penicillin G and be used (see Table 33–2).
33Ciccone(p)-33 1/30/07 4:10 PM Page 505
Discussing all the clinical applications of the gram-negative bacteria, but they have limited effects
penicillins goes well beyond the scope of this chapter. on gram-positive cocci. Fourth-generation agents have
These agents are a mainstay in the treatment of infec- the broadest antibacterial spectrum of the cephalospo-
tion and remain the drugs of choice in a diverse array rins, and they are effective against gram-positive and
of clinical disorders. Table 33–5 gives some indication gram-negative organisms. Specific indications for
of the clinical uses of the penicillins. Clearly, these cephalosporins are listed in Table 33–5.
agents continue to be one of the most important and
effective antibacterial regimens currently available. Adverse Effects
In some patients, cephalosporins may cause an allergic
Adverse Effects reaction similar to the penicillin hypersensitivity
One of the primary problems with penicillin drugs is described previously. A cross-sensitivity often exists: a
the potential for allergic reactions.65 Hypersensitivity patient who is allergic to penicillin drugs will also dis-
to penicillin is exhibited by skin rashes, hives, itching, play hypersensitivity to cephalosporin agents. Other
and difficult breathing. In some individuals, these principal adverse effects of cephalosporins include gas-
reactions may be minor and can often be resolved by trointestinal problems such as stomach cramps, diar-
changing the type of penicillin or the method of rhea, nausea, and vomiting.
administration. In others, however, penicillin hyper-
sensitivity may be severe and lead to an anaphylactic Other Agents That Inhibit
reaction (severe bronchoconstriction and cardiovascu-
lar collapse).
Bacterial Cell Wall Synthesis
During prolonged administration, penicillin Aztreonam. Aztreonam (Azactam) is another type
drugs may also cause central nervous system (CNS) of beta-lactam antibiotic, but this drug is classified as
problems (e.g., confusion, hallucinations), as well as a carbapenam agent rather than a penicillin or ceph-
certain blood disorders, such as hemolytic anemia and alosporin.4 Nonetheless, aztreonam acts like the other
thrombocytopenia. Other relatively minor side effects beta-lactam agents and inhibits the synthesis and struc-
of penicillin drugs include gastrointestinal problems ture of the cell membrane in susceptible bacteria.
such as nausea, vomiting, and diarrhea. Aztreonam has a limited spectrum, but it may be use-
ful against serious infections caused by certain gram-
negative bacilli (Enterobacter aerogenes and Pseudomonas
Cephalosporins aeruginosa). The principal problems associated with
The cephalosporin drugs, which are also classified as aztreonam include skin rashes, redness, and itching
beta-lactam antibiotics, exert their bactericidal effects due to hypersensitivity in susceptible individuals.
in a manner similar to that of the penicillins (inhibition Bacitracin. Bacitracin refers to a group of poly-
of PBPs, resulting in inadequate peptidoglycan pro- peptide antibiotics that have similar chemical and
duction).56 Generally, the cephalosporins serve as pharmacologic properties. These compounds inhibit
alternative agents to penicillins if the penicillin drugs bacterial cell wall synthesis by inhibiting the incorpo-
are ineffective or poorly tolerated by the patient. ration of amino acids and nucleic acid precursors into
Cephalosporins may also be the drugs of choice in cer- the bacterial cell wall. Bacitracin compounds, which
tain types of urinary tract infections (see Tables 33–5). have a broad range of antibacterial activity, are effec-
Cephalosporins can be subdivided into first-, sec- tive against many gram-positive bacilli and gram-
ond-, third-, and fourth-generation groups, according positive cocci, as well as several other microorganisms.
to their spectrum of antibacterial activity (see Table Bacitracin is usually applied topically to prevent and
33–2). First-generation cephalosporins, which are gen- treat infection in superficial skin wounds and certain
erally effective against gram-positive cocci, may also ophthalmic infections. Commercial preparations con-
be used against some gram-negative bacteria. Second- taining bacitracin may also contain other antibiotics,
generation cephalosporins are also effective against such as neomycin and polymyxin B. The primary
gram-positive cocci, but they are somewhat more problem associated with bacitracin is local hypersensi-
effective than first-generation agents against gram- tivity, as indicated by skin rashes and itching.
negative bacteria. Third-generation cephalosporins Colistin. Colistin (also known as colistimethate or
have the broadest spectrum of effectiveness against polymyxin E) is similar to polymyxin B in terms of
33Ciccone(p)-33 1/30/07 4:10 PM Page 506
pharmacologic mechanism and antibacterial effects.31 em.81 Meropenem, however, does not need to be ad-
Colistin is used primarily in combination with other ministered with cilastatin. This agent may likewise be
agents (neomycin and hydrocortisone) to treat local effective against certain forms of gram-positive and
infections of the external auditory canal. Adverse gram-negative bacteria that are resistant to other beta-
effects are relatively rare during the local and topical lactam drugs. Meropenem may cause CNS prob-
use of this drug. lems—including seizures—but the risk is relatively
Cycloserine. Cycloserine inhibits bacterial wall low when compared with the risk of seizures with
synthesis by interfering with the final stage of pepti- imipenem.23
doglycan synthesis. Adding two units of the amino Polymyxin B. Polymyxin antibiotics are cationic
acid D-alanine completes the synthesis of peptidogly- compounds that are attracted to negatively charged
cans. Cycloserine, which is similar in structure to D- phospholipids in the bacterial cell membrane. These
alanine, competitively inhibits the enzyme that adds drugs penetrate and disrupt the architecture and
the final D-alanine units onto the peptidoglycan struc- integrity of the surface membrane. Essentially, poly-
tures. Cycloserine is considered a broad-spectrum myxins act as detergents that break apart the phos-
antibiotic but is used primarily as an adjunct in the pholipid bilayer, which creates gaps in the bacterial
treatment of tuberculosis. The primary adverse effect cell wall, leading to the subsequent destruction of the
of this drug is CNS toxicity, which may occur during bacteria.31
prolonged use at relatively high dosages. Polymyxin B is effective against many gram-
Ertapenem. Ertapenem (Invanz) is another car- negative bacteria, including E. coli, Klebsiella, and
bapenam antibacterial agent that is similar to mero- Salmonella. Systemic administration of this drug, how-
penem (see below).11 Ertapenem is effective against ever, is often associated with extreme nephrotoxicity.
gram-positive and gram-negative aerobic and anaero- Hence, this agent is used primarily for the treatment
bic bacteria, and is often used to treat intra-abdominal of local, superficial infections of the skin, eyes, and
and pelvic infections, as well as infections in the skin, mucous membranes. When applied topically for these
urinary tract, and respiratory tract. Side effects include conditions, adverse reactions are relatively rare.
chest pain, gastrointestinal problems (nausea, diar- Polymyxin B is often combined with other antibio-
rhea), headache, and fever. tics such as bacitracin and neomycin in commercial
Imipenem and Cilastatin. Imipenem is a beta- topical preparations.
lactam drug that is classified as a carbapenam antibiot- Vancomycin. Vancomycin appears to bind direct-
ic.10 Imipenem exerts bactericidal effects similar to ly to bacterial cell wall precursors such as D-alanine
the other beta-lactam agents (penicillins and cephalo- and to impair the incorporation of these precursors
sporins); that is, imipenem inhibits PBP function and into the cell wall.41 Vancomycin is effective against
peptidoglycan synthesis. This drug is typically admin- gram-positive bacilli and cocci and primarily serves as
istered along with a second agent, cilastatin. Cilastatin an alternative to the penicillins in a variety of infec-
enhances the bactericidal effects of imipenem by tions (see Tables 33–5).16 The emergence of bacteria
inhibiting metabolic inactivation of imipenem within that are resistant to vancomycin, however, has gener-
the kidneys, even though cilastin does not exhibit any ated concern about the continued use of this drug (see
antibacterial activities by itself.68 “Resistance to Antibacterial Drugs” later in this chap-
Imipenem has one of the broadest antibacterial ter).6 The primary adverse effects associated with van-
spectrums of the beta-lactam drugs and may be useful comycin include hypersensitivity (e.g., skin rashes), a
against a variety of aerobic gram-positive or gram- bitter or unpleasant taste in the mouth, and gastroin-
negative bacteria, as well as some anaerobic bacterial testinal disturbances (nausea and vomiting). Van-
strains.81 Side effects associated with imipenem include comycin also has the potential to cause nephrotoxicity
nausea, hypotension, and hypersensitivity (skin rashes, and ototoxicity.
redness, itching). CNS abnormalities such as confu-
sion, tremors, and seizures have also been reported in
Use of Beta-Lactamase Inhibitors
certain patients. The risk of imipenem-induced seizure
is increased in patients who have a preexisting seizure A primary problem in using penicillins, cephalosporins,
disorder or if the drug dosage is too high, based on the and other beta-lactam antibiotics is that certain bacte-
patient’s body weight. ria produce enzymes known as beta-lactamases.26,70
Meropenem. Meropenem is a carbapenam anti- These beta-lactamase enzymes bind to the beta-lactam
bacterial with effects and spectrum similar to imipen- drug and destroy it before it can exert an antibacterial
33Ciccone(p)-33 1/30/07 4:10 PM Page 507
Neomycin (generic) Erythromycin gluceptate (Ilo- Oxytetracyline (Terramycin) Lincomycin (Lincocin, Lin-
tycin) corex)
gram-negative bacteria, including E. coli, Pseudomonas, drugs, for example, seem to have anti-inflammatory
and Salmonella.15 Aminoglycosides are active against effects, especially in diseases associated with airway
some aerobic gram-positive bacteria, such as certain inflammation.80 Hence, these drugs may be particu-
species of Staphylococcus, and many anaerobic bacteria. larly useful in treating certain airway infections in
Consequently, aminoglycosides are used to treat a vari- people with cystic fibrosis or other respiratory disor-
ety of tissue and wound infections (see Table 33–5). ders associated with infection and inflammation in
airway tissues.8,75
Adverse Effects
Adverse Effects
Aminoglycoside use is limited somewhat by problems
with toxicity.66 Nephrotoxicity, as indicated by bloody When given in high (bactericidal) dosages, gastroin-
urine, acute renal tubular necrosis, and so on, is one of testinal distress is a common problem with erythro-
the more common and serious adverse effects.49,66 mycin administration; for example, stomach cramps,
Ototoxicity, as indicated by dizziness and ringing or nausea, vomiting, and diarrhea may occur. Hence,
fullness in the ears, may also occur. This effect can be erythromycin is usually given in doses that only impair
irreversible in severe cases.67 Toxicity may occur more the growth of bacteria (bacteriostatic doses). Some of
frequently in certain individuals, such as patients with the newer macrolides (clarithromycin, dirithromycin)
liver or kidney failure, or in elderly patients. To reduce may be somewhat safer and produce fewer side effects
the risk of toxicity, drug levels in the bloodstream than erythromycin.46 However, various degrees of
must be periodically monitored so dosages can be allergic reactions—ranging from mild skin rashes to
adjusted for individual patients. Other adverse effects acute anaphylaxis—may occur when these drugs are
include hypersensitivity (e.g., skin rashes, itching) in used in susceptible individuals.
susceptible individuals.
Tetracyclines
Erythromycin and Other Macrolides Tetracycline and tetracycline derivatives (see Table
Erythromycin and its chemical derivatives (azithromy- 33–3) inhibit protein synthesis by binding to several
cin, clarithromycin, dirithromycin) comprise a group components of the ribosomal apparatus in susceptible
of agents known as macrolide antibiotics.16 These bacteria.3,12 Hence, these drugs may cause misreading
drugs inhibit bacterial protein synthesis by binding to of the mRNA code, as well as impair the formation of
specific parts of the ribosomes in susceptible bacteria.58 peptide bonds at the bacterial ribosome. Thus, tetra-
This binding impairs protein synthesis primarily by cyclines are very effective in preventing bacterial pro-
inhibiting the formation of peptide bonds between tein synthesis.
adjacent amino acids. In particular, erythromycin
seems to encourage the dissociation of transfer RNA Antibacterial Spectrum and General Indications
(tRNA) units from their binding site on the ribo-
Tetracyclines are active against a variety of bacteria,
some.27 Normally, the tRNAs bring amino acids to the
including many gram-positive and gram-negative bac-
ribosome, where the amino acids are linked together
teria, as well as other bacterial microorganisms (Rick-
to form proteins. By stimulating the detachment of
ettsia, spirochetes).16 Their use as a broad-spectrum
tRNA, peptide bond formation is averted.
antibiotic has diminished somewhat, however, because
of the development of tetracycline-resistant bacterial
Antibacterial Spectrum and General Indications
strains. (The problem of drug-resistant bacteria is dis-
Erythromycin and the other macrolides exhibit a very cussed in more detail in “Resistance to Antibacterial
broad spectrum of antibacterial activities and are active Drugs.”)
against many gram-positive bacteria, as well as some Some of the newer tetracycline derivatives such as
gram-negative bacteria. These agents are often used as doxycycline may be used to overcome bacterial strains
the primary or alternative drug in a variety of clinical that are resistant to the traditional drugs.16 Currently,
conditions (see Table 33–5). Macrolides may be espe- tetracyclines are used to treat specific infections relat-
cially useful in patients who are allergic to penicillin. ing to such bacilli as Chlamydia, Rickettsia, and certain
Macrolides may produce other beneficial effects spirochetes (see Table 33–5). Tetracyclines may also be
that compliment their antibacterial properties. These used as alternative agents in treating bacterial strains
33Ciccone(p)-33 1/30/07 4:10 PM Page 509
that are resistant to other drugs, such as chloram- phenicol is not typically used as a first-choice drug, but
phenicol, streptomycin, and various penicillins. is reserved for severe infections that do not respond to
Tetracyclines also seem to have anti-inflammatory other antibacterials, or situations where safer drugs are
and immunomodulating effects.53,71 Although the exact contraindicated (e.g., patients are allergic to other
reasons for these effects are unclear, tetracyclines have medications).16
been used in a variety of noninfectious diseases with an Clindamycin. Clindamycin (Cleocin) is derived
inflammatory or autoimmune basis, including sclero- from lincomycin. Both drugs are similar in structure
derma and rheumatoid arthritis.71 Clinical studies will and function to erythromycin and inhibit protein syn-
continue to investigate how these drugs can be used thesis by binding to the 50S ribosomal subunit of sus-
effectively in the long-term management of chronic ceptible bacteria. These agents are effective against
disease. most gram-positive bacteria and some gram-negative
microorganisms.16 Typically, clindamycin and lin-
Adverse Effects comycin are reserved as alternative drugs (rather than
primary agents) in the treatment of local and systemic
Gastrointestinal distress (nausea, vomiting, diarrhea) infections; these agents may be especially useful if
may be a problem with tetracycline use. Hypersensi- patients are unable to tolerate either penicillin or
tivity reactions (such as rashes) may also occur, as well erythromycin. The principal adverse effects associated
as an increase in skin sensitivity to ultraviolet light with these drugs include gastrointestinal distress (nau-
(photosensitivity).16 Tetracyclines form chemical com- sea, diarrhea, colitis) and various allergic reactions,
plexes with calcium that may impair the growth and ranging from mild skin rashes to anaphylactic shock.
development of calcified tissues such as bone and Ethionamide. Ethionamide (Trecator-SC) appears
teeth, especially in children.69 Tetracyclines also cause to inhibit bacterial protein synthesis, but the exact
discoloration of teeth in children and pregnant mechanism of action is unknown. This drug may act in
women, apparently because of the tetracycline-calcium a manner similar to that of some of the other drugs dis-
interaction.69 As mentioned previously, development cussed previously in this section (binding to bacterial
of tetracycline-resistant strains and resulting superin- ribosomes), or it may mediate its effect by some other
fections may be a serious problem during tetracycline means. Ethionamide is effective against M. tuberculosis
therapy. and is used primarily in the treatment of tuberculosis.
This drug is usually used as a secondary agent when
Other Agents That Inhibit primary antituberculosis drugs are ineffective. Gas-
trointestinal distress (nausea, vomiting) is the most fre-
Bacterial Protein Synthesis quent problem encountered with ethionamide use.
Chloramphenicol. Chloramphenicol (Chloromy- CNS disorders (drowsiness, mental depression, etc.),
cetin) is a synthetically produced agent that exerts anti- as well as severe postural hypotension, may also occur.
bacterial effects similar to those of erythromycin; that Lincomycin. Lincomycin (Lincocin, Lincorex) is
is, it binds to the 50S subunit of bacterial ribosomes similar in mechanism of action, clinical indications,
and inhibits peptide bond formation. Chlorampheni- and adverse side effects to clindamycin (see previously
col is a broad-spectrum antibiotic that is active against in this section).
many gram-negative and gram-positive bacteria. This Linezolid. Linezolid (Zyvox) binds to a specific
drug is administered systemically to treat serious infec- site on the bacterial ribosome and inhibits protein
tions such as typhoid fever, Haemophilus infections such synthesis in many gram-positive bacteria including
as osteomyelitis, rickettsial infections such as Rocky staphlocci, streptococci, and enterococci. Hence, this
Mountain spotted fever, and certain forms of meningi- drug is commonly used to treat pneumonia caused by
tis. Chloramphenicol may also be administered topi- S. aureus or S. pneumoniae, and other susceptible skin
cally to treat various skin, eye, and ear infections. and soft tissue infections. Common side effects
The most serious problem associated with chlo- include gastrointestinal problems (nausea, diarrhea),
ramphenicol is the potential for bone marrow aplasia, with more serious blood dyscrasias (anemia, leukope-
which can lead to aplastic anemia and possibly nia, thrombocytopenia) occurring in some patients
death.16,83 Chloramphenicol is also associated with during prolonged drug administration.
other blood dyscrasias such as agranulocytosis and Quinupristin and Dalfopristin. Quinupristin and
thrombocytopenia. Because of these risks, chloram- Dalfopristin are combined in the same product (Syn-
33Ciccone(p)-33 1/30/07 4:10 PM Page 510
ic material will prevent the bacteria from undergoing ial cell division. Fluoroquinolones inhibit these en-
mitosis. zymes, thereby impairing the normal DNA structure
Clofazimine is effective against Mycobacterium lep- and function that is needed for cell growth and repli-
rae and is used primarily as an adjunct in the treatment cation.64
of leprosy. During clofazimine therapy, many patients Fluoroquinolones are effective against a wide
experience problems with red to brownish-black dis- range of gram-positive and gram-negative aerobic bac-
coloration of the skin. Although this discoloration is teria and are especially useful in urinary tract infections
reversible, it may take several months to years before caused by E. coli, Klebsiella, Proteus, and Enterobacter
skin color returns to normal. Other adverse effects aerogenes.9,72 Other indications include the treatment of
include abdominal pain, nausea, vomiting, and rough, gastrointestinal infections, respiratory infections,
scaly skin. osteomyelitis, and certain sexually transmitted diseases
(gonorrhea).18,20 A specific agent, ciprofloxacin
(Cipro), is particularly effective against anthrax infec-
Dapsone tions, and this drug received considerable attention as
Dapsone (Avlosulfon) is a member of a class of chem- an intervention against bioterrorist activities that use
ical agents known as the sulfones. Dapsone is especial- anthrax.21 Primary adverse effects include CNS toxici-
ly effective against M. leprae and is used with rifampin ty, manifested by visual disturbances, headache, and
as the primary method of treating leprosy. Dapsone dizziness. Gastrointestinal distress (nausea, vomiting,
appears to exert its antibacterial effects in a manner diarrhea) and allergic reactions (skin rashes, itching)
similar to that of the sulfonamide drugs; that is, dap- may also occur.57 These drugs produce photosensitivi-
sone impairs folic acid synthesis by competing with ty and increase the skin’s sensitivity to ultraviolet
PABA in bacterial cells. Primary adverse effects asso- light.2,57 Rare but potentially serious cases of nephro-
ciated with dapsone include peripheral motor weak- toxicity may occur in certain patients.43
ness, hypersensitivity reactions (skin rashes, itching), Finally, these drugs may cause tendon pain and
fever, and blood dyscrasias, such as hemolytic anemia. inflammation (tendinopathy) that can be severe and
can ultimately lead to tendon rupture in some
patients.37,48 Tendinopathy seems to occur most com-
Ethambutol monly in the Achilles tendon, but other tendons such
The mechanism of ethambutol (Myambutol) is not as the patellar tendon and supraspinatus tendon may
fully understood. This drug apparently suppresses also be affected.38,84 Although the overall incidence of
RNA synthesis in susceptible bacteria, but it is not tendinopathy is fairly low, patients may be more sus-
known how this occurs. Ethambutol is primarily effec- ceptible if they are older, have renal failure, are taking
tive against M. tuberculosis infections and is a second- glucocorticoids, or have a history of fluoroquinolone-
ary agent in the treatment of tuberculosis.61 Adverse induced tendinopathy.37 Although all of the fluoro-
effects associated with this drug include joint pain, quinolones can potentially cause tendinopathy, the risk
nausea, skin rash and itching, and CNS abnormalities of tendon damage seems highest with ofloxacin.85
(dizziness, confusion, hallucinations). Hence, complaints of pain in any tendon should be
carefully evaluated in patients taking fluoroquinolones,
and the affected tendon(s) should not be exercised until
Fluoroquinolones the cause of tendinopathy can be determined. If it
The fluoroquinolone antibiotics include ciprofloxacin seems that fluoroquinolones are causing tendinopathy,
(Cipro), enoxacin (Penetrex), gatifloxacin (Tequin), le- these drugs should be discontinued, and efforts should
vofloxacin (Levaquin), lomefloxacin (Maxaquin), mox- be made to protect the tendon from excessive stress
ifloxacin (Avelox), norfloxacin (Noroxin), ofloxacin until the tendinopathy is resolved.
(Floxin), and sparfloxacin (Zagam). These drugs
inhibit two specific enzymes—DNA-gyrase and topoi-
Metronidazole
somerase IV—that affect DNA function in certain
bacteria.9,18 DNA-gyrase is responsible for controlling The exact mechanism of metronidazole (Flagyl, Proto-
the amount of DNA winding (supercoiling) in bacter- stat, others) is not fully understood. This drug appears
ial cells. Topoisomerase IV enzymatically separates to be incorporated into bacterial cells, where it under-
two new DNA strands that are formed during bacter- goes chemical reduction. Apparently, the reduced
33Ciccone(p)-33 1/30/07 4:10 PM Page 512
metabolite of metronidazole interacts with bacterial agents used to treat tuberculosis and leprosy. Typically,
DNA and causes it to lose its characteristic double- this drug is combined with another agent—for exam-
helix structure. This leads to the disintegration of ple, rifampin plus dapsone for leprosy, or rifampin plus
DNA molecules and loss of the ability to replicate and isoniazid for tuberculosis—to increase effectiveness
carry out normal genetic functions. Further details of and to prevent the development of resistance to rifam-
this bactericidal effect remain to be determined. pin. Rifampin is also used in combination with eryth-
Metronidazole is effective against most anaerobic romycin to treat Legionnaire disease and certain forms
bacteria and is useful in treating serious infections of meningitis (see Table 33–5).
caused by Bacteroides, Fusobacterium, and other anaero- Common adverse effects include gastrointestinal
bic bacteria. Metronidazole, is also effective against distress (nausea, vomiting, stomach cramps) and vari-
certain protozoa and is discussed in Chapter 35 with ous hypersensitivity reactions (rashes and fever). Dis-
regard to its antiprotozoal effects. Common side turbances in liver function have also been noted, and
effects associated with metronidazole include gastroin- serious hepatic abnormalities may occur in patients
testinal distress (nausea, diarrhea), allergic reactions with preexisting liver disease.
(such as rashes), and CNS symptoms (confusion, dizzi-
ness, mood changes). This drug may also cause periph-
eral neuropathies as indicated by numbness and Sulfonamides
tingling in the hands and feet. The sulfonamides include sulfadiazine, sulfamethizole,
and similar agents (see Table 33–4). Sulfonamides
interfere with bacterial nucleic acid production by dis-
Mupirocin rupting folic acid synthesis in susceptible bacteria. Sul-
Mupirocin (Bactroban) inhibits a specific enzyme fonamide drugs are structurally similar to PABA,
responsible for tRNA synthesis in susceptible bacteria. which is the substance used in the first step of folic acid
This drug is used topically to treat skin infections synthesis in certain types of bacteria (see Fig. 33–2).
caused by Staphylococcus aureus or Streptococcus pyogenes. Sulfonamides either directly inhibit the enzyme
Likewise, mupirocin can be administered by nasal responsible for PABA utilization or become a substi-
spray to treat local colonization of S. aureus in the nasal tute for PABA, which results in the abnormal synthesis
mucosa. This idea may be especially helpful in pre- of folic acid. In either case, folic acid synthesis is
venting systemic infection in individuals such as health reduced, and bacterial nucleic acid synthesis is
care workers who are exposed to an outbreak of resist- impaired.
ant strains of S. aureus. Local/topical administration of Sulfonamides have the potential to be used against
this drug is well tolerated, although some irritation of a wide variety of bacteria, including gram-negative and
the skin may occur during topical use, and cough and gram-positive bacilli and cocci. The development of
respiratory irritation can occur when mupirocin is resistance in various bacteria, however, has limited the
administered by nasal spray. use of these drugs. Currently, sulfonamides are used
systemically to treat certain urinary tract infections and
infections caused by Nocardia bacteria. Sulfonamides
Rifampin may also be applied topically to treat vaginal infections,
Rifampin (Rifadin, Rimactane), and similar agents ophthalmic conditions, and other local infections. A
such as rifabutin (Mycobutin) and rifapentine (Priftin), specific agent, sulfadiazine, can also be combined with
directly impair DNA replication by binding to and silver nitrate to form silver sulfadiazine, which is often
inhibiting the DNA-dependent RNA polymerase applied topically to control bacterial infection in
enzyme in susceptible bacteria. This enzyme initiates burns.19,52
the replication of genetic material by generating the The problems encountered most frequently with
formation of RNA strands from the DNA template. sulfonamide drugs include gastrointestinal distress,
By inhibiting this enzyme, rifampin blocks RNA chain increased skin sensitivity to ultraviolet light, and aller-
synthesis and subsequent replication of the nucleic gic reactions. Serious disturbances in the formed
acid code in bacterial cells. blood elements, including blood dyscrasias such as
Rifampin is effective against many gram-negative agranulocytosis and hemolytic anemia, may also occur
and gram-positive bacteria and is one of the principal during systemic sulfonamide therapy.
33Ciccone(p)-33 1/30/07 4:10 PM Page 513
nitrofurantoin is initiated. This pneumonitis appears Bacterial resistance can occur because of several
to be a direct chemical effect of the drug and usually mechanisms.28,76 Certain bacterial strains may be able
disappears within hours after the drug is withdrawn. to enzymatically destroy the antibacterial drug. The
best example is the beta-lactamase enzyme that is
found in bacteria that are resistant to beta-lactam drugs
Pyrazinamide (penicillins and cephalosporins).54,86 As previously dis-
Pyrazinamide (generic) is used primarily as an adjunct cussed, bacteria containing this enzyme can destroy
to other drugs in treating tuberculosis. This drug’s certain penicillin and cephalosporin drugs, thus ren-
mechanism of action against M. tuberculosis is dering the drug ineffective against these strains.
unknown. Problems associated with pyrazinamide Resistance may also occur because the bacterial
include hepatotoxicity and lower-extremity joint pain. cell modifies or masks the site where the antibacterial
drug typically binds on or within the cell. For instance,
penicillins, aminoglycosides, vancomycin, and other
Clinical Use of Antibacterial drugs must bind to membrane proteins, intracellular
proteins, ribosomes, and the like to exert their effect.
Drugs: Relationship to Specific Differences in the affinity of these binding sites may be
Bacterial Infections acquired by bacterial mutation, thus decreasing the
An incredible array of antibacterial agents is currently drug’s effectiveness.7,30 Bacteria may also develop
being used clinically. As mentioned previously, selec- resistance through genetic mutations that change the
tion of a particular agent is based on the effectiveness enzymes targeted by certain drugs. For example, fluo-
of the drug against a range or spectrum of different roquinolones, rifampin, and other drugs that normally
bacteria. The clinical application of antibacterial drugs inhibit enzymes responsible for bacterial DNA/RNA
according to their effectiveness against specific bacte- function will be ineffective if enzymes are modified
ria is summarized in Table 33–5. As this table indicates, within resistant bacteria.7,35
various antibacterial drugs can serve as either the pri- Resistance can likewise occur if the drug’s ability
mary or the alternative agents against specific bacterial to penetrate the bacterial cell is reduced. Most drugs
infections. The actual selection of an antibacterial must first penetrate the cell membrane and then enter
agent is often highly variable, depending on the partic- the bacterial cell to exert their bactericidal effects. Spe-
ular patient, the type and location of the infection, the cific bacteria that have a natural or acquired opposition
experience of the physician, and many other factors. to drug penetration render the drug useless, thus lead-
ing to the development of strains that are resistant to
aminoglycosides and other agents.28,76 Certain bacteria
Resistance to also develop drug efflux pumps that expel the drug
from the bacterial cell, thus rendering the drug inef-
Antibacterial Drugs fective.44 These pumps are a common way that bacte-
One of the most serious problems of antibacterial ria develop resistance to tetracyclines and a number of
therapy is the potential for development of strains of other antimicrobial agents.22,60
bacteria that are resistant to one or more antibacterial Consequently, a number of factors may be
agents.1 Certain bacterial strains have a natural or responsible for mediating the formation of bacterial
acquired defense mechanism against specific antibac- resistance to penicillins, cephalosporins, aminoglyco-
terial drugs. This enables the strain to survive the sides, tetracyclines, and other antibacterial agents.
effects of the drug and continue to grow and repro- Antibacterial resistance is typically categorized accord-
duce similar resistant strains, thus representing a ing to the name of the drug and the associated resist-
genetic selection process in which only the resistant ant bacterial strain. For example, some of the best
strains survive the drug. As a result, bacteria that are known and most important types of resistance include
invulnerable to the drug can breed. If other drugs are vancomycin-resistant Staphylococcus aureus (VRSA),
not effective against the resistant strain, or if cross- methicillin-resistant S. aureus (MRSA), vancomycin-
resistance to several antibacterial drugs occurs, the resistant Enterococcus (VRE), and penicillin-resistant
resistant bacteria become especially dangerous because Streptococcus pneumoniae (PRSP).1 Even though a resist-
of their immunity from antibacterial chemotherapy.1 ant organism may be linked to a specific drug by name,
Text continued on page 517
33Ciccone(p)-33 1/30/07 4:10 PM Page 515
Gram-negative bacilli
Acinetobacter Infections in various tis- An aminoglycoside ⫹ Imipenem or meropenem;
sues; hospital-acquired ticarcillin ciprofloxacin; trimethoprim-
infections sulfamethoxazole; ampi-
cillin/sulbactam
Gram-positive cocci
Enterococcus Endocarditis or other seri- Ampicillin or penicillin G ⫹ Vancomycin ⫹ gentamicin or
faecalis ous infection (bac- gentamicin or streptomycin streptomycin
teremia)
Gram-negative cocci
Moraxella catarrhalis Otitis; pneumonia; sinusitis Amoxicillin ⫹ clavulanate; A cephalosporin; azithro-
ampicillin ⫹ sulbactam mycin; clarithromycin;
doxycycline; erythro-
mycin; trimethoprim-
sulfamethoxazole
Spirochetes
Borrelia burgdorferi Lyme disease Amoxicillin; doxycycline; Azithromycin; cefotaxime;
ceftriaxone; cefuroxime clarithromycin; penicillin
(high dose)
Other Microorganisms
Chlamydia pneumoniae Pneumonia Doxycycline Azithromycin; clar-
ithromycin; erythromycin;
a fluoroquinolone
*Selection of primary or alternative agents varies depending on the identification of specific bacterial strains and
the presence or absence of resistance to each drug. Drug selection will also be influenced by other factors
such as the patient’s age, comorbidities, drug allergies, pregnancy, and its possible interactions with other med-
ications.
the organism is typically resistant to other drugs as al strains continues to progressively increase in certain
well (multidrug resistance).1,51 institutions and in the community.29,90 To limit the
Development of resistant bacteria is understand- development of resistant strains, antibacterial drugs
ably a very serious problem in contemporary drug should be used judiciously and not overused.62 For
therapy.1 In addition, the number of resistant bacteri- instance, it is often worthwhile to perform culture and
33Ciccone(p)-33 1/30/07 4:10 PM Page 518
CA S E ST U DY
Antibacterial Drugs occupational therapy were also requested to help maintain the
patient’s upper body strength and functional activity while
Brief History. J.B. is a 40-year-old former truck driver awaiting surgery. The physical therapist also suggested that
who was injured in a traffic accident 5 years ago, sustaining a ultraviolet radiation might be helpful in resolving the infection.
spinal cord transection that resulted in complete paraplegia at Problem/Influence of Medication. Tetracyclines
the L1–2 level. He underwent extensive physical rehabilitation, and several other antibacterial agents increase the sensitivity
including vocational retraining, and had recently been working of the skin to ultraviolet light.
as a computer programmer when he began to develop a pres- Decision/Solution. The therapist carefully deter-
sure area in the region of the right ischial tuberosity. Despite mined the minimal erythemal dosage for the patient prior to
conservative management, a pressure ulcer developed. initiating ultraviolet treatments. In addition to using careful
Because the patient was in relatively good health otherwise, draping techniques, the therapist confined the treatment to
the ulcer was treated with local debridement and reconstruc- the ulcer site, so that a minimum of the surrounding skin was
tive surgery, using skin flaps. The patient was admitted to the exposed to the ultraviolet light. This approach ensured that
hospital, and a routine preoperative culture of the ulcer the surrounding tissues would not be endangered if the
revealed the presence of E. coli. The patient had a history of patient’s response to the ultraviolet treatment changed during
sensitivity to penicillin drugs and was therefore given a tetra- the course of tetracycline treatment. The combination of drug
cycline antibiotic (Achromycin V, 250 mg orally every 6 hours) therapy and ultraviolet radiation quickly resolved the infection,
to resolve the infection prior to surgery. Physical therapy and allowing the surgery to proceed as planned.
thesis or bacterial DNA/RNA synthesis and function. drugs for conditions that are directly or indirectly
Although most bacterial infections can be effectively related to the need for physical therapy and occupa-
treated with one or more agents, the development of tional therapy. Therapists should be cognizant of the
bacterial strains that are resistant to drug therapy con- potential side effects of these drugs and should know
tinues to be a serious problem. Rehabilitation special- how these drugs may interfere with specific physical
ists will routinely treat patients receiving antibacterial therapy and occupational therapy procedures.
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64. Richter S, Parolin C, Palumbo M, Palu G. Antiviral 83. Turton JA, Andrews CM, Havard AC, Williams TC.
properties of quinolone-based drugs. Curr Drug Targets Studies on the haemotoxicity of chloramphenicol
Infect Disord. 2004;4:111–116. succinate in the Dunkin Hartley guinea pig. Int J
65. Rodriguez-Pena R, Antunez C, Martin E, et al. Aller- Exp Pathol. 2002;83:225–238.
gic reactions to beta-lactams. Expert Opin Drug Saf. 84. van der Linden PD, Sturkenboom MC, Herings
2006;5:31–48. RM, et al. Fluoroquinolones and risk of Achilles ten-
66. Rougier F, Claude D, Maurin M, Maire P. Aminogly- don disorders: case-control study. BMJ. 2002;324:
coside nephrotoxicity. Curr Drug Targets Infect Disord. 1306–1307.
2004;4:153–162. 85. van der Linden PD, van de Lei J, Nab HW, et al.
67. Rybak LP, Whitworth CA. Ototoxicity: therapeu- Achilles tendinitis associated with fluoroquinolones.
tic opportunities. Drug Discov Today. 2005;10: Br J Clin Pharmacol. 1999;48:433–437.
1313–1321. 86. Wilke MS, Lovering AL, Strynadka NC. Beta-lactam
68. Sader HS, Gales AC. Emerging strategies in infectious antibiotic resistance: a current structural perspective.
diseases: new carbapenem and trinem antibacterial Curr Opin Microbiol. 2005;8:525–533.
agents. Drugs. 2001;61:553–564. 87. Yonath A. Antibiotics targeting ribosomes: resistance,
69. Sanchez AR, Rogers RS, 3rd, Sheridan PJ. Tetracycline selectivity, synergism and cellular regulation. Annu
and other tetracycline-derivative staining of the teeth Rev Biochem. 2005;74:649–679.
and oral cavity. Int J Dermatol. 2004;43:709–715. 88. Young KD. Bacterial shape. Mol Microbiol.
70. Sandanayaka VP, Prashad AS. Resistance to beta- 2003;49:571–580.
lactam antibiotics: structure and mechanism based 89. Zhanel GG, Karlowsky JA, Rubinstein E, Hoban DJ.
design of beta-lactamase inhibitors. Curr Med Chem. Tigecycline: a novel glycylcycline antibiotic. Expert
2002;9:1145–1165. Rev Anti Infect Ther. 2006;4:9–25.
71. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibi- 90. Zirakzadeh A, Patel R. Epidemiology and mechanisms
otic properties and their clinical implications. J Am of glycopeptide resistance in enterococci. Curr Opin
Acad Dermatol. 2006;54:258–265. Infect Dis. 2005;18:507–512.
33Ciccone(p)-33 1/30/07 4:10 PM Page 522
Chapter 34
Treatment of Infections II:
Antiviral Drugs
A virus is one of the smallest microorganisms, consist- common viruses affecting humans, and their associated
ing of only a nucleic acid core that is surrounded by a diseases, are listed in Table 34–1. The table shows that
protein shell.18 Several types of viruses commonly infect viruses can be divided into two categories, depending
human cells and are responsible for a diverse range of on the type of genetic material contained in the virus
pathologies. Viral infections extend from relatively mild (DNA or RNA viruses). Families within each major
disorders such as the common cold to serious, life- subdivision are classified according to physical charac-
threatening conditions such as acquired immu- teristics (configuration of the genetic material, shape of
nodeficiency syndrome (AIDS). Viruses are somewhat the virus capsule) and other functional criteria.
unique in that they must rely totally on the metabolic
processes of the host (human) cell to function.62 Hence, Characteristics of Viruses
the pharmacologic treatment of viral infections is com-
Viruses are somewhat unique in structure and function
plex, because it is often difficult to selectively destroy
as compared with other microorganisms. The basic
the virus without also destroying human cells.
components of viral microorganisms are illustrated in
This chapter describes the basic characteristics of
Figure 34–1. A virus essentially consists of a core of
viruses and the relatively limited number of drugs that
viral DNA or RNA.18,62 The genetic core is surround-
can act selectively as antiviral agents. Methods of pre-
ed by a protein shell, or capsid. This structure—the
venting viral infections (antiviral vaccines) are also
capsid enclosing the nucleic acid core—is referred to
briefly discussed. Finally, the current methods of treat-
as the nucleocapsid. In some viruses, the nucleocapsid is
ing a specific viral-induced disease—AIDS—are pre-
also surrounded by a viral membrane, or envelope,
sented. Rehabilitation specialists often treat patients
which is composed of glycoproteins extending out-
who are in the active stages of a viral infection, as well
ward from a lipid bilayer.
as those suffering from the sequelae of viral disorders,
The virus, however, does not contain any of the
such as gastroenteritis, encephalitis, and influenza.
cellular components necessary to replicate itself or
Hence, the pharmacotherapeutic treatment and pro-
synthesize proteins and other macromolecules; that is,
phylaxis of viral infections should concern physical
the virus lacks ribosomes, endoplasmic reticulum, and
therapists and occupational therapists.
so on.18 The virus contains only the genetic code (viral
genome) that will produce additional viruses. To repli-
cate itself, the virus must rely on the biochemical
Viral Structure and Function machinery of the host cell.95 In essence, the virus
invades the host cell, takes control of the cell’s meta-
Classification of Viruses bolic function, and uses the host cell’s macromolecu-
Viruses are classified according to several criteria, lar-synthesizing apparatus to crank out new viruses.
including physical, biochemical, and pathogenic char- Specific steps in the viral replication process are
acteristics.18,62 The classifications of some of the more described in the next section.
523
34Ciccone(p)-34 1/30/07 2:39 PM Page 524
DNA viruses
Adenoviridae Adenovirus, types 1–33 Respiratory tract and eye infections
Hepatitis B Hepatitis B virus Hepatitis B
Herpesviridae Cytomegalovirus Cytomegalic inclusion disease (i.e., widespread
involvement of virtually any organ, especially the
brain, liver, lung, kidney, intestine)
Epstein-Barr virus Infectious mononucleosis
Herpes simplex, types 1 and 2 Local infections of oral, genital, and other mucocuta-
neous areas; systemic infections
Varicella-zoster virus Chickenpox; herpes zoster (shingles); other systemic
infections
Poxviridae Smallpox virus Smallpox
RNA viruses
Coronaviradae Coronavirus Upper respiratory tract infection
Flaviviridae Hepatitis C virus Hepatitis C
Orthomyxoviridae Influenza virus, types A and B Influenza
Paramyxoviridae Measles virus Measles virus
Mumps virus Mumps
Respiratory syncytial virus Respiratory tract infection in children
Picornaviridae Hepatitis A virus Hepatitis A
Polioviruses Poliomyelitis
Rhinovirus, types 1–89 Common cold
Retroviridae Human immunodeficiency virus (HIV) AIDS
Rhabdoviridae Rabies virus Rabies
Togaviridae Alphavirus Encephalitis
Rubella virus Rubella
Viral Replication the virus to adhere to the outer surface of the host-cell
membrane.
Self-replication of a virus occurs in several distinct Penetration and Uncoating. The virus enters the
steps:17,80 (1) adsorption, (2) penetration and uncoat- host cell either by passing directly through the cell
ing, (3) biosynthesis, and (4) maturation and release. membrane or by fusing with the host-cell membrane
These steps are illustrated in Figure 34–2, and are and releasing the viral genetic material into the host
briefly discussed below. cell. Once inside the host cell, its proteolytic enzymes
Adsorption. Initially, the virus attaches or adsorbs usually remove any coating that remains on the virus.
to the surface of the host cell. Most viruses are attract- Biosynthesis. When viral genetic material is
ed to the host cell because of the interaction between released within the host cell, the virus takes control of
proteins on the outer surface of the virus and recep- the cell’s molecular synthesizing machinery to initiate
torlike proteins on the host-cell membrane. The inter- the biosynthesis of new viral enzymes and proteins.
action of the virus with these surface proteins causes Different viruses exert their effects on the host cell in
34Ciccone(p)-34 1/30/07 2:39 PM Page 525
Nucleocapsid:
nucleic acid “core”
“capsid” (protein shell)
Envelope:
lipid bilayer
glycoproteins
FIGURE 34–1 ▼ Basic components of a virus. Note the relative lack of most cellular organelles
(ribosomes, endoplasmic reticulum, etc.).
different ways, but many viruses control the host cell Regardless of the exact mechanism of infection,
through a direct effect on the cell’s nucleus. Some the virus essentially commands the cell to synthesize
viruses, including the virus that causes AIDS, actually the enzymes that produce more copies of viral DNA
insert their genetic material directly into the host cell’s or RNA and to synthesize structural proteins that
DNA, thereby becoming integrated within the genet- will ultimately be used to form new viral shells or cap-
ic control of the infected cell. sids. Thus, the virus uses the biosynthetic machinery
as well as the structural components and nutrients of
the cell (amino acids, nucleic acids, etc.) to replicate
itself. Likewise, the virus often incapacitates the
Host Cell infected cell so that the infected cell cannot carry out
1. Adsorption
its normal physiologic activities.
Maturation and Release. The component parts of
the virus (the genetic core and surrounding shell) are
assembled into mature viruses and released from the
2. Penetration and host cell. In some cases, the virus is released by a
Uncoating viral DNA/RNA
process of exocytosis, leaving the host cell relatively
intact (although still infected with the original virus).
Alternatively, the host cell may simply be destroyed
3. Biosynthesis (undergo lysis), thus releasing the viral offspring. Lysis
host ribosomes of the host cell not only results in the release of the virus
and the death of the cell, but also may stimulate the
viral DNA/RNA production of inflammatory mediators (prostaglandins,
4. Maturation and
Release kinins, etc.), which create a hypersensitivity response.
The steps involved in viral replication are impor-
tant pharmacologically because antiviral drugs may
interrupt this process at one or more of the steps. Spe-
cific agents currently used as antiviral drugs and their
pharmacodynamic aspects are discussed next.
Amantadine Symadine, Symmetrel Prevention and treatment of influenza A infections (also used
as an antiparkinsonism drug; see Chapter 10)
severity of these CNS symptoms, and overdose may against HIV type 2 (types of HIV are addressed later;
cause seizures. see “HIV and the Treatment of AIDS”).77
Enfuvirtide must be administered parenterally; it
Cidofovir is associated with frequent and potentially serious side
effects (see below). At the time of this writing, enfu-
Antiviral Efficacy and Clinical Use. Cidofovir (Vis- virtide is the only drug of its type, but other HIV entry
tide) is used primarily to treat CMV retinitis in people inhibitors are currently in development, and the use of
with AIDS.111 When used clinically, this drug is often these drugs may be expanded in the future if newer,
combined with probenecid, an agent that inhibits safer agents reach the market.86
renal excretion of cidofovir, thereby providing higher Mechanism of Action. As indicated, enfuvirtide
plasma levels of this antiviral agent.112 inhibits the ability of HIV to bind to, and enter, sus-
Mechanism of Action. Cidofovir works like acy- ceptible host cells such as CD4 lymphocytes. The drug
clovir and ganciclovir; these drugs inhibit viral DNA actually binds to specific components on the outer gly-
replication by inhibiting DNA polymerase activity and coprotein envelop of the virus, thereby retarding the
by halting elongation of viral DNA chains.42 ability of the virus to change its shape in preparation
Adverse Effects. Cidofovir may cause nephrotoxi- for adsorbing to the surface of the host cell. If the virus
city, especially at higher doses. This drug may also de- cannot attach to host cells, the risk of infection is
crease the number of neutrophilic leukocytes, resulting reduced.
in neutropenia and related symptoms such as fever, Adverse Effects. Enfuvirtide must be adminis-
chills, and sore throat. Other side effects include tered by subcutaneous injection, and local pain and
headache and gastrointestinal disturbances (anorexia, irritation occurs at the injection site in most patients.
nausea, diarrhea). Other common side effects include peripheral neu-
ropathy and immune complex reactions that can lead
Docosanol to serious problems including respiratory distress syn-
Antiviral Efficacy and Clinical Use. Docosanol drome, kidney dysfunction, and possibly Guillain-
(Abreva) is applied topically to treat blisters and cold Barré syndrome.
sores caused by herpes virus simplex.42 This drug is
available as an over-the-counter product, and is used Famciclovir and Penciclovir
primarily to treat recurrent outbreaks of orofacial her-
pes lesions. Antiviral Efficacy and Clinical Use. Penciclovir
Mechanism of Action. Docosanol does not inacti- (Denavir) is similar to acyclovir in terms of its antivi-
vate the herpes virus, but appears to act on the host ral effects and clinical indications. However, penci-
(human) cells so that the virus cannot adsorb to the clovir is absorbed poorly from the gastrointestinal
surface of the cell. As such, it must be applied early in tract. This drug is primarily administered topically to
the course of outbreaks before the virus has a chance treat recurrent herpes simplex infections of the lips
to cause substantial lesions. and face (cold sores).58
Adverse Effects. Patients may experience head- Famciclovir (Famvir) is the precursor (prodrug)
ache and some local skin irritation during topical use to penciclovir; the drug is converted to penciclovir
of this drug. following oral administration.91 This situation is anal-
ogous to the relationship between acyclovir and vala-
cyclovir, where it is advantageous to administer the
Enfuvirtide prodrug because it will be absorbed more completely
Antiviral Efficacy and Clinical Use. Enfuvirtide and will ultimately result in higher plasma levels of the
(Fuzeon) is the first approved drug that limits the abil- drug’s active form. Hence, famciclovir is administered
ity of human immunodeficiency virus (HIV) to enter orally to treat infections related to herpes simplex
host cells.77,86 As such, this drug is used as part of the (e.g., genital herpes) and varicella zoster (e.g., herpes
antiviral regimen against HIV infection. Enfuvirtide is zoster).87,91,104 However, the actual antiviral effects of
typically added to other agents (reverse transcriptase famciclovir occur because this drug is converted to
inhibitors, protease inhibitors) in patients who do not penciclovir within the body.
respond adequately to traditional anti-HIV treatment. Mechanism of Action. Penciclovir acts like
This drug is effective against HIV type 1, but not acyclovir (see earlier); that is, the drug is activated
34Ciccone(p)-34 1/30/07 2:39 PM Page 529
(phosphorylated) within virus-infected cells, where it such as acyclovir and ganciclovir. Hence, foscarnet is
subsequently inhibits viral DNA synthesis and viral often used in patients with thymidine-kinase–resistant
replication. As indicated, famciclovir exerts its antivi- viruses who do not respond to acyclovir or ganciclovir.
ral effects after being converted to penciclovir in vivo. Adverse Effects. The primary problem associated
Adverse Effects. Topical application of penciclovir with foscarnet is impaired renal function, including
may cause some skin reactions (rashes, irritation) at the acute tubular necrosis. Hematologic disorders (ane-
application site, but the incidence of these reactions is mia, granulocytopenia, leukopenia), gastrointestinal
fairly low. Systemic (oral) administration of famciclovir disturbances (cramps, nausea, vomiting), and CNS
is generally well tolerated, with only minor side effects toxicity (confusion, dizziness) may also occur during
such as headache, dizziness, and gastrointestinal dis- foscarnet treatment.
turbances (nausea, diarrhea).
Ganciclovir and Valganciclovir
Fomivirsen Antiviral Efficacy and Clinical Use. Ganciclovir
Antiviral Efficacy and Clinical Use. Fomivirsen (Cytovene) is given primarily to patients with AIDS to
(Vitravene) is injected into the vitreous humour to treat problems related to CMV infection, including
treat CMV infection in the eye.42 This drug is often CMV retinitis, polyradiculopathy, and other systemic
used to treat ocular CMV infections that are resistant CMV infections.39,49 Valganciclovir (Valcyte) is the
to more traditional agents such as ganciclovir or fos- precursor (prodrug) form that is converted to ganci-
carnet. clovir within the body. Ganciclovir and similar agents
Mechanism of Action. Fomivirsen has a unique (acyclovir and valacyclovir; see earlier) can also help
mechanism of antiviral action. This drug contains an reduce the risk of CMV infection in people receiving
amino acid sequence that is opposite or complimenta- solid organ transplants such as kidney transplants.44
ry to the messenger RNA sequence controlling CMV Mechanism of Action. Ganciclovir, like acyclovir,
replication. Because of this opposing or “antisense” inhibits viral DNA replication by inhibiting DNA
sequence, fomivirsen inhibits several aspects of CMV polymerase activity and by halting elongation of viral
replication, and also inhibits the viruses’ ability to DNA chains.
adsorb to the surface of host cells. Adverse Effects. The most serious problems asso-
Adverse Effects. Injecting fomivirsen into the eye ciated with ganciclovir include anemia, granulocy-
may cause localized pain, redness, or swelling, but topenia, thrombocytopenia, and related hematologic
serious side effects or vision disturbances are rare. disorders. Ganciclovir may also cause gastrointestinal
disturbances (nausea, loss of appetite) and CNS dis-
turbances (mood changes, nervousness, tremor).
Foscarnet
Antiviral Efficacy and Clinical Use. Foscarnet (Fos-
cavir) is primarily given to treat CMV retinitis in
Imiquimod
patients with AIDS.6,24 This agent may also help con- Antiviral Efficacy and Clinical Use. Imiquimod
trol other infections in patients with a compromised (Aldara) is applied topically to treat condylomata
immune system, including serious cytomegaloviral acuminate infections that cause genital and perianal
infections (pneumonia, gastrointestinal infections) and warts.42 It can also be used to treat certain skin condi-
some herpesvirus infections (herpes simplex, varicella- tions such as actinic keratoses of the face and scalp.
zoster). Mechanism of Action. Although the details are
Mechanism of Action. Foscarnet works somewhat unclear, imiquimod enhances the local production of
like acyclovir and ganciclovir; that is, foscarnet interferons, tumour necrosis factor-alpha, and possi-
inhibits the DNA polymerase enzyme necessary for bly other cytokines that produce antiviral responses.
viral DNA replication. Foscarnet differs from these Hence, this drug does not act directly on the virus, but
other antiviral drugs, however, in that it does not instead modulates the host (human) immune respons-
require phosphorylation (activation) by enzymes such es that have antiviral effects.
as viral thymidine kinase. Certain strains of viruses are Adverse Effects. Some local skin irritation and
thymidine-kinase deficient, meaning that these virus- blistering can occur when imiquimod is applied topi-
es lack the enzyme needed to activate antiviral agents cally.
34Ciccone(p)-34 1/30/07 2:39 PM Page 530
Reverse Transcription
Host
Chromosome
HIV
vRNA vDNA
Viral
DNA
FIGURE 34–3 ▼ Schematic illustration of HIV replication and the site of action of the reverse tran-
scriptase inhibitors (RTIs). These drugs interfere with the process of reverse transcription by inhibiting
the enzyme that converts viral RNA (vRNA) to viral DNA (vDNA). See text for further discussion.
various intracellular enzymes.32,37 The phosphorylated drugs are often used in severely immunocompromised
version of the drug then acts as a false nucleic acid, patients (such as patients with AIDS), adverse neuro-
competing with the real nucleic acid (thymidine) for muscular effects may be also be caused by other seque-
incorporation into growing viral DNA strands. This lae of AIDS in addition to the drug’s effects. Hence,
competition slows down the reverse transcriptase neuromuscular problems are seen frequently in patients
enzyme because the enzyme cannot handle the false with advanced cases of HIV infection and AIDS.
nucleic acid (the drug) as easily as the real nucleic acid Other effects associated with NRTIs include pan-
(thymidine). Even if the reverse transcriptase is suc- creatitis, CNS toxicity (headache, irritability, insomnia),
cessful in incorporating the drug into viral DNA and gastrointestinal disturbances (nausea, diarrhea).
strands, this action prematurely terminates DNA Abacavir can cause an allergic (hypersensitivity) reac-
strand synthesis because a false nucleic acid has been tion that produces symptoms such as fever, joint and
added to the viral DNA instead of the real nucleic acid. muscle pain, skin rashes, abdominal pain, nausea, diar-
The newer agents (NNRTIs) such as delaviridine, rhea, and vomiting.32 In severe cases, this reaction can
efavirenz, and nevirapine directly inhibit the reverse progress to anaphylactic shock and possibly death.
transcriptase enzyme by binding to the enzyme’s active Skin rashes are the most common side effect of
(catalytic) site and preventing this enzyme from con- the NNRTIs, and efavirenz may cause nervous system
verting viral RNA to viral DNA.37,94 Thus, these symptoms such as headache, dizziness, and insomnia.41
agents offer an alternative way to impair reverse tran-
scriptase function and prevent viral replication.
Adverse Effects. RTIs are associated with a num-
Ribavirin
ber of bothersome side effects, and certain agents can Antiviral Efficacy and Clinical Use. Ribavirin (Vira-
also cause potentially serious problems. The most com- zole) is active against several RNA and DNA viruses,
mon problems associated with zidovudine are blood including respiratory syncytial virus (RSV).106 Clinical-
dyscrasias, such as anemia and granulocytopenia. Other ly, this drug is used to treat severe RSV pneumonia in
symptoms occurring during zidovudine administration infants and young children,106 and RSV in certain adult
may include fever, chills, nausea, diarrhea, dizziness, populations, including the elderly, people with car-
headache, and excessive fatigue. NRTI drugs may also diopulmonary problems, and people with a compro-
cause myopathy, as indicated by skeletal muscle tender- mised immune system.29 Ribavirin may also be useful
ness, weakness, and atrophy.63 Likewise, peripheral as a secondary agent in the treatment of influenza A
neuropathies are common, especially when NRTIs and B in young adults. The combination of ribavirin
such as didanosine, stavudine, and zacitabine are and interferons (see section on “Interferons,” later) is
administered in higher doses.63 These adverse neuro- often the treatment of choice in chronic hepatitis C
muscular effects are probably due to the toxic effects infection.30,72
of these drugs on mitochondrial function in muscle Ribavirin is administered through oral inhalation.
and nerve tissues.19,63 However, considering that these This drug is suspended in an aerosol form and admin-
34Ciccone(p)-34 1/30/07 2:39 PM Page 533
istered to the patient by a mechanical aerosol genera- therapy. This fact is true for other microorganisms,
tor and a ventilation mask, mouthpiece, or hood. including most types of virus. Viruses can mutate and
Mechanism of Action. The mechanism of action alter their structural or functional characteristics so
of this drug is not fully understood. Ribavirin appears that previously effective drugs will be unable to con-
to impair viral messenger RNA (mRNA) synthesis, trol specific viral infections adequately. It is beyond
probably by selectively inhibiting enzymes responsible the scope of this chapter to address all the resistant
for RNA replication.35 Inadequate viral mRNA pro- viral strains, and how these strains acquired resistance
duction leads to impaired viral protein synthesis, which against antiviral drugs. Viral resistance, like bacterial
ultimately curtails viral replication. resistance, is a growing concern. Efforts should be
Adverse Effects. Ribavirin produces relatively few made to limit the indiscriminate or inappropriate use
adverse effects when administered by inhalation. Most of antiviral drugs, and to contain the spread of resist-
of the drug’s action is confined to local pulmonary tis- ant viruses. Developing methods to overcome viral
sues, and severe systemic effects are rare. One adverse resistance using new drugs or different drug combina-
effect that may occur is local irritation of the eyes tions is also a critical area of laboratory and clinical
(conjunctivitis), due to the direct contact of aerosol research.
with the eyes. This occurrence may be a problem if
the drug is administered via some sort of hood or tent
that encloses the patient’s entire head.
Interferons
Interferons are a group of proteins that produce a
Vidarabine number of beneficial pharmacologic and physiologic
Antiviral Efficacy and Clinical Use. Vidarabine effects.40,71 These agents were first recognized as
(Vira-A) was the first systemic agent used to treat her- endogenous substances that exert nonspecific antiviral
pesvirus infections, including CMV, herpes simplex activity; that is, interferons enable healthy cells to
virus, and varicella-zoster virus.42 In the past, this drug resist infection from many viruses.60 Interferons pro-
was administered by continuous intravenous infusion duce other beneficial effects, including the control of
to treat severe systemic infections caused by these cell differentiation, the limiting of excessive cell pro-
viruses, but systemic use of vidarabine has been re- liferation, and the modification of certain immune
placed by safer and less toxic agents. Vidarabine is cur- processes.17,40
rently used primarily to treat local viral infections of There are three primary classes of human inter-
the eye (e.g., herpes simplex keratoconjunctivitis); it is ferons: alpha, beta, and gamma (Table 34–4). Certain
applied topically by ophthalmic ointment to treat cells and tissues produce each primary interferon class.
these infections. Of these three types, alpha and beta interferons are
Mechanism of Action. Vidarabine appears to exert often grouped together as type I interferons; these
its antiviral effects in a manner similar to acyclovir (see type I interferons seem more important in terms of
section on “Acyclovir”). Both drugs selectively inhibit antiviral activity.40,96 Type II (gamma) interferons
viral enzymes that are responsible for viral DNA repli- appear to be more important in regulating other
cation.42 aspects of the immune response and are responsible
Adverse Effects. The primary problems associat- for promoting the growth of T lymphocytes and other
ed with systemic administration of vidarabine include responses promoting local inflammation.42
gastrointestinal distress (nausea, vomiting, diarrhea) The possibility that interferons can be used as
and CNS disturbances (dizziness, hallucinations, mood pharmacologic agents has aroused a great deal of inter-
changes). Ophthalmic application may produce local est. Recombinant DNA techniques and cell tissue cul-
irritation (itching, redness, swelling) in some indi- tures have been used to produce sufficient quantities of
viduals. interferons for clinical drug trials. The rationale is that
exogenously administered interferons will produce
antiviral and other beneficial effects in healthy cells in
a manner similar to their endogenously produced
Viral Resistance counterparts. Some of the pertinent aspects of inter-
As discussed in the last chapter, certain bacteria can feron action and clinical applications are presented
develop strategies that render them resistant to drug below.
34Ciccone(p)-34 1/30/07 2:39 PM Page 534
Type II
Gamma Gamma-1b (Actimmune) Chronic granulomatous disease; osteopetrosis
*Specific agents are synthesized using recombinant DNA or other biosynthetic techniques to mimic the effects
of naturally-occurring type I or type II interferons.
Synthesis and Cellular interferons then travel to noninfected cells, where they
Effects of Interferons bind to specific receptors located on the surface of the
healthy cells. Binding of the interferon induces the
The basic sequence of events in the cellular production healthy cell to synthesize its own antiviral proteins.
and antiviral action of interferons is illustrated in Fig- Interferons apparently direct the healthy cell to syn-
ure 34–4. Virtually all of the body’s cells are capable of thesize the enzymes that inhibit viral messenger RNA
producing interferons, and these substances serve as an and protein synthesis.17,42 Thus, even if the virus does
early step in preventing the virus from infecting penetrate into the healthy cell, the virus cannot repli-
healthy cells.50 As illustrated in Figure 34–4, cells that cate because of an inability to synthesize viral proteins.
have been infected by a virus produce interferons that The manner in which interferons control cell
are subsequently released from the infected cell. These growth and proliferation is not fully understood.
virus
i
i antiviral
i
i proteins
interferons
Interferons may limit excessive cell division by activat- effect seems to occur because these beta interferons
ing lymphocytes and other cytotoxic cells that combat modulate several aspects of the autoimmune response
the cancer, and by controlling specific gene segments that initiates the pathological changes associated with
in normal and cancerous cells.71 In particular, interfer- MS.36,88 Although the details are unclear, it appears
ons may inhibit specific gene-regulatory segments that type I interferons can reduce the activity of mac-
of tumor cells known as oncogenes. The inhibition of rophages, lymphocytes, and other immune system
oncogenes would attenuate the excessive proliferation components that are responsible for the autoimmune
and lack of cell differentiation typifying neoplastic dis- destruction of glial cells and neuronal structures in
ease.8 Interferons may also limit cancer growth by acti- patients with MS.
vating certain aspects of the immune system, including
increased activity of natural killer cells and other
cytotoxic cells that attack cancerous tissues.8 Hence,
Adverse Effects of Interferons
interferons have proved effective in controlling sever- Interferons may cause flulike symptoms including
al forms of cancer (see Table 34–4); the use of these fever, sweating, chills, muscle aches, and general
agents as anticancer drugs is discussed in more detail malaise. Other side effects such as loss of appetite,
in Chapter 36. nausea, vomiting, diarrhea, and unusual tiredness can
also occur, depending on the type of interferon and the
Pharmacologic Applications dosage. Interferons may also cause behavioral side
effects such as depression, presumably because these
of Interferons drugs inhibit serotonin activity in the brain.5,105 When
When interferons were first discovered, there was a interferons are administered by intramuscular or sub-
great deal of optimism about their use as antiviral cutaneous injection, some irritation may develop
agents. Although early clinical trials with interferons around the injection site. Finally, anti-interferon anti-
were somewhat disappointing, their use as antiviral bodies may be produced by the immune system, espe-
agents gained acceptance as more was learned about cially when interferons are administered for prolonged
the three primary classes and subclasses of the inter- periods.25 These antibodies can neutralize the interfer-
ferons. We now realize that interferons cannot be used ons, thus decreasing their effectiveness in controlling
interchangeably as antiviral drugs, but that certain viral infections and other conditions such as cancer
types of interferons can be administered to treat spe- and MS.
cific viruses (see Table 34–4). Currently, type I inter-
ferons (interferons alpha and beta) seem especially
beneficial in treating hepatitis B and C infections.42,70 Control of Viral Infection
These interferons can also be injected locally to treat
certain forms of viral-induced warts such as condylo-
with Vaccines
mata acuminate infections (see Table 34–4). The clin- Vaccines prevent viral infection by stimulating the
ical use of interferons as antiviral drugs should endogenous production of immune factors that will
continue to increase as more is learned about various selectively destroy the invading virus. Hence, the vac-
interferon subclasses and other factors influencing cine can be administered to healthy individuals to pro-
their effectiveness.71 vide them with immunity from certain viral infections.
As mentioned, interferons also help control A vaccine acts as an antigen that induces the immune
abnormal cell proliferation, and these drugs have been system to generate virus-specific antibodies. The vac-
approved for use in certain cancers. Interferons are cine, however, does not cause any appreciable viral
often used as part of the treatment for certain leuke- infection because the vaccine contains a virus that has
mias, lymphomas, and several other forms of cancer been modified in some way so that it retains its anti-
(see Table 34–4). Interferon use in cancer chemother- genic properties but lacks the ability to produce infec-
apy is discussed in more detail in Chapter 36. tion. Vaccines, for example, typically consist of a whole
Finally, certain interferons may decrease exacer- virus or part of the virus (viral particle or fragment)
bations of multiple sclerosis (MS).36,88 Specifically, that has been completely inactivated (killed vaccines)
interferon beta-1a (Avonex) and interferon beta-1b or partially inactivated (live attenuated vaccines).53
(Betaseron) may help reduce the incidence and sever- Thus, most antiviral vaccinations are accomplished by
ity of relapses in exacerbating-remitting MS.36,64 This administering small amounts of the modified virus.
34Ciccone(p)-34 1/30/07 2:39 PM Page 536
In general, it is somewhat easier to develop vac- AIDS is a life-threatening disorder because of the
cines that prevent viral infection than to develop drugs susceptibility of the immunocompromised patient to
that destroy the virus once it has infected human cells. severe infections and certain forms of cancer.65,73,76,
This notion is reasonable when one considers that the 101,113 In particular, patients with AIDS often suffer
virus is essentially coexisting with the host cell. As from severe viral infections (CMV, various herpesvirus
indicated previously, there are currently only a limited infections), bacterial infections (Mycobacterium tubercu-
number of drugs that are able to selectively inhibit the losis), fungal infections (Pneumocystis jiroveci), and infec-
virus without harming the host cell. A more practical tions caused by various other microbes and parasites.
strategy is to use vaccines to enable the body to Patients with AIDS also develop relatively unusual
destroy the virus before an infection is established. neoplastic diseases, such as Kaposi sarcoma.
At present, vaccines are available for several seri- Considerable neuromuscular involvement also
ous viral infections, including polio, smallpox, rabies, occurs in patients with AIDS.47,100 Peripheral neuropa-
measles, mumps, rubella, hepatitis A and B, and influ- thies, myopathies, and various CNS manifestations
enza. In some situations, vaccination against certain (dementia, other psychological manifestations) can
viral infections is routine. For instance, schoolchildren occur directly from HIV infection or secondarily, due
must periodically show evidence of polio, measles, and to some other opportunistic infection.31,85,100 Likewise,
other vaccinations according to state and local laws. In peripheral neuropathies are a common side effect of
other cases, vaccines are administered prior to poten- certain anti-HIV drugs (didanosine, stavudine, zal-
tial exposure to the virus or in high-risk groups. Influ- citabine), and myopathies are a side effect of zidovu-
enza vaccinations, for example, are often administered dine therapy.63 Patients with HIV disease often have
to elderly and debilitated patients during seasonal painful symptoms such as joint pain, back pain, and
influenza outbreaks.75,109 pain related to neuropathies and myopathies.100
Although vaccines exist for many serious viral Hence, HIV disease can often be regarded as a degen-
infections, some drawbacks still exist. Some vaccines erative neuromuscular disorder from the standpoint of
are only partially effective, and viral infection still a rehabilitation professional. Therapists can therefore
occurs in a significant percentage of vaccinated indi- help improve function and decrease pain in patients
viduals. Other vaccines, especially killed vaccines, with HIV infection and AIDS.1,33
often require periodic readministration (boosters) to Individuals who are infected with HIV may
help maintain antiviral immunity. In addition, certain remain very asymptomatic for several years before
types of viruses still lack an effective vaccination. For developing the full-blown clinical picture of AIDS.
example, no vaccine is currently approved for the HIV Even people exposed to HIV who do not initially
that causes AIDS.51,98 Hence, the improvement of develop AIDS carry the virus for the rest of their
existing vaccines and the development of new vaccines lives and are thus capable of transmitting the virus to
remain two of the more important aspects of antiviral others. Transmission of HIV from one individual to
chemotherapy.4 another occurs primarily through intimate sexual con-
tact and through sharing intravenous needles. Trans-
fusions of blood from HIV-infected donors are also a
potential source of HIV transmission. Hence, prac-
HIV and the Treatment of AIDS tices such as safe sex, not sharing needles, and
HIV is a member of the retrovirus family (see Table improved blood-screening techniques are crucial in
34–1).32 HIV impairs the function of certain cells in preventing the transmission of HIV and the subse-
the immune system such as CD4⫹ (T-helper) lym- quent risk of developing AIDS.
phocytes.11,26 Destruction of immune system compo- The treatment of patients with AIDS and individ-
nents often leads to the severe immunocompromised uals infected by HIV is continually being modified as
state known as AIDS. This virus exists in at least two new drugs become available and more information is
forms: HIV-1 and HIV-2. Both forms of the virus are gained about the nature of the AIDS virus. Currently,
capable of causing AIDS, but HIV-1 is more preva- the pharmacologic management of HIV-infected
lent.32 Hence, HIV-1 is also referred to informally as patients consists of two principal strategies: (1) con-
the “AIDS virus.” Because there is currently no effec- trolling the proliferation and effects of HIV in indi-
tive way to kill the AIDS virus in humans, there is no viduals infected with this virus and (2) treatment and
cure for AIDS. prevention of various opportunistic infections that
34Ciccone(p)-34 1/30/07 2:39 PM Page 537
attempt to take advantage of the compromised im- TIs also inhibit the reverse transcriptase enzyme’s
mune system in patients with AIDS. The pharmaco- ability to perform one of the initial steps in HIV repli-
logic methods used to accomplish these principal cation. The NNRTIs, however, directly inhibit the
strategies are presented here. active (catalytic) site on this enzyme, whereas zidovu-
dine and other NRTIs serve as false substrates that take
Inhibition of HIV Proliferation the place of the substance (thymidine) normally acted
on by this enzyme (see “Reverse Transcriptase Inhib-
in Infected Individuals itors: Mechanism of Action”). Hence, NNRTIs pro-
No drugs are currently available that selectively kill vide another way to impair one of the key steps in HIV
HIV in humans, hence the lack of a cure for this replication, and these drugs can be used along with
viral infection. Nonetheless, several antiviral drugs are other agents (NRTIs, protease inhibitors) to provide
given to inhibit the replication of this virus, thus optimal benefits in preventing HIV replication and
decreasing the morbidity and mortality of HIV infec- proliferation (see the next section).
tion. These drugs are usually specific for the HIV-1 Finally, a group of agents known as HIV entry
form of the virus, because HIV-1 is more prevalent in inhibitors is beginning to reach the market. These
people infected by HIV. Several pharmacologic strate- drugs impair the ability of the virus to attach to the
gies for treating HIV infection are currently available, host cell’s surface, thereby inhibiting HIV entry into
and these strategies are discussed briefly here. susceptible lymphocytes. If the virus cannot enter the
Zidovudine (Retrovir, AZT) was the first drug cell, it cannot infect that cell or begin the process of
approved as an anti-HIV agent.32 Other agents that act viral replication. Enfuviritide (Fuzeon) is the first HIV
like zidovudine were subsequently approved to prevent entry inhibitor to be approved, and other drugs of this
HIV replication. These drugs include abacavir (Zia- type will hopefully be available in the near future.
gen), didanosine (Videx), lamivudine (Epivir), stavu- The arsenal of anti-HIV agents has therefore
dine (Zerit), tenofovir (Viread), and zalcitabine grown steadily since the development of the first anti-
(HIVID) (see Table 34–3). As discussed in “Specific HIV drug (zidovudine). In addition, other drugs and
Antiviral Drugs,” zidovudine and similar drugs are strategies that inhibit HIV infection continue to be
classified as NRTIs because they share a common explored.32,61 As more is learned about the structure
mechanism of action (illustrated in Figure 34–3); that and function of this virus, drugs can be developed that
is, these drugs inhibit the reverse transcriptase enzyme impair specific steps in the absorption and replication
that HIV uses to synthesize viral DNA from viral of HIV in human cells. If clinical trials using these
RNA. This action impairs one of the early steps in other drugs are favorable, they may also be approved
viral replication, thus slowing the progression of HIV for future use in individuals infected with HIV.
infection and the development of AIDS.
Protease inhibitors were the second major break- Anti-HIV Drug Combinations: Use of
through in the pharmacologic treatment of HIV
infection. Protease inhibitors are typically identified
Highly Active Antiretroviral Therapy
by generic names containing an “-avir” suffix. Pro- Several anti-HIV drugs are often administered simul-
tease inhibitors currently available include amprenavir taneously to provide optimal inhibition of HIV repli-
(Agenerase), atazanavir (Reyataz), fosamprenavir cation and proliferation. The idea of combining several
(Lexiva), indinavir (Crixivan), lopinavir (Kaltetra; agents is referred to as highly active antiretroviral ther-
combination with Ritonavir), nelfinavir (Viracept), apy, or HAART.54 HAART often involves the simulta-
ritonavir (Norvir), and saquinavir (Fortovase, Invi- neous use of at least three anti-HIV agents.114 A typical
rase). As indicated earlier, these drugs impair the HIV HAART strategy, for example, involves the use of two
protease enzyme that is responsible for several steps in RTIs and one protease inhibitor.54,90 There are, how-
HIV replication. Like the NRTIs, these drugs do not ever, many variations of the specific drug combinations
kill the virus but can slow its replication and prevent used during HAART. Moreover, HAART regimens are
the spread of HIV to noninfected cells. continually being revised as new drugs reach the mar-
The third strategy developed to inhibit HIV re- ket or problems arise with existing strategies. Hence,
plication is the NNRTIs. These drugs include delavir- the exact number and types of drugs used during
dine (Rescriptor), efavirenz (Sustiva), and nevirapine HAART are selected based on the specific needs of
(Viramune). Like their nucleoside counterparts, NNR- each patient.
34Ciccone(p)-34 1/30/07 2:39 PM Page 538
Regardless of the exact drugs used, there is ample incorporate new agents into a comprehensive and suc-
evidence that HAART can successfully delay the pro- cessful regimen for people infected with HIV.
gression of HIV disease in people infected with the
virus. In many cases, strict adherence to HAART reg-
imens can reduce the viral load (that is, the amount of
HIV Vaccines
viral RNA present in the bloodstream) to levels that An HIV vaccine has not yet been successfully devel-
are undetectable with current testing procedures.32 oped and approved for use in the United States. As
This fact does not mean that HAART has successfully indicated earlier, vaccines are typically an altered form
eliminated the virus from the infected host or that the of the original virus that is administered to stimulate
person infected with HIV has been cured. Even if the immune system, so that the immune system can
HAART successfully reduces evidence of the virus in recognize and destroy the virus if a person is exposed to
the plasma, the virus can be sequestered into T cells it. Creation of an HIV vaccine is understandably a
and other tissue “reservoirs” so that viral components complicated endeavor, given the complexity of this
cannot be detected in the bloodstream.32,92 Still, virus and its tendency to evolve and mutate into differ-
HAART regimens can prevent the progression of HIV ent types of HIV.78,108 Nonetheless, the development of
infection and help sustain immune function by allow- a safe, effective vaccine remains the best pharmacolog-
ing increases in the number of functioning CD4 lym- ic method for dealing with the spread of the virus, espe-
phocytes.54 The use of HAART is therefore associated cially in underdeveloped nations that continue to
with a substantial reduction in the incidence of AIDS experience a rise in the incidence of HIV and AIDS.15,48
and with improved clinical outcomes (fewer infections, Hence, efforts continue to develop an HIV vac-
decreased cancers, prolonged survival) in people who cine that will produce adequate immunity from HIV
are infected with HIV.54,81 infection without severe untoward side effects.57
HAART regimens are, however, associated with There is concern, however, that a successful vaccine
several problems and limitations. A certain percentage may be very difficult to produce.27,78 For example,
of people with HIV do not respond adequately to development of an HIV vaccine that is not 100 per-
HAART; that is, HAART may not be very successful in cent effective might give recipients a false sense of
producing a sustained and complete reduction in viral security; that is, a vaccine that confers only partial
load in anywhere from 30 to 50 percent of patients immunity (e.g., a 50 to 75 percent reduction in the risk
receiving these regimens.32 The lack of effectiveness of contracting HIV) might encourage the recipient to
may be a consequence of poor adherence to the forgo other precautions, such as safe sex, not sharing
HAART regimen. Adherence to HAART is often dif- intravenous needles, and so forth. Likewise, the ques-
ficult because of the potential for side effects with these tion arises about whether a single vaccine will be suc-
drugs and because of difficulties in remembering the cessful in providing immunity from all the various
complicated dosage regimens associated with taking HIV strains and subtypes.48,93 An HIV vaccine is
three or more agents.32,54,90 Resistance to anti-HIV urgently needed and would undoubtedly be received
drugs can also develop,20,74 especially if there is poor as one of the most important pharmacologic advance-
adherence to HAART regimens.20,32 As mentioned ments of our time. The development of such a vaccine
earlier, HAART does not completely eliminate the may be delayed, however, until we have a better
virus from the infected host, because some of the viral understanding of HIV and how to best modify this
components remain sequestered within tissues, where virus into a successful vaccine.
they remain hidden from HAART drugs.92 Finally, the We must therefore remember that zidovudine
simultaneous use of several drugs during HAART and other drugs currently available for treating HIV
increases the risk for drug-drug interactions, and like- are not curative and may be helpful only in delaying or
wise increases the chance for toxicity to the liver and reducing AIDS-related deaths. A cure for AIDS, if
other organs.2,23 possible, will take several years or even several decades
Nonetheless, HAART can suppress HIV disease before becoming a reality. As with many viruses, devel-
in many people who are infected with this virus. Drug oping a vaccine against the AIDS virus is somewhat
combinations can be used successfully for the long- easier than making a drug that selectively destroys
term management of HIV disease, and they offer hope HIV. The development of an HIV vaccine, however, is
that people with HIV do not have to progress inex- probably still years away. Until a vaccine is developed,
orably toward AIDS and death. Research continues to preventing transmission of HIV remains the best
find the best way to combine existing agents and to method of controlling the spread of AIDS.
34Ciccone(p)-34 1/30/07 2:39 PM Page 539
Management of simply do not have the ability to fight off various viral,
Opportunistic Infections bacterial, and other microbial invaders.12 Consequent-
ly, much of the pharmacologic approach to the treat-
If HIV infection is not treated successfully, the body is ment of AIDS is associated with trying to curtail
open to infection from various other microorganisms. various infections by using the respective antimicrobial
These infections are known commonly as opportunis- drugs that are currently available.
tic infections because microorganisms take advantage It is beyond the scope of this chapter to give a
of the chance to infect people who lack normal im- detailed description of the pharmacologic treatment
mune defenses.110 Fortunately, newer anti-HIV drugs of all the possible opportunistic infections that occur
and the use of HAART regimens have reduced the risk in patients with AIDS. Nonetheless, some of the
of opportunistic infections.79,110 Hence, the best pre- more common types of opportunistic infections and
vention against opportunistic infections is aggressive the drugs commonly used to treat them are listed in
anti-HIV treatment that promotes T lymphocyte sur- Table 34–5. Early recognition of infectious symptoms
vival and helps maintain a functioning immune sys- is crucial in helping initiate drug therapy before the
tem.12,99 Still, some patients are prone to opportunistic infection becomes uncontrollable.9 Because patients
infections, including patients who are newly diagnosed with AIDS essentially lack endogenous defense sys-
with HIV infection, or patients that cannot tolerate, tems, drug therapy must often be continued indefi-
respond to, or adhere to HAART regimens.45,110 Like- nitely, or the infection will recur. On the other hand,
wise, opportunistic infections are still a major cause of successful implementation or reinstitution of HAART
illness and death in areas of the world where HAART strategies can restore immune function in certain
regimens are unavailable or unaffordable (i.e., devel- patients, and drugs for opportunistic infections can
oping countries).14 When immune function deterio- sometimes be discontinued.38,43 Nonetheless, strate-
rates beyond a certain point (typically less than 200 gies for dealing with various infections are constantly
CD4 lymphocytes per microliter), these patients are changing, and drug therapy for HIV and opportunis-
said to have AIDS. tic infections will surely be modified as new antimi-
Because of a virtual lack of immunologic defenses, crobial agents are developed and new evidence is
patients with AIDS often succumb to a variety of provided about how these agents can be used in vari-
opportunistic infections.45 Essentially, these patients ous infections.
Herpes simplex Unusually severe vesicular and necrotizing Acyclovir, famciclovir, or valacyclovir
lesions of mucocutaneous areas (mouth,
pharynx) and gastrointestinal tract
Bacterial infections
Mycobacterium Involvement of bone marrow, reticuloen- Clarithromycin plus ethambutol; rifabutin
avium complex dothelial tissues
Fungal infections
Candida Inflammatory lesions in oropharyngeal region Oral infections: clotrimazole, fluconazole, or
and esophagitis nystatin; Esophageal infections: flucona-
zole or ketoconazole
Protozoal infections
Toxoplasma Central nervous system infections (cerebral Pyrimethamine and sulfadiazine
degeneration, meningoencephalitis)
*Choice of specific drugs varies according to disease status, presence of other infections, and so forth. Pharma-
cotherapeutic rationale is also constantly changing as new agents are developed and tested.
of current developments in antiviral pharmacology, health care professionals will enrich their
own knowledge while serving as a reliable source of information for their patients.
In addition, viral infections may produce pain and other symptoms that can be treated by
physical rehabilitation. In particular, chronic HIV infection and the drug therapy for this disor-
der can both produce neuromuscular problems such as myopathy and peripheral neuropa-
thy.63,83 Neuromuscular impairments can occur at any stage in the disease process, but they
become especially problematic in advanced cases of HIV infection, or when this disease pro-
gresses to AIDS.7,63 Hence, therapists can use various physical agents to help decrease pain, and
likewise implement aerobic and resistive exercise programs to help maintain muscle strength
and function.68 These interventions can be invaluable in helping maintain quality-of-life in peo-
ple with HIV infection and AIDS.
CA S E ST U DY
Antiviral Drugs were attributed to radiculopathy caused by infection of periph-
eral nerves by HIV or by some other opportunistic infection.
Brief History. R.K. is a 28-year-old man who was The physical therapy department was consulted to determine
infected with HIV after sharing hypodermic syringes with a fel- what could be done to alleviate the neuropathic pain and dys-
low drug abuser. He began a pharmacologic regimen of high- function.
ly active antiretroviral therapy, consisting of two reverse Decision/Solution. The therapist initiated a program
transcriptase inhibitors (zidovudine [Retrovir], 600 mg/d and of transcutaneous electrical nerve stimulation (TENS) along
didanosine [Videx], 400 mg/d) and one protease inhibitor the affected nerve pathways. The patient was instructed in the
(indinavir [Crixivan], 2400 mg/d). This regimen was initially use of the TENS unit, and intensity and other stimulation
successful in controlling HIV replication and proliferation, but parameters were adjusted to tolerance by the patient. The
the patient began to lapse into periods of noncompliance and therapist also found that cold neon laser treatment helped
frequently failed to take his medications according to the prop- decrease pain and increase function along the more severely
er dosing schedule. Hence, HIV proliferated and suppressed affected nerves, and daily laser treatments were instituted.
immune function to the point where he was considered to The combination of TENS and laser therapy helped to
have developed AIDs. Recently, he developed a fever and res- decrease the pain in this viral-related disorder, thus improving
piratory infection due to Pneumocystis jiroveci pneumonia. He the patient’s well being without the use of additional pharma-
was admitted to the hospital and treated with a combination of cologic agents (pain medications). Progressive involvement of
pentamidine and trimethoprim-sulfamethoxazole. The patient other peripheral neurons occurred over the course of the next
also exhibited muscular weakness and began to develop few weeks, however, and the patient eventually died of respi-
burning pain in both lower extremities. The weakness and pain ratory failure.
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CT. New advances in HIV entry inhibitors develop- herpes: the combined data from two randomized con-
ment. Curr Drug Targets Infect Disord. 2004;4:339–355. trolled trials. J Cutan Med Surg. 2003;7:449–454.
87. Sacks SL. Famciclovir suppression of asymptomatic 105. Valentine AD, Meyers CA. Neurobehavioral effects
and symptomatic recurrent anogenital herpes simplex of interferon therapy. Curr Psychiatry Rep. 2005;
virus shedding in women: a randomized, double-blind, 7:391–395.
double-dummy, placebo-controlled, parallel-group, 106. Ventre K, Randolph A. Ribavirin for respiratory syn-
single-center trial. J Infect Dis. 2004;189:1341–1347. cytial virus infection of the lower respiratory tract in
88. Sandberg-Wollheim M. Interferon-beta1a treatment infants and young children. Cochrane Database Syst
for multiple sclerosis. Expert Rev Neurother. 2005;5: Rev. 2004;CD000181.
25–34. 107. Vivet-Boudou V, Didierjean J, Isel C, Marquet R.
89. Sandy MC. Herpes zoster: medical and nursing man- Nucleoside and nucleotide inhibitors of HIV-1 repli-
agement. Clin J Oncol Nurs. 2005;9:443–446. cation. Cell Mol Life Sci. 2006;63:163–186.
90. Sax PE, Gathe JC, Jr. Beyond efficacy: the impact of 108. Wang LX. Toward oligosaccharide- and glycopeptide-
combination antiretroviral therapy on quality of life. based HIV vaccines. Curr Opin Drug Discov Devel.
AIDS Patient Care STDS. 2005;19:563–576. 2006;9:194–206.
91. Shafran SD, Tyring SK, Ashton R, et al. Once, twice, 109. While A, George C, Murgatroyd B. Promoting
or three times daily famciclovir compared with aciclovir influenza vaccination in older people: rationale and
for the oral treatment of herpes zoster in immunocom- reality. Br J Community Nurs. 2005;10:427–430.
petent adults: a randomized, multicenter, double-blind 110. Willemot P, Klein MB. Prevention of HIV-associated
clinical trial. J Clin Virol. 2004;29:248–253. opportunistic infections and diseases in the age of
92. Shehu-Xhilaga M, Tachedjian G, Crowe SM, Kedzier- highly active antiretroviral therapy. Expert Rev Anti
ska K. Antiretroviral compounds: mechanisms underly- Infect Ther. 2004;2:521–532.
ing failure of HAART to eradicate HIV-1. Curr Med 111. Williams-Aziz SL, Hartline CB, Harden EA, et al.
Chem. 2005;12:1705–1719. Comparative activities of lipid esters of cidofovir
93. Slobod KS, Coleclough C, Bonsignori M, et al. HIV and cyclic cidofovir against replication of herpes-
vaccine rationale, design and testing. Curr HIV Res. viruses in vitro. Antimicrob Agents Chemother. 2005;
2005;3:107–112. 49:3724–3733.
94. Sluis-Cremer N, Temiz NA, Bahar I. Conformational 112. Wolf DL, Rodriguez CA, Mucci M, et al. Pharmaco-
changes in HIV-1 reverse transcriptase induced by kinetics and renal effects of cidofovir with a reduced
nonnucleoside reverse transcriptase inhibitor binding. dose of probenecid in HIV-infected patients with
Curr HIV Res. 2004;2:323–332. cytomegalovirus retinitis. J Clin Pharmacol. 2003;43:
95. Smith AE, Helenius A. How viruses enter animal cells. 43–51.
Science. 2004;304:237–242. 113. Wood C, Harrington W, Jr. AIDS and associated
96. Smith PL, Lombardi G, Foster GR. Type I inter- malignancies. Cell Res. 2005;15:947–952.
ferons and the innate immune response—more 114. Young B. Review: mixing new cocktails: drug interac-
than just antiviral cytokines. Mol Immunol. 2005;42: tions in antiretroviral regimens. AIDS Patient Care
869–877. STDS. 2005;19:286–297.
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Chapter 35
Treatment of Infections
III: Antifungal and
Antiparasitic Drugs
In addition to bacteria and viruses, several parasitic apists with the nature of these types of infections and
microorganisms may produce infections in humans. the basic chemotherapeutic techniques and agents that
In particular, certain species of fungi, protozoa, and are used to treat these problems.
helminths (worms) frequently cause infections in
humans. Although some types of parasitic infections
are limited or unknown in developed nations such as
the United States, parasitic infections generally repre-
Antifungal Agents
sent the most common form of disease world- Fungi are plantlike microorganisms that exist ubiqui-
wide. These infections are especially prevalent in tously throughout the soil and air and in plants
tropical and subtropical environments and in impov- and animals. Although abundant in nature (about
erished areas of the world where sanitation and 100,000 species exist), only a few species produce seri-
hygiene are inadequate. In addition, the incidence of ous infections in humans.25,67 A disease caused by
serious fungal and other parasitic infections has been fungal infection is also referred to as a mycosis. Some
increasing in industrialized nations because of the fungal infections are relatively local or super-
increased susceptibility of immunocompromised ficial, affecting cutaneous and mucocutaneous tissue.
patients, such as patients with acquired immunodefi- Examples of common superficial fungal infections
ciency syndrome (AIDS), to these infections.2,16,70 include the tinea (ringworm) infections that cause
Hence, the effective pharmacologic treatment of these problems such as athlete’s foot. Common mucocuta-
infections remains an important topic in the global neous fungal infections include candidiasis and yeast
management of disease. infections of vaginal tissues. Other fungal infections
The pharmacologic treatment of parasitic infec- are deeper or more systemic. For instance, fungal
tions is a complex and extensive topic. In this limited infections may affect the lungs, central nervous system
space, it is difficult to describe the many species of (CNS), or other tissues and organs throughout the
each parasite, all the diseases caused by parasites, and body.43,44,54
the chemical methods currently available to selec- Often, fungal infections are relatively innocuous
tively destroy various fungi, protozoa, and helminths because they can be destroyed by the body’s normal
in humans. Consequently, the general aspects of each immune defense mechanisms. However, some infec-
type of parasitic infection are reviewed briefly, follow- tions require pharmacologic treatment, especially if
ed by the primary drugs used to treat specific fungal, the patient’s endogenous defense mechanisms are
protozoal, and helminthic infections. This discussion compromised in some way. For instance, patients
will acquaint physical therapists and occupational ther- undergoing immunosuppressive drug treatment with
545
35Ciccone(p)-35 1/30/07 2:55 PM Page 546
Secondary/Alternative
Type of Infection Principal Sites of Infection Principal Agent(s) Agent(s)
Aspergillosis Lungs, other organs, body Amphotericin B Itraconazole, voriconazole
orifices
*Drugs indicated here are administered systemically (orally, intravenously) to treat widespread or invasive fungal
infections. Some of these agents are also available in topical preparations, especially in the treatment of candidi-
asis and tinea infections in the skin and mucocutaneous tissues (see text). Selection of a specific drug or prepa-
ration will also depend on patient-specific factors, such as immune function, age, pregnancy, and identification
of resistant fungal species.
35Ciccone(p)-35 1/30/07 2:55 PM Page 547
Tolnaftate Aftate; Tinactin; many Aerosol powder; aerosol solution; Tinea (ringworm) infections
others powder; solution
Note: Drugs listed here are only available in topical or local preparations. Certain systemic agents listed in Table
35–1 can also be applied locally to treat various superficial fungal infections.
species of pathogenic fungi (see Table 35–1). Ampho- Several newer forms of amphotericin B (Abelcet,
tericin is also effective against certain protozoal infec- AmBisome, Amphotec) have also been developed.
tion such as leishmaniasis.5 Typically, this drug is These drugs are encapsulated in small lipid spheres
administered by slow intravenous infusion. Local and (liposomes) and then injected slowly by intravenous
topical administration may also be used to treat limit- infusion.26,57 The lipid-based preparations appear to
ed infections caused by susceptible fungi. deliver higher doses of amphotericin B to the site of
35Ciccone(p)-35 1/30/07 2:55 PM Page 548
fungal infections more directly, thereby reducing the sterols results in impaired membrane function and
risk of adverse effects such as renal toxicity.20,29 Clini- other metabolic abnormalities within the fungal cell.
cal studies suggest that these lipid forms can therefore Fluconazole also directly damages the fungal mem-
be used to treat serious fungal infections while reduc- brane by destroying certain membrane components
ing the risk of nephrotoxicity and other side effects.39 such as triglycerides and phospholipids. Loss of nor-
Mechanism of Action. Amphotericin B appears to mal membrane structure and function results in the
work by binding to specific steroidlike lipids (sterols) destruction of the fungus.
located in the cell membrane of susceptible fungi.7 Adverse Effects. Hepatotoxicity is the most seri-
This binding causes increased permeability in the cell ous adverse effect of fluconazole; this drug should be
membrane, leading to a leaky membrane and loss of used cautiously in patients with impaired liver func-
cellular components. tion. Other common side effects include headache and
Adverse Effects. The effectiveness of amphoteri- gastrointestinal disturbances (abdominal pain, nausea,
cin B against serious systemic fungal infections is tem- vomiting).
pered somewhat by a high incidence of side effects.39
Most patients experience problems such as headache,
Flucytosine
fever, muscle and joint pain, muscle weakness, and gas-
trointestinal distress (nausea, vomiting, stomach pain Clinical Use. The antifungal spectrum of flucyto-
or cramping). As indicated, nephrotoxicity may also sine (Ancobon) is limited primarily to the Candida and
occur in some patients, but the use of the lipid-based Cryptococcus species.7 This drug is used systemically to
formulations of this drug may reduce this risk. Consid- treat endocarditis, urinary tract infections, and the
ering the life-threatening nature of some fungal infec- presence of fungi in the bloodstream (fungemia) during
tions such as meningitis, certain side effects of candidiasis. Flucytosine is also used to treat meningitis
amphotericin B must often be tolerated while the drug and severe pulmonary infections caused by cryptococ-
exerts its antifungal actions. cosis. This drug is often combined with amphotericin
B to provide optimal effects and to decrease the chance
of fungal resistance.4,8
Fluconazole Mechanism of Action. Flucytosine is incorporat-
Clinical Use. Fluconazole (Diflucan) can be ad- ed into susceptible fungi, where it undergoes enzy-
ministered orally to treat serious systemic fungal in- matic conversion to fluorouracil,7 which acts as an
fections.15 This drug is often the primary treatment antimetabolite during RNA synthesis in the fungus.
for urinary tract infections, pneumonia, and infections Fluorouracil is incorporated into RNA chains but acts
of the mouth and esophagus caused by the Candida as a false nucleic acid. This event ultimately impairs
species of fungus.19,63 This agent may also be used to protein synthesis, thus disrupting the normal function
treat cryptococcal meningitis and may help prevent of the fungus.
recurrence of cryptococcal infections in patients with Adverse Effects. Flucytosine may cause hepato-
AIDS. Fluconazole is somewhat less toxic than more toxicity and may also impair bone marrow function,
traditional agents such as amphotericin B, and can be resulting in anemia, leukopenia, and several other
administered orally, which is an advantage over blood dyscrasias.69 This drug may also produce severe
amphotericin B. gastrointestinal disturbances, including nausea, vomit-
There is some concern, however, about flucona- ing, diarrhea, and loss of appetite.
zole’s effectiveness in treating deep, systemic fungal
infections in severely ill patients.35 Hence, this drug
Griseofulvin
can be combined with other antifungals such as
amphotericin B to provide optimal treatment for Clinical Use. Griseofulvin (Fulvicin, Grisactin,
certain cases of candidiasis and other severe fungal other names) is used primarily in the treatment of
infections.4 common fungal infections of the skin known as tinea,
Mechanism of Action. Fluconazole and similar or ringworm.33,56 For example, this drug is adminis-
agents (itraconazole, ketoconazole) inhibit certain tered to treat fungal infections of the feet (tinea pedis,
enzymes in fungal cells that are responsible for the or “athlete’s foot”), infections in the groin area (tinea
synthesis of important sterols.9,15 A deficiency of these cruris, or “jock rash”), and similar infections of the
35Ciccone(p)-35 1/30/07 2:55 PM Page 549
skin, nails, and scalp. Griseofulvin is administered also used to treat tinea infections of the skin, scalp,
orally. and other body areas. Ketoconazole is available in top-
Mechanism of Action. Griseofulvin enters suscep- ical preparations for the treatment of tinea infections
tible fungal cells and binds to the mitotic spindle dur- and other relatively localized infections, including cer-
ing cell division.9 This binding impairs the mitotic tain vaginal infections.
process, thus directly inhibiting the ability of the cell Mechanism of Action. Ketoconazole selectively
to replicate itself. inhibits certain enzymes that are responsible for the
Adverse Effects. Common side effects of griseo- synthesis of important sterols in fungal cells.9 A defi-
fulvin administration include headaches—which may ciency of sterols results in impaired membrane func-
be severe—and gastrointestinal disturbances (nausea, tion and other metabolic abnormalities within the
vomiting, diarrhea). Some individuals may exhibit fungal cell. At higher concentrations, ketoconazole
hypersensitivity to this drug as evidenced by skin rash- may also directly disrupt the cell membrane, resulting
es. Skin photosensitivity (increased reaction to ultravi- in the destruction of the fungus.
olet light) may also occur. Adverse Effects. Gastrointestinal disturbances
(nausea, vomiting, stomach pain) are the most com-
mon adverse effects when ketoconazole is administered
Itraconazole
systemically. Some degree of hepatotoxicity may occur,
Clinical Use. Itraconazole (Sporanox) is an azole and severe or even fatal hepatitis has been reported on
antifungal agent that is effective against many systemic rare occasions. In large, prolonged dosages, this drug
fungal infections.64 For example, this drug is used to may also impair testosterone and adrenocorticosteroid
treat blastomycosis and histoplasmosis infections in synthesis, resulting in breast tenderness and enlarge-
the lungs and other tissues, especially in patients ment (gynecomastia) and decreased sex drive in some
with a compromised immune system.10,37 Itraconazole men. Because of these side effects, other drugs such
may also be used as the primary or alternative treat- as itraconazole have largely replaced systemic use of
ment for other fungal infections, such as aspergillo- ketoconazole.
sis, chromomycosis, coccidioidomycosis, and various
infections caused by the Candida species. Like flu-
Echinocandins
conazole, itraconazole can be administered orally
and can be given intravenously in severe systemic Clinical Use. Echinocandins comprise a relatively
infections.64 new group of antifungals that includes drugs such as
Mechanism of Action. Itraconazole works like caspofungin (Cancidas) and micafungin (Mycamine).7
fluconazole and similar azoles. These drugs disrupt These drugs are administered intravenously to treat
membrane function of the fungal cell by inhibiting the severe esophageal infections caused by Candida.
synthesis of key membrane components such as Caspofungin is also used to treat systemic aspergillosis
sterols, and by directly damaging other membrane infections in patients who cannot tolerate other drugs
components such as phospholipids. Impaired mem- such as amphotericin B or fluconazole.45 Other echi-
brane function leads to metabolic abnormalities and nocandin drugs are currently being developed, and
subsequent death of the fungal cell. their use may expand in the future if newer agents
Adverse Effects. Side effects associated with itra- reach the market.
conazole include headache, gastrointestinal distur- Mechanism of Action. These drugs inhibit
bances (nausea, vomiting), and skin rash. the glucan synthase enzyme that is responsible for the
biosynthesis of beta-D-glucan—a component of the
fungal cell membrane.45 Loss of this membrane com-
Ketoconazole
ponent disrupts the integrity of the fungal cell wall,
Clinical Use. Ketoconazole (Nizoral) is used to resulting in death of the fungus.
treat a variety of superficial and deep fungal infec- Adverse Effects. Primary side effects of caspofun-
tions.9,35,72 This drug can be administered orally to gin and micafungin include gastrointestinal distur-
treat pulmonary and systemic infections in candidiasis, bances (nausea, vomiting) and headache. Some local
coccidioidomycosis, histoplasmosis, and several other irritation may also occur at the injection site when
types of deep fungal infections. Oral administration is these drugs are administered intravenously.
35Ciccone(p)-35 1/30/07 2:55 PM Page 550
if azole lozenges are swallowed. Other problems asso- thousand species of protozoa, approximately 35 repre-
ciated with topical use include local burning or irrita- sent a threat of parasitic infection in humans.25
tion of the skin or mucous membranes. One relatively common disease caused by proto-
zoal infection is malaria. Malaria is caused by several
species of a protozoan parasite known as plasmodia.
Other Topical Agents Although this disease has been virtually eliminated in
Clinical Use. Other topical antifungals include North America and Europe, malaria continues to be a
nystatin (Mycostatin, Nilstat, others), naftifine primary health problem throughout many other parts
(Naftin), butenafine (Mentax), and tolnaftate (Aftate, of the world.44 Individuals who live in these areas, as
Tinactin, other names) (see Table 35–2). well as those traveling to parts of the world where
Nystatin has a wide spectrum of activity against malaria is prevalent, must often undergo antimalarial
various fungi, but is not used to treat systemic in- chemotherapy. Hence, drugs that prevent and treat
fections because it is not absorbed from the gastroin- malaria are extremely important.
testinal tract. Therefore, nystatin is administered via In addition to malaria, several other serious inf-
several topical preparations to treat cutaneous, oropha- ections may occur in humans due to parasitic invasion
ryngeal, or vaginal candidiasis. Topical and local (oro- by protozoa.2,44 Severe intestinal infections (dysen-
pharyngeal) use of nystatin is especially important in tery) produced by various protozoa occur quite fre-
treating candidiasis in immunocompromised patients, quently, especially in areas where contaminated food
including patients with AIDS.1 and drinking water are prevalent. Infections in tissues
Naftifine, tolnaftate, and butenafine are used pri- such as the liver, heart, lungs, brain, and other organs
marily to treat local and superficial cases of tinea may also occur because of protozoal infestation. As
infection. These agents are found in several over-the- mentioned in this chapter’s introduction, individuals
counter products that are administered topically to with a compromised immune system may be especial-
treat tinea infections such as tinea pedis and tinea ly susceptible to these intestinal and extraintestinal
cruris. infections.2,70
Mechanism of Action. Nystatin exerts its antifun- The primary agents used to treat protozoal infec-
gal effects in a manner similar to that of amphotericin tions are listed in Tables 35–3 and 35–4, and each
B; that is, this drug binds to sterols in the cell mem- agent is described subsequently. Drugs that are pri-
brane, which causes an increase in membrane perme- marily used to treat and prevent malaria are grouped
ability and a loss of cellular homeostasis. Naftifine and together, followed by drugs that are used to treat other
butenafine inhibit a fungal enzyme (squalene epoxi- types of protozoal infections (intestinal and extrain-
dase) that is responsible for the synthesis of a key mem- testinal infections).
brane component (ergosterol), resulting in the loss of
membrane integrity and death of the fungus. Tolnaf- Antimalarial Agents
tate appears to stunt the growth of fungal cell bodies,
but the exact mechanism of this drug is unknown. Chloroquine
Adverse Effects. Nystatin is generally well toler- Clinical Use. Historically, chloroquine (Aralen)
ated when applied locally. Systemic absorption has been one of the primary antimalarial drugs.27 This
through mucous membranes may cause some gas- drug provides a safe, effective, and relatively inexpen-
trointestinal disturbances (nausea, vomiting, diarrhea), sive method for treating malaria, and is also adminis-
but these side effects are generally mild and transient. tered routinely to individuals who are traveling to areas
Topical use of butenafine, naftifine, and tolnaftate is of the world where they may be exposed to malaria
likewise safe, although local burning and irritation of infection.49 Resistance to this drug, however, has
the skin may occur in some individuals. emerged in many areas of the world where malaria is
prevalent.55 That is, the parasite that causes this disease
(the Plasmodium amoeba) has developed mechanisms
that render this drug ineffective. If these chloroquine-
Antiprotozoal Agents resistant strains are encountered, other antimalarial
Protozoa are single-celled organisms that represent the drugs such as quinine or artemisinin derivatives must
lowest division of the animal kingdom. Of the several be used (see Table 35–3).21
35Ciccone(p)-35 1/30/07 2:55 PM Page 552
Chloroquine is also used for the treatment of treat infections in the liver and pericardium. As discus-
conditions other than malaria. This drug is effective sed in Chapter 16, chloroquine is effective in rheuma-
against other types of protozoal infections such as ame- toid disease and is used in the treatment of conditions
biasis and may be used with iodoquinol or emetine to such as rheumatoid arthritis and systemic lupus erythe-
matosus. However, the reasons why this antiprotozoal drug with other antimalarials such as an artemisinin
agent is also effective against rheumatoid disease are derivative may provide more effective treatment
unclear. Chloroquine is administered orally. against malaria.14
Mechanism of Action. Although the exact mecha- Mechanism of Action. Although the drug’s exact
nism is unknown, chloroquine may impair metabolic mechanism of action is unknown, mefloquine may
and digestive function in the protozoa by becoming exert antimalarial effects similar to chloroquine; that
concentrated within subcellular vacuoles and raising is, these drugs inhibit hemoglobin digestion in malar-
the pH of these vacuoles.65 This effect may inhibit the ial parasites, thus causing heme by-products to accu-
ability of the parasite to digest hemoglobin from the mulate within the protozoa and cause toxicity and
blood of the host erythrocytes. Impaired hemoglobin death of this parasite.65
digestion leads to the accumulation of toxic heme by- Adverse Effects. Mefloquine is safe and well tol-
products in the protozoa, which subsequently leads to erated when used at moderate doses to prevent malar-
death of this parasite.28 Chloroquine may also bind ial infection. At higher doses, such as those used
directly to DNA within susceptible parasites and to treat infection, mefloquine may cause dizziness,
inhibit DNA/RNA function and subsequent protein headache, fever, joint and muscle pain, and gastroin-
synthesis. The ability to impair protein synthesis may testinal problems (abdominal pain, nausea, vomit-
contribute to the antiprotozoal actions of this drug. ing, diarrhea). These side effects, however, may be
Adverse Effects. The most serious problem difficult to distinguish from the symptoms associated
associated with chloroquine is the possibility of toxic- with malaria. Although rare, neuropsychiatric symp-
ity to the retina and subsequent visual disturbances. toms such as confusion, psychosis, and seizures may
This issue is usually insignificant, however, when this occur, especially when this drug is used at higher
drug is used for short periods in relatively low doses dosages for prolonged periods.60
(see Chapter 16). Other relatively mild side effects
may occur, including gastrointestinal distress (nausea,
Primaquine
vomiting, stomach cramps, diarrhea), behavior and
mood changes (irritability, confusion, nervousness, Clinical Use. Primaquine is typically used to treat
depression), and skin disorders (rashes, itching, discol- the relapses of specific forms of malaria,12 and is gen-
oration). erally administered in acute or severe exacerbations, or
when other drugs (chloroquine, mefloquine) are inef-
fective in suppressing malarial attacks. Primaquine may
Hydroxychloroquine
also be used to prevent the onset of malaria in individ-
Hydroxychloroquine (Plaquenil) is derived chemically uals who are especially at risk because of prolonged
from chloroquine and is similar to it in clinical use, exposure to the disease.50 This drug is administered
mechanism of action, and adverse effects. Hydroxy- orally.
chloroquine does not have any distinct therapeutic Mechanism of Action. Primaquine appears to
advantages over chloroquine, but it may be substituted impair DNA function in susceptible parasites. The
in certain individuals who do not respond well to exact manner in which this occurs is unknown.
chloroquine. Adverse Effects. Gastrointestinal disturbances
(nausea, vomiting, abdominal pain), headache, and
visual disturbances may occur during primaquine
Mefloquine
therapy. A more serious side effect, acute hemolytic
Clinical Use. Mefloquine (Lariam) has emerged as anemia, may occur in patients who have a specific defi-
one of the most important antimalarial agents.61 This ciency in the enzyme glucose-6-phosphate dehydro-
drug is especially important in the prevention and genase. This enzymatic deficiency is genetic, and is
treatment of malaria that is resistant to traditional more common in certain individuals of African,
antimalarial drugs such as chloroquine and quinine.50 Mediterranean, and Asian descent; hence there is an
Mefloquine is often the drug of choice for antimalari- increased risk of hemolytic anemia in these groups.61
al prophylaxis, especially in areas of the world where People with specific cases of this enzyme deficiency
chloroquine-resistant strains of malaria are common.23 should be identified so that alternative antimalarial
Mefloquine can be used alone, but combining this drugs can be used.34
35Ciccone(p)-35 1/30/07 2:55 PM Page 554
Pyrimethamine Quinine
Clinical Use. Quinine is one of the oldest forms of
Clinical Use. When used alone, pyrimethamine
antimalarial chemotherapy, having been obtained
(Daraprim) is only of minor use in treating and pre-
from the bark of certain South American trees as early
venting malaria. However, the antimalarial effective-
as the 1600s.61 Although quinine was the principal
ness of pyrimethamine is increased dramatically by
method of preventing and treating malaria for many
combining it with the antibacterial drug sulfadoxine.61
years, the use of this drug has diminished somewhat
The combination of these two drugs (known commer-
because it is relatively toxic and expensive to pro-
cially as Fansidar) has been used to prevent or treat cer-
duce.61 Hence, the routine use of this drug has largely
tain forms of chloroquine-resistant malaria (see Table
been replaced by newer, safer agents such as meflo-
35–3).61 Regrettably, resistance to pyrimethamine/
quine and artemisinin derivatives. Quinine, however,
sulfadoxine treatment has also increased in many areas
remains one of the most effective antimalarial drugs
to the point where this drug combination is no longer
and is currently used to treat severe malaria that is
effective.62
resistant to other drugs.40,68 Quinine sulfate is admin-
Pyrimethamine may also be combined with other
istered orally, and quinine dihydrochloride is adminis-
antimalarials such as artemisinin derivatives, but these
tered by slow intravenous infusion.
regimens should only be used if the malarial parasites
Mechanism of Action. The exact mechanism of
are not resistant to the specific drugs in the regimen.13
quinine is not known. This drug probably exerts anti-
Pyrimethamine can also be combined with a sulfon-
malarial effects similar to those of chloroquine—that
amide drug such as dapsone, sulfadiazine, or sul-
is, inhibition of hemoglobin digestion and subsequent
famethoxazole to treat protozoal infections that cause
accumulation of toxic heme by-products that lead to
toxoplasmosis, or fungal infections that cause Pneumo-
death in susceptible protozoa.22
cystis pneumonia.These agents are administered orally.
Adverse Effects. Quinine is associated with many
Mechanism of Action. Pyrimethamine blocks the
adverse effects involving several primary organ sys-
production of folic acid in susceptible protozoa by
tems. This drug may produce disturbances in the CNS
inhibiting the function of the dihydrofolate reductase
(headache, visual disturbances, ringing in the ears),
enzyme. Folic acid helps catalyze the production of
gastrointestinal system (nausea, vomiting, abdominal
nucleic and amino acids in these parasites. Therefore,
pain), and cardiovascular system (cardiac arrhythmias).
this drug ultimately impairs nucleic acid and protein
Problems with hypersensitivity, blood disorders, liver
synthesis by interfering with folic acid production.
dysfunction, and hypoglycemia may also occur in some
The action of sulfadoxine and other sulfonamide anti-
individuals.
bacterial agents was discussed in Chapter 33. These
agents also inhibit folic acid synthesis in certain bacte-
rial and protozoal cells.
Other Antimalarials: Use
Adverse Effects. The incidence and severity of
of Artemisinin Derivatives
side effects from pyrimethamine-sulfadoxine are relat-
ed to the dosage and duration of therapy. Toxicity is Clinical Use. Artemisinin derivatives are natur-
fairly common when these drugs are given in high ally occurring compounds that appear to be effective
dosages for prolonged periods, and adverse effects against many forms of the protozoa that cause malar-
include gastrointestinal disturbances (vomiting, stom- ia.71 These drugs consist of the parent compound
ach cramps, loss of appetite), blood dyscrasias (agran- (artemisinin) and several products that can be synthe-
ulocytosis, leukopenia, thrombocytopenia), CNS sized from artemisinin such as artesunate, artemether,
abnormalities (tremors, ataxia, seizures), and hyper- and dihydroartemisinin.61 It does not appear that any
sensitivity reactions (skin rashes, anaphylaxis, liver one derivative is superior to another in treating malar-
dysfunction). As indicated above, resistance may also ia, hence the term artemisinin derivative can be used
occur during repeated use, and this drug strategy may to collectively describe this group.71 These agents act
be ineffective in certain strains of malaria that have rapidly and appear to be effective against all malarial
already developed resistant mechanisms. Hence, parasites that infect humans.55 Moreover, resistance to
pyrimethamine-sulfadoxine is usually administered on artemisinin derivatives has not yet emerged, so these
a very limited basis, such as a single dose at the onset drugs have moved to the forefront as primary anti-
of malarial symptoms. malarial agents, especially in parts of the world where
35Ciccone(p)-35 1/30/07 2:55 PM Page 555
Other adverse effects include gastrointestinal distress inhibiting energy metabolism in these parasites. This
(nausea, vomiting, cramps) and various skin reactions drug may have other antiprotozoal effects that remain
(rashes, itching, discoloration), but these effects are to be determined.
relatively mild and transient. Adverse Effects. This drug is generally well toler-
ated. Gastrointestinal disturbances (vomiting, diar-
rhea) and headache have been reported, but these
Metronidazole
effects may be due to the intestinal infection rather
Clinical Use. Metronidazole (Flagyl, Protostat, than the drug.
other names) is effective against a broad spectrum of
protozoa and is often the primary agent used against
Paromomycin
protozoal infections in intestinal and extraintestinal
tissues.51 Metronidazole is often the drug of choice for Clinical Use. Paromomycin (Humatin) is an
treating several intestinal infections (amebiasis, giar- aminoglycoside antibacterial (see Chapter 33) that is
diasis) and amebic abscesses in other tissues such as used primarily to treat mild to moderate intestinal
the liver. Metronidazole is also the primary drug used infections (amebiasis).51 This drug may also be used as
to treat trichomoniasis, a sexually transmitted proto- an adjunct to other amebicides during the treatment
zoal disease affecting the vagina and male genitouri- of more severe protozoal infections. Paromomycin is
nary tract.59 also effective against some bacteria and tapeworms,
As indicated in Chapter 33, metronidazole has and may be used as a secondary agent in certain bacte-
bactericidal effects and is used in certain gram-negative rial or helminthic infections. This drug is adminis-
bacterial infections. This drug may be administered tered orally.
orally or intravenously. Other agents have also been Mechanism of Action. Paromomycin acts selec-
developed that are structurally and functionally similar tively on protozoa within the intestinal lumen and
to metronidazole. Tinidazole (Tindamax), for example, destroys these parasites by a direct toxic effect.
can be used in cases where metronidazole is not toler- Adverse Effects. Paromomycin is not absorbed
ated or is ineffective.24 from the intestine to any great extent, so adverse
Mechanism of Action. The exact mechanism of effects are fairly limited. Nonetheless, problems with
action of metronidazole is not known. It is believed gastrointestinal distress (nausea, vomiting, abdominal
that this drug is reduced chemically within the para- pain) may occur as this drug exerts amebicidal effects
sitic cell to a metabolite that impairs nucleic acid and within the intestine.
DNA synthesis.32 The exact nature of this metabolite,
however, and other features of the cytotoxic effects of
Pentamidine
this drug remain to be determined.
Adverse Effects. Gastrointestinal disturbances Clinical Use. Pentamidine (Nebupent, Pentam,
including nausea, vomiting, diarrhea, stomach pain, other names) is effective against several types of
and an unpleasant taste in the mouth are relatively extraintestinal protozoal infections, including certain
common with metronidazole. Other adverse effects forms of trypanosomiasis (African sleeping sickness)
such as hypersensitivity reactions, peripheral neuropa- and visceral infections caused by Leishmania proto-
thy, hematologic abnormalities, and genitourinary zoa. Typically, pentamidine is reserved as a secondary
problems have been reported, but their incidence is agent in treating these infections and is used when the
relatively low. principal drug in each case is not available or is toler-
ated poorly (see Table 35–4). Use of this drug as a pri-
mary agent has increased, however, in the treatment of
Nitazoxanide
pneumocystis infections in patients with AIDS.51 This
Clinical Use. Nitazoxanide (Alinia) is a relatively drug is usually administered by parenteral routes such
new agent that is used primarily to treat diarrhea as deep intramuscular injection or slow intravenous
caused by intestinal cryptosporidia and giardia infec- infusion. Pentamidine may also be administered by
tions.51 This drug is approved for use in children aged oral inhalation to treat lung infections, and this strat-
1 to 11, and is administered orally. egy is now commonly used as prophylaxis and treat-
Mechanism of Action. Nitazoxanide appears to ment of pneumocystis pneumonia in patients with
inhibit electron transport in susceptible protozoa, thus AIDS.47
35Ciccone(p)-35 1/30/07 2:55 PM Page 557
Mechanism of Action. The exact mechanism of from human tissues.44,52 Common examples include
this drug is not clear, and pentamidine may affect dif- tapeworms (cestodes), roundworms (nematodes), and
ferent parasites in different ways. Some possible flukes (trematodes).52 Worms can enter the body by
antiprotozoal actions of this drug include the inhibi- various routes but often are ingested as eggs in con-
tion of protein and nucleic acid synthesis, cellular taminated food and water. Once in the body, the eggs
metabolism, and oxidative phosphorylation in suscep- hatch, and adult worms ultimately lodge in various tis-
tible parasites. sues, especially the digestive tract. Some types (flukes)
Adverse Effects. The primary adverse effect of may also lodge in blood vessels such as the hepatic
systemic pentamidine administration is renal toxicity. portal vein. Depending on the species, adult worms
Renal function may be markedly impaired in some may range from a few millimeters to several meters in
patients, but kidney function usually returns to normal length. The adult worms begin to steal nutrients from
when the drug is withdrawn. Other adverse effects their human host and may begin to obstruct the intes-
include hypotension, hypoglycemia, gastrointestinal tinal lumen or other ducts if they reproduce in suffi-
distress, blood dyscrasias (leukopenia, thrombocy- cient numbers.
topenia), and local pain and tenderness at the site of Some of the common anthelmintics used to kill
injection. Adverse effects are reduced substantially the basic types of worms in humans are listed in Table
when the drug is given by inhalation, and this method 35–5. These agents are often very effective; a single
of administration is desirable when pentamidine is oral dose is usually sufficient to selectively destroy the
used to prevent pneumocystis pneumonia in patients parasite. Brief descriptions of the basic pharmacologic
with human immunodeficiency virus (HIV) disease. effects and possible adverse effects of the primary
anthelmintic agents are presented below. Several
authors have also extensively reviewed the pharmaco-
Other Antiprotozoal Drugs logic treatment of helminthic infections.36,41,52,58,66
Several additional agents have been developed to treat
intestinal and extraintestinal infections caused by vari- Albendazole
ous protozoa. These agents include melarsoprol, nifur-
timox, sodium stibogluconate, and suramin. The use Albendazole (Albenza) is primarily used to treat infec-
and distribution of these drugs, however, is quite dif- tions caused by the larval form of certain cestodes
ferent from the agents described previously. In the (tapeworms). These infections often cause cysts
United States, these additional drugs are usually avail- (hydatid disease) in the liver, lungs, and other tissues;
able only from the Centers for Disease Control albendazole is used as an adjunct to the surgical
(CDC), in Atlanta, Georgia. At the request of the removal of these cysts or as the primary treatment if
physician, the CDC dispenses the drug to the physi- these cysts are inoperable. This drug is also effective
cian, who then provides the agent to the patient. against many gastrointestinal roundworms and hook-
Clinical applications of individual drugs in this worms, and is typically used as a secondary agent if
category are indicated in Table 35–4. In general, these other anthelmintics are not effective in treating these
drugs are reserved for some of the more serious or infections.
rare types of protozoal infections. As might be expect- Albendazole exerts its anthelmintic effects by act-
ed, adverse side effects of these drugs are quite com- ing on the intestinal cells of parasitic worms and by
mon. However, these drugs may be lifesaving in some inhibiting glucose uptake and glycogen storage by
of the more severe infections, which is why the CDC these parasites. This effect ultimately leads to lack of
controls their distribution. For more information energy production, degeneration of intracellular com-
about specific agents in this group, the reader is ponents, and subsequent death of the parasite. Alben-
referred to other sources.51 dazole is usually well tolerated when used for
short-term treatment of infections in gastrointestinal
or other tissues. Long-term treatment for conditions
such as hydatid disease may result in abnormal liver
Anthelmintics function tests (e.g., increased serum aminotransferase
Infection from helminths, or parasitic worms, is the activity), and liver function should therefore be moni-
most common form of disease in the world.41,44 There tored periodically to prevent hepatotoxicity if this
are several types of worms that may invade and subsist drug is used for extended periods.
35Ciccone(p)-35 1/30/07 2:55 PM Page 558
Tapeworms (cestodes)
Beef tapeworm Niclosamide, praziquantel —
Flukes (trematodes)
Blood flukes Praziquantel Oxamniquine
Diethylcarbamazine Ivermectin
Diethylcarbamazine (Hetrazan) is used to treat certain Ivermectin (Mectizan, Stromectol) is the primary
roundworm infections of the lymphatics and connec- treatment for filarial nematode infections (onchocer-
tive tissues, including loiasis, onchocerciasis, and Ban- ciasis) that invade ocular tissues and cause loss of
croft filariasis. This agent immobilizes immature vision (river blindness). Ivermectin may also be used in
roundworms (microfilariae) and facilitates the filarial infections in other tissues (lymphatics, skin).
destruction of these microfilariae by the body’s This drug is a secondary agent for treating intestinal
immune system. Diethylcarbamazine is also effective nematodes such as strongyloidosis.
against the adult forms of certain roundworms, but the Ivermectin binds to chloride ion channels in par-
mechanism of this anthelmintic action against mature asitic nerve and muscle cells, thereby increasing mem-
nematodes is not known. brane permeability to chloride. Increased intracellular
Side effects associated with diethylcarbamazine chloride results in hyperpolarization of nerve and
include headache, malaise, weakness, and loss of muscle tissues, which results in paralysis and death of
appetite. More severe reactions (fever, acute inflam- the parasite. Ivermectin is well tolerated during short-
matory response) may also occur following diethylcar- term use in mild-to-moderate infections. Administra-
bamazine use, but these reactions may be caused by tion in more severe infections may cause swollen or
the release of antigenic substances from the dying tender lymph glands, fever, skin rash, itching, and
roundworms rather than from the drug itself. joint and muscle pain, but these reactions may be
35Ciccone(p)-35 1/30/07 2:55 PM Page 559
caused by the death of the infectious parasites rather to paralyze the worm by blocking the effect of acetyl-
than by the drug itself. choline at the parasite’s neuromuscular junction. The
paralyzed worm can then be dislodged and expelled
from the host (human) intestine during normal bowel
Mebendazole movements. Side effects such as headache, dizziness,
Mebendazole (Vermox) is effective against many types and gastrointestinal disturbance may occur during
of roundworms and a few tapeworms that parasitize piperazine citrate administration, but these effects are
humans. Like albendazole, this drug selectively dam- generally mild and transient.
ages intestinal cells in these worms, thus inhibiting the
uptake and intracellular transport of glucose and other
nutrients into these parasites. This activity leads to the
Praziquantel
destruction of the epithelial lining and subsequent Praziquantel (Biltricide) is one of the most versatile
death of the parasite. Mebendazole is a relatively safe and important anthelmintic agents, and is the drug of
drug, although some mild, transient gastrointestinal choice in treating all major trematode (fluke) infec-
problems may occur. tions and several common types of tapeworm infec-
tions (see Table 35–5). This drug’s exact mechanism of
action is unknown. Praziquantel may stimulate muscu-
Niclosamide lar contraction of the parasite, resulting in a type of
Niclosamide (Niclocide) is effective against several spastic paralysis, which causes the worm to lose its
types of tapeworm (see Table 35–5). This drug inhibits hold on intestinal or vascular tissue. At higher concen-
certain mitochondrial enzymes in these parasites, trations, this drug may initiate destructive changes in
which ultimately results in the breakdown of the pro- the integument of the worm, allowing the host defense
tective integument of the worm, thus allowing the mechanisms (e.g., enzymes, phagocytes) to destroy the
digestive enzymes in the host (human) intestine to parasite. Praziquantel is associated with a number of
attack the parasite. Ultimately, the worm is digested frequent side effects, including gastrointestinal prob-
and expelled from the gastrointestinal tract. There are lems (abdominal pain, nausea, vomiting), CNS effects
relatively few adverse effects of niclosamide treatment, (headache, dizziness), and mild hepatotoxicity. These
probably because the drug is not absorbed to any great effects can usually be tolerated, however, for the rela-
extent from the human intestine. Thus, this drug tively short time that the drug is in effect.
remains in the intestinal lumen, where it can act
directly on the tapeworm.
Pyrantel Pamoate
Pyrantel pamoate (Antiminth, other names) is one of
Oxamniquine the primary agents used in several types of round-
Oxamniquine (Vansil) is effective against a genus of worm and pinworm infections (see Table 35–5). This
parasitic worms known as blood flukes (schistosomes). drug stimulates acetylcholine release and inhibits
These parasites typically adhere to the wall of blood acetylcholine breakdown at the neuromuscular junc-
vessels such as the hepatic portal vein. Oxamniquine tion, thus producing a prolonged state of excitation
inhibits muscular contraction of the sucker that holds and muscular contraction that causes spastic paralysis
the fluke to the vessel wall, thus allowing the worm to of the worm. The worm is unable to retain its hold on
dislodge and travel to the liver. In the liver, the para- the intestinal tissue and can be expelled from the
site is engulfed and destroyed by hepatic phagocytes. digestive tract by normal bowel movements. This
Common side effects associated with this drug include drug is generally well tolerated, with only occasional
headache, dizziness, and drowsiness. However, these problems of mild gastrointestinal disturbances.
adverse effects are generally mild and transient.
Thiabendazole
Piperazine Citrate Thiabendazole (Mintezol) is often used in trichinosis
Piperazine citrate is typically used as a secondary and several other types of roundworm infections (see
agent in ascariasis (roundworm) and enterobiasis (pin- Table 35–5). The anthelmintic mechanism of this
worm) infections (see Table 35–5). This drug appears drug is not fully understood, but selective inhibition of
35Ciccone(p)-35 1/30/07 2:55 PM Page 560
certain key metabolic enzymes in susceptible parasites mon side effects associated with this drug involve gas-
is probable. Although thiabendazole is quite effective, trointestinal distress (nausea, vomiting, loss of
the use of this drug has declined somewhat in favor of appetite). Allergic reactions (skin rash, itching, chills)
less toxic agents such as mebendazole. The most com- may also occur in some individuals.
CA S E ST U DY
Antifungal Drugs Decision/Solution. The physician prescribed a topi-
cal antifungal preparation containing miconazole (Monistat-
Brief History. A physical therapist working with a col- Derm). The athlete was instructed to apply this preparation
lege football team was taping a team member’s ankle when twice daily. The physical therapist also instructed the athlete
he noticed redness and inflammation between the athlete’s in proper skin hygiene (such as thoroughly washing and dry-
toes. The athlete reported that the redness and itching had ing the feet, wearing clean socks). In addition, the physical
developed within the last few days and was becoming pro- therapist had the locker room floors and shower areas thor-
gressively worse. The therapist suspected a cutaneous fungal oughly disinfected to prevent transmission of the fungus to
infection (probably tinea pedis) and reported this information other team members. This isolated case of tinea pedis was
to the team physician. resolved without further incident.
35Ciccone(p)-35 1/30/07 2:55 PM Page 561
29. Goldman RD, Koren G. Amphotericin B nephrotoxic- 48. Patel SN, Kain KC. Atovaquone/proguanil for the
ity in children. J Pediatr Hematol Oncol. 2004;26: prophylaxis and treatment of malaria. Expert Rev Anti
421–426. Infect Ther. 2005;3:849–861.
30. Gupta AK, Ryder JE, Lynch LE, Tavakkol A. The use 49. Pellegrini M, Ruff TA. Malaria. The latest in advice
of terbinafine in the treatment of onychomycosis in for travelers. Aust Fam Physician. 1999;28:683–688.
adults and special populations: a review of the evi- 50. Petersen E. Malaria chemoprophylaxis: when should
dence. J Drugs Dermatol. 2005;4:302–308. we use it and what are the options? Expert Rev Anti
31. Herbrecht R. Voriconazole: therapeutic review of a Infect Ther. 2004;2:119–132.
new azole antifungal. Expert Rev Anti Infect Ther. 2004; 51. Phillips MA. Stanley SL. Chemotherapy of protozoal
2:485–497. infections: amebiasis, giardiasis, trichomoniasis, try-
32. Hrdy I, Cammack R, Stopka P, et al. Alternative path- panosomiasis, leishmaniasis, and other protozoal infec-
way of metronidazole activation in Trichomonas vagi- tions. In: Brunton LL, et al, eds. The Pharmacological
nalis hydrogenosomes. Antimicrob Agents Chemother. Basis of Therapeutics. 11th ed. New York: McGraw-Hill;
2005;49:5033–5036. 2006.
33. Huang DB, Ostrosky-Zeichner L, Wu JJ, et al. Thera- 52. Plorde JJ. Introduction to pathogenic parasites: patho-
py of common superficial fungal infections. Dermatol genesis and chemotherapy of parasitic diseases. In:
Ther. 2004;17:517–522. Ryan KJ, Ray CG, eds. Sherris Medical Microbiology.
34. Jalloh A, Tantular IS, Pusarawati S, et al. Rapid epi- 4th ed. New York: McGraw-Hill; 2004.
demiologic assessment of glucose-6-phosphate dehy- 53. Polak A. Antifungal therapy—state of the art at the
drogenase deficiency in malaria-endemic areas in beginning of the 21st century. Prog Drug Res. 2003;
Southeast Asia using a novel diagnostic kit. Trop Med Spec No:59–190.
Int Health. 2004;9:615–623. 54. Rao S, Ali U. Systemic fungal infections in neonates. J
35. Kam LW, Lin JD. Management of systemic candidal Postgrad Med. 2005;51(suppl 1):S27–S29.
infections in the intensive care unit. Am J Health Syst 55. Rathore D, McCutchan TF, Sullivan M, Kumar S.
Pharm. 2002;59:33–41. Antimalarial drugs: current status and new develop-
36. Keiser J, Utzinger J. Chemotherapy for major food- ments. Expert Opin Investig Drugs. 2005;14:871–883.
borne trematodes: a review. Expert Opin Pharmacother. 56. Roberts BJ, Friedlander SF. Tinea capitis: a treatment
2004;5:1711–1726. update. Pediatr Ann. 2005;34:191–200.
37. Kurowski R, Ostapchuk M. Overview of histoplasmo- 57. Sastry PS, Parikh PM, Kulkarni PS, et al. Use of lipo-
sis. Am Fam Physician. 2002;66:2247–2252. somal amphotericin B in bone marrow transplant. J
38. Kyle AA, Dahl MV. Topical therapy for fungal infec- Postgrad Med. 2005;51(suppl 1):S49–S52.
tions. Am J Clin Dermatol. 2004;5:443–451. 58. Schantz PM. Progress in diagnosis, treatment and
39. Lemke A, Kiderlen AF, Kayser O. Amphotericin B. elimination of echinococcosis and cysticercosis. Para-
Appl Microbiol Biotechnol. 2005;68:151–162. sitol Int. 2006;55(suppl):S7–S13.
40. Lesi A, Meremikwu M. High first dose quinine regi- 59. Schwebke JR, Burgess D. Trichomoniasis. Clin Micro-
men for treating severe malaria. Cochrane Database Syst biol Rev. 2004;17:794–803.
Rev. 2004;CD003341. 60. Shanks GD, Edstein MD. Modern malaria chemopro-
41. Loukas A, Hotez PJ. Chemotherapy of helminth infec- phylaxis. Drugs. 2005;65:2091–2110.
tions. In: Brunton LL, et al, eds. The Pharmacological 61. Shapiro TA, Goldberg DE. Chemotherapy of proto-
Basis of Therapeutics. 11th ed. New York: McGraw-Hill; zoal infections: malaria. In: Brunton LL, et al, eds. The
2006. Pharmacological Basis of Therapeutics. 11th ed. New
42. Marty F, Mylonakis E. Antifungal use in HIV infec- York: McGraw-Hill;2006.
tion. Expert Opin Pharmacother. 2002;3:91–102. 62. Sibley CH, Hyde JE, Sims PF, et al. Pyrimethamine-
43. Mavor AL, Thewes S, Hube B. Systemic fungal infec- sulfadoxine resistance in Plasmodium falciparum: what
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tion process and virulence attributes. Curr Drug 63. Sims CR, Ostrosky-Zeichner L, Rex JH. Invasive can-
Targets. 2005;6:863–874. didiasis in immunocompromised hospitalized patients.
44. McAdam AJ, Sharpe AH. Infectious diseases. In: Arch Med Res. 2005;36:660–671.
Kumar V, Abbas AK, Fausto N, eds. Pathologic Basis of 64. Slain D, Rogers PD, Cleary JD, Chapman SW. Intra-
Disease. 7th ed. New York: Elsevier Saunders; 2005. venous itraconazole. Ann Pharmacother. 2001;35:
45. McCormack PL, Perry CM. Caspofungin: a review of 720–729.
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2005;65:2049–2068. the Plasmodium falciparum digestive vacuole: holy
46. Meshnick SR. Artemisinin: mechanisms of action, grail or dead-end trail? Trends Parasitol. 2002;18:
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1655–1660. 66. Tisch DJ, Michael E, Kazura JW. Mass chemotherapy
47. Obaji J, Lee-Pack LR, Gutierrez C, Chan CK. The options to control lymphatic filariasis: a systematic
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pentamidine: a 5-year surveillance study in HIV- 67. Tournu H, Serneels J, Van Dijck P. Fungal pathogens
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Targets. 2005;6:909–922. HIV infected patients. Curr HIV Res. 2006;4:
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review: severe malaria. Crit Care. 2003;7:315–323. 71. Woodrow CJ, Haynes RK, Krishna S. Artemisinins.
69. Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a Postgrad Med J. 2005;81:71–78.
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Chapter 36
Cancer Chemotherapy
Cancer encompasses a group of diseases that are mation about the location and morphology of particu-
marked by rapid, uncontrolled cell proliferation and a lar forms of cancer.41,76
conversion of normal cells to a more primitive and The exact cause of many cases of neoplastic dis-
undifferentiated state.11,41 Large tumors, or neoplasms, ease is unknown. However, a great deal has been
may form from excessive cell proliferation. Although learned about possible environmental, viral, genetic,
some types of tumors are well contained (benign), and other elements, or carcinogens, that may cause
malignant tumors continue to proliferate within local or increase a person’s susceptibility to various types of
tissues and can possibly spread (metastasize) to other cancer. Conversely, certain positive lifestyles, includ-
tissues in the body. The term cancer specifically refers ing adequate exercise, a high-fiber diet, and the avoid-
to the malignant forms of neoplastic disease, which ance of tobacco products, may be crucial in preventing
can often be fatal as tumors invade and destroy tissues certain forms of cancer. Of course, routine checkups
throughout the body. However, benign tumors can and early detection play a vital role in reducing cancer
also be life threatening; for example, a large benign mortality.
tumor may produce morbidity and mortality by When cancer is diagnosed, three primary treat-
obstructing the intestinal tract or by pressing on ment modalities are available: surgery, radiation treat-
crucial central nervous system (CNS) structures. ment, and cancer chemotherapy. The purpose of this
Cancer cells, however, are unique in their progressive chapter is to describe the basic rationale of cancer
invasion of local tissues and their ability to metastasize chemotherapy and to provide an overview of the
to other tissues.41 drugs that are currently available to treat specific forms
Cancer ranks second to cardiovascular disease as of cancer. Rehabilitation specialists will routinely work
the leading cause of death in the United States.31 with patients undergoing cancer chemotherapy. For
There are many different types of cancer, and malig- reasons that will become apparent in this chapter,
nancies are classified by the location and the type of these drugs tend to produce toxic effects that directly
tissue from which the cancer originated.41 For influence physical therapy and occupational therapy
instance, cancers arising from epithelial tissues (e.g., procedures. Therefore, this chapter should provide
skin, gastrointestinal lining) are labeled as carcinomas; therapists with a better understanding of the pharma-
cancers arising from mesenchymal tissues (e.g., bone, codynamic principles and beneficial effects, as well as
striated muscle) are labeled as sarcomas. In addition, the reasons for the potential adverse effects of these
cancers associated with the formed blood elements are important drugs.
connoted by the suffix “-emia” (e.g., “leukemia” is the
cancerous proliferation of leukocytes). Many other
descriptive terms are used to describe various malig- General Principles
nancies, and certain forms of cancer are often named
after a specific person (e.g., Hodgkin disease, Wilms
Cytotoxic Strategy
tumor). We cannot, however, describe all the various The basic strategy of anticancer drugs is to limit cell
types of malignancies. The reader may want to consult proliferation by killing or attenuating the growth of
a pathology text or similar reference for more infor- the cancerous cells. However, the pharmacologic treat-
565
36Ciccone(p)-36 1/30/07 2:55 PM Page 566
Paclitaxel
Vinblastine, Vincristine
G0
M (resting)
(mitosis)
G2
(post-DNA
synthesis)
G1
(pre-DNA
synthesis)
S
Cytarabine (DNA synthesis)
Doxorubicin
Fluorouracil
6-Mercaptopurine
Methotrexate
Cell-cycle nonspecific:
Alkylating agents
Anticancer antibiotics
Dacarbazine
FIGURE 36–1 ▼ Phases of the cell cycle. Examples of cell-cycle–specific drugs are listed next
to the phase of the cycle they act on. Examples of cell-cycle–nonspecific drugs are listed below the
figure. See text for more details.
cer cells, however, tend to suffer these toxic effects to a vomiting, loss of appetite) may be relieved to some
greater extent because of their increased rate of repli- extent by administering traditional antiemetic agents
cation and cell division. Still, healthy cells often exhib- such as glucocorticoids (dexamethasone) or drugs that
it some toxic effects, even at the minimum effective block dopamine receptors (metoclopramide).4,30 In
doses of the chemotherapeutic agents. addition, newer antiemetic and antinausea agents
Consequently, antineoplastic drugs typically have such as dolasetron (Anzemet), granisetron (Kytril),
a very low therapeutic index compared with drugs that ondansetron (Zofran), and palonosetron (Aloxi) have
are used to treat less serious disorders (see Chapter 1). been developed to treat chemotherapy-induced nausea
Considering that cancer is usually life threatening, and vomiting. These newer agents, which block a spe-
these toxic effects must be expected and tolerated cific type of CNS serotonin receptor known as the 5-
during chemotherapeutic treatments. Some side hydroxytryptamine type 3 (5-HT3) receptor, reduce
effects, however, can be treated with other drugs. In the nausea and vomiting caused when serotonin binds
particular, gastrointestinal disturbances (e.g., nausea, to that receptor.1,4 Likewise, a new agent known as
36Ciccone(p)-36 1/30/07 2:55 PM Page 568
R N CH2 CH2 CI
CH2
CH2 OH
CH2 CH2 CI N
N
R N
CH2 CH2 CI
N N NH2
R
G
N R
CH2 CH2 G
HO CH2 CH2 OH
N N
N N
H2N N N N N NH2
Cross-linked Guanines
DNA
FIGURE 36–2 ▼ Mechanism of action of anticancer alkylating agents. The alkylating agent (R)
causes alkylation of guanine nucleotides located in the DNA strand. Cross-links are then formed
between two alkylated guanines, thus creating strong bonds between or within the DNA strands
that inhibit DNA function and replication.
36Ciccone(p)-36 1/30/07 2:55 PM Page 569
reproduced, and cell reproduction is arrested. In addi- drug and the normal metabolite and waste their time
tion, cross-linking within the double helix impairs cel- trying to convert the antimetabolite into a normal
lular protein synthesis because the DNA double helix metabolic product. The enzyme, however, cannot
cannot unwind to allow formation of messenger RNA effectively act on the drug, so the normal metabolic
strands. The cell therefore cannot synthesize vital cel- products are not formed. In either case, the cell’s abil-
lular proteins (enzymes, transport proteins, etc.). Alky- ity to synthesize normal DNA and RNA is impaired,
lating agents likewise initiate a process of cell death and the cell cannot replicate its genetic material or
(apoptosis) by disrupting DNA function, in which sev- carry out normal protein synthesis because of a lack of
eral degradative enzymes (nucleases, proteases) are functional DNA and RNA.
released and begin to destroy the cell.11 Cancer chemotherapeutic agents that act as
Alkylating agents are so named because they typ- antimetabolites and the principal neoplastic diseases
ically generate a chemical alkyl group on one of the for which they are indicated are listed in Table 36–2.
bases, such as guanine in the DNA chain. This alkyl As stated previously, these drugs interrupt cellular
group acts as the bridge that ultimately links two bases pathways that synthesize DNA and RNA; the primary
in the DNA molecule (see Fig. 36–2). The bonds sites where specific antimetabolites interrupt these
formed by this cross-linking are strong and resistant to pathways are indicated in Figure 36–3. As with most
breakage. Thus, the DNA double helix remains tied anticancer drugs, these agents are especially toxic to
up for the cell’s life. cells that have a large growth fraction and undergo
Anticancer drugs that work primarily as alkylat- extensive replication. These cells have a great need to
ing agents are listed in Table 36–1. As indicated, these synthesize nucleic acids—hence the preferential effect
agents represent the largest category of anticancer of antimetabolites on these cells.
drugs and are used to treat a variety of leukemias, car-
cinomas, and other neoplasms. Common side effects
of alkylating agents are also listed in Table 36–1. As
Antibiotics
previously discussed, most of these adverse effects are Several anticancer drugs are chemically classified as
caused by the effect of the alkylating agent on DNA antibiotics but are usually reserved for neoplastic dis-
replication in normal, healthy tissues. eases because of their relatively high toxicity. The
exact mechanism of action for these antibiotics to
exert antineoplastic effects is still being investigated.
Antimetabolites These drugs may act directly on DNA by becoming
Cells are able to synthesize genetic material (DNA, intercalated (inserted) between base pairs in the DNA
RNA) from endogenous metabolites known as purine strand. This insertion would cause a general disrup-
and pyrimidine nucleotides (Fig. 36–3). Certain anti- tion or even lysis of the DNA strand, thus preventing
cancer drugs are structurally similar to these endoge- DNA replication and RNA synthesis.25 Alternatively,
nous metabolites and compete with these compounds these antibiotics may act in other ways, including hav-
during DNA/RNA biosynthesis. These drugs are ing direct effects on the cancerous cell membrane,
therefore called antimetabolites because they interfere inhibiting DNA-related enzymes, and forming highly
with the normal metabolites during cellular biosyn- reactive free radicals that directly damage the DNA
thesis.16,80 molecule.51,83 Regardless of their exact mechanism,
Antimetabolites can impair the biosynthesis of these agents play a role in the treatment of several
genetic material in two primary ways.11 First, the drug neoplastic diseases. Antibiotic agents used for cancer
may be incorporated directly into the genetic material, chemotherapy are listed in Table 36–3.
thus forming a fake and nonfunctional genetic product.
This effect would be like baking a cake but substituting
an inappropriate ingredient (salt) for a normal ingredi-
Plant Alkaloids
ent (sugar). Obviously, the product would not work (or Alkaloids are nitrogen-based compounds frequently
taste) very well. The second manner in which antime- found in plants. Plant alkaloids that are used in treat-
tabolites may impair DNA/RNA biosynthesis is by ing cancer in humans include traditional agents, such
occupying the enzymes that synthesize various compo- as vincristine and vinblastine, and newer agents, such
nents of the genetic material. These enzymes do not as vinorelbine, paclitaxel, and docetaxel (Table 36–4).
recognize the difference between the antimetabolite These agents are also known as antimitotic drugs be-
Text continued on page 573
36Ciccone(p)-36 1/30/07 2:55 PM Page 570
Primary Antineoplastic
Generic Name Trade Name Indication(s)* Common Adverse Effects
Altretamine Hexalen Ovarian cancer GI distress (nausea, vomiting, loss of
appetite); blood disorders (leukope-
nia, thrombocytopenia); CNS neu-
rotoxicity (unusual tiredness,
dizziness, confusion, depression,
anxiety); peripheral neuropathies
Carmustine BCNU, BiCNU Primary brain tumors; Hodgkin Blood disorders (thrombocytopenia,
disease; non-Hodgkin lym- leukopenia); GI distress (nausea,
phomas; multiple myeloma vomiting); hepatotoxicity; pulmonary
toxicity
Cyclophosphamide Cytoxan, Neosar Acute and chronic lymphocytic Blood disorders (anemia, leukopenia,
leukemia; acute and chronic thrombocytopenia); GI distress
myelocytic leukemia; carcino- (nausea, vomiting, loss of appetite);
ma of ovary, breast; Hodgkin bladder irritation; hair loss; car-
disease; non-Hodgkin lym- diotoxicity; pulmonary toxicity
phomas; multiple myeloma
Lomustine CeeNU Brain tumors; Hodgkin disease Blood disorders (anemia, leukopenia);
GI disorders (nausea, vomiting)
Primary Antineoplastic
Generic Name Trade Name Indication(s)* Common Adverse Effects
Melphalan Alkeran Ovarian carcinoma; multiple Blood disorders (leukopenia, thrombo-
myeloma cytopenia); skin rashes/itching
Thiotepa Thioplex Carcinoma of breast, ovary, and Blood disorders (anemia, leukopenia,
bladder; Hodgkin disease thrombocytopenia, pancytopenia)
Uracil mustard Generic Chronic lymphocytic leukemia; Blood disorders (anemia, leukopenia,
chronic myelocytic leukemia; thrombocytopenia); GI distress (nau-
non-Hodgkin lymphomas sea, vomiting, diarrhea, loss of
appetite)
*
Only the indications listed in the U.S. product labeling are included here. Many anticancer drugs are used for
additional types of neoplastic disease.
GI = gastrointestinal; CNS = central nervous system.
Primary Antineoplastic
Generic Name Trade Name Indication(s)* Common Adverse Effects
Capecitabine Xeloda Breast cancer Blood disorders (anemia, neutropenia, throm-
bocytopenia); GI distress (abdominal pain,
nausea, vomiting); dermatitis; stomatitis;
unusual tiredness
Cladribine Leustatin Hairy cell leukemia Blood disorders (anemia, neutropenia, throm-
bocytopenia); fever; infection; GI distress
(loss of appetite, nausea, vomiting); skin
rash; headache; unusual tiredness
Cytarabine Cytosar-U, Depocyt Several forms of acute and Blood disorders (anemia, megaloblastosis,
chronic leukemia; non- reticulocytopenia, others); GI distress
Hodgkin lymphomas (nausea, vomiting); skin rash; hair loss
Primary Antineoplastic
Generic Name Trade Name Indication(s)* Common Adverse Effects
Fludarabine Fludara Chronic lymphocytic Blood disorders (anemia, leukopenia,
leukemia thrombocytopenia); infection; pneumo-
nia; GI distress (nausea, vomiting, diar-
rhea); skin rash; unusual tiredness; hair
loss
Methotrexate Generic (when used Acute lymphocytic Blood disorders (anemia, leukopenia,
for cancer) leukemia; meningeal thrombocytopenia); GI distress (includ-
leukemia; carcinoma of ing ulceration of GI tract); skin disor-
head and neck region, ders (rashes, photosensitivity, hair
lung; non-Hodgkin lym- loss); hepatotoxicity; CNS effects
phomas (headaches, drowsiness, fatigue)
PURINE
PURINE PYRAMIDINE the nuclear material becomes disrupted and dispersed
NUCLEOTIDES
NUCLEOTIDES NUCLEOTIDES throughout the cytosol. This effect causes direct dam-
age to the chromosomes, leading to subsequent cell
dysfunction and death.
Other drugs classified as plant alkaloids include
etoposide, irinotecan, teniposide, and topotecan (see
Table 36–4). These drugs inhibit specific enzymes
known as topoisomerase enzymes, which are necessary
for DNA replication.11 Inhibition of these enzymes
METHOTREXATE causes a break in both strands of the DNA double
MERCAPTOPURINE helix, which leads to DNA destruction and cell death.
THIOGUANINE Etoposide and teniposide inhibit the topoisomerase I
form of this enzyme, and irinotecan and topotecan
RIBONUCLEOTIDES inhibit the topoisomerase II form of this enzyme.
These drugs are therefore used to limit cell division
and cancer growth in various types of neoplastic dis-
ease (see Table 36–4).
Hormones
DEOXYNUCLEOTIDES
Several forms of cancer are referred to as hormone
sensitive because they tend to be exacerbated by cer-
CYTARABINE
FLUOROURACIL
tain hormones and attenuated by others. In particular,
FLOXURIDINE adrenocorticosteroids (see Chapter 29) and the sex
hormones (androgens, estrogens, progesterone; see
DNA Chapter 30) may influence the proliferation of certain
tumors. Hence, drugs that either mimic or block
(antagonize) the effects of these hormones may be use-
ful in treating certain hormone-sensitive forms of can-
cer.29 Hormonal anticancer drugs are typically used as
adjuvant therapy; that is, they are used in conjunction
RNA with surgery, radiation treatment, and other anticancer
drugs.
FIGURE 36–3 ▼ Sites of anticancer antimetabolite action. Various The primary drugs that inhibit neoplasms
drugs interfere with DNA/RNA production by inhibiting nucleic acid
biosynthesis at specific sites indicated by the dashed lines.
via hormonal mechanisms are listed in Table 36–5.
In some cases, these drugs work by direct inhibitory
effects on cancerous cells (e.g., adrenocorticoid
cause they directly impair cell division. These drugs suppression of lymphocyte function) or by negative
exert their antimitotic effects by binding to cellular feedback mechanisms that decrease the endogenous
microtubules and altering the function of these micro- hormonal stimulation of the tumor (e.g., gonadotro-
tubules.38,92 In particular, these drugs disrupt the func- pin-releasing hormones). In other cases, drugs can
tion of the microtubules that are involved in the directly block the effects of the endogenous hormone
mitotic apparatus of the cell (the mitotic spindle). Cer- and prevent that hormone from stimulating spe-
tain agents (vincristine, vinblastine, vinorelbine) cific tumors. In particular, androgen receptor block-
inhibit the formation of the mitotic apparatus, where- ers (flutamide, others) can treat prostate cancer by
as others (paclitaxel, docetaxel) inhibit breakdown of blocking the effects of testosterone on the prostate
these microtubules, thereby creating a stable but non- gland.28
functional mitotic apparatus.38,58 In either situation, Estrogen receptor blockers (fulvestrant, tamox-
these drugs disrupt the normal function of the mitot- ifen) can likewise help prevent and treat breast and
ic apparatus and prevent the cell from dividing and uterine cancers that are stimulated by estrogen.37 Ful-
proliferating. In fact, when the cell attempts to divide, vestrant (Faslodex) is classified as a “pure” antiestrogen
Text continued on page 577
36Ciccone(p)-36 1/30/07 2:55 PM Page 574
Primary Antineoplastic
Generic Name Trade Name Indication(s)* Common Adverse Effects
Bleomycin Blenoxane Carcinoma of head, neck, cer- Pulmonary toxicity (interstitial pneu-
vical region, skin, penis, monitis); skin disorders (rash, discol-
vulva, and testicle; Hodgkin oration); mucosal lesions; fever; GI
disease; non-Hodgkin lym- distress; general weakness and
phomas malaise
*Only the indications listed in the U.S. product labeling are included here. Many anticancer drugs are used for
additional types of neoplastic disease.
GI = gastrointestinal.
36Ciccone(p)-36 1/30/07 2:55 PM Page 575
Primary Antineoplastic
Generic Name Trade Name Indication(s)* Common Adverse Effects
Docetaxel Taxotere Breast cancer Blood disorders (anemia, leukopenia,
neutropenia); fever; fluid retention;
paresthesias/dysthesias; skin rash-
es/itching; stomatitis; GI distress
(nausea, diarrhea);
Paclitaxel Taxol Carcinoma of the breast, ovaries; Blood disorders (anemia, leukopenia,
Kaposi sarcoma; nonsmall cell neutropenia, thrombocytopenia);
lung cancer hypersensitivity reaction (skin
rash/itching, shortness of breath);
joint/muscle pain; peripheral neu-
ropathies; GI distress (nausea,
vomiting, diarrhea)
Topotecan Hycamtin Ovarian cancer; small lung cell Blood disorders (anemia, leukopenia,
carcinoma neutropenia, thrombocytopenia);
dyspnea; fever; neurological effects
(muscle weakness, paresthesias);
stomatitis; GI distress (abdominal
pain, loss of appetite, nausea, vom-
iting, diarrhea, constipation)
Vinblastine Velban, Velsar Carcinoma of breast, testes, Blood disorders (primarily leukope-
other tissues; Hodgkin dis- nia); GI distress (nausea, vomiting);
ease; non-Hodgkin lym- hair loss; central and peripheral
phomas; Kaposi sarcoma neuropathies; local irritation at
injection site
Primary Antineoplastic
Generic Name Trade Name Indication(s)* Common Adverse Effects
Vincristine Oncovin, Acute lymphocytic leukemia; Neurotoxicity (peripheral neu-
Vincasar neuroblastoma; Wilms tumor; ropathies, CNS disorders); hair
Hodgkin disease; non-Hodgkin loss; local irritation at injection site
lymphomas; Ewing sarcoma
Vinorelbine Navelbine Nonsmall cell lung cancer Blood disorders (anemia, granulocy-
topenia, leukopenia); unusual
weakness/fatigue; GI distress (loss
of appetite, nausea, vomiting, con-
stipation); hair loss
*
Only the indications listed in the U.S. product labeling are included here. Many anticancer drugs are used for
additional types of neoplastic disease.
GI = gastrointestinal; CNS = central nervous system.
Antiandrogens Inhibits the cellular uptake and effects of andro- Nausea; vomiting; diarrhea;
Bicalutamide gens in advanced, metastatic prostate cancer decreased sex drive
Flutamide
Nilutamide
Aromatase inhibitors Inhibits estrogen biosynthesis to reduce the Nausea; vomiting; dizziness; hot
Anastrozole effects of estrogen in estrogen-sensitive flashes; joint and muscle pain;
Exemestane breast cancer dyspnea; (generally well-tolerated
Letrozole relative to other antineoplastic hor-
mones; side effects vary depend-
ing on the specific drug)
Gonadotropin-releasing Works by negative feedback mechanisms to Hot flashes; bone pain; CNS effects
hormone drugs inhibit testosterone or estrogen production; (headache, dizziness); GI distur-
Abarelix used primarily in advanced prostate cancer or bances (nausea, vomiting)
Leuprolide breast cancer
Goserelin
Triptorelin
*
Only the indications listed in the U.S. product labeling are included here. Many anticancer drugs are used for
additional types of neoplastic disease.
GI = gastrointestinal; CNS = central nervous system.
because this drug binds to all estrogen receptors with- sponse modifiers because they enhance the body’s
out activating them; that is, fulvestrant is a true estro- ability to respond to neoplasms; that is, these drugs are
gen receptor antagonist or blocker. As indicated in not necessarily cytotoxic, but they affect the mecha-
Chapter 30, tamoxifen is actually classified as a selec- nisms that regulate cell division or influence specific
tive estrogen receptor modulator (SERM), meaning aspects of immune function that help inhibit or
that this drug blocks estrogen receptors on certain tis- destroy the cancerous tissues. These drugs are listed in
sues (breast, uterus), while stimulating other estrogen Table 36–6, and are addressed briefly below.
receptors in bone, cardiovascular tissues, skin, and so The chemistry and pharmacology of the interfer-
forth.23,37 ons were discussed in Chapter 34. These peptide com-
In contrast to estrogen blockers, aromatase pounds exert a number of beneficial effects, including
inhibitors such as anastrozole (Arimidex), letrozole antiviral and antineoplastic activity. However, the
(Femara), and exemestane (Aromasin) can decrease exact mechanism of action for interferons to impair
estrogen production in breast and other tissues by cancerous cell growth is not clear. It is possible that
inhibiting the aromatase enzyme that is responsible interferons affect several aspects of tumor growth,
for estrogen biosynthesis.8,24 That is, these aromatase including the inhibition of cancerous genes (onco-
inhibitors do not block estrogen receptors, but instead genes), the activation of cytotoxic immune cells (natu-
reduce estrogen production, thereby decreasing the ral killer cells), and the inhibition of other aspects of
influence of estrogen on breast tumors.17 Hence, cell metabolism and proliferation in cancerous tis-
several options are now available for controlling sues.6 These agents are currently used to treat certain
hormone-sensitive cancers that are responsive to types of leukemias, lymphomas, Kaposi sarcoma, and
estrogen and androgens in women and men, respec- cancer in other organs and tissues (Table 36–6).11,33
tively. Refer to Chapter 30 for more details about the Interleukin-2 (IL-2) is an endogenous cytokine
effects of androgens, estrogens, and their respective that normally exerts a number of beneficial immuno-
receptor blocking agents. logic responses. In particular, IL-2 stimulates the
growth and differentiation of T-cell lymphocytes that
are selectively toxic for tumor cells.11,33 Hence, recom-
Biologic Response Modifiers binant DNA techniques are now used to synthesize
Agents such as the interferons, interleuklin-2, and IL-2 so that this agent can be used to treat cancers
monoclonal antibodies are classified as biologic re- such as renal cancer and malignant melanoma (see
36Ciccone(p)-36 1/30/07 2:55 PM Page 578
Primary Antineoplastic
Drug(s) Indication(s)* Common Adverse Effects
Biologic response modifiers
Interferons Hairy-cell leukemia; Kaposi sarco- Flulike syndrome (mild fever, chills, malaise)
Interferon alfa-2a ma; chronic myelocytic leukemia;
(Roferon-A) renal and bladder cancers
Interferon alfa-2b
(Intron-A)
Monoclonal antibodies
Alemtuzumab (Campath) Chronic lymphocytic leukemia Blood disorders (anemia, leukopenia, neu-
tropenia, thrombocytopenia); chest pain,
dyspnea; infection; nausea
Gemtuzumab (Mylotarg) Acute myeloid leukemia Hemorrhage; liver toxicity; infection; joint
pain; lung toxicity; GI distress (nausea,
vomiting, diarrhea); others
Cisplatin (Platinol) Carcinoma of bladder, ovaries, tes- Nephrotoxicity; GI distress (nausea, vomit-
ticles, and other tissues ing); neurotoxicity (cranial and peripheral
nerves); hypersensitive reactions (e.g.,
flushing, respiratory problems, tachycardia)
36Ciccone(p)-36 1/30/07 2:55 PM Page 579
Primary Antineoplastic
Drug(s) Indication(s)* Common Adverse Effects
Oxaliplatin Colorectal cancer Blood disorders (anemia, leukopenia, neu-
tropenia, thrombocytopenia); joint pain,
chest pain
Geftinib Nonsmall cell lung cancer Blurred vision; dyspnea; rash; GI distress
(nausea, vomiting, diarrhea)
Table 36–6). Research continues to identify the anti- that selectively inhibit or kill cancer cells with minimal
neoplastic role of interleukins, interferons, and other or no effects on healthy tissues may be available in the
cytokines, as well as to define how these agents can be future.34,75
used alone or in combination to treat various forms of Certain monoclonal antibodies such as beva-
cancer.33,77 cizumab (Avastin) can also be used as angiogenesis
Monoclonal antibodies represent a method for inhibitors; that is, these agents inhibit the formation
targeting an anticancer drug against cancerous tis- of new blood vessels in growing tumors.65,88 Because
sues.53,75 These drugs are manufactured using cell tumors often need a rich vascular supply to grow and
cloning techniques that produce an antibody that is proliferate, angiogenesis inhibitors can literally starve
specific for an antigen on the surface of a particular the tumor of oxygen and nutrients.87,91 Bevacizumab
type of cancer cell. When administered, the mono- binds specifically to vascular endothelial growth factor
clonal antibody is attracted directly to the cancer cell, (VEGF), and prevents it from stimulating the forma-
without any appreciable affect on healthy tissues. That tion of blood vessels in the tumor.62,88 Hence, this
is, healthy cells lack the antigen that is present on the intervention can be used along with other more tradi-
cancerous cell, and should therefore remain unaffected tional anticancer drugs to treat specific cancers such as
by the drug. Once it has reached the cancerous cell, advanced colorectal cancer. Other strategies to pre-
monoclonal antibodies exert several complex effects vent angiogenesis are currently being developed, and
that limit cell function, inhibit mitosis, and can possi- various types of angiogenesis inhibitors may be forth-
bly result in the cell’s death.34 Some newer monoclon- coming.21,65
al agents known as bispecific antibodies may also
contain a second antibody that produces an additional
beneficial effect such as stimulating production of
Heavy Metal Compounds
cytotoxic T lymphocytes or other immune system Heavy metal compounds used to treat cancer include
components that attack the tumor.47 Although the use cisplatin, carboplatin, and oxaliplatin (see Table 36–6).
of monoclonal antibodies is still relatively new, several These drugs, which contain platinum, are also known
agents are currently available (Table 36–6). Likewise, as platinum coordination complexes.10,27 Heavy metal
development of anticancer antibodies continues to be drugs act like the alkylating agents; that is, they form
an important area of research, and other antibodies strong cross-links between and within DNA strands,
36Ciccone(p)-36 1/30/07 2:55 PM Page 580
thereby preventing DNA translation and replication. tion about optimal use of tyrosine kinase inhibitors
The chemical nature of these cross-links, however, will surely be forthcoming.
involves the platinum component of the drug rather
than actual formation of an alkyl side group. Heavy
metal compounds are especially important in treating
Miscellaneous Agents
certain epithelial cancers, including testicular cancer, Certain chemotherapy agents do not fall into one of
ovarian cancer, bladder cancer, and others (see Table the categories addressed above. These miscellaneous
36–6).11,89 drugs are listed in Table 36–7, and are described
briefly below.
Arsenic trioxide. Arsenic is a heavy metal that can
Aspirin and Other NSAIDs exert toxic, poisonous effects. Therapeutic dosages of
Considerable evidence exists that aspirin and similar arsenic trioxide (Trisenox), however, may limit the
nonsteroidal anti-inflammatory drugs (NSAIDs) can growth of certain leukemias such as acute promyelo-
prevent colorectal cancer, and that these drugs might cytic leukemia.11 However, because of its potential
also decrease malignancies in other tissues such as the toxicity, arsenic trioxide is not usually an initial treat-
stomach, esophagus, breast, bladder, and lungs.79,82 ment, but is reserved for patients who relapse or who
This effect seems to be dose-related, with increased are resistant to other treatments. Although the exact
protection occurring in people who use aspirin on a mechanism of action is unclear, this drug apparently
regular basis.82 Although the exact reason for this anti- induces several cytotoxic effects by directly damaging
cancer effect is unknown, certain prostaglandins such DNA and proteins that regulate DNA synthesis and
as prostaglandin E2 may promote the growth and replication.
proliferation of certain tumors.12,82 As indicated in Asparaginase. Asparaginase (Elspar) is an enzyme
Chapter 15, aspirin and similar drugs inhibit the cyclo- that converts the amino acid asparagine into aspartic
oxygenase enzyme that synthesizes prostaglandins in acid and ammonia. Most normal cells are able to syn-
various cells in the body. Hence, aspirin and other thesize sufficient amounts of asparagine to function
NSAIDs may reduce the risk of colorectal cancer and properly. Some tumor cells (especially certain leukemic
other cancers by inhibiting the synthesis of certain cells) must rely on extracellular sources for a supply of
prostaglandins. In addition, the COX-2 form of the asparagine, however. By breaking down asparagine in
cyclooxygenase enzyme seems to be prevalent in the bloodstream and extracellular fluid, asparaginase
certain tumors, and inhibition of this enzyme using deprives tumor cells of their source of asparagine, thus
COX-2 selective drugs may ultimately provide optimal selectively impairing cell metabolism in these cells.36
results in certain cancers.13 More information will Asparaginase is used primarily in the treatment of
surely be forthcoming about how aspirin and other acute lymphocytic leukemia (see Table 36–7).
NSAIDs can help prevent specific types of cancer. Bortezomib. Bortezomib (Velcade) inhibits pro-
teasome activity in mammalian cells.11 Mammalian
proteasome is responsible for degrading certain cellu-
Tyrosine Kinase Inhibitors lar proteins affecting cell function and division. By
As discussed in Chapter 4, tyrosine kinase is an enzyme prolonging the activity of these proteins, bortezomib
found in many cells and is responsible for transmitting brings about complex changes in cell function that
signals from the cell membrane to other functional lead to cell dysfunction and death. Certain types of
components throughout the cell. In certain types of cancer, such as multiple myeloma, are more sensitive
cancer, defective function of tyrosine kinases leads to to impaired proteasome regulation, hence the use of
abnormal cell function and proliferation. Hence, drugs this drug in these cancers.
that inhibit tyrosine kinase activity will be especially Denileukin Diftitox. Denileukin Diftitox (Ontak)
useful in some cancers.11 Several tyrosine kinase drugs is formulated by combining interleukin-2 with diph-
are currently available including erlotinib (Tarceva), theria toxin.11 Certain leukemia and lymphoma cells
geftinib (Iressa), and imatinib (Glivec). These drugs have a surface receptor that has a high affinity for
are gaining acceptance as a part of the treatment of interleukin-2, thus attracting this drug directly to these
certain leukemias, as well as cancers affecting other tis- cells. Upon binding with the receptor, the diphtheria
sues such as the lungs, stomach, and pancreas. Use of toxin component of the drug inhibits cellular protein
these drugs is fairly new, however, and more informa- synthesis, which ultimately results in cell death. This
36Ciccone(p)-36 1/30/07 2:55 PM Page 581
Primary Antineoplastic
Drug Indication(s)* Common Adverse Effects
Arsenic trioxide (Trisenox) Acute promyelocytic leukemia Dyspnea; GI distress (nausea, vomiting,
diarrhea); headache; fatigue; others
Asparaginase (Elspar) Acute lymphocytic leukemia Allergic reactions; renal toxicity; hepatic
toxicity; delayed hemostasis; CNS toxici-
ty (fatigue, mood changes); GI distress
(nausea, vomiting); pancreatitis
Denileukin Diftitox (Ontak) Cutaneous T-cell lymphomas Acute allergic reactions; joint and muscle
pain; flulike symptoms; infection; GI dis-
tress (nausea, vomiting, diarrhea)
Estramustine (Emcyt) Prostate cancer Sodium and fluid retention; blood disorders
(leukopenia, thrombocytopenia); throm-
bosis; GI distress (nausea, diarrhea)
Mitotane (Lysodren) Suppresses adrenal gland; used pri- GI distress (nausea, vomiting, diarrhea,
marily to treat adrenocortical car- loss of appetite); CNS toxicity (lethargy,
cinoma fatigue, mood changes); skin rashes
Tretinoin (Vesanoid) Acute promyelocytic leukemia Cardiac arrhythmias; edema; blood pres-
sure abnormalities (hypotension, hyper-
tension); phlebitis; respiratory tract
problems; muscle pain; paresthesias;
CNS toxicity (depression, anxiety, confu-
sion); skin rash; GI distress (abdominal
distension; nausea, vomiting)
*Only the indications listed in the U.S. product labeling are included here. Many anticancer drugs are used for
additional types of neoplastic disease.
GI = gastrointestinal; CNS = central nervous system.
36Ciccone(p)-36 1/30/07 2:55 PM Page 582
drug is used primarily to treat recurrent cutaneous T- of anticancer drugs are combined in the same regimen
cell lymphoma. to provide optimal results.11 For instance, a particular
Estramustine. Estramustine (Emcyt) is a chemical drug regimen may include an alkylating agent, an anti-
combination of mechlorethamine (an alkylating agent) neoplastic antibiotic, a hormonal agent, or some other
and estrogen. It is not clear, however, how this drug combination of anticancer drugs.
exerts antineoplastic effects. The beneficial effects of Some common anticancer drug combinations and
this drug are probably not related to any alkylating the types of cancer in which they are used are listed in
effects. Rather, they may be the direct result of its Table 36–8. These drug combinations are often indi-
estrogenic component, or its inhibitory effect on the cated by an acronym of the drug names. For instance,
microtubules that comprise the mitotic apparatus.11 “FAC” indicates a regimen of fluorouracil, doxorubicin
This drug is typically used for the palliative treatment (Adriamycin), and cyclophosphamide. These abbrevia-
of advanced prostate cancer.60 tions are used to summarize drug therapy in a patient’s
Hydroxyurea. It is believed that hydroxyurea medical chart, so therapists should be aware of the
(Hydrea) impairs DNA synthesis by inhibiting a spe- more common chemotherapy combinations.
cific enzyme (ribonucleoside reductase) involved in
synthesizing nucleic acid precursors.11 The uses of
hydroxyurea are listed in Table 36–7.
Mitotane. Although the exact mechanism of this
Use of Anticancer Drugs
drug is unknown, mitotane (Lysodren) selectively in- with Other Treatments
hibits adrenocortical function. This agent is used Cancer chemotherapy is only one method of treating
exclusively to treat carcinoma of the adrenal cortex. neoplastic disease. The other primary weapons in the
Thalidomide. Thalidomide (Thalomid) was origi- anticancer arsenal are surgery and radiation treat-
nally developed as a sedative and antinausea drug, but ment.18,61 The choice of one or more of these tech-
was withdrawn from the market because it caused niques depends primarily on the patient, the type of
severe birth defects when administered to pregnant cancer, and the tumor location. In many situations,
women. This drug, however, has reemerged as a chemotherapy may be the primary or sole form of
potential treatment for cancers such as multiple treatment in neoplastic disease, especially for certain
myeloma.39,73 Although the exact reasons for its anti- advanced or inoperable tumors, or in widely dissemi-
cancer effects are not clear, thalidomide exerts a num- nated forms of cancer, such as leukemia or lym-
ber of complex effects on immune function, including phoma.6 In other situations, chemotherapy is used in
the suppression of tumor necrosis factor alpha.40 This combination with other techniques, such as an adju-
drug also inhibits angiogenesis, and may therefore vant to surgery and radiation treatment.18,27 Primary
limit the growth of solid tumors by inhibiting vascu- examples of adjuvant cancer chemotherapy include
larization and nutrient supply.63 using anticancer drugs following a mastectomy or sur-
Tretinoin. Tretinoin (Vesanoid), also known as gical removal of other carcinomas.19,54,43,61
all-trans-retinoic acid, is derived from vitamin A Whether anticancer drugs are used as the primary
(retinol).86 This drug is not cytotoxic, but it may help treatment or as adjuvant therapy, a common general
cells differentiate and replicate at a more normal rate. strategy is upheld. To achieve a total cell kill, all rea-
However, the exact way that this agent affects cell dif- sonable means of dealing with the cancer must be
ferentiation is not known. Tretinoin is used primarily employed as early as possible. Cancer is not the type of
to treat certain forms of leukemia.7 disease in which a wait-and-see approach can be used.
The general strategy is more aligned with the idea that
a barrage of anticancer modalities (i.e., surgery, radia-
tion, and a combination of several different antineo-
Combination Chemotherapy plastic drugs) may be necessary to achieve a successful
Frequently, several different anticancer drugs are outcome. In addition, a multimodal approach (com-
administered simultaneously. This process of combi- bining chemotherapy with radiation or using several
nation chemotherapy increases the chance of success- drugs simultaneously) may produce a synergistic effect
fully treating the cancer because of the additive and between these modalities. For instance, certain drugs
synergistic effect of each agent. Often, different types may sensitize cancer cells to radiation treatment.71,90
36Ciccone(p)-36 1/30/07 2:55 PM Page 583
Chemotherapeutic
Regimen* Components of Regimen Primary Indication
ABVD Doxorubicin (Adriamycin), bleomycin (Blenoxane), vin- Hodgkin Disease
blastine (Velban), dacarbazine (DTIC)
Likewise, several drugs working together may increase However, several types of cancer do not respond
the antineoplastic effects of one another through a syn- well to treatment. For example, the majority of
ergistic cytotoxic effect.11 metastatic cancers cannot be cured by current
chemotherapeutic methods or by any other type of
treatment.11 In addition, some of the most com-
mon forms of adult neoplastic disease are difficult
Success of Anticancer Drugs to treat by using anticancer drugs. As indicated in
Various forms of cancer exhibit a broad spectrum of Table 36–9, the number of deaths associated with col-
response to antineoplastic medications. Some forms of orectal, prostate, and breast cancer is unacceptably
cancer (choriocarcinoma, Wilms tumor) can be cured high, and the mortality rate for lung cancer and
in more than 90 percent of affected patients. In other pancreatic cancer is well over 90 percent in both men
neoplastic disorders, chemotherapy may not cure the and women.
disease but may succeed in mediating remission and Exactly why some forms of cancer are more
prolonging survival in a large patient percentage. Of difficult to treat pharmacologically than others
course, other factors such as early detection and the remains unclear. Differences in the biochemistry,
concomitant use of other interventions (surgery, radi- genetics, and location of certain cancer cells may
ation) will greatly influence the success of chemother- make them less sensitive to the toxic effects of
apy drugs. anticancer drugs.6 Resistance to anticancer drugs
36Ciccone(p)-36 1/30/07 2:55 PM Page 584
anticancer agents that do not cause resistance (see trials of other angiogenesis inhibitors are ongoing,
the next section, “Future Perspectives”), should help and these agents will hopefully become a more com-
increase the effectiveness of chemotherapy in certain mon component in the treatment of various neo-
types of cancer. plasms.87,91
A number of other experimental strategies
that limit the metabolism and proliferation of cancer-
ous cells are likewise being explored. These strategies
Future Perspectives typically capitalize on some enzymatic process or
Several new strategies are being explored to increase other unique aspect of cancer cell metabolism so
the effectiveness and decrease the toxicity of anti- that normal tissues remain largely unaffected by the
cancer drugs.57,64 As discussed previously, most of the drug.11 An example is the use of drugs such as
traditional drugs are toxic not only to tumor cells but imatinib and geftinib that inhibit abnormal tyro-
also to normal cells. Nonetheless, if the drug can be sine kinase activity in certain cancerous cells (see
delivered or targeted specifically for tumor cells, it will “Tyrosine Kinase Inhibitors” above). As more is
produce a more selective effect. One way to accom- learned about the unique aspects of cancer cell metab-
plish this targeting is by attaching the drug to another olism, other agents will be developed that selectively
substance that is attracted specifically to tumor cells. impair the biochemistry of the cancer cell with
An example of this strategy is the use of monoclonal minimal effects on the metabolism and function of
antibodies (see the section on “Biological Response normal cells.
Modifiers”). By joining the drug with an antibody Additionally, strategies are being explored to
that recognizes receptors only on cancerous cells, the administer drugs that can protect healthy cells from
drug is delivered directly to the neoplastic tissues. the more traditional anticancer agents.32,44 An exam-
Although the use of antibodies in treating cancer is ple is the possible use of antioxidants or free-
still relatively new, these and other vehicles that radical scavengers that reduce chemotherapy-induced
specifically target the tumor will almost certainly damage to healthy cells.55,67 Hence, several prelimi-
expand in the future.35,69 nary strategies have been developed to provide
Drugs may likewise be delivered more effectively more selective and less toxic chemotherapeutic regi-
to cancerous cells by encapsulating the drug in a mens. Future research will almost certainly expand
microsphere or liposome that becomes lodged in the these ideas to provide effective and safer treatments
tumor.3,66 Drug microspheres or other drug formula- for cancer.
tions can also be implanted surgically so that the drug Finally, important advances have been made
remains fairly localized at the tumor site, thereby in understanding how the body’s immune system can
reducing its systemic effects.26 Variations on these be recruited to help prevent and treat certain cancers.
techniques and other delivery methods continue to be If the body’s immune system recognizes the cancer
explored and may someday be used on a widespread cell as an invader, then various endogenous
basis to increase effectiveness, while decreasing the immune responses can be initiated to combat the can-
toxicity of anticancer drugs. cerous cells. Hence, various strategies are being
Other unique strategies are being developed to explored to help stimulate this immunologic response,
selectively impair the chemistry or metabolism of including genetic modification of the cancer cells
cancerous tissues. As indicated earlier, drugs such as to increase their antigenic properties and expose these
bevacizumab act as angiogenesis inhibitors that cells to immune attack.5,81 The most promising efforts
restrict the formation of new blood vessels in develop- center around the development of anticancer vaccines,
ing tumors. This effect can limit tumor growth whereby the immune system can be sensitized to
and promote the death of cancerous cells by starving search out and destroy cancerous cells before they
the tumor of oxygen and nutrients. This idea is can develop into serious cancers.42,46,72 Increased
especially attractive because agents that inhibit angio- knowledge about the nature of cancer, combined
genesis can have a fairly selective effect on the tumor with a better understanding of the endogenous
without producing excessive effects on the vasculariza- control of cell replication, may ultimately provide
tion of normal tissues.21,91 Although the number of drugs that are safe and effective in curing all forms
angiogenesis inhibitors is currently limited, clinical of cancer.
36Ciccone(p)-36 1/30/07 2:55 PM Page 586
CA S E ST U DY
Cancer Chemotherapy destruction at the site of the skeletal lesion. Her current phar-
macologic regimen consists of an antineoplastic antimetabo-
Brief History. R.J. is a 57-year-old woman who was lite (doxorubicin) and an antiestrogen (tamoxifen). She was
diagnosed with metastatic breast cancer 1 year ago, at which also given a combination of narcotic and non-narcotic anal-
time she underwent a modified radical mastectomy followed gesics (codeine and aspirin) to help control pain. Physical
by antineoplastic drugs. The cancer, however, had evidently therapy was initiated to help control pain and maintain func-
metastasized to other tissues, including bone. She recently tion in this patient.
developed pain in the lumbosacral region, which was attrib- Problem/Influence of Medication. The patient
uted to metastatic skeletal lesions in the lower lumbar verte- began to experience an increase in gastrointestinal side
brae. She was admitted to the hospital to pursue a course effects, including nausea, vomiting, loss of appetite, and epi-
of radiation treatment to control pain and minimize bony gastric pain. These problems may have been caused by the
36Ciccone(p)-36 1/30/07 2:55 PM Page 587
analgesic drugs or by the combination of the analgesics and Decision/Solution. The therapist instituted a program
the antimetabolite. However, the patient, experienced ade- of local heat (hot packs) and TENS to help control pain in the
quate pain relief from the aspirin-codeine combination and lumbosacral region. This approach provided a nonpharmaco-
was reluctant to consider alternative medications. The persist- logic means of alleviating pain, thereby decreasing the patient’s
ent nausea and loss of appetite had a general debilitating analgesic drug requirements and related gastrointestinal prob-
effect on the patient, and the physical therapist was having dif- lems. The patient was able to participate actively in a rehabili-
ficulty engaging the patient in an active general conditioning tation program throughout the course of her hospitalization,
program. thus maintaining her overall strength and physical condition.
18. Elshaikh M, Ljungman M, Ten Haken R, Lichter AS. phoblastic leukemia in first bone marrow relapse: A
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Chapter 37
Immunomodulating Agents
The immune system is responsible for controlling the saving because of their ability to prevent and treat
body’s response to various types of injury and for organ rejection and to decrease immune-mediated tis-
defending the body from invading pathogens, includ- sue damage in other diseases.
ing bacteria, viruses, and other parasites.16,18 The Drugs that increase immune function, or immu-
importance of this system in maintaining health is nostimulants, are also addressed in this chapter. This
illustrated by the devastating effects that can occur in group of agents is rather small, and the clinical use
people who lack adequate immune function, such as of immunostimulants is limited when compared with
patients with acquired immunodeficiency syndrome the indications for immunosuppressive drugs.
(AIDS). The use of drugs to modify immune respons- Nonetheless, the development and use of immunos-
es, or immunomodulating agents, is therefore an timulants is an exciting area of pharmacology, and
important area of pharmacology. For example, it may some insight into the therapeutic use of these drugs
be helpful to augment immune function if a person’s is provided.
immune system is not functioning adequately. By con- This chapter begins with a brief overview of the
trast, it is sometimes necessary to suppress immune immune response, followed by the drugs that are cur-
function pharmacologically to prevent immune-medi- rently available to suppress or stimulate this response.
ated injury to certain tissues or organs. Following Physical therapists and occupational therapists may be
organ transplants and tissue grafts, the immune system involved in the rehabilitation of patients who have
may cause the rejection of tissues transplanted from received organ transplants, skin grafts, or similar pro-
other donors (allografts) or from other sites in the cedures that necessitate the use of immunosuppressant
patient’s body (autografts).60,72 Likewise, immunosup- drugs. Rehabilitation specialists also treat patients
pression may be helpful when the immune system with autoimmune disorders or immunodeficiency syn-
causes damage to the body’s tissues. Such conditions dromes that affect the musculoskeletal system; these
are often referred to as autoimmune diseases. Clinical patients are also likely to be taking immunomodulat-
disorders such as rheumatoid arthritis, myasthenia ing drugs. Hence, this chapter will provide therapists
gravis, and systemic lupus erythematosus are now rec- with knowledge about the pharmacology of these
ognized as having an autoimmune basis.25,44,68 drugs and how the drugs’ effects and side effects can
This chapter addresses immunosuppressive drugs, affect physical rehabilitation.
or immunosuppressants, that are currently available
to prevent the rejection of transplants or to treat speci-
fic diseases caused by an autoimmune response. Clear- Overview of the
ly, these drugs must be used very cautiously because
too much suppression of the immune system will
Immune Response
increase a patient’s susceptibility to infection from for- As indicated, one of the primary responsibilities of the
eign pathogens. Likewise, these drugs are rather toxic immune system is to protect the body from bacteria,
and often cause a number of adverse effects to the kid- viruses, and other foreign pathogens. The immune
neys, lungs, musculoskeletal system, and other tissues. response consists of two primary components: innate
Nonetheless, immunosuppressive agents are often life- and adaptive (acquired) immunity.18,23 Innate immuni-
591
37Ciccone(p)-37 1/30/07 2:37 PM Page 592
of IL-1 and other lymphokines, B cells prolifer- A second major indication for these drugs is to
ate and differentiate into plasma cells. Plasma limit immune-mediated damage to the body’s tissues—
cells ultimately release specific antibodies that is, suppression of an autoimmune response.11,25
known as immunoglobulins (IgG, IgA, IgM, and Autoimmune responses occur when the immune
the like). Likewise, T-cell and macrophage- system loses the ability to differentiate the body’s
derived lymphokines recruit additional cellular own tissues from foreign or pathogenic tissues.67
components, including other macrophages, Exactly what causes this defect in immune recognition
cytotoxic lymphocytes (natural killer, or NK, is often unclear, but prior exposure to some pathogen
cells), and various cells that can participate in such as a virus may activate the immune response in a
the destruction of the foreign antigen. way that causes the immune system to mistakenly
attack normal tissues while trying to destroy the virus.
Clearly, the immune response is an intricate This autoimmune activation may remain in effect even
sequence of events that involves a complex interaction after the original pathogen has been destroyed, thus
between a number of cellular and humoral com- leading to chronic immune–mediated injury to the
ponents. The overview provided here is just a brief body’s tissues.
summary of how some of the primary components Autoimmune responses seem to be the underlying
participate in mediating acquired immunity. Readers basis for a number of diseases, including rheumatoid
are referred to additional sources for more informa- arthritis, diabetes mellitus, myasthenia gravis, systemic
tion on this topic.16,18,49 lupus erythematosus, scleroderma, polymyositis/der-
matomyositis, and several other disorders.25,27,44 As
indicated previously, it is not exactly clear what factors
Pharmacologic Suppression cause autoimmune responses, as well as why certain
individuals are more prone to autoimmune-related dis-
of the Immune Response eases. Nonetheless, drugs that suppress the immune
Drugs are used to suppress the immune system for two system can limit damage to various other tissues, and
basic reasons (Table 37–1). First, the immune response these drugs may produce dramatic improvements in
is often attenuated pharmacologically following the patients with diseases that are caused by an autoim-
transplantation of organs or tissues to prevent the mune response.
rejection of these tissues.5,72 Sometimes, organs and
other tissues can be attacked by the recipient’s im-
mune system, even if these tissues appear to be cross- Specific Immunosuppressive
matched between donor and recipient. This rejection
is often caused by membrane proteins on the donor
Agents
tissue that are recognized as antigens by the host’s Drugs commonly used to suppress the immune system
immune system.60 Hence, drugs that suppress the cel- are listed in Table 37–1; the pharmacology of specific
lular and chemical response to these membrane pro- agents follows.
teins can help prevent them from destroying the
transplanted tissues and causing additional injury to
the host’s tissues.
Azathioprine
Often, several different types of immunosuppres- Clinical Use. Azathioprine (Imuran) is a cytotoxic
sants are used together in fairly high doses to prevent agent that is structurally and functionally similar to
or treat transplant rejection.5,72 For instance, a gluco- certain anticancer drugs, such as mercaptopurine.22,30
corticoid such as betamethasone is often administered Azathioprine is primarily used to prevent the rejection
with nonsteroidal drugs such as cyclosporine and aza- of transplanted organs, especially in patients with
thioprine to provide optimal success and viability of kidney transplants. Azathioprine may also be used to
the transplant. Of course, giving several powerful suppress immune responses in a wide range of other
drugs at high doses often causes unpleasant or even conditions, such as systemic lupus erythematosus,
toxic side effects. These effects must often be tolerat- dermatomyositis, inflammatory myopathy, hepatic
ed, however, considering the limited number of organs disease, myasthenia gravis, and ulcerative colitis. As
available for transplantation and the need to ensure the presented in Chapter 16, azathioprine is also used as
survival of the transplant as much as possible. an antiarthritic disease–modifying agent.
37Ciccone(p)-37 1/30/07 2:37 PM Page 594
Primary Indications*
Prevention or Treatment Diseases That Have an
Generic Name Trade Name(s) of Transplant Rejection Autoimmune Response
Antibodies Names vary according to Bone marrow, other organ Idiopathic thrombocytic pur-
specific lymphocyte transplants (see Table pura, other hemolytic
targets; see Table 37–2 37–2) disorders
Cyclophosphamide Cytoxan, Neosar Bone marrow, other organ Rheumatoid arthritis, multiple
transplants sclerosis, SLE, dermato-
myositis, glomerulonephritis,
hematologic disorders
Cyclosporine Neoral, Sandimmune Kidney, liver, heart, lung, Psoriasis, rheumatoid arthritis,
pancreas, bone marrow nephrotic syndrome
Glucocorticoids See text for listing Heart, kidney, liver, bone Multiple sclerosis, rheumatoid
marrow arthritis, SLE, inflammatory
bowel disease, hemolytic
disorders, others.
Mechanism of Action. Although the exact mecha- during DNA synthesis. Azathioprine is structurally
nism of azathioprine is unknown, this drug probably similar to these purines, and this drug acts as a false
interferes with DNA synthesis in cells mediating the ingredient that competes with the naturally occurring
immune response. Azathioprine appears to act like the substances to slow down and disrupt DNA synthe-
antimetabolite drugs used in cancer chemotherapy sis. Impaired nucleic acid synthesis slows down the
(see Chapter 36). The cell normally uses various replication of lymphocytes and other key cellular
endogenous substances such as purines as ingredients components that direct the immune response. Thus,
37Ciccone(p)-37 1/30/07 2:37 PM Page 595
azathioprine directly limits cellular proliferation Cyclosporine is used to a somewhat lesser extent in
through this inhibitory effect on DNA synthesis and treating autoimmune diseases, but it may be helpful in
ultimately limits the production of humoral compo- conditions such as psoriasis, rheumatoid arthritis,
nents (antibodies) produced by these cells. inflammatory bowel disease, and glomerulonephri-
Adverse Effects. The primary side effects of aza- tis.15,32,63 As discussed in Chapter 32, cyclosporine has
thioprine are related to suppression of bone marrow also been used in the early stages of type 1 diabetes
function, including leukopenia, megaloblastic anemia, mellitus to help control immune-mediated destruction
and similar blood dyscrasias. Other side effects include of pancreatic beta cells, thus decreasing the severity of
skin rash and gastrointestinal distress (appetite loss, this disease in some patients.9
nausea, vomiting); hepatic dysfunction can also occur Although cyclosporine is one of the most effective
when higher doses are used. immunosuppressants, the traditional form of this drug
is associated with unpredictable absorption from the
gastrointestinal (GI) tract and potentially severe side
Cyclophosphamide effects, such as nephrotoxicity and neurotoxicity.33,58
Clinical Use. Cyclophosphamide (Cytoxan, In a newer form of cyclosporine (Neoral), the drug is
Neosar) is an anticancer alkylating agent that is com- modified into microemulsion capsules that disperse
monly used in a variety of neoplastic disorders (see more easily within the GI tract, thereby enabling the
Chapter 36). This drug may also be helpful in sup- drug to be absorbed in a more predictable fashion.26
pressing the immune response in certain autoimmune The microemulsion form of cyclosporine appears to
diseases, such as multiple sclerosis, systemic lupus ery- be safer because it is not as toxic to the kidneys and
thematosus, and rheumatoid arthritis.12,43 High doses other tissues as is the regular formulation.8 Hence, this
of cyclophosphamide are also used to prevent tissue microemulsion formulation is often the optimal way
rejection in patients receiving bone marrow trans- to administer cyclosporine following organ trans-
plants and other organ transplants. plantation or other situations requiring immunosup-
Mechanism of Action. The mechanism of cyclo- pression.26,36
phosphamide as an anticancer alkylating agent is de- Mechanism of Action. Cyclosporine and tacro-
scribed in Chapter 36. This drug causes the formation limus (see below) are known as calcineurin inhibitors
of strong cross-links between strands of DNA and because they inhibit a specific protein (calcineurin) in
RNA, thus inhibiting DNA/RNA replication and lymphoid tissues. This inhibition ultimately suppress-
function. Cyclophosphamide probably exerts immuno- es the production of IL-2, a cytokine that plays a crit-
suppressant effects in a similar manner; that is, this ical role in immune response by promoting the growth
drug inhibits DNA and RNA function in lymphocytes and proliferation of activated T lymphocytes and other
and other key cells, thus limiting the rapid prolifera- immune cells, such as NK cells (see Fig. 37–1).5,52
tion of these cells during the immune response. Thus, cyclosporine is one of the premier immunosup-
Adverse Effects. Cyclophosphamide is used very pressants because of its relative selectivity for T cells
cautiously as an immunosuppressant because of the and its inhibition of a key mediator of the immune
possibility of severe side effects, including carcino- response (IL-2).41 This relatively specific inhibition is
genic effects during long-term use. Other side effects often advantageous when compared with other nonse-
include hematologic disorders (leukopenia, thrombo- lective drugs such as azathioprine, cyclophosphamide,
cytopenia), cardiotoxicity, nephrotoxicity, and pul- and glucocorticoids that inhibit virtually all the cells
monary toxicity. and chemical mediators involved in the immune
response.
Adverse Effects. The primary problem associ-
Cyclosporine ated with cyclosporine is nephrotoxicity, which can
Clinical Use. Cyclosporine (Neoral, Sandimmune) range from mild, asymptomatic cases to severe kidney
is one of the primary medications used to suppress im- dysfunction, which requires discontinuation of the
mune function following organ transplantation.14,21,69 drug.33,46 Hypertension is also a common adverse
This medication can be used alone or combined with effect, especially when cyclosporine is used for pro-
glucocorticoids, azathioprine, and other immunosup- longed periods.58 Other problems include neurotoxici-
pressants to prevent the rejection of a kidney, lung, ty, gingival hyperplasia, hair growth (hirsutism), and
liver, heart, pancreas, and other organ transplants. increased infections. These problems, however, tend to
37Ciccone(p)-37 1/30/07 2:37 PM Page 596
be less severe with cyclosporine than with other less- breakdown of muscle, bone, skin, and various other tis-
selective immunosuppressants. sues is a common adverse effect. Glucocorticoids also
produce other side effects, including hypertension,
adrenocortical suppression, growth retardation in
Glucocorticoids children, an increased chance of infection, glaucoma,
Clinical Use. As described in Chapter 29, gluco- decreased glucose tolerance, and gastric ulcer. These
corticoids are powerful anti-inflammatory and immu- side effects can be especially problematic when gluco-
nosuppressive drugs. Glucocorticoids exert a rather corticoids are used to prevent transplant rejection
nonspecific inhibition of virtually all aspects of cell- because these drugs are often given in high dosages for
and chemical-mediated immunity, thus enabling these extended periods.
drugs to be used in a variety of situations when it is Therefore, glucocorticoids are typically combined
necessary to suppress immune function. Hence, these with other nonsteroidal immunosuppressants such as
drugs are a mainstay in preventing transplant rejection cyclosporine, azathioprine, or immunosuppressive
and in treating various diseases associated with an antibodies so that synergistic effects can be obtained
autoimmune response.29,72 and immunosuppression can be achieved with relative-
Glucocorticoids commonly used as immunosup- ly low doses of each drug.54 In addition, efforts are
pressants include the following: often made to progressively decrease the glucocorti-
coid dose so that immunosuppression is achieved by
• betamethasone (Celestone)
using the lowest possible dose. In some cases, the glu-
• cortisone (Cortone)
cocorticoid may even be withdrawn during mainte-
• dexamethasone (Decadron, others)
nance immunosuppressive therapy, and nonsteroidal
• hydrocortisone (Cortef)
drugs (cyclosporine, tacrolimus, mycophenolate mofe-
• methylprednisolone (Medrol)
til) are used to provide long-term immunosuppression
• prednisolone (Pediapred, Prelone, others)
following organ transplantation.39
• prednisone (Deltasone, others)
• triamcinolone (Aristocort, others)
Mechanism of Action. Although their exact mech-
Methotrexate
anism of immunosuppression is unclear, glucocorti- Clinical Use. Methotrexate (Folex, Rheumatrex)
coids probably interrupt the immune response by a was originally developed as an anticancer agent (see
complex effect at the genomic level of various immune Chapter 36), but this drug is also used occasionally
cells.5,57 These drugs enter immune system cells, where in certain noncancerous conditions that have an
they bind to a cytoplasmic receptor. The drug-recep- autoimmune component.15,78 As indicated in Chapter
tor complex then migrates to the cell’s nucleus, where 16, methotrexate is commonly used as a disease-
it acts directly on specific immunoregulatory genes. In modifying drug in rheumatoid arthritis. Methotrexate
particular, glucocorticoids influence the expression of is also approved for use in psoriasis. This agent has
cytokines and other chemicals that orchestrate the only mild immunosuppressive effects, however, and
immune response; that is, glucocorticoids inhibit the is not typically used to treat organ transplants or other
transcription of messenger RNA units that are normal- conditions that require more extensive immunosup-
ly translated into immunostimulatory signals such as pression.
interleukin-1, gamma interferon, and other substances Mechanism of Action. The pharmacology of
that activate the cells responsible for mediating the methotrexate is described in Chapter 36. This drug
immune response. Hence, these drugs disrupt the pro- acts as an antimetabolite that interferes with the pro-
duction of chemical signals that activate and control duction of DNA and RNA precursors in rapidly pro-
various immune system cellular components. For more liferating cells. This interference produces a general
details about how glucocorticoids exert their effects on inhibition of the replication of lymphocytes inherent
various cells and tissues, see Chapter 29. in the immune response.
Adverse Effects. The immunosuppressive effects Adverse Effects. The major problems associated
of glucocorticoids are balanced by several side effects. with methotrexate include hepatic and pulmonary tox-
As described in Chapter 29, glucocorticoids typically icity. These problems are dose-related, however, and
produce a catabolic effect on collagenous tissues, and serious adverse effects tend to occur less frequently at
37Ciccone(p)-37 1/30/07 2:37 PM Page 597
doses used for immunosuppression than at those for cells. Other effects may be related to the drug’s break-
anticancer treatment. down into active metabolites, including sulfapyridine
and mesalamine, which exert antibiotic and anti-
inflammatory effects, respectively.
Mycophenolate Mofetil Adverse Effects. Primary side effects include
Clinical Use. Mycophenolate mofetil (CellCept) headache, blood dyscrasias (agranulocytosis, anemia,
is primarily used to prevent or treat organ rejection thrombocytopenia), increased sensitivity to ultraviolet
following cardiac and renal transplantation. This drug light, and hypersensitivity reactions (fever, skin rash,
is typically combined with other immunosuppressants itching). Hypersensitivity can be severe or even fatal
(cyclosporine, glucocorticoids) to provide optimal im- in susceptible individuals.
munosuppression in patients receiving these trans-
plant types.39,40,70 Mycophenolate mofetil may also be Sirolimus
useful in suppressing the immune response associated
with autoimmune conditions such as systemic lupus Clinical Use. Sirolimus (rapamycin, Rapamune) is
erythematosus.2 one of the newest immunosuppressants and is an
Mechanism of Action. Mycophenolate mofetil antibiotic that also has substantial immunosuppressant
inhibits a specific enzyme (inosine monophosphate effects. This drug is used primarily to prevent organ
dehydrogenase) that is responsible for the synthesis rejection in people with solid organ transplants (kid-
of DNA precursors in T and B lymphocytes.39,50 Be- ney, heart, and so forth).42,55 Sirolimus is especially
cause these lymphocytes cannot synthesize adequate helpful following kidney transplants because it helps
amounts of DNA, their ability to replicate and prolif- prevent organ rejection without adversely affecting
erate is impaired, thus blunting the immune response. glomerular filtration and other aspects of the kidney
This drug may also inhibit lymphocyte attraction and function.45 Likewise, this drug is often used preferen-
adhesion to the vascular endothelium, thereby impair- tially in patients with renal dysfunction instead of more
ing the lymphocytes’ ability to migrate to the site of nephrotoxic drugs (cyclosporine, tacrolimus).45,55
the foreign (transplanted) tissues and to infiltrate from To provide optimal immunosuppressant effects,
the bloodstream into these tissues.50 sirolimus is typically combined with glucocorticoids
Adverse Effects. The primary adverse effects asso- or other immunosuppressants. Sirolimus exerts a
ciated with mycophenolate mofetil are blood disorders number of other beneficial effects, including the abil-
(anemia, leukopenia, neutropenia) and gastrointestinal ity to inhibit smooth muscle proliferation in blood
problems (abdominal pain, nausea, vomiting, heart- vessel walls. For this reason, sirolimus is sometimes
burn, diarrhea, constipation).50 Other side effects in- incorporated into drug-eluting stents; that is, a sup-
clude chest pain, cough, dyspnea, muscle pain, portive tubular structure (stent) is placed in the lumen
weakness, and cardiovascular problems (hypertension, of a partially occluded artery, and the drug is released
arrhythmias). slowly from the stent to help reduce vessel occlusion.64
Mechanism of Action. Unlike other immunosup-
pressants (cyclosporine, tacrolimus), sirolimus does
Sulfasalazine not interfere directly with cytokine production.
Clinical Use. Sulfasalazine (Azulfidine, other Instead, sirolimus inhibits the function of a specific
names) has unique properties, with some antibacter- enzyme commonly known as the mammalian target of
ial characteristics similar to sulfonamide drugs (see rapamycin (mTOR).37,42 This enzyme plays a key role
Chapter 33) and some of anti-inflammatory character- in signaling pathways that promote the growth and
istics similar to the salicylates (see Chapter 15). This proliferation of T and B cells.37,45 By inhibiting this
drug is primarily used to suppress the immune enzyme, sirolimus causes cell division to stop at a spe-
response associated with rheumatoid arthritis and cific stage (G1), thereby limiting the ability of these
inflammatory bowel disease.38,61 cells to mount an attack on transplanted tissues.65
Mechanism of Action. The exact mechanism of Adverse Effects. Sirolimus may cause blood lipid
this drug in immune-related disorders is not fully disorders, including hypercholesterolemia and hyper-
understood. Sulfasalazine may affect key components triglyceridemia.42 Other side effects include blood
in the immune system, including suppression of NK disorders (anemia, leukopenia, thrombocytopenia),
37Ciccone(p)-37 1/30/07 2:37 PM Page 598
diarrhea, skin rash, joint and muscle pain, and hyper- lymphocytes and other immune cells, such as NK cells
tension.42 (see Fig. 37–1). This binding provides a somewhat
more selective inhibition of immune function than
Tacrolimus other drugs that exert a general or nonselective inhibi-
tion of the immune response.
Clinical Use. Tacrolimus (Prograf) is similar to Adverse Effects. Common side effects of tacroli-
cyclosporine in structure and in immunosuppressive mus include gastrointestinal disturbances (cramps,
effects, but tacrolimus is approximately 10 to 100 times nausea, diarrhea, constipation), weakness, fever, and
more potent than cyclosporine.41 Tacrolimus may be skin rashes and itching. More serious problems include
somewhat less toxic than cyclosporine and other im- renal and central nervous system (CNS) toxicity (head-
munosuppressants, although serious side effects may ache, anxiety, nervousness, seizures).41 Tacrolimus is
still occur at higher doses (see “Adverse Effects” in this also associated with problems with glucose metabolism
section). Tacrolimus is used primarily to prevent rejec- (hyperglycemia, glucose intolerance), and can cause
tion of kidney and liver transplants.76,77 This drug may diabetes mellitus in certain individuals.73
also be useful in preventing or treating the rejection of
other organs and tissues including heart, lung, pan-
creas, and bone marrow transplants.36,41 Topical prepa- Other Methods of
rations of tacrolimus or an analogous drug known as Immunosuppression
pimecrolimus (Elidel) can also be used to treat skin dis-
Immunosuppressant Antibodies
orders such as atopic dermatitis.7,31
Mechanism of Action. Tacrolimus acts like cyclo- Immune function can also be suppressed by using anti-
sporine by binding to a specific protein (calcineurin) in bodies that interact with specific immune system cells
lymphoid tissues and inhibiting the production of key and interfere with the cell’s function (Table 37–2).13,47
immune mediators such as IL-2.5 IL-2 plays a critical These antibodies can be obtained from animal sources
role in the immune response because this substance and cell culture techniques (monoclonal antibodies)
promotes the growth and proliferation of activated T to provide a rather selective method of suppressing
Muromonab-CD3 monoclonal Orthoclone OKT3 Acute rejection of heart, liver, and kidney trans-
antibody plants
RhO(D) immune globulin BayRho-D, RhoGAM, others Prevention of Rh hemolytic disease of the new-
born
immune function. For example, antibodies such as agents are similar to methotrexate; they exert cyto-
Rho(D) immunoglobulin are used routinely to sup- toxic effects that interfere with the proliferation of
press immune response in mothers who have been immune system cellular components. These drugs are
exposed to a fetus’s incompatible blood type. This im- used primarily as anticancer agents; the pharmacology
munosuppression prevents the mother from develop- of these drugs is described in more detail in Chapter
ing antibodies that will be passed on to the fetus or to 36. The use of these agents as immunosuppressants,
a fetus in a subsequent pregnancy, thus blocking the however, has generally declined in favor of drugs that
production of maternal antibodies that can attack the have a more selective and strategic effect on immune
fetus’s blood and cause a potentially fatal condition function. Nonetheless, these drugs may be helpful in
known as hemolytic anemia of the newborn.41 certain autoimmune disorders, or in preventing the
Antibodies have also been developed that are very rejection of tissue and organ transplants in specific sit-
selective for antigens located on the surface of specif- uations.
ic T cells and other lymphocytes; these antibodies Finally, thalidomide can be used as an immuno-
inhibit cell function or cause destruction of the cell.20 suppressant in conditions such as systemic lupus
Anti–T-cell antibodies are primarily used to help pre- erythematosus (SLE)53 and in preventing graft-versus-
vent or treat rejection of organ and bone marrow host disease following bone marrow transplant.35,71
transplants (see Table 37–2).13,75 This drug was originally developed as a sedative, but
Antibodies that block the interleukin-2 receptor, was later discovered to produce severe birth defects
thus preventing interleukin-2 from activating T lym- when administered to women during pregnancy.
phocytes, have also been developed.24,62 These anti– Nonetheless, thalidomide may help blunt immunolog-
interleukin-2 receptor agents, such as basiliximab ic responses by regulating the genes that express tumor
(Simulect) and daclizumab (Zenapax), may be helpful necrosis factor-alpha.53 Decreased production of this
in reducing the incidence of acute transplant rejec- factor results in diminished activation of neutrophils
tion.13 Antibodies seem to be especially useful in the and other immune components, thereby reducing the
initial (induction) phase of antirejection treatment severity of immunologic reactions. The effects of
because these drugs can delay or supplant the use of thalidomide on immune function appear to be very
more toxic immunosuppressants such as the glucocor- complex, however, and this drug may actually increase
ticoids and calcineurin inhibitors (cyclosporine and the production of tumor necrosis factor alpha in cer-
tacrolimus).3,56 tain conditions such as human immunodeficiency virus
Finally, antibodies such as adalimumab (Humira) (HIV) infection.41 Hence, thalidomide’s immunomod-
and infliximab (Remicade) have been developed that ulatory effects continue to be investigated, and use
bind directly to tumor necrosis factor alpha (TNF- of this drug in specific diseases may be modified in
alpha), thereby preventing this cytokine from causing the future.
damage to joints and other tissues. These anti-
TNF–alpha drugs are therefore helpful in autoimmune
diseases such as rheumatoid arthritis; their pharmacol-
ogy is addressed in more detail in Chapter 16.
Immunostimulants
Immunosuppressant antibodies continue to gain A number of agents can suppress the immune system.
acceptance as a method for preventing rejection of However, there has been considerable interest in
transplanted tissues and for treating various autoim- developing pharmacologic methods to modify or even
mune diseases.17,47 For more information on the use of stimulate immune function in specific situations. In
specific antibodies in specific disorders, please refer to particular, agents that have a positive immunomodulat-
other sources on this topic.17,41,47,56 ing effect could be beneficial to patients with compro-
mised immune function (such as AIDS or certain
cancers) or chronic infections.19,41 Development of
Miscellaneous Immunosuppressants immunostimulants, however, is understandably a com-
A variety of other agents with cytotoxic effects has plex and potentially dangerous proposition. Excessive
been used to suppress the immune system. These or incorrect immune activation could trigger myriad
drugs include chlorambucil (Leukeran), dactinomycin problems that resemble autoimmune diseases. Like-
(Cosmegen), mercaptopurine (Purinethol), vinblastine wise, it may be difficult to selectively stimulate cer-
(Velban), and vincristine (Oncovin, Vincasar).41 These tain aspects of the immune system to treat a specific
37Ciccone(p)-37 1/30/07 2:37 PM Page 600
problem without also causing a more widespread and nous immunoglobulins. These preparations therefore
systemic immunologic response. Nonetheless, a few directly act as antibodies against infectious agents.
strategies are currently available to modify or stimulate They can also help modulate the activity of T lympho-
immune function in a limited number of situations. cytes, macrophages, and other immune system cells to
maintain immune system competence.6,59
Bacille Calmette-Guérin Adverse Effects. Immune globulin may cause sev-
eral side effects, such as joint and muscle pain,
Clinical Use. Bacille Calmette-Guérin (BCG, headache, general malaise, and gastrointestinal distur-
TheraCys, others) is an active bacterial strain that can bances (nausea, vomiting).34 Although rare, allergic
be administered systemically as a vaccine against tuber- reactions, including anaphylaxis, can occur in some
culosis. This agent may also stimulate immune func- individuals. Because immune globulin is obtained from
tion and can be administered locally within the bladder human blood, care must also be taken to prevent trans-
(intravesicularly) to treat certain forms of superficial mission of hepatitis and HIV from infected donors.
bladder cancer.66
Mechanism of Action. The exact reason that this
agent is effective in treating cancer is unknown. Some Levamisole
evidence suggests that it may activate macrophages
Clinical Use. Levamisole (Ergamisol) is primarily
locally at the site of the cancer and that these mac-
used to treat colorectal carcinoma. Specifically, this
rophages engulf and destroy tumor cells.79
drug is administered with fluorouracil (see Chapter
Adverse Effects. When administered directly into
36) to prevent recurrence of colorectal cancer after
the bladder, common side effects include bladder irri-
surgical removal of the primary tumor.1
tation and infection. Systemic administration (immu-
Mechanism of Action. Although the exact effects
nization) may also cause dermatologic reactions
are not known, levamisole may augment immune
(peeling or scaling of the skin), allergic reactions,
function by activating macrophages and immune cells
inflammation of lymph nodes, and local irritation or
that selectively engulf and destroy any residual cancer-
ulceration at the injection site.
ous cells.41
Adverse Effects. Levamisole may cause blood dis-
Immune Globulin orders such as agranulocytosis, leukopenia, or throm-
Clinical Use. Immune globulin (Gamimune, bocytopenia. Other side effects include nausea,
Gammagard, other names) is prepared by extracting diarrhea, and a metallic taste in the mouth.
immunoglobulins from donated human blood.41
These preparations contain all subclasses of immu-
noglobulin (Ig) but consist primarily of IgG. Immune
globulin is administered intravenously to boost
Other Immunomodulators
immune function in several conditions, including pri- Cytokines are a potential way to modify the immune
mary immunodeficiency syndromes (congenital agam- system in several situations because of their ability
maglobulinemia, common variable immunodeficiency, to act as immunoregulatory chemicals. For exam-
and severe combined immunodeficiency), idiopathic ple, cytokines such as interferon-alpha and inter-
thrombocytopenic purpura, Kawasaki disease, chro- leukin-2 can be administered to treat certain forms
nic lymphocytic leukemia, and HIV infection in chil- of cancer (see Chapter 36). Likewise, certain interfer-
dren.4,59 Other potential indications for immune ons can help control viral infections, and interferon-
globulin include dermatomyositis, Guillain-Barré syn- beta may be helpful in autoimmune diseases such as
drome, demyelinating polyneuropathies, Lambert- multiple sclerosis (see Chapter 34). Researchers con-
Eaton myasthenia syndrome, and relapsing-remitting tinue to investigate how immune function can be
multiple sclerosis. manipulated to treat various diseases, and additional
Mechanism of Action. Commercial preparations immune system modulators will almost certainly be
of immune globulin mimic the normal role of endoge- forthcoming.
37Ciccone(p)-37 1/30/07 2:37 PM Page 601
Significance of Immunomodulating
Agents in Rehabilitation
■ ■ ■ Physical therapists and occupational therapists are often involved in the rehabilitation of
patients who have received heart, liver, kidney, and other organ transplants. Therapists also fre-
quently deal with patients who have received autologous grafts, such as skin grafts for treating
burns, and bone marrow transplants during the treatment of certain cancers. Hence, therapists
frequently deal with patients taking drugs to prevent tissue rejection.
Therapists also deal with the rehabilitation of musculoskeletal disorders that are caused by
an autoimmune response. Many of these diseases attack connective tissues, and autoimmune dis-
eases such as rheumatoid arthritis, dermatomyositis, and systemic lupus erythematosus are often
the primary reason that patients undergo rehabilitation. Patients with a compromised immune
system may develop musculoskeletal problems related to their immunodeficient state. Hence,
immunomodulating drugs are frequently used in many patients receiving physical therapy and
occupational therapy.
The most significant impact of these drugs on rehabilitation is related to their side effects,
especially those of the immunosuppressants. These drugs are typically used in high doses to pro-
duce immunosuppressive effects, which are often achieved at the expense of serious and toxic
side effects. Many immunosuppressants, especially the glucocorticoids, exert catabolic effects on
bone, muscle, and other tissues. Other immunosuppressants, such as cyclosporine and tacroli-
mus, are neurotoxic and may cause peripheral neuropathies and CNS-related problems in bal-
ance and posture.
Hence, rehabilitation specialists can play a critical role in offsetting some of these adverse
effects. Therapists can institute strengthening and general conditioning exercises to prevent
breakdown of muscle, bone, and other tissues, as well as to maintain cardiovascular function.
Problems associated with peripheral neuropathies, such as pain and weakness, may respond to
TENS and other electrotherapeutic treatments. Balance and gait training may help patients
overcome problems caused by CNS toxicity and vestibular problems. Thus, therapists can
implement specific strategies as required to help patients cope with the adverse drug effects
associated with immunomodulating agents.
CA S E ST U DY
Immunomodulating Agents each day. After 15 days, the dosage was decreased to 8 mg/
kg per day, and was progressively decreased over the next 2
Brief History. A.S. is a 47-year-old concert musician months until a maintenance dosage of 2 mg/kg per day was
who experienced a progressive decline in renal function that achieved. On the day of surgery, he also received an intra-
ultimately led to renal failure. Kidney function was maintained venous dose of 0.5 g of methylprednisolone. Oral doses of
artificially through renal dialysis until a suitable kidney trans- methylprednisolone were then administered in dosages of 16
plant became available from a donor who died in an automo- mg/d for the first 3 months, 12 mg/d for the next 3 months,
bile accident. The kidney was transplanted successfully, and and 8 mg/d thereafter. Azathioprine was administered at a
A.S. was placed on a prophylactic regimen of three different dosage of 1 mg/kg per day throughout the posttransplant
immunosuppressive drugs to prevent the rejection of the period. Physical therapy was initiated in the intensive care unit
transplanted kidney. At the time of the transplant, cyclospo- (ICU) 1 day after the transplant to increase strength and to
rine was initiated at a dosage of 10 mg/kg of body weight facilitate recovery from the surgery.
37Ciccone(p)-37 1/30/07 2:37 PM Page 602
Problem/Influence of Medication. The therapist pist also initiated weight-bearing activities as soon as the
noted that several drugs were being used to prevent rejection, patient was able to tolerate standing. Weight-bearing activi-
including rather high doses of methylprednisolone, a gluco- ties were progressively increased, and the patient was able to
corticoid agent. Glucocorticoids are notorious for their cata- walk independently for distances up to 1000 feet and climb
bolic effects, and the therapist was aware that a program of two flights of stairs at the time of discharge. The therapist also
strengthening and weight-bearing exercise would help offset worked closely with the patient and the patient’s family to
the breakdown of muscle and bone that can often occur with make sure that strengthening exercises and a progressive
prolonged glucocorticoid administration. ambulation program were continued at home. The patient did
Decision/Solution. Gentle resistance exercises were not experience any problems related to tissue rejection, and
initiated in the ICU as soon as the patient was alert and could he was able to resume his musical career and maintain an
follow basic instructions. Strengthening exercises were pro- active lifestyle that included daily walks and regular visits to a
gressively increased using manual resistance, and various health club, where he participated in a supervised program of
weights and exercise machines were incorporated into the strength training.
strengthening regimen as tolerated by the patient. The thera-
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betes mellitus. Int Rev Immunol. 2005;24:327–339. 47. Liossis SN, Tsokos GC. Monoclonal antibodies and
28. Esche C, Stellato C, Beck LA. Chemokines: key play- fusion proteins in medicine. J Allergy Clin Immunol.
ers in innate and adaptive immunity. J Invest Dermatol. 2005;116:721–729.
2005;125:615–628. 48. Luster AD. The role of chemokines in linking innate
29. Franchimont D. Overview of the actions of glucocorti- and adaptive immunity. Curr Opin Immunol. 2002;14:
coids on the immune response: a good model to char- 129–135.
acterize new pathways of immunosuppression for new 49. McCullough KC, Summerfield A. Basic concepts of
treatment strategies. Ann N Y Acad Sci. 2004;1024: immune response and defense development. ILAR J.
124–137. 2005;46:230–240.
30. Gearry RB, Barclay ML. Azathioprine and 6-mercap- 50. Mele TA, Halloran PF. The use of mycophenolate
topurine pharmacogenetics and metabolite monitoring mofetil in transplant recipients. Immunopharmacology.
in inflammatory bowel disease. J Gastroenterol Hepatol. 2000;47:215.
2005;20:1149–1157. 51. Munz C, Steinman RM, Fujii S. Dendritic cell matura-
31. Gisondi P, Ellis CN, Girolomoni G. Pimecrolimus in tion by innate lymphocytes: coordinated stimulation of
dermatology: atopic dermatitis and beyond. Int J Clin innate and adaptive immunity. J Exp Med. 2005;202:
Pract. 2005;59:969–974. 203–207.
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52. Parekh K, Trulock E, Patterson GA. Use of cyclo- 67. Shi F, Ljunggren HG, Sarvetnick N. Innate immu-
sporine in lung transplantation. Transplant Proc. 2004; nity and autoimmunity: from self-protection to self-
36(suppl):318S–322S. destruction. Trends Immunol. 2001;22:97–101.
53. Pelle MT, Werth VP. Thalidomide in cutaneous lupus 68. Sieb JP. Myasthenia gravis: emerging new therapy
erythematosus. Am J Clin Dermatol. 2003;4:379–387. options. Curr Opin Pharmacol. 2005;5:303–307.
54. Ponticelli C, Tarantino A, Campise M, Montagnino G, 69. Sivathasan C. Experience with cyclosporine in heart
Aroldi A, Passerini P. From cyclosporine to the future. transplantation. Transplant Proc. 2004;36(suppl):
Transplant Proc. 2004;36(suppl):557S–560S. 346S–348S.
55. Radovancevic B, Vrtovec B. Sirolimus therapy in car- 70. Srinivas TR, Kaplan B, Schold JD, Meier-Kriesche
diac transplantation. Transplant Proc. 2003;35(suppl): HU. The impact of mycophenolate mofetil on long-
171S–176S. term outcomes in kidney transplantation. Transplanta-
56. Regazzi MB, Alessiani M, Rinaldi M. New strategies tion. 2005;80(suppl):S211–S220.
in immunosuppression. Transplant Proc. 2005;37: 71. Svennilson J. Novel approaches in GVHD therapy.
2675–2678. Bone Marrow Transplant. 2005;35(suppl 1):S65–S67.
57. Reichardt HM. Immunomodulatory activities of gluco- 72. Taylor AL, Watson CJ, Bradley JA. Immunosuppres-
corticoids: insights from transgenesis and gene target- sive agents in solid organ transplantation: mechanisms
ing. Curr Pharm Des. 2004;10:2797–2805. of action and therapeutic efficacy. Crit Rev Oncol
58. Rezzani R. Cyclosporine A and adverse effects on Hematol. 2005;56:23–46.
organs: histochemical studies. Prog Histochem Cytochem. 73. van Hooff JP, Christiaans MH, van Duijnhoven EM.
2004;39:85–128. Tacrolimus and posttransplant diabetes mellitus in
59. Rhoades CJ, Williams MA, Kelsey SM, Newland AC. renal transplantation. Transplantation. 2005;79:
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Blood Rev. 2000;14:14–30. nity, and autoimmunity. Clin Immunol. 2005;114:
60. Sacks SH, Zhou W. Allograft rejection: effect of local 17–26.
synthesis of complement. Springer Semin Immunopathol. 75. Webster A, Pankhurst T, Rinaldi F, et al. Polyclonal
2005;27:332–344. and monoclonal antibodies for treating acute rejection
61. Sandborn WJ, Feagan BG. Review article: mild to episodes in kidney transplant recipients. Cochrane
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treatment algorithm. Aliment Pharmacol Ther. 2003;18: 76. Webster AC, Woodroffe RC, Taylor RS, et al.
263–277. Tacrolimus versus ciclosporin as primary immunosup-
62. Sandrini S. Use of IL-2 receptor antagonists to reduce pression for kidney transplant recipients: meta-analysis
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63. Sands BE. Immunosuppressive drugs in ulcerative 77. Wong W, Venetz JP, Tolkoff-Rubin N, Pascual M.
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64. Schluter M, Schofer J. Direct stenting with sirolimus- Transplantation. 2005;80:289–296.
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65. Sehgal SN. Sirolimus: its discovery, biological proper- genesis of acute graft-versus-host disease: implications
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66. Sengupta S, Blute ML. The management of superfi- 79. Zlotta AR, Schulman CC. Biological response modi-
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Chapter 38
Complementary and
Alternative Medications
In addition to traditional medications, consumers have ficult to determine the exact prevalence of CAM use,
access to many substances that are not considered a it is estimated that over 38 million adults in the Unit-
part of conventional or mainstream pharmacothera- ed States use some form of CAM.41,75 Interest in
peutics. These substances often consist of natural CAMs will almost certainly continue to increase as the
products such as herbal preparations, vitamins, miner- popular media, the Internet, and other resources pro-
als, and other nutritional substances that are taken to mote the potential benefits of CAMs.
promote optimal health or to treat various conditions. Because CAMs represent such a broad range of
These products are usually classified as dietary supple- substances and interventions, it is difficult to address
ments by the Food and Drug Administration (FDA), this topic in a single chapter. This chapter will, how-
and are therefore not subjected to the rigorous testing ever, present a general overview of the topic and will
and scrutiny required for prescription drugs and many then describe some of the common CAMs that are
over-the-counter medications. taken by persons undergoing physical rehabilitation.
These nontraditional products are often described This chapter aims to alert readers to some of the more
as complementary or alternative medications (CAMs), pertinent and unique aspects of CAM use, and to help
to differentiate them from the more conventional clinicians understand how these substances can affect
medications that are classified as drugs by the FDA. To how patients respond to rehabilitation interventions.
be specific, a complementary medication is a substance
that is used in addition to a conventional treatment,
whereas an alternative medication is used as a substi- Unique Aspects of CAMs
tute for a more traditional or mainstream treatment.44
Other terms are applied to specific interventions, such
Misconceptions about CAM Safety
as herbal remedies, naturopathic treatments, phy- Many CAMs are derived from natural sources such as
tomedicines, and so forth. However, for the purpose of herbs and other plants. Therefore, some consumers
this chapter the term CAM will be used to encompass assume that a “natural” product is inherently safer than
the array of substances that fall outside conventional a synthetic or manufactured chemical.57 These individ-
pharmacotherapeutic regimens. uals may likewise believe that they can take an unlim-
CAMs and other nontraditional healing philoso- ited amount of a CAM; that is, they may exceed dose
phies (meditation, yoga, acupuncture, and so forth) limits with the idea that the product can do no harm.
have been a mainstay in certain cultures and societies. These misconceptions can lead to tragic consequences,
Western cultures, however, have generally been more as was the case with ephedra. Ephedra, derived from an
aligned with conventional treatments and medica- evergreen shrub, also contains epinephrine (adrena-
tions. Nonetheless, the interest and use of CAMs in line). As discussed in Chapter 20, epinephrine is a pow-
persons living in the United States has increased dra- erful agonist (stimulant) of alpha and beta receptors
matically over the past several years. Although it is dif- on various tissues throughout the body. People took
605
38Ciccone(p)-38 1/30/07 2:56 PM Page 606
ephedra to capitalize on these effects, especially its medications.7 As a result, the active ingredients in cer-
adrenalinelike effects in promoting weight loss and tain products may vary considerably or may be inade-
enhancing athletic performance.1,19 Unfortunately, quate to exert a therapeutic effect.49,64 This fact seems
ephedra is also a powerful cardiovascular stimulant of especially true for CAMs that are derived from plant
beta-1 receptors on the heart and alpha-1 receptors on sources. Plants that grow under different environmen-
the peripheral vasculature. Hence, some well-docu- tal or soil conditions will invariably contain different
mented cases of heart attack and stroke were attributed amounts of the active ingredients. In addition, some
to ephedra, especially when it was taken in high doses CAMs may inadvertently contain toxins that are
to promote weight loss.1 Concerns about the safety of sequestered by the plant when it is growing in its nat-
ephedra prompted the FDA to ban dietary supple- ural environment. There is also the possibility that the
ments containing ephedra in 2004.66 wrong plants will be harvested and subsequently mar-
Patients should be reminded that CAMs are sub- keted as a specific type of CAM. Hence, consumers
ject to all the same restrictions and potential problems should be aware that the quality of CAMs may vary
as conventional medications. The case of ephedra from product to product, and that poor quality can
serves as a primary example of how a product can pro- result in a lack of therapeutic effects or an increased
duce powerful physiologic effects regardless of risk of toxic effects.
whether it is derived from natural or synthetic sources.
It might also help to remind patients that some very
important and powerful traditional medications such Delayed Use of
as opioids (Chapter 14), digoxin (Chapter 24), and Conventional Medications
certain anticancer drugs (Chapter 36) were originally A major concern among health care providers is that
derived from plant sources. Hence, patients should the use of ineffective alternative medications can delay
adhere to proper dosages even if the CAM originated or postpone the use of effective conventional inter-
from a natural source. ventions.12 Consumers may begin to self-treat various
conditions with alternative medications, hoping that
Failure to Report CAM Use these treatments will provide relief and that they can
forego conventional or mainstream treatments. If the
Patients are sometimes reluctant to tell their physician, alternative treatment is not effective, however, the
nurse, pharmacist, or therapist that they are using condition can worsen to the point where convention-
CAMs.41 These patients are often afraid that health al treatment is no longer effective or takes much
care providers will criticize the use of these products as longer to achieve beneficial effects. Consumers should
being unscientific and not consistent with convention- be counseled to avoid over-reliance on these alterna-
al health care. This lack of reporting may result in an tive medications, and to seek conventional medical
adverse interaction if a specific traditional medication treatment if symptoms fail to resolve quickly or if they
is administered with a CAM. Likewise, CAMs can alter worsen during alternative medication use.
the metabolism of other medications (see “Potential
Adverse Effects of CAMs,” below), necessitating a
change in the dose of the traditional medication to Potential Adverse
maintain efficacy or avoid an adverse drug reaction.
Hence, patients should be encouraged to disclose
Effects of CAMs
CAM use as well as the use of any other nontradition- CAMs are often safe and are not typically associated
al interventions, and clinicians should maintain a con- with severe adverse effects when taken as recommend-
structive, nonjudgmental dialogue with patients about ed by reasonably healthy persons.20 CAMs, however,
the potential benefits and adverse effects of CAMs.25 can interact with conventional medications, and direct-
ly increase or decrease these medications’ effects.35
Lack of Standards for Moreover, CAMs often influence the absorption, dis-
tribution, metabolism, and excretion of conventional
Quality and Purity of CAMs medications.11,37 In particular, CAMs can stimulate the
Because many CAMs are classified as food or dietary liver to synthesize more drug-metabolizing enzymes, a
supplements, these substances are not subject to the process known as enzyme induction (the phenomenon
same standards for quality and purity as traditional of enzyme induction is addressed in Chapter 3).80 Dur-
38Ciccone(p)-38 1/30/07 2:56 PM Page 607
Chondroitin Chondroitin sulfate Bovine tracheal carti- Osteoarthritis (combined with glu-
lage cosamine)
Echinacea Echinacea species (E. Roots and seeds from Immune stimulant; treatment of colds
angustifolia; E. pallida; E. the echinacea plant and upper respiratory tract infec-
purpurea) tions; applied topically to promote
wound healing
Garlic Allium sativum L Bulb of the garlic plant Decrease cholesterol and other plas-
ma lipids; anti-inflammatory; antimi-
crobial; antioxidant; other effects
Ginkgo Ginkgo biloba Leaf of the gingko tree Improve memory and cognition;
increase vascular perfusion of brain
and other tissues; antioxidant; anti-
inflammatory
Ginseng Panax ginseng Root of the ginseng Increase well-being; reduce fatigue;
plant used in the treatment of cancer,
diabetes, cardiovascular dysfunc-
tion, and various other diseases
Kava Piper methysticum Root of the kava plant Sedative-hypnotic and antianxiety
effects
Saw palmetto Serenoa repens Fruit of the saw pal- Benign prostatic hypertrophy
metto palm
Ginseng Kava
Ginseng, derived from the root of the Panax plant, is Kava originates from the root of the Piper methysticum
renowned as an herbal remedy for various conditions. (kava) plant that grows predominately in the South
It is often administered to increase general well-being, Pacific islands. This drug has been used for centuries
reduce fatigue, improve mental acuity, and promote by various local cultures because of its sedative and
optimal health.18,40 Ginseng has likewise been advo- antianxiety effects. Kava has likewise gained popularity
cated in the prevention and treatment of many dis- in western societies, and studies suggest that kava
eases including cancer, diabetes, neurodegenerative extracts can be used as an alternative to traditional
disorders, and cardiovascular disease.13,33,68,83 The sedative-hypnotic and anxiolytic drugs, such as benzo-
potential benefits of ginseng products are typically diazepines (see Chapter 6).21,39 Kava may also produce
38Ciccone(p)-38 1/30/07 2:56 PM Page 610
analgesic and muscle relaxant effects, and some urine flow in mild to moderate cases of BPH.24,82 This
patients may use this product for self-treatment of back effect is apparently due to a reduction in swelling and
pain and other musculoskeletal injuries. Although the inflammation of the prostate, but the exact mechanism
exact mechanism of action is unclear, kava extracts of saw palmetto on BPH is not clear.26 Possible side
probably affect receptors within the limbic system, and effects include headache, GI upset, and allergic reac-
enhance the inhibitory effects of GABA and other neu- tions. Saw palmetto treatments, however, are general-
rotransmitters. Liver toxicity is the most serious effect ly well tolerated, especially when compared to
associated with kava, and the risk of liver damage is conventional medications such as finasteride (Proscar)
especially problematic when higher dosages are taken (see Chapter 30).27,82
for prolonged periods.77 Because of the potential for
liver toxicity, kava products are banned in many coun-
tries throughout Europe.2 St. John’s Wort
St. John’s wort is derived from the flowers of the
Melatonin Hypericum perforatum plant that grows throughout
England, Europe, Asia, and parts of the United States.
Melatonin is an endogenous neurohormone that is This herbal supplement has been used extensively
produced primarily by the pineal gland. In humans, to treat symptoms of depression and anxiety. Although
melatonin is normally released at night, with plasma the details are unclear, St. John’s wort probably
levels tending to peak between 2 and 4 AM.47 Mela- contains several chemicals that alter the balance of
tonin is associated with the ability to regulate sleep- central nervous system (CNS) neurotransmitters
wake cycles, and perhaps other circadian rhythms.3,31 affecting mood and behavior.46,84 As discussed in
Because of this effect, synthetic melatonin supple- Chapter 7, depression seems to be associated with a
ments have been used primarily to treat insomnia, fundamental defect in amine neurotransmitters such
especially in individuals with disturbed sleep cycles or as serotonin, norepinephrine, and dopamine. St.
persons who are blind and cannot regulate melatonin John’s wort may promote changes in these neuro-
release because they are unable to respond visually to transmitters in a manner similar to conventional pre-
normal light-dark cycles.3 scription antidepressants.56,84 Many people have
Melatonin is also associated with antioxidant therefore used St. John’s wort as an alternative med-
effects; these effects may be beneficial in several situa- ication to help improve mood and resolve the symp-
tions, such as preventing the neurodegenerative toms of depression.46,72
changes in Parkinson disease,54,81 reducing migraine Several studies have suggested that products con-
headaches,65 and improving insulin responses in type 2 taining adequate amounts of the active chemicals from
diabetes mellitus.62 Melatonin may also stimulate and St. John’s wort may be successful in treating mild-to-
support the immune system, and may therefore be moderate depression.46,72 The success of this product
helpful in treating certain forms of cancer.58,59 Clearly, in more severe or resistant forms of depression
melatonin has the ability to regulate a number of remains unclear.50 St. John’s wort is generally well tol-
important physiologic functions, and researchers erated,43,51 but use of this product can accelerate the
continue to investigate the potential benefits of mela- metabolism of other therapeutic medications such as
tonin supplements in a number of conditions. Side warfarin (Chapter 25), reverse transcriptase inhibitors
effects of melatonin are usually minor, consisting pri- (Chapter 34), cyclosporine (Chapter 37), and certain
marily of headache, change in sleep cycles, vivid anticancer agents (Chapter 36).16,72 Hence, St. John’s
dreams, GI disturbances, and allergic reactions (skin wort can prevent these other medications from reach-
rashes and itching). ing therapeutic levels, and dosages of other medica-
tions may have to be adjusted to maintain their
Saw Palmetto efficacy when administered with St. John’s wort.46
Adverse Effects of
Vitamin RDA/AI* Physiological Function Excessive Consumption
Biotin Men & women: 30 Coenzyme in the synthesis of No adverse effects have been
μg/d fat, glycogen, and amino reported**
acids
Folic acid Men & women: 400 Coenzyme in the metabolism of Adverse effects have not been
μg/d nucleic acids and amino documented, but high
acids; prevents megaloblastic doses may mask neurologi-
anemia cal complications in people
with Vitamin B12 deficiency
Pantothenic acid Men & women: 5 Coenzyme in fatty acid metabo- No adverse effects have been
mg/d lism reported**
Adverse Effects of
Vitamin RDA/AI* Physiological function Excessive Consumption
Vitamin A (retinol) Men: 900 μg/d Required for normal vision, Teratological effects; liver toxi-
Women: 700 μg/d gene expression, reproduc- city
tion, embryonic development,
and immune function
Vitamin B1 (thiamin) Men: 1.2 mg/d Coenzyme in the metabolism of No adverse effects have been
Women: 1.1 mg/d carbohydrates and certain reported**
amino acids; prevents
beriberi
Vitamin B2 (riboflavin) Men: 1.3 mg/d Coenzyme in numerous oxida- No adverse effects have been
Women: 1.1 mg/d tive metabolic reactions reported**
Vitamin B6 (pyridoxine) Men: 1.3–1.7 mg/d Coenzyme in the metabolism of No adverse effects have been
Women: 1.3–1.5 amino acids and glycogen reported**
mg/d
Vitamin B12 (cobalamin) Men & women: Coenzyme in nucleic acid No adverse effects have been
2.4 μg/d metabolism; prevents mega- reported**
loblastic/pernicious anemia
Vitamin C (ascorbic Men: 90 mg/d Cofactor for reactions requiring Gastrointestinal disturbances,
acid) Women: 75 mg/d reduced copper or iron met- kidney stones, excess iron
alloenzyme and as a protec- absorption
tive antioxidant; prevents
scurvy
Vitamin D (calciferol) Men & women: Maintain serum calcium and Hypercalcemia secondary to
5–15 μg/d phosphorus concentrations; elevated vitamin D metabo-
prevents rickets lites in plasma
Vitamin K Men: 120 μg/d Coenzyme during the synthesis No adverse effects have been
Women: 90 μg/d of many proteins involved in reported**
blood clotting and bone
metabolism
*Recommended daily requirement (RDA) or adequate intake (AI) for men and nonpregnant women over 20
years old. Recommended values for certain vitamins (e.g., folic acid) may be higher in women who are preg-
nant. Values for children are typically lower, and are adjusted according to the child’s age.
**Absence of reported adverse effects does not mean that there is no potential for adverse effects from high
intake. Caution should still be used when taking doses well in excess of the recommended daily amounts.
Adapted from: Institute of Medicine of the National Academies (www.iom.edu): Food & Nutrition Dietary
Reference Intakes DRI Tables Vitamins.
38Ciccone(p)-38 1/30/07 2:56 PM Page 613
vitamins needed. People with diets that are extremely specific questions can also be referred to a registered
poor in nutrients or lacking in certain foods may dietician who can analyze the person’s vitamin needs,
benefit from vitamin supplements. Certain metabolic and suggest whether supplements may be helpful.
disorders may likewise impair the absorption or uti-
lization of specific vitamins, and supplements can help
resolve a potential vitamin imbalance in these situa-
Minerals
tions.32 In other situations, the body’s demand for cer- Minerals are small chemical substances that play key
tain vitamins may increase, and dietary sources may be roles in various physiologic processes.55 Consider, for
unable to provide enough of a specific vitamin. Dur- example, the ways that minerals such as sodium, potas-
ing pregnancy, for example, a supplement with folic sium, chloride, and calcium influence the function and
acid is helpful in supplying an adequate source of this homeostasis of virtually every cell in the body. These
vitamin for the mother and developing fetus. minerals and several other major minerals (see Table
Hence, vitamin supplements should be adminis- 38–3) are essential for life. Other minerals, known
tered to make up any differences between the dietary commonly as trace minerals, are not as abundant in
supply and the body’s demand for specific vitamins. the body, but are still needed to promote the function
Some individuals, however, self-administer large of specific cells and tissues.
dosages of vitamins on a regular basis with the miscon- The primary roles and the recommended daily
ception that these supplements will promote better intake of major and trace minerals are listed in Table
health and offer protection from disease. Excessive 38–3. Similar to vitamins, these minerals are typically
dosages of vitamins are unnecessary and can be harm- obtained from dietary sources. Specific minerals may
ful if they begin to accumulate in certain tissues and likewise be included in various multivitamins and other
organs. This fact is especially true for the fat soluble dietary supplements, with the intent that these miner-
vitamins A, D, E, and K.4,55 Water soluble vitamins (B als will promote good health and prevent disease.
complex, vitamin C) are generally less problematic Again, there is generally no need for mineral supple-
because excess doses of these vitamins are excreted in ments for most people eating a reasonably balanced
the urine. Fat-soluble vitamins, however, can accumu- diet. On the other hand, mineral supplements can be
late in adipose tissue, the liver, and various other sites helpful in specific situations where the body’s need for
throughout the body. Excess vitamin administration a mineral may exceed dietary supply. Some examples of
can result in various signs of toxicity, including drowsi- appropriate supplementation include calcium supple-
ness, headache, fatigue, nausea, muscle weakness, and ments for people with osteoporosis (see Chapter 31),
enlargement of the liver and spleen (see Table 38–2).4 potassium supplements for people on diuretics (see
Clinicians should therefore advise patients about Chapter 21), and iron supplements for people with
the need for adequate dietary vitamin intake, but certain anemias. Hence, mineral supplements may be
should also caution patients about the indiscriminate helpful in certain individuals, but the dose and type of
or excessive use of vitamin supplements. Patients with supplement should be adjusted carefully.
CA S E ST U DY
Complementary and Alternative that the St. John’s wort would provide an alternative way to
Medications improve his mood while recovering from the most recent knee
surgery.
Brief History. S.G. is a 75-year-old man who began Problem/Influence of Medication. St. John’s wort
experiencing osteoarthritic changes in his right knee when can cause enzyme induction, which results in an increase in
he was in his 50s. This condition worsened progressively, the liver’s ability to metabolize other medications, including
necessitating a total knee arthroplasty, which was performed warfarin. This process could result in the warfarin being
two years ago. The initial knee replacement, however, became metabolized too rapidly and therefore failing to reach thera-
unstable, and was recently revised surgically to decrease peutic levels. Lack of adequate anticoagulant effects would
pain and to promote better function. While in the hospital place the patient at increased risk for subsequent thrombosis
for this revision, the patient developed a deep vein thrombo- and pulmonary embolism.
sis, and was placed on heparin followed by warfarin Decision/Solution. The therapist called the physician
(Coumadin) to control excessive coagulation. He continued and related the fact that the patient had recently started tak-
taking the warfarin when he was discharged, and a physical ing St. John’s wort. To get an indication of warfarin efficacy,
therapist began providing home care on a regular basis. the physician ordered blood tests to assess the patient’s clot-
During the initial visit, the therapist asked the patient if he ting times. These tests revealed that clotting times were
was taking any additional medications. He replied that he indeed slightly decreased, indicating that the blood was clot-
had recently started taking St. John’s wort on the advice of ting too rapidly and that the dose of warfarin needed to be
a friend. Apparently, this patient had become very discour- increased. The dose of warfarin was adjusted accordingly,
aged and despondent because of problems with his knee and clotting time was monitored periodically to ensure that
replacement and his inability to resume his hobbies and social the new dose was appropriate. The patient recovered from
activities (playing golf, gardening, and so forth). He hoped the surgery without any further thrombotic events.
38Ciccone(p)-38 1/30/07 2:56 PM Page 616
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more effectively than either agent alone. Osteoarthritis Parkinson’s disease. Endocrine. 2005;27:169–178.
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39Ciccone(p)-Appendix 1/30/07 2:56 PM Page 619
Appendix A
Drugs Administered
by Iontophoresis
and Phonophoresis
Drugs that may be administered by iontophoresis and primarily on clinical observation and anecdotal
phonophoresis are listed here. Administration of these reports in the literature. Likewise, the preparation
agents by these techniques is largely empirical. The strengths given here are merely suggestions based on
use of these substances in the conditions listed is based currently available information.
Principal Treatment
Drug Indication(s) Rationale Iontophoresis Phonophoresis
Acetic acid Calcific tendinitis Acetate is believed to increase 2%–5% aqueous —
solubility of calcium deposits in solution from negative
tendons and other soft tissues pole
Principal Treatment
Drug Indication(s) Rationale Iontophoresis Phonophoresis
Iodine Adhesive capsulitis and Iodine is a broad-spectrum 5%–10% solution 10% ointment
other soft-tissue adhe- antibiotic, hence its use or ointment from neg-
sions; microbial infec- in infections, etc.; the scle- ative pole
tions rolytic actions of iodine are not
fully understood
Lidocaine Soft-tissue pain and Local anesthetic effects (see 4%–5% solution or 5% ointment
inflammation (e.g., Chapter 12) ointment from
bursitis, tenosynovitis) positive pole
Magnesium Skeletal muscle Muscle relaxant effect may be 2% aqueous solution 2% ointment
sulfate spasms; myositis caused by decreased or ointment from posi-
excitability of the skeletal mus- tive pole
cle membrane and decreased
transmission at the neuromus-
cular junction
Salicylates Muscle and joint pain Aspirinlike drugs with anal- 10% trolamine salicy- 10% trolamine
in acute and chronic gesic and anti- late ointment or salicylate oint-
conditions (e.g., over- inflammatory effects 2%–3% sodium salicy- ment or 3%
use injuries, rheuma- (see Chapter 15) late solution from neg- sodium salicy-
toid arthritis) ative pole late ointment
Tolazoline Indolent cutaneous Increases local blood flow and 2% aqueous solution —
hydrochloride ulcers tissue healing by inhibiting or ointment from posi-
vascular smooth muscle con- tive pole
traction
Zinc oxide Skin ulcers; other der- Zinc acts as a general 20% ointment from 20% ointment
matologic disorders antiseptic; may increase positive pole
tissue healing
39Ciccone(p)-Appendix 1/30/07 2:56 PM Page 621
Appendix B
Use of the Physicians’
Desk Reference
Several drug indexes are available that can supplement followed by the name of the manufacturer (in
this text by serving as a detailed source of information parentheses) and by a page number, which indi-
about individual drugs. One of the most readily avail- cates where the drug is described in the “Prod-
able and frequently used indexes is the Physicians’ Desk uct Information” section. Some trade names are
Reference, or PDR. The PDR is published annually by preceded by a small diamond and will usually
Thomson PDR, Montvale, NJ 07645-1742. have two page numbers following the name.
Drug manufacturers submit information about This diamond indicates that a color photograph
the indications, dosages, adverse effects, and so on, of of the actual medication is provided in the spe-
individual agents for inclusion in the PDR. The PDR cial section of the PDR known as the “Product
is then published annually, providing a relatively cur- Identification Guide.” The first page number
rent source of information. The PDR is also updated following the drug name is the page that illus-
within a given year through periodic supplements. trates a picture of the drug, and the second
The PDR begins by listing all the manufacturers page number identifies where the written infor-
who submitted information to the PDR in the “Manu- mation can be found.
facturers’ Index.” Immediately following the “Manu- Many drugs listed in the “Brand and Generic
facturers’ Index,” drugs are listed according to the Name Index” have several variations on the
“Brand and Generic Name Index” and the “Product trade name, depending on different forms of
Category Index.” These listings are followed by the drug and routes of administration. For
detailed descriptions of the drugs in the “Product example, a drug that is available in tablets, cap-
Information Section,” which constitutes the bulk of sules, and injectable forms may have slight vari-
the PDR. ations on the trade name that reflect these
Using the PDR for the first time can be somewhat different preparations.
confusing because drugs are listed in several different 2. If the Generic or Chemical Name Is
ways. This brief outline may help individuals use the Known. If you are using an edition of the PDR
PDR more effectively to obtain information about published in 1994 or later, begin by looking in
specific agents. the “Brand and Generic Name Index” (PINK
pages). This section integrates generic names
1. If the Trade Name or Brand Name of the into the alphabetical listing of trade names. The
Drug Is Known. Begin by looking in the generic name of each drug is followed by the
“Brand and Generic Name Index” in the front trade name, manufacturer (in parentheses),
of the PDR, easily found by locating the PINK and pages where the drug is illustrated and
pages. Drugs are listed alphabetically according described. Often, the generic heading in this
to the name given by the drug manufacturer section is followed by several different trade
(trade, or brand name) as well as by the generic names, indicating that several different manu-
name (see section 2, below). Each trade name is facturers market the drug.
621
39Ciccone(p)-Appendix 1/30/07 2:56 PM Page 622
Older editions of the PDR (1993 and earlier) 4. If You Want to Contact the Manufacturer
list generic and chemical names in a separate for More Information about the Drug. Look
section called the “Generic and Chemical in the “Manufacturers’ Index” located in the
Name Index,” marked by YELLOW pages. If WHITE pages at the very beginning of the
you are using an older edition, consult this sec- PDR. Manufacturers who have contributed to
tion if you know only the generic name. the PDR are listed alphabetically, with an
3. To Find Out What Drugs Are Available to address and phone number that serve as a
Treat a Given Disorder. The best place to source for inquiries. In addition, a partial
begin is the “Product Category Index” located listing of the products available from each
in the BLUE pages. Here, drugs are listed manufacturer is included following the
according to the principal pharmacologic classi- manufacturer’s name and address.
fications, such as anesthetics, laxatives, and 5. If You Want to Identify the Name of a Spe-
sedatives. Major categories in this section are cific Pill, Capsule, or Tablet. Locate the
often subdivided into subcategories that are “Product Identification Guide,” which contains
more specific. For example, cardiovascular glossy color photographs of many of the drugs.
preparations are subdivided into antiarrhyth- Drugs are categorized alphabetically according
mics, beta-adrenergic blocking agents, vasodila- to their manufacturer. Often, individual pills,
tors, and others. Drugs in each category (or tablets, and other forms have the name of the
subcategory) are listed according to their trade manufacturer scored or printed directly on the
name, followed by the manufacturer (in paren- medication. An unknown medication can be
theses) and the pages on which the drug is illus- identified by matching the drug to the pictures
trated and described. listed under that manufacturer.
39Ciccone(p)-Appendix 1/30/07 2:56 PM Page 623
Appendix C
Drugs of Abuse
Some of the more frequently abused drugs are listed have a strong potential for abuse when taken indiscrim-
here. Agents such as cocaine and the psychedelics are inately. Finally, drugs such as alcohol, caffeine, and nico-
illicit drugs with no major pharmacotherapeutic value. tine are readily available in various commercial products
Other drugs such as barbiturates, benzodiazepines, and but may also be considered drugs of abuse when con-
opioids are routinely used for therapeutic reasons but sumed in large quantities for prolonged periods.
Barbiturates Sedative-hypnotic Oral or injected Relaxation and a Physical depend- See Chapter 6
Nembutal (IM, IV) sense of calm- ence; possible
Seconal ness; drowsiness death from over-
Others dose; behavior
changes (irri-
tability, psy-
chosis)
following pro-
longed use
Benzodiazepines Similar to barbitu- Similar to barbitu- Similar to barbitu- Similar to barbitu- Similar to barbi-
Valium rates rates rates rates turates
Librium
Others
Caffeine CNS stimulant Oral; from coffee, Increased alertness; Sleep disturbances; See Chapter 26
tea, other bever- decreased irritability; nerv-
ages fatigue; improved ousness; cardiac
work capacity arrhythmias
Cocaine CNS stimulant “Snorted” Euphoria; excite- Physical depend- See Chapter 12
(when taken (absorbed via ment; feelings of ence; acute CNS
systemically) nasal mucosa); intense pleasure and cardiac toxi-
smoked (in and well-being city; profound
crystalline form) mood swings
Narcotics Natural and syn- Oral or injected Relaxation; eupho- Physical depend- See Chapter 14
Demerol thetic opioids; (IM, IV) ria; feelings of ence; respiratory
Morphine analgesics tranquility; pre- depression; high
Heroin vent onset of opi- potential for
Others ate withdrawal death due to
overdose
Glossary
Common terms related to pharmacology and a brief Alpha receptors: A primary class of receptors that
definition of each term are listed here. Synonyms are responsive to epinephrine and norepinephrine.
(SYN), antonyms (ANT), and common abbreviations Alpha receptors are subclassified into alpha-1 and
(ABBR) are also included, whenever applicable. alpha-2 receptors based on their sensitivity to
various drugs.
Acetylcholine: A neurotransmitter in the somatic
and autonomic nervous systems; principal synapses Anabolic steroids: Natural and synthetic male hor-
using acetylcholine include the skeletal neuromuscu- mones that may be misused in an attempt to increase
lar junction, autonomic ganglia, and certain pathways muscle size and improve athletic performance (SYN:
in the brain. androgens).
Adenylate cyclase: An enzyme located on the inner Analgesia: To lessen or relieve pain. Drugs with this
surface of many cell membranes; it is important in ability are known as analgesics.
mediating biochemical changes in the cell in
response to drug and hormone stimulation (SYN: Androgen: A male steroid such as testosterone.
adenyl cyclase). Angina pectoris: Severe pain and constriction in the
Adrenergic: Refers to synapses or physiologic chest region, usually associated with myocardial
responses involving epinephrine and norepinephrine. ischemia.
Adrenocorticosteroids: The group of steroid hor- Angiogenesis: The development of new blood ves-
mones produced by the adrenal cortex. These drugs sels. Drugs that inhibit this effect can be useful in
include the glucocorticoids (cortisol, cortisone), min- limiting the growth and proliferation of certain
eralocorticoids (aldosterone), and sex hormones tumors.
(androgens, estrogens, progestins). Antagonist: A drug that binds to a receptor but does
Affinity: The mutual attraction between a drug and a not cause a change in cell activity (SYN: blocker).
specific cellular receptor. Anthelmintic: A drug that destroys parasitic worms
Agonist: A drug that binds to a receptor and causes (e.g., tapeworms, roundworms) in the gastrointestinal
some change in cell function (ANT: antagonist). tract and elsewhere in the body.
Akathisia: A feeling of extreme motor restlessness Anticholinergic: Drugs that decrease activity at
and an inability to sit still; may occur because of acetylcholine synapses. These agents are often used
antipsychotic drug therapy. to diminish activity in the parasympathetic nervous
system (SYN: parasympatholytic).
Allergy: A state of hypersensitivity to foreign sub-
stances (e.g., environmental antigens and certain Anticoagulation: A decrease in the blood’s capacity
drugs), manifested by an exaggerated response of the to coagulate (clot). Drugs with the ability to decrease
immune system. coagulation are known as anticoagulants.
625
40Ciccone(p)-Glossary 1/30/07 2:57 PM Page 626
626 Glossary
Antimetabolite: The general term for drugs that Catecholamine: A group of chemically similar com-
impair function in harmful cells and microorganisms pounds that are important in the modulation of
by antagonizing or replacing normal metabolic sub- cardiovascular activity and many other physiologic
strates in those cells. Certain anti-infectious and anti- functions. Common catecholamines include epi-
neoplastic agents function as antimetabolites. nephrine, norepinephrine, and dopamine.
Antineoplastic: A drug that prevents or attenuates Cathartic: An agent that causes a relatively rapid
the growth and proliferation of cancerous cells. evacuation of the bowels.
Antipyresis: The reduction of fever. Drugs with the Ceiling effect: The point at which no further
ability to reduce fevers are known as antipyretics. increase in response occurs as a drug dose is progres-
Antitussive: A drug that reduces coughing. sively increased; this effect is represented by a plateau
on the drug’s dose-response curve (SYN: maximal
Aromatase: An enzyme responsible for estrogen efficacy).
biosynthesis.
Chemical name: A drug name that is derived from
Asthma: A chronic disease of the respiratory system the specific chemical structure of the compound.
characterized by bronchoconstriction, airway inflam- Chemical names are not used clinically but are
mation, and the formation of mucous plugs in the shortened in some way to form the drug’s
airway. generic name.
Bactericidal: An agent that kills or destroys bacteria. Chemotherapy: The use of chemical agents to treat
Bacteriostatic: An agent that inhibits the growth infectious or neoplastic disease.
and proliferation of bacteria. Cholinergic: Refers to synapses or physiologic
Beta receptor: A primary class of the receptors that responses involving acetylcholine.
are responsive to epinephrine and (to a lesser extent) Cholinesterase: The enzyme that breaks down
norepinephrine. Beta receptors are subclassified into acetylcholine (SYN: acetylcholinesterase).
beta-1 and beta-2 receptors based on their sensitivity
to various drugs. Clearance: The process by which the active form of
the drug is removed from the bloodstream by either
Bioavailability: The extent to which a drug reaches metabolism or excretion.
the systemic circulation following administration by
various routes. Congestive heart failure: A clinical syndrome of
cardiac disease that is marked by decreased myocar-
Biotransformation: Biochemical changes that occur dial contractility, peripheral edema, shortness of
to the drug within the body, usually resulting in the breath, and decreased tolerance for physical exertion.
breakdown and inactivation of the drug (SYN: drug
metabolism). Cretinism: A congenital syndrome of mental retar-
dation, decreased metabolism, and impaired physical
Bipolar disorder: A psychological disorder charac- development secondary to insufficient production of
terized by mood swings ranging from excitable thyroid hormones.
(manic) periods to periods of depression (SYN:
manic-depression). Cyclic adenosine monophosphate (ABBR:
cAMP): The ring-shaped conformation of adenosine
Blood-brain barrier: The specialized anatomic
monophosphate, which is important in acting as a
arrangement of cerebral capillary walls that serves to
second messenger in mediating the intracellular
restrict the passage of some drugs into the brain.
response to drug stimulation.
Blood dyscrasia: A pathologic condition of the
Cyclooxygenase (ABBR: COX): The key enzyme
blood, usually referring to a defect in one or more of
involved in prostaglandin biosynthesis. This enzyme
the blood’s cellular elements.
converts arachidonic acid into prostaglandin G2,
Carcinogen: Any substance that produces cancer or thereby providing the precursor for the cell to syn-
increases the risk of developing cancer. thesize additional prostaglandins.
40Ciccone(p)-Glossary 1/30/07 2:57 PM Page 627
Glossary 627
Cytokine: The general term used to describe pro- icity; sometimes used in patients with advanced cases
teins produced by various immune and inflammatory of Parkinson disease.
cells. These proteins act as intercellular chemical sig-
Drug microsomal metabolizing system (ABBR:
nals that help orchestrate immune and inflammatory
DMMS): A series of enzymes located on the smooth
responses. Common cytokines include the interfer-
endoplasmic reticulum that are important in catalyz-
ons, interleukins, and certain growth factors.
ing drug biotransformation.
Demand dose: Amount of drug administered when a
patient activates certain drug delivery systems, such Dysentery: The general term for severe gastroin-
as those used during patient-controlled analgesia. testinal distress (diarrhea, cramps, bloody stools) that
is usually associated with the presence of infectious
Desensitization: A brief and transient decrease in microorganisms in the intestines.
the responsiveness of cellular receptors to drug
effects. Eicosanoids: The general term for the group of 20-
carbon fatty acids that includes the prostaglandins,
Diabetes insipidus: A disease marked by increased thromboxanes, and leukotrienes. These substances
urination (polyuria) and excessive thirst (polydipsia) are involved in mediating inflammation and other
due to inadequate production of antidiuretic hor- pathologic responses.
mone (ADH) and/or a decrease in the renal response
to ADH. Emetic: A drug that initiates or facilitates vomiting.
628 Glossary
Expectorant: A drug that facilitates the production Hypersensitivity: An exaggerated response of the
and discharge of mucous secretions from the respi- immune system to a foreign substance (SYN: allergic
ratory tract. response).
First-pass effect: The phenomenon in which drugs Hypertension: A pathologic condition characterized
absorbed from the stomach and small intestine must by a sustained, reproducible increase in blood pres-
pass through the liver before reaching the systemic sure.
circulation. Certain drugs undergo extensive hepatic
Hypnotic: A drug that initiates or maintains a rela-
metabolism because of this first pass through the
tively normal state of sleep.
liver.
Hypokalemia: An abnormally low concentration of
Food and Drug Administration (ABBR: FDA):
potassium in the bloodstream (ANT: hyperkalemia).
The official government agency involved in regulat-
ing the pharmaceutical industry in the United States. Hyponatremia: An abnormally low concentration
of sodium in the bloodstream (ANT: hypernatremia).
Gamma-aminobutyric acid (ABBR: GABA): An
inhibitory neurotransmitter in the brain and spinal Immunosuppressant: A drug used to attenuate the
cord. body’s immune response. These agents are often used
to prevent rejection of organ transplants or to treat
Generic name: The name applied to a drug, which
diseases caused by overactivity in the immune system
is not protected by a trademark; usually a shortened
(ANT: immunostimulant).
version of the drug’s chemical name (SYN: nonpro-
prietary name). Interferon: A member of the group of proteins that
exert a number of physiologic and pharmacologic
Glucocorticoid: The general class of steroid agents
effects, including antiviral and antineoplastic activity.
that affect glucose metabolism and are used pharma-
cologically to decrease inflammation and suppress Intrathecal: Administration of substances within a
the immune system. Principle examples include cor- sheath; typically refers to injection into the subarach-
tisol and corticosterone. noid space surrounding the spinal cord.
Glycosuria: The presence of glucose in the urine. Laxative: An agent that promotes peristalsis and
evacuation of the bowel in a relatively slow manner
Gonadotropin: A hormone that produces a stimula-
(as opposed to a cathartic).
tory effect on the gonads (ovaries and testes); pri-
mary gonadotropins include luteinizing hormone Leukotriene: One of the 20-carbon fatty acid com-
(LH) and follicle-stimulating hormone (FSH). pounds (eicosanoids) formed from arachidonic acid
by the lipoxygenase enzyme. Leukotrienes are impor-
G proteins: Proteins that bind with guanine
tant in mediating certain allergic and inflammatory
nucleotides and regulate cell activity. G proteins
responses, especially in respiratory tissues.
often serve as a link between surface receptors and
intracellular enzymes such as adenylate cyclase. Lipoxygenase (ABBR: LOX): The enzyme that ini-
tiates leukotriene biosynthesis. This enzyme converts
Half-life: The time required to eliminate 50 percent
arachidonic acid into precursors that the cell uses to
of the drug existing in the body.
synthesize specific leukotrienes.
Histamine: A chemical produced by various cells in
Loading dose: Amount of drug administered at the
the body that is involved in the modulation of certain
onset of treatment to rapidly bring the amount of
physiologic responses (e.g., secretion of gastric acid),
drug in the body to therapeutic levels.
as well as in the mediation of hypersensitivity (aller-
gic) responses. Lockout interval: The minimum amount of time
that must expire between each dose of medication
Hypercalcemia: An excessive concentration of
that is administered by patient-controlled analgesia
calcium in the bloodstream (ANT: hypocalcemia).
(PCA). The PCA pump is inactivated during the
Hyperglycemia: An excessive concentration of glu- lockout interval so that the patient cannot self-
cose in the bloodstream (ANT: hypoglycemia). administer excessive amounts of drugs.
40Ciccone(p)-Glossary 1/30/07 2:57 PM Page 629
Glossary 629
Lymphokines: Chemicals released from activated and antagonists also have a relatively selective affinity
lymphocytes that help mediate various aspects of the for muscarinic receptors.
immune response. Common lymphokines include the Myxedema: The adult or acquired form of hypothy-
interleukins and gamma interferon. roidism characterized by decreased metabolic rate,
Malignancy: A term usually applied to cancerous lethargy, decreased mental alertness, weight gain, and
tumors that tend to become progressively worse. other somatic changes.
Maximal efficacy: The maximum response a drug Neuroleptic: A term frequently used to describe
can produce; the point at which the response does antipsychotic drugs, referring to the tendency of
not increase even if the dosage continues to increase these drugs to produce a behavioral syndrome of apa-
(SYN: ceiling effect). thy, sedation, decreased initiative, and decreased
responsiveness (SYN: antipsychotic).
Median effective dose (ABBR: ED50 ): The drug
dose that produces a specific therapeutic response in Nicotinic receptor: A primary class of cholinergic
50 percent of the patients in whom it is tested. receptors, named according to their affinity for nico-
tine, as well as certain other cholinergic agonists and
Median lethal dose (ABBR: LD50 ): The drug dose antagonists.
that causes death in 50 percent of the experimental
animals in which it is tested. Norepinephrine: A neurotransmitter that is impor-
tant in certain brain pathways and in the terminal
Median toxic dose (ABBR: TD50 ): The drug dose synapses of the sympathetic nervous system (SYN:
that produces a specific adverse (toxic) response in noradrenaline).
50 percent of the patients in whom it is tested.
On-off phenomenon: The fluctuation in response
Metabolite: The compound that is formed when the seen in certain patients with Parkinson disease, in
drug undergoes biotransformation and is chemically which the effectiveness of medications may suddenly
altered by some metabolic process. diminish at some point between dosages.
Metastasize: The transfer or spread of diseased Opioid: An analgesic drug with morphinelike effects;
(i.e., cancerous) cells from a primary location to commonly refers to the synthetic forms of these anal-
other sites in the body. gesics (SYN: narcotic).
Mineralocorticoid: A steroid hormone (e.g., aldos- Orthostatic hypotension: A sudden fall in blood
terone) that is important in regulating fluid and elec- pressure that occurs when the patient stands erect;
trolyte balance by increasing the reabsorption of this is a frequent side effect of many medications.
sodium from the kidneys. Ototoxicity: The harmful side effect of some drugs
Monoamine oxidase (ABBR: MAO): An enzyme and toxins influencing the ear’s hearing and balance
that breaks down monoamine neurotransmitters such functions.
as dopamine, norepinephrine, and serotonin. Over-the-counter drugs (ABBR: OTC): Drugs
Monoclonal antibody: An antibody created by fus- that can be purchased directly by the consumer with-
ing a mouse myeloma cell with a human B lympho- out a prescription (SYN: nonprescription drugs).
cyte. These antibodies recognize specific cell-surface Parenteral administration: Administration of drugs
antigens on cancer cells or other tissues to target the by routes other than via the alimentary canal: by
drug directly to that tissue. injection, transdermally, topically, and so on.
Mucolytic: A drug that decreases the viscosity and Parkinson disease or parkinsonism: The clinical
increases the fluidity of mucous secretions in the res- syndrome of bradykinesia, rigidity, resting tremor,
piratory tract, thus making it easier for the patient to and postural instability associated with neurotrans-
cough up secretions. mitter abnormalities within the basal ganglia.
Muscarinic receptor: A primary class of cholinergic Pharmacodynamics: The study of how drugs affect
receptors that are named according to their affinity the body; that is, the physiologic and biochemical
for the muscarine toxin. Certain cholinergic agonists mechanisms of drug action.
40Ciccone(p)-Glossary 1/30/07 2:57 PM Page 630
630 Glossary
Pharmacokinetics: The study of how the body han- Receptor: The component of the cell (usually a
dles drugs; that is, the manner in which drugs are protein) to which the drug binds, thus initiating a
absorbed, distributed, metabolized, and excreted. change in cell function.
Pharmacologic dose: An amount of drug given that Salicylate: The chemical term commonly used to
is much greater than the amount of a similar sub- denote compounds such as aspirin that have anti-
stance produced within the body; this increased dose inflammatory, analgesic, antipyretic, and anticoagu-
is used to exaggerate the beneficial effects normally lant properties.
provided by the endogenous compound.
Second messenger: The term applied to com-
Pharmacotherapeutics: The study of how drugs are pounds formed within the cell, such as cyclic AMP.
used in the prevention and treatment of disease. The second messenger initiates a series of biochemi-
cal changes within the cell following stimulation of a
Pharmacy: The professional discipline dealing with
receptor on the cell’s outer surface by drugs, hor-
the preparation and dispensing of medications.
mones, and so on.
Physical dependence: A phenomenon that develops
Sedative: A drug that produces a calming effect and
during prolonged use of addictive substances, signi-
serves to pacify the patient. These agents are some-
fied by the onset of withdrawal symptoms when the
times referred to as minor tranquilizers.
drug is discontinued.
Seizure: A sudden attack of symptoms usually associ-
Physiologic dose: The amount of drug given that
ated with diseases such as epilepsy. Epileptic seizures
is roughly equivalent to the amount of a similar sub-
are due to the random, uncontrolled firing of a group
stance normally produced within the body; this dose
of cerebral neurons, which results in a variety of sen-
is typically used to replace the endogenous substance
sory and motor manifestations.
when the body is no longer able to produce the
substance. Selective toxicity: A desired effect of antineoplastic
and anti-infectious agents, wherein the drug kills the
Placebo: A medication that contains inert or inactive
pathogenic organism or cells without damaging
ingredients; used to pacify a patient or test a patient’s
healthy tissues.
psychophysiologic response to treatment.
Serotonin: A neurotransmitter located in the central
Potency: The dose of a drug that produces a given
nervous system (CNS) that is important in many
response in a specific amplitude. When two drugs are
functions, including mood, arousal, and inhibition
compared, the more potent drug will produce a given
of painful stimuli (SYN: 5-hydroxytryptamine).
response at a lower dose.
Side effect: Any effect produced by a drug that
Progestins: The general term for the natural and
occurs in addition to the principal therapeutic
synthetic female hormones such as progesterone.
response.
Prostaglandin: A member of the family of 20-
Spinal nerve block: Administration of local anesthe-
carbon fatty acid compounds (eicosanoids) formed
sia into the spinal canal between the arachnoid mem-
from arachidonic acid by the cyclooxygenase enzyme.
brane and the pia mater (i.e., the subarachnoid
Prostaglandins help regulate normal cell activity, and
space).
may help mediate certain pathologic responses,
including pain, inflammation, fever, and abnormal Status epilepticus: An emergency characterized by
blood coagulation. a rapid series of epileptic seizures that occur without
any appreciable recovery between seizures.
Psychosis: A relatively severe form of mental illness
characterized by marked thought disturbances and an Steroid: The general term used to describe a group
impaired perception of reality. of hormones and their analogs that have a common
40Ciccone(p)-Glossary 1/30/07 2:57 PM Page 631
Glossary 631
chemical configuration but are divided into several Thyrotoxicosis: Abnormally high production of thy-
categories depending on their primary physiologic roid hormones resulting in symptoms such as nerv-
effects. Common types of steroids include the gluco- ousness, weight loss, and tachycardia (SYN:
corticoids (cortisone, prednisone, many others), min- hyperthyroidism).
eralocorticoids (aldosterone), androgens/anabolic
Tolerance: The acquired phenomenon associated
steroids (testosterone), and steroids related to female
with some drugs, in which larger dosages of the drug
physiologic function (estrogen, progesterone).
are needed to achieve a given effect when the drug is
Supersensitivity: An increased response to drugs and used for prolonged periods.
endogenous compounds caused by an increase in the
number and/or sensitivity of receptors for that drug. Toxicology: The study of the harmful effects of
drugs and other chemicals.
Sympatholytics: Drugs that inhibit or antagonize
function within the sympathetic nervous system. Trade name: The name given to a drug by the phar-
maceutical company; it is protected by a trademark
Sympathomimetics: Drugs that facilitate or increase and used by the company for marketing the drug
activity within the sympathetic nervous system. (SYN: proprietary name).
Tardive dyskinesia: A movement disorder character- Vaccine: A substance typically consisting of a modi-
ized by involuntary, fragmented movements of the fied infectious microorganism that is administered to
mouth, face, and jaw (i.e., chewing, sucking, tongue help prevent disease by stimulating the endogenous
protrusion, and the like). This disorder may occur immune defense mechanisms against infection.
during the prolonged administration of antipsychotic
drugs. Viscosupplementation: Injection of a polysaccha-
ride (hyaluronin) into osteoarthritic joints to help
Therapeutic index (ABBR: TI): A ratio used to restore the viscosity of synovial fluid.
represent the relative safety of a particular drug; the
larger the therapeutic index, the safer the drug. It is Volume of distribution (ABBR: Vd): A ratio used
calculated as the median toxic dose divided by the to estimate the distribution of a drug within the
median effective dose. (In animal trials, the median body relative to the total amount of fluid in the
lethal dose is often substituted for the median toxic body. It is calculated as the amount of drug admin-
dose.) istered divided by the plasma concentration of
the drug.
Therapeutic window: The range of drug concentra-
tions in the body that will promote optimal beneficial Withdrawal syndrome: The clinical syndrome of
effects. Drug concentrations less than the lower end somatic and psychologic manifestations that occur
of this range will be ineffective, and concentrations when a drug is removed from a patient who has
greater than the upper end of this range will create become physically dependent on a drug (SYN:
excessive side effects. abstinence syndrome).
40Ciccone(p)-Glossary 1/30/07 2:57 PM Page 632
Index
NOTE: An “f” following a page number indicates a figure; a “t” following a page number indicates a table.
A Actonel, 468t Adrucil, 572t
Abacavir, 531, 537 Actos, 488 Adsorbocarpine, 265t
Abarelix, 440, 577t Acutrim, 279 Advil, 208t
Abbokinase, 350t Acyclovir, 526t, 527 Aerius, 372t
Abciximab, 350t, 353 Adalat, 311t, 312 AeroBid, 379t, 422t
Abelcet, 547–548 Adalimumab, 224t, 227, 598t, 599 Aerolate, 377t
Abilify, 96t Addiction, opioid, 192, 193–195 Affective disorders. See Bipolar syndrome;
Abitrate, 359, 359t Adenohypophysis, 404t, 405 Depression
Abortion, drug-induced, 449–450 Adenosine, 377 Affinity, 44
Abreva, 526t, 528 Adenosine diphosphate (ADP) receptor, Afrin, 275, 371t
Abscess, 516t 354 Aftate, 547t, 551
Acarbose, 487t, 488 Adenylate cyclase-cyclic adenosine Age, effects on drug response, 36
Access port, 240, 240f monophosphate (cAMP) system, 43, Agenerase, 530, 537
Accolate, 380 43f, 479–480 Aggrastat, 350t, 353
Accupril, 335t Adhesion molecules, 420 Agonists, 46–48, 47f. See also Beta-adrener-
Acebutolol, 282–283, 282t, 310t, 335t Adipose tissue gic agonists
ACE inhibitors. See Angiotensin-converting drug storage in, 22 adrenergic, 274–278
enzyme (ACE) inhibitors effects of insulin, 479 alpha, 275–276, 278–279, 370, 371t
Acetaminophen ADP receptor inhibitors, 350t mineralocorticoid, 428
liver damage, 23 Adrenal gland, 404t, 406–407 mixed alpha and beta, 278–279
osteoarthritis, 230 Adrenalin, 278–279 opioid, 185–186
pain and inflammation, 210–211, 211f Adrenal medulla, 255–256 AIDS, 524t, 536–540
rheumatoid arthritis, 220 Adrenergic drugs, 273–285 Akathisia, antipsychotics and, 100
Acetohexamide, 487t agonists, 274–279 Akineton, 127t
Acetylcholine, 58, 58t antagonists (See Beta blockers) Albendazole, 557, 558t
autonomic pharmacology, 257 Adrenergic receptors, 257, 257f Albenza, 557
chemical structure, 268f classification and types, 258f, 259–261 Albuterol, 375t
classifications, 258f locations and responses, 259t Alclometasone, 422t
postganglionic neurons, 257f specificity, 274t Alcohol, sedative effects of, 68–69
Parkinson disease and, 120, 120f subclassifications, 273–273 Aldactone, 428
receptors for, 41, 41f, 258–259, 258f, Adrenocortical suppression, 423 Aldara, 529
263, 264f Adrenocorticosteroids, 415–430, 576t Aldesleukin, 578t
Acetylsalicylic acid. See Aspirin adrenocortical hormone biosynthesis Aldomet, 276
Acid-fast bacilli, 501t inhibitors, 426 Aldose reductase inhibitors (ARIs), 489
Acinar cells, 477 case study, 430 Aldosterone, 406
AcipHex, 391–392, 392t drug inhibitors, 426 ACE inhibitors and, 340
Aclovate, 422t glucocorticoids, 415–426 (See also Gluco- biosynthesis and structure, 416f
ACTH (adrenocorticotropic hormone), corticoids) effects of, 426–428, 427f
409, 417, 417f mineralocorticoids, 415, 426–428 release, 426
Actifed, 372t rehabilitation patients, 429 Alemtuzumab, 578t
Actinomycetes, 501t steroid synthesis, 415–417, 416f Alendronate, 468t, 469
Action potential, cardiac, 321–322, 321f Adrenocorticotropic hormone (ACTH), Aleve, 209t
Activase, 350t 409, 417, 417f Alfentanil, 239t
Active transport, 19f, 20–21 Adriamycin RDF, 574t Alimta, 572t
633
41Ciccone(p1) Index 2/6/07 4:26 PM Page 634
634 Index
Alinia, 556 Analgesics. See Anesthetic drugs; Nons- Angiogenesis inhibitors, 579
Alkaloids, 284, 569, 573, 575–576t teroidal anti-inflammatory drugs Angiotensin-converting enzyme (ACE)
Alkeran, 571t (NSAIDs); Opioid analgesic drugs; inhibitors, 298, 335t, 339–340
Alkylating agents, 568–569, 568f, 570–571t Patient-controlled analgesia (PCA) Angiotensin II
Allegra, 371, 372t Anaprox, 207t, 209t aldosterone release, 426
Allergy treatment, 369–373 Anastrozole, 576t, 577 receptor blockers
Allosteric modulator, 44 Anavar, 441t antihypertensives, 291t, 296t, 297–299,
Alpha agonists, 275–276, 278–279, 370, Ancobon, 548 297f
371t Androderm, 439t congestive heart failure, 335t, 339–340
Alpha-1 and -2 receptors, 259t, 260 Androgen-binding protein (ABP), 436, 436f Animal bite, 516t
Alpha antagonists. See under Antagonists Androgen receptor blockers, 573 Animal studies, 6, 6t
Alphagan, 276 Androgens Anisindione, 350t
Alpha-glucosidase inhibitors, 487t abuse, 440–443, 441t Anisotropine, 269t
Alpha-tocopherol, 612t adverse effects, 439–440 Anisoylated plasminogen-streptokinase acti-
Alprazolam, 71t antineoplastics, 576t vator complex (APSAC), 356
Altace, 335t clinical use, 437–438, 439t Anistreplase, 350t, 356
Alteplase, 350t physiologic effects, 437 Annexins, 221, 420
Alternative medicine. See Complementary source and regulation, 435–437 Ansaid, 207t, 208t
and alternative medications (CAMs) specific drugs, 438, 439t Antacids, 141, 143t, 389–390, 390f
Altretamine, 570t Android, 439t Antagonists, 46–48, 47f. See also Beta block-
Alurate, 66t Andronate, 439t ers
Alzapam, 108t Anectine, 143t alpha, 279–281
Alzheimer disease Anemia, 438 antihypertensives, 293–294, 293t
adrenergic antagonists, 281 Anesthetic drugs interleukin-1 receptor, 598t
antipsychotics, 98 general opioid, 187
cholinergic stimulants, 266 adjuvants, 141–144, 142–143t Anterior pituitary, 404t, 405
estrogen replacement, 446 case study, 145 Anthelmintic drugs, 557–560
Amantadine, 100, 122t, 128, 526t, 527–528 epilepsy, 114 Anthrax, 515t
Amaryl, 487t inhalation anesthetics, 136, 137f, 137t Antiandrogens, 440, 576t
Ambenonium, 265t intravenous anesthetics, 136, 137–138t, Antianginal drugs, 308–315. See also Angina
Ambien, 66t, 68 139 pectoris
AmBisome, 547–548 mechanisms, 139–140, 140f Antianxiety drugs
Amcinonide, 422t pharmacokinetics, 139 antidepressants, 72
Americaine, 151t rehabilitation patient, 145 benzodiazepines, 70–71, 71t, 72
Amicar, 357 requirements, 135 buspirone, 71–72, 72–73
Amidate, 138t, 139 route of administration, 136 problems and side effects, 72–73
Amino acids, 59 specific agents, 136–139, 137–138t rehabilitation patients, 73
Aminocaproic acid, 357 stages of anesthesia, 135–136 Antiarrhythmic drugs, 324–327
Aminoglutethimide, 426 local, 149–158 case study, 328
Aminoglycosides, 502, 507–508, 507t, 508 case study, 157 classification, 324, 325t
Aminopenicillins, 504t clinical use, 150, 152–154 rehabilitation patients, 328
Aminophylline, 377t common, 151–152t Antibacterial drugs, 499–519
Aminosalicylic acid, 510 differential nerve block, 155–156, 156t case study, 519
Amiodarone, 326 mechanism of action, 154–155, 155f common infections and agents, 515–517t
Amitriptyline, 80t, 85t patient-controlled analgesia (PCA), inhibitors
Amlodipine, 311t 240, 242 cell wall synthesis and function,
Amobarbital, 66t, 108t, 142t pharmacokinetics, 150 501–502, 502f, 503–507, 504t
Amoxapine, 80t, 85t rehabilitation patients, 157 DNA/RNA synthesis and function,
Amoxicillin, 504 systemic effects, 156–157 502–503, 502f, 503f, 510–513,
Amphetamines, 278 types, 149–150 510t
Amphocin, 546–548 Angina pectoris, 307–317 protein synthesis, 502, 502f, 507–510,
Amphotec, 547–548 anticoagulants, 312–313 507t
Amphotericin B, 546–548, 546t, 552t beta-adrenergic blockers, 310–311, 310t mechanisms, 501–503
Ampicillin, 504 calcium channel blockers, 311–312, 311t, other antibacterials, 513–514
Amprenavir, 530, 537 314, 315 rehabilitation patients, 518
Amrinone, 338 case study, 316–317 resistance to, 514, 517–518
Amyl nitrite, 308t, 310 myocardial ischemia equation, 307f treatment principles, 500–501
Amytal, 66t, 108t nonpharmacologic management, 315 Antibiotics, 499, 569, 574t
Anabolic steroids, 440–443, 441f organic nitrates, 308–310, 308t Antibodies, 578t, 594t, 598–599
Anadrol, 439t, 441t rehabilitation patients, 316 Anticholinergic drugs
Anafranil, 80t types and treatments, 313– 315, 313t clinical applications, 268–271
Anakinra, 223t, 228 Angioedema, hereditary, 438 common drugs, 269t
41Ciccone(p1) Index 2/6/07 4:26 PM Page 635
Index 635
636 Index
Index 637
Bronchodilators, 277, 378, 382 antibiotics, 569, 574t estrogen and progesterone therapy,
Bronkaid Mist, 278–279 antimetabolites, 569, 571–572t, 573f 447–448
B-type natriuretic peptide (BNP), 342 aspirin and other NSAIDs, 204, 580 levodopa, 124
Buccal administration, 14–15, 14t biologic response modifiers, 577, 578t, thyroid hormones, 461
Budesonide, 378, 379t, 422t 579 Cardizem, 311t, 312
Bundle of His, 323, 323f classification according to cell cycle Cardura, 280
Bupivacaine, 151t specificity, 566, 567f Carisoprodol, 165t, 168t
Buprenex, 187 heavy metal compounds, 578–579t, Carmustine, 570t
Buprenorphine, 187, 194, 239t 579–580 Carrier-mediated transport, 19f, 20–21
Bupropion, 80t, 83t, 85t hormones, 576–577t Carteolol (Cartrol), 282t, 283, 310t, 335t
Buserlin, 440 androgens, 438 Carvedilol, 310, 335t, 341
Busodium, 66t estrogen, 446 Casodex, 440
Buspirone (BuSpar), 71–72, 72–73 estrogen receptor blockers, 573, Caspofungin, 549
Busulfan, 570t 577 Catapres, 276
Butabarbital, 66t, 142t selective estrogen receptor modula- Catecholamines, 59
Butamben, 151t tors (SERMs), 448–449 Catechol-O-methyltransferase inhibitors,
Butazolidin, 209t other categories, 578–579t 128–129
Butenafine, 547t, 551 plant alkaloids, 569, 573, 575–576t Cathartics, 395
Butesin, 151t tyrosine kinase inhibitors, 579t, 580 Caudal block, 153f
Butisol, 66t Candida, 549 Causalgia, 154
Butoconazole, 547t, 550 Candesartan, 340 C cells, 466
Butorphanol, 138t, 142t, 185, 187, 187t Cannabinoids, 397 CeeNU, 570t
Cantil, 269t Ceiling effect, 9, 9f
C Capastat, 513 Celebrex, 210
Cabergoline, 122t, 126–127 Capecitabine, 571t Celecoxib, 210
Caffeine, 376, 376f Capoten, 335t, 339 Celestone, 379t, 422t, 596
Calan, 311t, 312 Capreomycin, 513 Celexa, 80t, 83t
Calcifediol, 468t Capsid, 523, 525f CellCept, 594t, 597
Calciferol, 468t, 612t Captopril, 335t, 339 Cell junction, 20
Calcimar, 468t, 470 Carafate, 393 Cellular drug delivery, 24
Calcimimetics, 469 Carbachol, 265t Cellulitis, 516t
Calcineurin inhibitors, 595, 599 Carbacot, 165t Celontin, 108t, 109
Calcionate, 468t Carbamazepine, 87, 108t, 109, 112t Central nervous system (CNS)
Calciparin, 350t Carbastat, 265t blood-brain barrier, 57
Calcitonin, 466, 468t, 469–470 Carbidopa, 123, 124f effects of drugs, 60–62
Calcitriol, 468t Carbinoxamine, 372t effects of opioids, 188–189, 189f
Calcium, 465 Carbocaine, 151t neurotransmitters, 57–60, 58t, 59
Calcium channel blockers Carbohydrate metabolism, 479 organization, 55–57
antianginals, 311–312, 311t, 314, 315 Carboplatin, 578t, 579 receptors, 140–139
antiarrhythmics, 325t, 327 Carboxylic acids, 108t Cephalosporins, 504t, 505
antihypertensives, 291t, 296t, 299–300 Carcinogens, 565. See also Cancer Cerebellum, 56, 56f
tardive dyskinesia, 99 chemotherapy Cerebrum, 55, 56f
Calcium supplements, 467–469, 468t, 613t Carcinomas, 565. See also Cancer Cerebyx, 108, 108t
Calderol, 468t chemotherapy Cerubidine, 574t
Campath, 578t Cardene, 311t Cetirizine, 371, 372t
Camptosar, 575t Cardiac arrhythmias, 321–329 Cetuximab, 578t
Cancer chemotherapy, 565–587 antiarrhythmics, 324–327, 325t Channel blockers, sodium, 324–326, 325t.
case study, 586–587 cardiac action potential, 321–322, 321f See also Calcium channel blockers
combination drugs, 582, 583t cardiac electrophysiology, 321–323 Chemical names, 4
general principles, 565–568 conduction system, 322–323, 323f Chemical synapse, 58
miscellaneous drugs, 580–582, 581t mechanisms, 323 Chemotherapy, cancer. See Cancer
mortality rates, 584t nonpharmacological treatment, 327 chemotherapy
new strategies, 585 normal rhythm, 322 Chenodeoxycholic acid (chenodiol), 397
other treatments, 582–583 types, 324, 324t Chickenpox, 524t
rehabilitation patients, 586 Cardiac preload and afterload, 308 Child birth, hormones in, 445
resistance to drugs, 584–584 Cardiovascular system. See also Angina Pec- Children, drug metabolism and, 36
specific drugs, 568–582 toris; Cardiac arrhythmias; Congestive Chirocaine, 151t
success of drugs, 583–584 heart failure Chloral hydrate, 66t
types of drugs aldosterone, 427–428 Chlorambucil, 570t, 599
alkylating agents, 568–569, 568f, antimuscarinic drugs, 270 Chloramphenicol, 509
570–571t aspirin, 204 Chlordiazepoxide, 71t, 142t
41Ciccone(p1) Index 2/6/07 4:26 PM Page 638
638 Index
Index 639
640 Index
Index 641
642 Index
General anesthetics. See under Anesthetic Gold compounds, 223–224t, 225, 225f heparin-induced thrombocytopenia
drugs Gold sodium thiomalate, 225, 225f (HIT), 352
Generic drugs, substitution of, 5 Gonadotropin-releasing hormone low molecular weight heparins
Generic name, 4–5 (GnRH) (LMWH), 313, 350–351
Genetics and effects on drug response, androgen synthesis, 436–437 Heparin lock, 350
34–35 anti-cancer drugs, 577t Hepatitis, 524t
Genital infection, 517t Gonadotropins, 435–437, 436f, 444f Herpes zoster, 524t
Gentamicin, 502, 507 Gonads, 404t, 407 HERS (Heart and Estrogen/Progesterone
Geodon, 96t Goserelin, 440, 577t Replacement Study), 446
Gesterol, 447t G proteins, 43–44, 43f, 189 Hetrazan, 558
Ginger, 608t, 609 Gram-negative and -positive bacilli, 501t, Hexalen, 570t
Ginkgo, 608t, 609 515–516t High-density lipoproteins (HDLs), 358,
Ginseng, 608t, 609 Gram-positive cocci, 500, 501t, 359–360
Glargine, 484, 484t 516–517t Highly active antiretroviral therapy
Glaucoma, 264, 266–267 Grand mal seizures, 106t (HAART), 537–538
Glimepiride, 487t Graves disease, 462–463 Hiprex, 513
Glipizide, 487t Gray matter, 57 Histamine, 370–371, 390
Glivec, 580 Grisactin, 548–549 HIV. See Human immunodeficiency virus
Glucagon, 479–480, 488 Griseofulvin, 546t, 548–549 (HIV)
Glucagon-like Peptide 1, 488 Growth fraction, 566 HIV entry inhibitors, 531t, 537
Glucocorticoids (corticosteroids), 406, 415. Growth hormone, 461 HIVID, 531, 537
See also Adrenocorticosteroids Guanabenz, 276, 295 HMG-CoA reductase inhibitors (dp
adverse effects, 221–222, 423, 425–426 Guanadrel, 284, 295 w/statins)
asthma, 381 Guanethidine, 284, 295 hyperlipidemia, 358–359, 359t
clinical uses, 421, 423 Guanfacine, 276, 295 HMS liquifilm, 422t
COPD-related respiratory problems, Guanine, 568f, 569 Homapin, 269t
378–379, 379t, 382 Gyne-lotrimin, 547t Homatropine, 269t
cystic fibrosis-related respiratory prob- Hormone-receptor complex, 44, 417–418
lems, 382 H Hormone(s). See also Endocrine system;
immunosuppressants, 594t, 596 HAART (highly active antiretroviral thera- Steroids
mechanism of action, 417–418 py), 537–538 androgens, 435–443
nonendocrine disorders, 421, 423, Halazepam, 71t abuse, 440–443
424t Halcinonide, 422t clinical use, 437–440, 439t
physiologic effects, 418–421 Halcion, 66t, 70t biosynthesis and structure, 416f
rheumatoid arthritis, 219t, 411 Haldol, 95, 96t cancer treatment and (See under Cancer
route of administration, 421 Half-life, 33–34, 33f chemotherapy)
specific drugs, 421, 422–423t Halobetasol, 422t chemistry of, 407
synthesis, 415–417, 416f Halog, 422t definition, 403
Gluconeogenesis, 419, 419f, 479 Haloperidol, 95, 96t, 97t as drug therapy, 411
Glucophage, 487t, 488 Halotestin, 439t effects on target cell, 409–410, 410f
Glucosamine, 230–231, 608t, 609 Halothane, 137t estrogen and progesterone, 443–450
Glucose Hashimoto disease, 463 clinical use, 445–448, 447t
effects of insulin, 479 H2 blockers, 390–89, 391t hypothalamus, 403, 404t
metabolism, 418–419, 419f, 479f Headache, 280 male and female, 435–454
transporters, 479 Heart and Estrogen/Progesterone Replace- case study, 453–454
Glucotrol, 487t ment Study (HERS), 446 contraceptives 450–453, 451t
Glulisine, 483, 484t, 485 Heart attack, 354–355 rehabilitation patients, 453
Glutamate, 58t, 59 Heartburn, 389, 390 other endocrine glands, 404t, 405–407
Glutathione (GHS), 211, 211f Heart disease, 357–358. See also Angina pancreatic, 477–580
Glutethimide, 66t Pectoris; Congestive heart failure parathyroid, 465
GLUT protein, 479 Heavy metal compounds, 578–579t, peptide, hormone(s)
Glyburide, 487t 579–580 pituitary gland, 403, 404t, 405
Glycine, 58t, 59 Helicobacter pylori, 392–393 receptors, 409–410, 409f, 410f
Glycogenolysis, 479 Helminths, infections of, 557, 558t synthesis and release, 407–408
Glycoprotein (GP) IIb-IIIa inhibitors, 350t, Hemophilia, 356–357 thyroid, 404t, 406–406, 459–461,
353–354 Hemostasis, 347. See also Coagulation dis- 460f
Glycopyrrolate, 142t, 269t orders transport, 408–409
Glycosuria, 482 Heparin Hospital-acquired infections, 515t, 516t
Glyset, 487t, 488 angina pectoris, 313 H. pylori infection, 392–393
Goiter. See Thyroid coagulation disorders, 349–351, 350t, 352 H receptors, 371, 390
41Ciccone(p1) Index 2/6/07 4:26 PM Page 643
Index 643
H2 receptor blockers, 141, 143t, 389–390, Hypotension, 292 Injection of drugs, 14t, 15–16
390f Hypothalamus, 56, 403, 404t, 405 vs. patient-controlled analgesia (PCA),
Humalog, 483, 484t Hypothyroidism, 462t, 463–464 243–245
Human chorionic gonadotropin (HCG), Hytakerol, 468t Innohep, 350t
445 Hytrin, 281 Inorganic sulfate, 613t
Human immunodeficiency virus (HIV) Inotropes, 335t
clotting factor and, 357 I Inspra, 428
inhibitors, 531–532, 531t Ibandronate, 468t Insulin, 477–479, 479f
opportunistic infections, 539–540, Ibuprofen, 207t, 208t Insulin-dependent diabetes mellitus
539–540t Ibutilide, 326 (IDDM), 481
replication, 532f Idamycin, 574t Insulin receptor substrates (IRSs), 479
treatment for muscle wasting, 438 Idarubicin, 574t Insulin resistance, 481–482
treatment of AIDS, 536–540 IFEX, 570t Insulin zinc, 484t
Human studies, 6–7, 6t Ifosfamide, 570t Integrilin, 350t, 353
Humatin, 556 Imatinib, 579t, 580 Interactions
Humira, 224t, 227, 598t, 599 Iminostilbenes, 108t, 109 drug-drug, 35–36
Humorsol, 265t Imipenem, 506 drug-receptor, 44–48
Humulin, 484t Imipramine, 80t, 85t food-drug, 36–37
Hyaluronan, 230 Imiquimod, 526t, 529 Interferons
Hycamtin, 575t Immune globulin, 600 adverse effects, 535
Hycodan, 186t Immune system, 591–593, 592f. See also antiviral effects, 533–535, 534f
Hydantoins, 108–109, 108t Immunomodulating drugs cancer treatment, 577, 578t
Hydralazine, 296, 336t, 342 Immunoglobulins, 593 pharmacologic applications, 535
Hydrea, 581t, 582 Immunomodulating drugs, 591–602 types, 533, 534t
Hydrocodone, 186t, 370t case study, 601–602 Interleukins
Hydrocortisone, 379t, 422t, 596 immune response, 591–593 antagonists of, 598t, 599
Hydrocortone, 422t immunostimulants, 591, 599–600 glucocorticoid inhibition of, 420
Hydrolysis, 30–31, 30t immunosuppressants, 591, 593–599 interleukin-2, 577–579, 578t
Hydromorphone, 138t, 186t, 239t, 370t diabetes mellitus, 489 rheumatoid arthritis, 228
Hydropane, 370t glucocorticoids, 420 Intermediate-density lipoproteins (IDLs),
Hydrostat, 138t, 186t rehabilitation patients, 601 358
Hydroxychloroquine, 222, 223t, 553 Imodium, 394t Intermediate pituitary, 405
Hydroxyprogesterone, 447t, 577t Implantable drug delivery system, 23–24 Intra-arterial injection, 15–16
Hydroxyurea, 581t, 582 Imuran, 223t, 224–225, 593–595, 594t Intracellular receptor, 44
Hydroxyzine, 141, 142t, 372t Inactive drug. See Biotransformation Intramuscular (IM) injection, 16
Hylorel, 284 Inamrinone, 335t, 338 vs. patient-controlled analgesia (PCA),
Hylutin, 447t Inderal, 282t, 283, 310t 243–245
Hyoscyamine, 269t Indigestion, 389, 390 Intrathecal injection, 16
Hyperaldosteronism, 428 Indinavir, 530, 537 Intravenous injection, 15
Hypercalcemia, 466, 467t, 469 Indocin, 207t, 208t Intron-A, 578t
Hyperfibrinolysis, 357 Indomethacin, 207t, 208t Intropin, 277, 335t
Hyperglycemia, 482 Induction, enzyme, 31 Invanz, 506
Hyperlipidemia, 347, 357–360, 359t Infections and treatments Inverse agonist, 48
Hyperparathyroidism, 467t anthelmintics, 557–560 Investigational new drug (IND), 6
Hyperstat, 296 antibacterials, 499–519 (See also Antibac- Invirase, 530, 537
Hypertension, 287–289. See also Antihyper- terial drugs) Iodide, 463
tensive drugs antifungals, 545–551 Iodine, 463, 613t
blood pressure classification, 287, 287t antiprotozoals, 551–557 Iodoquinol, 552t, 555–556
case study, 301–302 antivirals, 523–541 (See also Antiviral Ionization, 19, 20f
drug therapy, 289–300 drugs) Iontophoresis, 17, 188
nonpharmacologic treatment, 300 Inflammation. See Glucocorticoids; Non- Ipratropium, 269t, 271, 378, 382
pathogenesis, 288–289 steroidal anti-inflammatory drugs Iressa, 580
possible mechanisms, 288–289, 290f Infliximab, 224t, 227, 598t, 599 Irinotecan, 573, 575t
rehabilitation patients, 301 Influenza, 524t Iron, 613t
Hyperthyroidism, 462–463, 462t Infundibulum, 403 Irritable bowel syndrome, 269t, 270
Hypoglycemia, 486 Infusion, drug. See Patient-controlled anal- Ischemic stroke, 355
Hypogonadism, 446 gesia (PCA) Islets of Langerhans, 406, 477
Hypokalemia, 292 Infusion pumps, 242–243, 243t, 244f Ismelin, 284
Hyponatremia, 292 INH, 513 Isocarboxazid, 80t
Hypoparathyroidism, 467, 467t Inhalation of drugs, 14t, 15 Isoetharine, 375t
41Ciccone(p1) Index 2/6/07 4:26 PM Page 644
644 Index
Index 645
646 Index
Index 647
648 Index
Petit mal seizures, 106t Plicamycin, 574t Proarrythmic effect, 325, 326
pH, 20f Pneumonia, 515t, 516t, 517t Pro-Banthine, 269t
Pharmacodynamics, 3–4, 4f Poisoning, cholinergic, 271 Procainamide, 325
Pharmacogenetics, 35 Polaramine, 372t Procaine, 152t
Pharmacokinetics, 3, 4f Poliomyelitis, 524t Procarbazine, 571t
drug absorption and distribution, 17–21 Polocaine, 151t Procardia, 311t, 312
drug administration, 13–17, 14t Polymyxin B, 506 Prochlorperazine, 96t, 97t
drug distribution within body, 21–22, 22t Polymyxin E, 505–506 Procyclidine, 127t
drug elimination, 29–37 Polysynaptic inhibitors, 165–168, 165t, Prodrox, 447t
drug storage, 22–23 168t Progesterone, 447t
newer drug delivery techniques, 23–24 Ponstel, 207t, 208t Progestins, 577t
Pharmacologic dose, 415 Pontocaine, 152t Prograf, 594t, 598
Pharmacology, basic principles of, 3–11, 4f Positive inotropic agents, 334, 335t, Proleukin, 578t
Pharmacotherapeutics, 3, 4f 336–339 Proliferative phase, 443–444
Pharmacy, 4 Posterior pituitary, 404t, 405 Prolixin, 95, 96t
Phenelzine, 80t, 85t Postganglionic neuron, 253–254, 257f Prolonged-action preparation, 23
Phenergan, 66t Postmarketing surveillance, 6–7, 6t Proloprim, 513
Phenindamine, 372t Postsynaptic receptor, 60f, 61 Promethazine, 66t, 141
Phenobarbital, 142t Postural hypotension, 124–125 Prometrium, 447t
antiepileptic, 107, 108t, 112t, 114 Posture (calcium supplement), 468t Propafenone, 325
sedative-hypnotic, 66t Potassium, 613t Propagest, 279
Phenoxybenzamine, 281 Potassium-sparing diuretics, 291t, 292 Propantheline, 269t
Phensuximide, 109 Potency, 9–10, 9f Propofol, 138t, 139
Phentolamine, 281 PPIs (proton pump inhibitors), 220, Propoxyphene, 186t
Phenylbutazone, 207t, 209t 391–392, 392–393, 392t Propranolol, 100, 282t, 283, 310t
Phenylephrine, 371t Pramipexole, 122t, 126–127 Propylthiouracil (Propyl-Thyracil), 463
Phenylephrine, 275 Pramoxine, 151t Proscar, 440
Phenylpropanolamine, 279 Prandin, 487t, 488 ProSom, 66t, 70t
Phenytoin, 108–109, 108t, 112t, 114 Pravachol, 358, 359t Prostaglandins
Phonophoresis, 17 Pravastatin, 358, 359t gastric ulcers, 393
Phosphate, 613t Prax, 151t inhibition of, 202–203, 420
Phosphodiesterase (PDE) inhibitors, Praziquantel, 558t, 559 physiological effects, 201–202, 202t
338–339, 376 Prazosin, 281, 294, 336t, 342 rheumatoid arthritis and, 220
Phospholine Iodide, 265t Preclinical studies, 6, 6t synthesis, 200–201, 200f
Phospholipids, 18, 18f Precose, 487t, 488 Prostigmin, 265t
Phyllocontin, 377t Prednicarbate, 423t Protease inhibitors, 530, 531t, 537
Physical dependence. See Dependence Prednisolone, 379t, 423t, 576t, 596 Protein metabolism, 479
Physiologic dose, 415 Prednisone, 379t, 382, 423t, 576t, 596 Protein tyrosine kinases, 42
Physostigmine, 265t Preganglionic neuron, 253–254, 257f Protonix, 391–392, 392t
Picrate, 151t Pregnancy, hormones in, 445 Proton pump inhibitors (PPIs), 220,
Pilocar, 265t Prelone, 379t, 423t, 596 391–392, 392–393, 392t
Pilocarpine, 265t Premarin, 447t, 468t Protostat, 511–512, 556
Pimecrolimus, 598 Preoperative medication, 141, 142–143t, Protozoa, 551–557, 552t
Pindolol, 282t, 283, 310t 270 Protriptyline, 80t, 85t
Pioglitazone, 488 Presynaptic action potential, 60, 60f Provera, 447t
Pipecuronium, 143t Presynaptic adrenergic inhibitors Prozac, 80t, 82, 83t
Piperazine citrate, 559 antihypertensives, 293t, 294–295 Pseudoephedrine, 275, 371t
Pirbuterol, 375t Presynaptic autoreceptor, 60f, 61 Pseudoparkinsonism, 100
Pirenzepine, 393 Presynaptic inhibition, 60 Psychosis, 93
Piroxicam, 207t, 209t Prevacid, 205, 391–392, 392t Puberty, delayed, 438
Pituitary gland, 403, 404t, 405 Priftin, 512 Pulmicort, 379t
Placidyl, 66t Prilocaine, 151t Pulmicort Turbohaler, 422t
Plant alkaloids, 569, 573, 575–576t Prilosec, 205, 220, 391–392, 392t Pulmonary administration, 14t, 15
Plaquenil, 222, 223t, 553 Primacor, 335t Pulmozyme, 383
Plasma concentration, 34, 34f Primaquine, 553 Pumps, infusion, 242–243, 243t, 244f
Plasmin, 348f, 349 Primatene Mist, 278–279 Purine nucleotides, 569, 573f
Platinol, 578t Primidone, 107, 108t, 112t Purinergic substances, 257
Plavix, 350t, 354 Prinivil, 335t Puri-nethol, 572t, 599
Plenaxis, 440 Prinzmetal ischemia, 314–315 Purkinje fibers, 321f, 323, 323f
Plendil, 311t ProAmatine, 275 Pyrantel pamoate, 558t, 559
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Index 649
650 Index
S Sex (gender), effects on drug response, 37 Steroids, 407, 409–410, 409f, 410f. See also
Salmeterol, 374, 375t, 381 Sex hormones. See Hormones, male and Adrenocorticosteroids; Glucocorti-
Sandimmune, 223t, 228, 594t, 595–596 female coids, Mineralocorticoids
Sandostatin, 395 Shingles, 524t male and female hormones, 435–454
Saquinavir, 530, 537 Simulect, 598t, 599 synthesis, 415–417, 416f
Sarcomas, 565. See also Cancer Simvastatin, 358, 359t Stimulants, cholinergic, 264–267, 264f,
chemotherapy Sinemet, 124 265t
Saw palmetto, 608t, 610 Sinequan, 80t St. John’s wort, 608t, 610
Schedules, drug, 8 Singulair, 380 Stool softeners, 396–397, 396t
Schizophrenia, 93–94 Sinus arrhythmias, 324t Streptase, 350t
Scopolamine, 141, 142t, 269t, 270, 397 Sinusitis, 515t, 516t, 517t Streptokinase, 350t, 355
Seasonal allergies, 369–373 Sirolimus, 594t, 597–598 Streptomycin, 502, 507
Secobarbital, 66t, 108t, 142t Skelaxin, 165t Streptozocin, 571t
Seconal, 66t, 108t Skeletal muscle relaxant drugs, 163–176 Stroke, 355
Second-generation agents agents for spasticity, 168–171, 169t Stromectol, 558–559
antidepressants, 80t, 82, 83–84t, 84, 85t botulinum toxin, 171–174, 172f Subcutaneous injection, 16
antiepileptics, 110–111, 110t case study, 175–176 Sublimaze, 138t, 186t
antihistamines, 371 pharmacokinetics, 174 Sublingual administration, 14–15, 14t
cephalosporins, 504t rehabilitation patients, 174–175 Substance P, 58t, 59
Second messenger, 43 spasms, 164–168, 165t Succinimides, 108t, 109
Secretory phase, 444 spasticity vs. spasms, 163–164 Succinylcholine, 143t
Sectral, 282–283, 282t, 310t, 335t Skelex, 165t Sucralfate, 393
Sedative-hypnotic agents, 65–70, 66t, 73 Smallpox, 524t Sudafed, 275, 371t
antipsychotics, 100 Sodium, 613t Sufentanil, 239t
barbiturates, 66t, 68 anesthetics and, 140, 140f, 154–155, Sulbactam, 507
benzodiazepines, 65–68, 66t, 67f, 70t 155f Sulconazole, 547t, 550
case study, 74 digitalis and, 336, 337f Sulcrate, 393
common drugs, 66t mineralocorticoids and, 427, 427f Sulfadiazine, 512
nonbenzodiazepines, 66t, 68–69 Sodium channel blockers, 324–326, Sulfamethizole, 512
pharmacokinetics, 69, 70t 325t Sulfasalazine, 224t, 228, 594t, 597
problems and side effects, 69–70 Sodium nitroprusside, 342 Sulfate, inorganic, 613t
rehabilitation patients, 73 Solfoton, 66t, 108t Sulfinpyrazone, 350t, 354
Seizures, epileptic, 105 Solganal, 223t, 225, 225f Sulfonamides, 503, 512
Selective estrogen receptor modulators Soma, 165t Sulfonylureas, 487–488, 487t
(SERMs), 448–449, 470 Somatostatin, 477 Sulindac, 208t, 209t
Selective serotonin reuptake inhibitors Sonata, 66t, 68 Supersensitivity of receptors, 49–50,
(SSRIs), 82, 83t Sotalol, 282t, 283, 310t 49f
Selective toxicity, 499, 566 Sparfloxacin, 511 depression and, 78–79, 78f
Selectivity, drug, 45–46, 45f Spasms, 164 Suprane, 137t
Selegiline, 122t, 128 Spasticity, 163–164, 163f, 172–173 Supraventricular arrhythmias, 324t
Selenium, 613t Specific receptor theory, 140, 140f Suprazine, 96t
Seminiferous tubules, 435, 436f Spectazole, 547t Suprefact, 440
Sensipar, 469 Spermatogenesis, 435, 437 Suramin, 552t
Sensorcaine, 151t Spinal cord, 56f, 57 Surface membrane receptors, 41–44, 409,
Septocaine, 151t Spinal nerve blockade, 153, 153f 409f
Serax, 71t Spinva, 269t Surmontil, 80t
Serentil, 96t Spiriva, 378 Surveillance, postmarketing, 6–7, 6t
Serophene, 449 Spirochetes, 501t, 517t Sustained-release preparation, 23
Seroquel, 96t Spironolactone, 341, 428 Sustiva, 531, 537
Serotonin, 58t, 59 Sporanox, 549 Symadine, 526t
blockers, 397 Stable angina, 313t, 314 Symmetrel, 128, 526t, 527–528
reuptake inhibitors, 82, 83t Stadol, 138t, 187t Sympathetic block, 154
Sertoli cells, 435–436, 436f Stanozolol, 439t Sympathetic nervous system, 253–255,
Sertraline, 80t, 82, 83t, 85t Starlix, 487t, 488 255t
Serzone, 80t, 83t Statins beta blockers, 340–341
Sevoflurane, 137t hyperlipidemia, 358–359, 359t digitalis, 337
Sevorane, 137t unstable angina, 315 hypertension, 289
Sex characteristics Status epilepticus, 113–114 Sympatholytic drugs, 291t, 292–296
female, 443 Stavudine, 531, 537 alpha blockers, 293–294, 293t
male, 437 Stelazine, 96t beta blockers, 292–293, 293t
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Index 651
centrally acting agents, 293t, 295 cypionate, 441t Timolol, 282t, 283, 310t
ganglionic blockers, 293t, 295–296 production, 435–437, 436f Tinactin, 547t, 551
presynaptic adrenergic inhibitors, 293t, Testred, 439t Tinzaparin, 350t
294–295 Tetanus, 515t Tioconazole, 547t, 550
Synalar, 422t Tetracaine, 152t Tiotropium, 269t, 271, 378, 382
Synapse, 60–61 Tetracyclines, 502, 507t, 508–509 Tirofiban, 350t, 353
Synarel, 440 Teveten, 335t Tissue factor, 348, 348f
Synercid, 509–510 Thalamus, 56, 56f Tissue plasminogen activator (t-PA), 348f,
Synovitis. See Rheumatoid arthritis Thalidomide, 581t, 582, 599 349, 356
Synthroid, 464t Thalotomy, 130 Tissue transplants
Syphilis, 517t Theobromine, 376, 376f diabetes mellitus, 490
Syringe driver pump, 242, 244f Theo-Dur, 377t Parkinson disease, 129
Systemic infections, 524t Theophylline, 376–377, 376f, 377t, 381, Tizanidine, 165t, 171, 276
Systole, 322 382 TNF-a, 227–228, 227f, 228, 598t
TheraCys, 600 TNKase, 356
T Therapeutic index, 11 Tofranil, 80t
Tacrine, 265t, 266 Thermogenesis, 256, 461 Tolazamide, 487t
Tacrolimus, 594t, 595, 598, 599 Thiabendazole, 559–560 Tolbutamide, 487t
Tagamet, 205, 391t Thiamin, 612t Tolcapone, 122t, 128–129
Talwin, 138t, 187t Thiazide diuretics, 291, 291t Tolectin, 208t, 209t
Tamiflu, 526t, 530 Thiazolidinediones, 487t, 488 Tolerance, drug (dp), 31
Tamoxifen, 448, 573, 577, 577t Thioguanine, 572t opioid analgesics, 192–193
Tapazole, 463 Thiopental, 137t sedative-hypnotics, 69–70
Tarceva, 580 Thioplex, 571t Tolinase, 487t
Tardive dyskinesia, 98–99 Thioridazine, 95, 96t, 97t Tolmetin, 208t, 209t
Targeted drug delivery, 24 Thiotepa, 571t Tolnaftate, 547t, 551
Tasmar, 128–129 Thiothixene, 96t, 97t Tolrestat, 489
Tavist, 372t Third-generation agents Tolterodine, 269t
Taxol, 575t beta blockers, 293, 341 Topamax, 110t, 111
Taxotere, 575t cephalosporins, 504t Topical administration, 14t, 16
Tazobactam, 507 Thoracolumbar nervous system. See Sym- Topicort, 422t
T cells, 592–593, 592f, 599 pathetic nervous system Topiramate, 110t, 111, 112t
Tegretol, 108t, 109 Thorazine, 95, 96t Topotecan, 573, 575t
Telachlor, 372t Thrombin, 348f, 349 Toprol-XL, 282t, 283
Telithromycin, 510 Thrombocytopenia, 352 Toradol, 204, 207t
Temazepam, 66t, 70t Thrombogenesis, 347 Total cell kill, 566
Temovate, 422t Thrombolytic drugs, 350t, 354–356, 361 Toxicity, selective, 499
Temperature, body, 256 Thromboplastin, 348, 348f Toxicology, 4
Tenecteplase, 356 Thromboxane Toxins
Tenex, 276 NSAIDs’ inhibition of, 202–203 cholinergic poisoning, 271
Teniposide, 573, 575t physiologic effects, 202, 202t Parkinson disease and, 121
Tenofovir, 531, 537 synthesis, 200–201, 200f Trachoma, 517t
Tenormin, 282t, 283, 310t, 335t Thyroglobulin (TGB), 460, 460f Tracrium, 143t
Tensilon, 265t Thyroid, 464t Trade name, 5
Tequin, 511 drugs Trandate, 282t, 283, 310t, 335t
Terazol, 547t hyperthyroidism, 462–463 Trandolapril, 335t
Terazosin, 281 hypothyroidism, 463–464, 464t Tranexamic acid, 357
Terbinafine, 550 rehabilitation patients, 469 Tranquilizers, 93
Terbutaline, 375t gland, 404t, 405–406, 473 Transdermal patch, 14t, 17
Terconazole, 547t, 550 hormones, 405, 407, 410 Transderm-Scop, 269t
Tessalon, 370t synthesis, 459–461, 460f Transplants, tissue. See Tissue transplants
Testamone, 439t Thyroid-stimulating hormone (TSH), 461 Tranxene, 71t, 107, 108t
Testaqua, 439t Thyrolar, 464t Tranylcypromine, 80t, 85t
Testex, 439t Thyrotoxicosis. See Hyperthyroidism Trazodone, 80t, 84t, 85t
Testoderm, 439t Thyroxine, 459–461, 460f Trecator-SC, 509
Testopel pellets, 439t Tiagabine, 110t, 111, 112t Tretinoin, 581t, 582
Testosterone Ticlid, 350t, 354 Triamcinolone, 378, 379t, 423t, 596
agents for clinical use, 439t Ticlopidine, 350t, 354 Triavil, 96t
antineoplastic indications, 576t Tigecycline, 510 Triazolam, 66t, 70t
biosynthesis and structure, 416f Timed-release preparation, 23 Tricor, 359t
41Ciccone(p1) Index 2/6/07 4:26 PM Page 652
652 Index
Tricyclics, 79, 80t, 81, 82–83, 85t Valacyclovir, 526t, 527 common viruses, 524t
Tridesilon, 422t Valcyte, 526t replication, 524–535, 525f
Trifluoperazine, 96t, 97t Valdecoxib, 210 structure and function, 523–525
Triflupromazine, 96t, 97t Valerian, 608t, 610–611 Viscosupplementation, 230
Trifluridine, 526t, 530 Valganciclovir, 526t Visine, 275
Trihexyphenidyl, 127t Valium, 70, 71f, 71t, 108t, 138t Visken, 282t, 283, 310t
Triiodothyronine, 459–461, 460f spasms, 164–165, 165t Vistaril, 372t
Trilafon, 96t spasticity, 165t Vistide, 526t, 528
Trileptal, 108t, 109 Valproic acid, 87, 108t, 109, 112t Vitamin D
Trimethaphan, 268 Valsartan, 335t, 340 bone mineral homeostasis, 466, 468t, 469
Trimethoprim, 513 Valtrex, 526t, 527 Vitamins
Trimipramine, 80t, 85t Vanadom, 165t alternative medications, 611–612t, 614
Trimpex, 513 Vanceril, 379t, 422t vitamin B3, 360
Tripelennamine, 372t Vancomycin, 506 vitamin K, 351, 351f, 357
Triprolidine, 372t Vansil, 559 Vitravene, 526t, 529
Triptorelin, 577t Variant angina, 313t, 314–315 Vivactil, 80t
Trisenox, 580 Vascor, 311, 311t Vivelle, 447t
Troglitazone, 487t, 488 Vasodilators Volatile liquids, 137t
Tronolane, 151t antihypertensives, 291t, 296–297, 296t Voltaren, 207t, 208t
Tubocurarine, 143t congestive heart failure, 336t, 342 Volume of distribution, 21–22, 22t
Tumor necrosis factor inhibitors, 227–228, Vasotec, 335t, 339 Voriconazole, 550
227f, 598t Vasoxyl, 275 Vumon, 575t
Tums, 468t Vazepam, 108t
Tussigon, 370t Vecuronium, 143t W
Tygacil, 510 Velban, 575t, 599 Warfarin, 349, 350t, 351, 351f
Types I and II diabetes, 481, 483, 486. See Velcade, 580 Wellbutrin, 80t, 83t
also Diabetes mellitus Velsar, 575t White matter, 57
Typhoid fever, 516t Venlafaxine, 72, 80t, 82, 84t, 85t Winstrol, 439t
Tyrosine Venous thrombosis, 349 Withdrawal syndrome, 193, 193t
chemical structure, 460f Ventricular arrhythmias, 324t Women’s Health Initiative (WHI),
kinase inhibitors, 579t, 580 VePesid, 575t 446
thyroid hormone synthesis, 459 Verapamil, 311t, 312, 327 Wyamine, 275
Verelan, 311t Wytensin, 276
U Vermox, 559
Ulcers, gastric, 392–393 Versed, 138t X
Ultravate, 422t Very-low-density lipoproteins (VLDLs), Xanax, 71t
Unipolar depression, 86. See also Depres- 358 Xanthine derivatives, 376–377, 376f,
sion Vesanoid, 581t, 582 377t
Unisom Nighttime Sleep-Aid, 372t Vesprin, 96t Xeloda, 571t
Unstable angina, 313t, 315 Vfend, 550 Ximelagatran, 352
Upper respiratory tract infections, 369–373, Vidarabine, 526t, 533 Xylocaine, 151t
524t Videx, 531, 537 Xylometazoline, 275, 371t
Urabeth, 265t Vinblastine, 569, 573, 575t, 599
Uracil mustard, 571t Vincasar, 576t, 599 Y
Urecholine, 265t Vincristine, 569, 573, 576t, 599 Yodoxin, 555–556
Urethritis, 517t Vinorelbine, 569, 573, 576t Yutopar, 277–278
Urex, 513 Vioxx, 210
Urinary tract and bladder infection, 515t, Vira-A, 526t, 533 Z
516t Viracept, 530, 537 Zafirlukast, 380, 381
antimuscarinic drugs 270–271 Viral replication, 524–535, 525f Zagam, 511
cholinergic stimulants, 266 Viral resistance, 533 Zalcitabine, 531, 537
Urokinase, 350t, 355 Viramune, 531, 537 Zaleplon, 66t, 68
Ursodeoxycholic acid (ursodiol), 397 Virazole, 526t, 532–533 Zanaflex, 165t, 171, 276
Viread, 531, 537 Zanamivir, 526t, 530
V Virilon, 439t Zanosar, 571t
Vaccines, 535–536, 538–539 Viroptic, 526t, 530 Zantac, 205, 391t
Vaginal ring, 450 Viruses. See also Antiviral drugs Zarontin, 108t, 109
Vagistat-1, 547t basic components, 525f Zebeta, 282t, 283
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