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Drug-Induced Diseases PDF
Drug-Induced Diseases PDF
Diseases
Prellelliion, Delectioll,
alld Manllgemel1l
TisdaleFM_i-xxii 1/27/10 9:46 PM Page i
Prevention, Detection,
and Management
Second Edition
The information presented herein reflects the opinions of the contributors and advi-
sors. It should not be interpreted as an official policy of ASHP or as an endorsement of
any product.
ISBN 978-1-58528-205-0
TisdaleFM_i-xxii 1/27/10 9:46 PM Page iii
CO N T E N T S
CHAPTER 1
CHAPTER 7
Drug Safety and Drug-Induced Diseases: The
Systemic Lupus Erythematosus-like
Regulatory, Legal, and Practice Environments 3
Syndrome 98
Henri R. Manasse Jr. and Cynthia Reilly Karen W. Lee and Marie M. Wenzel
CHAPTER 2 CHAPTER 8
Epidemiology and Public Health Impact of Photosensitivity 110
Drug-Induced Diseases 14
Julie M. Koehler
John R. Litaker and James P. Wilson
CHAPTER 3 CHAPTER 9
Factors Contributing to Drug-Induced Diseases 23 Alopecia, Hirsutism, and Hypertrichosis 135
Janis J. MacKichan and Mary W.L. Lee Kristine E. Keplar
v
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vi Contents
CHAPTER 11 CHAPTER 22
Stroke 190 Asthma and Bronchospasm 378
Denise H. Rhoney W. Greg Leader and Brice Labruzzo Mohundro
CHAPTER 12 SECTION VI
Movement Disorders 211 Drug-Induced Cardiovascular Diseases
Jack J. Chen and David M. Swope
CHAPTER 23
CHAPTER 13 Myocardial Ischemia and Acute Coronary
Peripheral Neuropathy 236 Syndromes 401
Dennis Parker, Jr. Kevin M. Sowinski
CHAPTER 14 C H A P T E R 24
Visual Disturbances 250 Heart Failure 428
Yaman Kaakeh and Steven R. Abel Ross T. Tsuyuki and Mark J. Makowsky
CHAPTER 15 CHAPTER 25
Delirium 275 Supraventricular Arrhythmias 445
Matthew A. Fuller and Mary C. Borovicka James E. Tisdale
CHAPTER 16 CHAPTER 26
Sleep Disorders 293 Ventricular Arrhythmias 485
Lisa L. Forsyth
James E. Tisdale
CHAPTER 17
Cognitive Disorders 301 CHAPTER 27
Hypertension 516
Michele Y. Splinter
Joseph J. Saseen
SECTION IV
CHAPTER 28
Drug-Induced Psychiatric Diseases
Hypotension 529
CHAPTER 18 Robert Lee Page II and Jean M. Nappi
Depression 317
Sheila Botts and Melody Ryan CHAPTER 29
Valvular and Pericardial Heart Disease 554
CHAPTER 19
Sarah A. Spinler and Frank E. Silvestry
Anxiety 333
Julie A. Dopheide SECTION VII
CHAPTER 20 Drug-Induced Endocrine Diseases
Psychosis 344 CHAPTER 30
Jessica L. Gören Glucose and Insulin Dysregulation 571
Devra K. Dang, Frank Pucino, Jr., Charles D. Ponte,
SECTION V and Karim Anton Calis
Drug-Induced Pulmonary Diseases
CHAPTER 31
CHAPTER 21
Thyroid Disorders 586
Interstitial Lung Disease/Pulmonary Fibrosis 359
Judy T. Chen, Betty J. Dong, Frank Pucino, Jr., and
CoraLynn B. Trewet
Karim Anton Calis
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Contents vii
C H A P T E R 32 SECTION IX
Hypothalamic, Pituitary, and Adrenal Drug-Induced Diseases of the Kidney &
Disorders 605 Fluid & Electrolyte Disorders
John G. Gums and Shawn D. Anderson
C H A P T E R 43
C H A P T E R 33 Acute Kidney Injury 853
Weight Gain 629 Amy Barton Pai and Darius L. Mason
Amy Heck Sheehan
CHAPTER 44
CHAPTER 34 Chronic Kidney Disease 872
Temperature Dysregulation 644 Mary K. Stamatakis
Susan M. Wilson
CHAPTER 45
CHAPTER 35 Syndrome of Inappropriate Antidiuretic Hormone
Sexual Dysfunction in Males 686 Secretion and Diabetes Insipidus 885
Mary Lee and Roohollah Sharifi Edward F. Foote
CHAPTER 36 CHAPTER 46
Gynecologic Diseases and Acid-Base Disorders 903
Infertility in Women 702 Lori D. Wazny, Colette B. Raymond, and Christine J.
Davis
Judith A. Smith
CHAPTER 38 CHAPTER 48
Diarrhea 738 Thromboembolic Diseases 941
Jane M. Gervasio Candice L. Garwood
C H A P T E R 39 CHAPTER 49
Constipation 760 Neutropenia and Agranulocytosis 962
Jane M. Gervasio Christopher A. Fausel
CHAPTER 40 CHAPTER 50
Hepatic and Cholestatic Diseases 771 Anemias 973
Robert MacLaren Edward Li, Estela Ceja, and James M. Hoffman
CHAPTER 41
Pancreatitis 800
SECTION XI
Drug-Induced Bone, Joint and Muscle
Pramodini B. Kale-Pradhan and Sheila M. Wilhelm
Diseases
C H A P T E R 42 C H A P T E R 51
Nausea, Vomiting, and Anorexia 819 Osteoporosis and Osteomalacia 991
Jon D. Herrington and Erika N. Brown Laura M. Borgelt and Sheryl F. Vondracek
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viii Contents
C H A P T E R 52 CHAPTER 54
Gout and Hyperuricemia 1005 Neoplastic Diseases 1031
Jasmine D. Gonzalvo Jessica Campaign and Mark T. Holdsworth
C H A P T E R 53 CHAPTER 55
Myopathy 1017 Ototoxicity 1049
Craig Williams Monica L. Miller and Crystal S. Blankenship
F O R E WO R D
ix
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x Foreword
vides needed structure to the identification and is the standard for understanding drug-induced
categorization of drug-induced diseases and it diseases and the broader topic of drug safety.
describes well the interactions of the many com-
ponents of the health care system that influence Joseph T. DiPiro, PharmD, FCCP
drug-induced diseases. Tisdale and Miller, along Dean
with their many contributors, are to be com- South Carolina College of Pharmacy
mended for producing an extraordinary work that August 2009
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xi
P R E FAC E
If you do not expect the unexpected you will not find it.
—Heraclitus (554-483 B.C.)
xii Preface
describes the structure and strategy of postmarket- more exhaustively referenced than DID-1 and the
ing surveillance for their detection and characteri- index has been expanded and improved.
zation, and provides a general approach to patient Each of the “agents implicated” tables in DID-
evaluation. The remainder is organized around spe- 2 includes an indication of the strength of the evi-
cific diseases for which drugs have been implicated dence that links a listed drug to the specific
as causative agents or, in some cases, the organ sys- drug-induced disease (thanks to Dr. Ross Tsuyuki
tem that is involved. Disease-related chapters fol- for this suggestion). A “Level of Evidence” designa-
low a consistent structure: causative agents, tion of “A” has been assigned when there is evi-
epidemiology, mechanisms, clinical presentation dence of causality from one or more randomized,
and differential diagnosis, risk factors, morbidity controlled clinical trials. A designation of “B” indi-
and mortality, methods of prevention, manage- cates that there is evidence of causality from non-
ment, and information for patients. Each chapter randomized clinical trials, prospective
underwent blinded external review by one or more observational studies, cohort studies, retrospective
content experts. studies, case-control studies, meta-analyses, and/or
Numerous changes and, we believe, significant postmarketing surveillance studies. A designation
improvements have been incorporated into DID-2. of “C” has been assigned when evidence of causal-
Two chapters have been added: “Drug Safety and ity is from one or more published case reports or
Drug-Induced Disease: The Regulatory, Legal, and case series.
Practice Environments” and “Evaluating Patients Undertaking a book such as this is not an easy
for Drug-Induced Diseases.” Chapters from DID-1 task, and we gratefully acknowledge the work of
have been expanded and, as would be expected, the chapter authors and expert external content
information throughout has been carefully updat- reviewers. Without their significant contributions,
ed by the contributors. “Diarrhea and this book could not have been completed. We also
Constipation” was a single chapter in DID-1, but gratefully acknowledge the support, guidance, and
has now been divided into two chapters. Similarly, assistance of the staff at the American Society of
the information regarding drug-induced arrhyth- Health-System Pharmacists. We sincerely hope that
mias now comprises two chapters: “Supraventric- this work assists practitioners in their efforts to
ular Arrhythmias” and “Ventricular Arrhythmias.” continually improve patient outcomes related to
Each chapter includes a series of standard drug therapy.
tables that are in a consistent format throughout.
New drugs implicated as the cause of specific dis- JAMES E. TISDALE
ease(s) have been added, as well as new informa- DOUGLAS A. MILLER
tion regarding epidemiology, mechanisms, risk September 2009
factors, prevention, and management. DID-2 is
CO N T R I B U TO R S
xiv Contributors
Contributors xv
xvi Contributors
Mark J. Makowsky, BSP, PharmD Robert Lee Page II, PharmD, MSPH, FAHA, FCCP,
Assistant Professor FASHP, FASCP, BCPS, CGP
Faculty of Pharmacy and Pharmaceutical Sciences Associate Professor of Clinical Pharmacy and
University of Alberta Physical Medicine
Edmonton, Alberta Clinical Specialist, Division of Cardiology
Canada University of Colorado Denver, Schools of
Pharmacy and Medicine
Henri R. Manasse, Jr., PhD, ScD, FFIP Aurora, Colorado
Executive Vice President and Chief Executive
Officer Amy Barton Pai, PharmD, BCPS, FASN
American Society of Health-System Pharmacists Associate Professor
Bethesda, Maryland Albany College of Pharmacy and Health Sciences
Albany, New York
Darius L. Mason, PharmD, BCPS
Assistant Professor Dennis Parker Jr., PharmD
ANephRx (Albany Nephrology Pharmacy Group) Assistant Professor
Department of Pharmacy Practice Department of Pharmacy Practice
Albany College of Pharmacy and Health Sciences College of Pharmacy and Health Sciences
Albany, New York Wayne State University
Clinical Specialist - Neuroscience
J. Russell May, PharmD, FASHP Detroit Receiving Hospital
Clinical Professor Detroit, Michigan
Department of Clinical and Administrative
Pharmacy Charles D. Ponte, PharmD, BC-ADM, BCPS, CDE,
University of Georgia College of Pharmacy CPE, FAPhA, FASHP, FCCP
Augusta, Georgia Professor of Clinical Pharmacy and Family
Medicine
Douglas A. Miller, PharmD West Virginia University
Professor Robert C. Byrd Health Sciences Center
Department of Pharmacy Practice Schools of Pharmacy and Medicine
College of Pharmacy and Health Sciences Morgantown, West Virginia
Wayne State University
Detroit, Michigan Frank Pucino, Jr., PharmD, BCPS, FASHP, FDPGEC
Senior Clinical Investigator
Monica L. Miller, PharmD, MSc National Institute of Arthritis and Musculoskeletal
Clinical Assistant Professor and Skin Diseases
School of Pharmacy & Pharmaceutical Sciences National Institutes of Health
Purdue University Bethesda, Maryland
Indianapolis, Indiana
Colette B. Raymond, PharmD, MSc, ACPR
Brice Labruzzo Mohundro, PharmD Staff Development/Practice Evaluation Pharmacist
Assistant Professor Winnipeg Regional Health Authority Pharmacy
University of Louisiana at Monroe College of Program
Pharmacy Winnipeg, Manitoba, Canada
Baton Rouge, Louisiana
Cynthia Reilly, BSPharm
Jean M. Nappi, PharmD, FCCP, BCPS Director, Practice Development Division
Professor of Clinical Pharmacy & Outcome American Society of Health-System Pharmacists
Sciences Bethesda, Maryland
South Carolina College of Pharmacy-MUSC
Campus Denise H. Rhoney, PharmD, FCCP, FCCM
Professor of Medicine Associate Professor
Medical University of South Carolina Department of Pharmacy Practice
Charleston, South Carolina College of Pharmacy and Health Sciences
Wayne State University
Detroit, Michigan
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xvii
Contributors xvii
Melody Ryan, PharmD, MPH Sarah A. Spinler, PharmD, FCCP, FAHA, BCPS (AQ
Associate Professor Cardiology)
Department of Pharmacy Practice and Science Professor of Clinical Pharmacy
University of Kentucky College of Pharmacy Department of Pharmacy Practice and Pharmacy
Department of Neurology Administration
University of Kentucky College of Medicine Philadelphia College of Pharmacy
Lexington, Kentucky University of the Sciences in Philadelphia
Philadelphia, Pennsylvania
Joseph J. Saseen, PharmD, FCCP, BCPS
Professor Michele Y. Splinter, PharmD, MS, BCPS
University of Colorado Denver Clinical Associate Professor
Anschutz Medical Campus University of Oklahoma HSC, College of
Schools of Pharmacy and Medicine Pharmacy
Aurora, Colorado Oklahoma City, Oklahoma
xviii Contributors
Ross T. Tsuyuki, BSc (Pharm), PharmD, MSc Craig Williams, PharmD, FNLA
(Clin Epi), FCSHP, FACC Clinical Associate Professor of Pharmacy
Professor of Medicine (Cardiology) OHSU College of Pharmacy
Director, EPICORE Centrre/COMPRIS Clinical Associate Professor of Medicine
Faculty of Medicine and Dentistry Oregon Health and Science University School of
University of Alberta Medicine
Edmonton, Alberta, Canada Portland, Oregon
REVIEWERS
Jennifer M. Anthone, PharmD Sheryl L. Chow, BS. Pharm, PharmD, BCPS (AQ
Creighton University Medical Center Cardiology)
Omaha, Nebraska Assistant Professor
Department of Pharmacy Practice and
Jacquelyn L. Bainbridge, PharmD, FCCP Administration
Professor, Department of Clinical Pharmacy and Western University of Health Sciences
Department of Neurology Pomona, California
University of Colorado Denver
Aurora, Colorado Catherine Christen, PharmD
Clinical Pharmacist
Gretchen M. Brophy, PharmD, BCPS, FCCP, University of Michigan Health System and
FCCM College of Pharmacy
Professor of Pharmacy and Neurosurgery Clinical Assistant Professor
Virginia Commonwealth University University of Michigan College of Pharmacy
Medical College of Virginia Ann Arbor, Michigan
Richmond, Virginia
Susan E. Conway, PharmD
Susan P. Bruce, PharmD, BCPS Associate Professor
Associate Professor & Chair, Pharmacy Practice University of Oklahoma College of Pharmacy
Northeastern Ohio Universities Oklahoma City, Oklahoma
Colleges of Medicine & Pharmacy
Rootstown, Ohio Tanna Cooper, PharmD, BCPS
Clinical Pharmacy Specialist, Digestive Diseases
Charles F. Caley, PharmD, BCPP Intensive Care Unit
Associate Clinical Professor Medical University of South Carolina
University of Connecticut School of Pharmacy Charleston, South Carolina
Storrs, Connecticut
xix
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xx
xx Reviewers
William E. Dager PharmD, BCPS, FCSHP, FCCP, Richard G. Fiscella, PharmD, MPH
FCCM Clinical Professor
Pharmacist Specialist, UC Davis Medical Center Department of Pharmacy Practice
Sacramento, California Adjunct Assistant Professor
Clinical Professor of Pharmacy, UC San Francisco Department of Ophthalmology
San Francisco, California Chicago, Illinois
Clinical Professor of Medicine, UC Davis School
of Medicine Dustin D. French, PhD
Sacramento, California Research Scientist
Clinical Professor of Pharmacy, Touro School of VA Center of Excellence on Implementing
Pharmacy Evidence Based Practice
Vallejo, California Regenstrief Institute Inc
Indiana University School of Medicine
John W. Devlin, PharmD, BCPS, FCCM, FCCP Indianapolis, Indiana
Associate Professor
Northeastern University School of Pharmacy Jeffrey A. Johnson, BSP, PhD
Adjunct Associate Professor Canada Research Chair in Diabetes Health
Tufts University School of Medicine Outcomes
Boston, Massachusetts Professor, School of Public Health
University of Alberta
Sarah E. Donegan, PharmD, BCOP Edmonton, Alberta
Senior Drug Information Analyst, Oncology Canada
Specialist
American Society Health-System Pharmacists Melissa C. Jones, PharmD, BCPS
Bethesda, Maryland Assistant Dean for Admissions
Associate Professor of Pharmacy Practice
Thomas C. Dowling, PharmD, PhD, FCP South University School of Pharmacy
Associate Professor and Vice Chair Savannah, Georgia
University of Maryland Baltimore School of
Pharmacy Melanie S. Joy, PharmD, FCCP
Baltimore, Maryland Associate Professor
UNC Schools of Medicine and Pharmacy
Kaelen C. Dunican, BSPharm, PharmD Division of Nephrology and Hypertension
Assistant Professor of Pharmacy Practice
UNC Kidney Center
Massachusetts College of Pharmacy and Health
Chapel Hill, North Carolina
Sciences
School of Pharmacy- Worcester/Manchester
Michael P. Kane, PharmD, FCCP, BCPS
Worcester, Massachusetts
Professor, Department of Pharmacy Practice
Krystal L Edwards, PharmD, BCPS Albany College of Pharmacy and Health Sciences
Associate Professor of Pharmacy Practice Clinical Pharmacy Specialist
Texas Tech University Health Sciences Center - The Endocrine Group, LLP
School of Pharmacy Albany, New York
Dallas, Texas
Joseph Kishel, PharmD, BCPS, AQ-ID
Jennifer D. Faulkner, PharmD, BCPP Clinical Scientific Director
Director of Education, Pharmacy Service Cubist Pharmaceuticals
Central Texas Veterans Health Care System Palmyra, Pennsylvania
Temple, Texas
Michael Kotlyar, PharmD
Marcus Ferrone, PharmD, BCNSP Associate Professor
Director, Drug Product Services Laboratory University of Minnesota
Associate Professor of Clinical Pharmacy Department of Experimental and Clinical
University of California, San Francisco Pharmacology
San Fransisco, California College of Pharmacy
Minneapolis, Minnesota
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xxi
Reviewers xxi
xxii Reviewers
SECTION I
MAGNITUDE/SIGNIFICANCE
OF DRUG-INDUCED DISEASES
Impact on the Health Care System
CHAPTER 1 Drug Safety and Drug-Induced Diseases: The Regulatory, Legal, and Practice
Environments
CHAPTER 1
3
TisdaleC01_1-13 1/20/10 10:48 PM Page 4
FDAA Reauthorized
Human Services)
1906 1938 1962 2002 2008
FIGURE 1–1 History of FDA
Late 1930 1953 1997 2007
Drug Safety Activities and
1860s
Regulations.5
address concerns about adulterated drug products notably, the 2007 reauthorization of the act grants
from overseas. However, it was not until 1906, when the FDA increased authority to request that manu-
the Federal Food and Drugs Act was passed, that the facturers complete postmarketing safety studies
focus of the agency shifted from a scientific to a reg- and requires that manufacturers develop and sub-
ulatory body. While that legislation permitted regu- mit risk evaluation and mitigation strategies
lation of drug-product labeling, the impetus for the (REMS) for all drug products for which they seek
law was not drug safety, but rather concerns for food FDA approval.6-8 While patient and prescriber edu-
safety, which were prompted by Upton Sinclair’s The cation programs are potential components of
Jungle. The novel exposed unsanitary conditions in REMS programs, more stringent programs, such as
the meatpacking industry, which at the time, was patient and provider registries or required laborato-
considered the greater threat to public safety. ry monitoring and reporting may be included in a
It wasn’t until passage of the Food, Drug, and more comprehensive restrictive drug distribution
Cosmetic Act in 1938 that legislation began to system, or RDDS. FDAA 2007 also requires that the
focus on premarket drug safety. Once again, this FDA establish a mechanism to increase and coordi-
authority was granted in response to a safety inci- nate postmarketing surveillance efforts. The
dent in which an antifreeze-like ingredient in the requirement was addressed by establishment of the
elixir sulfanilamide resulted in more than 100 Sentinel Initiative in 2008, which is discussed in
deaths.5 In 1962, the Kefauver–Harris Amendments greater detail in Chapter 4, “Postmarketing
to the 1938 Act introduced a requirement to Surveillance for Drug-Induced Diseases.”
demonstrate both efficacy and safety prior to drug
approval. This was the first legislation that focused
on adverse events caused by active ingredients and
The FDA’s Safety-Related
was spurred by reports of birth defects following the
Regulatory Actions
use of thalidomide abroad. Severe malformations, The FDA considers and may request a number of
including a flipper-like appearance of limbs caused regulatory actions when a serious or life-threat-
by very short or absent long bones resulted in with- ening safety concern is identified for a drug.
drawal of the drug from worldwide markets. A U.S.- Each action has the potential to decrease or
based drug manufacturer had applied for, but never eliminate patient access to drug therapy.
received, approval to market the drug in the U.S. Therefore, the decision about the specific course
Significant efforts to improve drug safety have of action to take must carefully balance the
been addressed within the FDA Amendments Acts effectiveness of the drug, other therapeutic
(FDAAs) of 1992, 1997, 2002, and 2007. Most options for the condition being treated, the type
TisdaleC01_1-13 1/20/10 10:48 PM Page 5
CHAPTER 1 • Drug Safety and Drug-Induced Diseases: The Regulatory, Legal, and Practice Environments 5
sequences that these programs may have on the entity responsible for drug safety. Historically,
continuity of care and patient access to these high- there has been significant litigation against
risk drugs. pharmaceutical manufacturers alleging that they
A recent trend toward shortened time frames hid, misrepresented, or otherwise failed to meet
for drug approval has been criticized as a signifi- the obligation to inform clinicians and patients
cant contributor to drug safety problems, but this about known or suspected risks associated with a
perception is misleading because it implies a direct drug’s use. In Feldman v. Lederle Laboratories
cause-and-effect relationship between shortened (1984), one of the more unusual cases, the New
average time to drug approval and drug with- Jersey Supreme Court ruled in favor of plaintiff
drawals or other safety issues. Safety concerns can Feldman, who claimed that the drug manufac-
arise throughout a product’s life cycle.14 An exam- turer had failed to provide sufficient informa-
ple is aprotinin, an antithrombolytic agent that tion and warnings to physicians about the
was used in cardiac surgery for 14 years before potential for tooth discoloration from its tetra-
accumulating reports of increased morbidity and cycline product, demeclocycline.17 Ms. Feldman
mortality led to its voluntary withdrawal from the was prescribed and dispensed samples of the
U.S. market in late 2007.15 drug by her father, a physician and pharmacist,
An FDA assessment of the timing of safety- several times when she was an infant and tod-
related actions for 444 new molecular entities dler. The company claimed that at the time Ms.
(NMEs) approved between 1991 and 2006 demon- Feldman received demeclocycline, information
strated that regulatory actions occur throughout a about this side effect was not fully known, and
product’s life cycle.16 Among drugs approved by therefore not included in the labeling and pre-
the FDA during that time frame, 78% had a least scribing information approved by the FDA.
one safety-related action and 3% were withdrawn However, abnormalities in tooth development
from U.S. market. A subanalysis of drugs approved and discoloration associated with tetracycline
from 1991 through 1995 (i.e., representing drugs products were reported in published studies of
that were marketed for a minimum of 13 years) laboratory animals and children with cystic
found that 27% of NMEs underwent changes or fibrosis who received high doses. A lower court
additions to boxed warnings, warnings, or precau- had found the manufacturer not liable because
tions sections of the FDA-approved labeling. No the company had asked the FDA for guidance on
drugs in this subgroup were removed from the whether to include a warning in the labeling of
market. For drugs marketed less than 5 years (i.e., all of its tetracycline products, but the agency
those approved from 2003 through 2006), 44% advised against including this information in
underwent safety-related labeling changes, and demeclocycline labeling based on a lack of suffi-
there were no market withdrawals. These data cient evidence. However, the state supreme court
demonstrate that safety actions occur on an ongo- disagreed with the lower court’s decision, noting
ing basis and that newer drugs are not necessarily that the FDA’s response did not prevent the
more prone to safety issues. Rather, it is likely that manufacturer from providing this information
new safety signals will be generated throughout or relieve the company of its responsibility to do
the life cycle of a drug. so.
There are several unusual circumstances in this
case, including uncertainty as to whether Ms.
Feldman received demeclocycline or another tetra-
DRUG SAFETY IN THE cycline. Because samples were used, no prescrip-
LEGAL ENVIRONMENT tion or dispensing records were available to
confirm the plaintiff’s assertion. In addition, most
Drug safety has been the subject of countless court product-liability cases include the manufacturer
rulings, with most cases focusing on who is respon- and prescriber as litigants, but in this instance,
sible for ensuring the safe use of drug products— legal action was directed only toward the drug
pharmaceutical manufacturers, prescribers, other manufacturer, not the prescriber (the patient’s
health care professionals, or a combination of father).
these entities. In Brown v. American Home Products Corporation
Diet Drugs, the federal courts approved a negotiat-
ed settlement in the class-action product-liability
Pharmaceutical Manufacturers case of fenfluramine–phentermine (“fen-phen”) or
State and federal courts have commonly found dexfenfluramine with phenteramine.18 The class-
pharmaceutical manufacturers to be the primary action lawsuit found that product manufacturers
TisdaleC01_1-13 1/20/10 10:48 PM Page 7
CHAPTER 1 • Drug Safety and Drug-Induced Diseases: The Regulatory, Legal, and Practice Environments 7
for fenfluramine (marketed as Pondomin by argument that it was protected from state-law
American Home Products, Inc.) and dexfenflu- claims because of federal labeling requirements and
ramine (marketed as Redux by Wyeth) possessed the FDA’s approval of the existing product’s label.
extensive information, including published case In general, those requirements allow a manufactur-
reports, animal studies, case reports in patients tak- er to change labeling only following FDA approval
ing drugs with similar effects on serotonin, and of the proposed change. However, the court noted
unpublished studies conducted by the manufactur- that the manufacturer could have strengthened the
er, showing that the drugs could cause damage to safety warning through the “Changes Being
heart valves and lead to valvular regurgitation. The Affected” regulation, which allows labeling changes
court found that despite having this information, that improve safety while the manufacturer is in
the manufacturer continued to market the drug the process of seeking the FDA’s official approval of
combination until the drugs were withdrawn from that change. In issuing its decision, the court
the market in 1997, without further investigating emphasized that the pharmaceutical manufacturer,
these reports or warning prescribers or patients not the FDA, is ultimately responsible for the accu-
through labeling or other mechanisms. The settle- racy and completeness of the product labeling and
ment created a $2.5 billion fund to compensate that the FDA’s regulatory authority is intended to
patients for harm and cover current and future be complementary to, not preemptive of, a state’s
associated health care costs based on factors such role in drug safety. This decision may have far-
as length of therapy and extent of harm. reaching impact on other ongoing product-liability
A 2001 U.S. Supreme Court case ruled that cases, including those asserting harm from altered
patients cannot sue pharmaceutical companies for glucose metabolism and diabetes from olanzapine
withholding information during the drug- use and drug-induced hepatitis associated with
approval process in instances in which the FDA troglitazone use. 19,21
has found no evidence of fraud or failure to dis-
close information. However, in Warner Lambert v.
Kent, a split decision by that court upheld a lower
Pharmacists’ and Other
court decision allowing an exemption in Michigan
Clinicians’ Duty to Warn
law that permitted patients who had received According to the National Association of Chain
troglitazone to sue the product manufacturers for Drug Stores, as of October 2008 there were approx-
punitive damages by alleging fraud, even in imately 50 state and federal lawsuits involving the
instances when the FDA did not allege or find evi- pharmacist’s duty to warn.22 The majority of these
dence of fraud.19 Similar exemptions exist in seven cases have found that pharmacists are not liable for
other states. patient harm resulting from adverse drug events or
A decision in March 2009 by the U.S. Supreme drug-induced disease. These decisions are generally
Court may have a pronounced effect on the man- based on the learned intermediary doctrine, which
ner in which pharmaceutical manufacturers view assigns responsibility for drug selection to the pre-
and operationalize their duty to warn of significant scriber based on his or her knowledge of the drug
adverse drug events in product labeling. In Wyeth v. and the individual patient. Pharmacists have gen-
Levine, the court upheld a state trial and supreme erally been considered “sellers” of the drug product
court decision that awarded damages to a Vermont or service, and the courts have considered dispens-
woman whose arm was amputated because of gan- ing to be an extension of the physicians’ order.
grene that developed following administration of Several decisions have noted that if pharmacists’
promethazine by intravenous (IV) push.20 The liability was permitted, it could undermine the
product’s FDA-approved labeling included informa- physician–patient relationship by calling pre-
tion on the preferred route of administration (deep scribers’ authority into question.23 Based on exist-
intramuscular injection), warnings about the ing case law, it is unclear how the learned
potential for gangrene (especially with intraarterial intermediary doctrine would be applied to phar-
or subcutaneous administration), and a preference macists who select drug therapy under collabora-
for IV infusion administration when the drug is tive practice agreements or with the significant
administered intravenously. However, the trial expansion of information that would be available
court found that the patient’s injuries would not to pharmacists from proposed national or univer-
have occurred if the product’s labeling included sal electronic health records. In Jones v. Irvin and K-
adequate warning, including specific information Mart, the plaintiff appellate argued that the
about the danger of IV push administration. The practice of pharmacy had changed dramatically,
Supreme Court agreed with the trial court and dis- that the pharmacist had greater knowledge of the
agreed with the pharmaceutical manufacturer’s dangers associated with drugs than physicians, and
TisdaleC01_1-13 1/20/10 10:48 PM Page 8
therefore the pharmacists’ duty to warn warranted with an erythropoietin product supplied by one
new consideration. The court found that while this manufacturer, but cases also occurred in patients
advanced knowledge may be true, the physician’s treated with a similar product. On further analyses,
role as learned intermediary is predominant.24 the dramatic increase in adverse events was attrib-
However, future courts may take a more expansive uted to a change in the stabilizers in one manufac-
view of the pharmacist’s role. turer’s product and subsequent storage, handling,
While the learned intermediary principle has and subcutaneous administration of that product.
frequently shielded pharmacists and their employ- Education regarding proper use of the various for-
ers from liability, it negatively affects efforts to mulations resulted in a significant decrease in the
establish pharmacists as medication experts and number of PRCA cases.
independent practitioners. Most importantly, Product contamination has also resulted in sig-
pharmacists have a professional obligation to nificant morbidity and mortality, most recently in
ensure safe care, regardless of legal liability. Patient the case of serious adverse events associated with
education, including risk communication, is a sig- heparin that occurred from November 2007
nificant component of the commitment that all through February 2008.4,27 Patient events included
pharmacists make through their education, licen- 62 deaths, with other reports of patients experienc-
sure, and subsequent practice. ing allergic symptoms or symptoms of hypoten-
sion. Voluntary product recalls occurred when a
pattern of serious events was determined. The
adverse drug events were later linked to the pres-
THE DRUG-APPROVAL PROCESS ence of oversulfated chondroitin sulfate in the
AND OTHER FACTORS THAT active pharmaceutical ingredient from an overseas
AFFECT DRUG-INDUCED DISEASE plant that processes heparin from pig intestines.
The contaminant was not detected in random sam-
The drug-approval process is expected to assess the pling of manufacturing plants, in part because it
efficacy and, to a certain extent, the safety of new mimics heparin in commonly used tests. Follow-up
drug products, but it should be noted that several tests conducted by the FDA found that the contam-
characteristics of that process and the subsequent inant accounted for 5% to 20% of the total mass of
environment of drug use contribute to drug- each sample tested. It was alleged that the contam-
induced disease. Patient populations in preap- ination with chondroitin was a purposeful act.28
proval clinical trials are, by necessity, narrowly Plans to increase overseas inspections and to mod-
structured and defined. Strict inclusion and exclu- ify current standards for assessing the purity of
sion criteria often exclude patients with multiple heparin were also announced. This incident illus-
diseases and advanced disease and patients of a cer- trated the importance of oversight and inspection
tain sex, age, or race. Even the largest clinical trial of the complete product-development process,
conducted across multiple study sites evaluates a including assessment of the raw materials. It also
drug’s use in a number of patients that is small in noted that even in a more robust system of inspec-
comparison with the broader use of the drug tions, purposeful adulteration may occur at any-
postapproval—use that includes individuals with time by unscrupulous suppliers of raw materials
characteristics not studied during the approval and manufacturers, as well as criminal acts by pri-
process. vate citizens, as occurred with acetaminophen
Drug-induced disease can also be attributed to adulteration in the early 1980s.
conditions of drug use postapproval, which can
differ dramatically from established conditions in
clinical studies. Drugs are often used for unap-
proved indications and for approved indications RECOMMENDATIONS TO
but with variations in dose or route of administra- IMPROVE DRUG SAFETY
tion. Subtle changes in manufacturing processes
can also contribute to drug-induced diseases. For During the past decade a number of public and pri-
example, between 1998 and 2001, there was a dra- vate entities have assessed drug safety efforts in the
matic increase in the number of pure red-cell apla- U.S. and made recommendations to improve that
sia (PRCA) cases in patients with chronic kidney process. Many of these recommendations, such as
disease.25,26 PRCA is a known, but very rare, side development of a national database for enhanced
effect that can occur when anti-erythropoietin collection and assessment of adverse drug events
antibodies form in response to erythropoietin and drug-induced diseases, were included in
treatment. Most events occurred in patients treated PDUFA IV, and their implementation is underway.
TisdaleC01_1-13 1/20/10 10:48 PM Page 9
CHAPTER 1 • Drug Safety and Drug-Induced Diseases: The Regulatory, Legal, and Practice Environments 9
The following describes major reports and the cur- ry actions. A major finding in the GAO report was
rent status of their recommendations. instances in which conflicting recommendations
were made by divisions within FDA’s Center for
Drug Evaluation and Research. As a result, deci-
Institute of Medicine (IOM) sions were either not made or were made counter
In its landmark 2006 report, The Future of Drug to the recommendations of another FDA group
Safety: Promoting and Protecting the Health of the without a clear process for resolving the disparate
Public, the IOM issued more than two dozen rec- views.
ommendations to improve drug safety.29 The The GAO identified a lack of collaboration and
report, which focused on postmarketing safety, communication between the two predominant
identified structural and procedural barriers at the offices involved in drug safety—the Office of New
FDA that hampered efforts to enhance drug safety. Drugs (OND), which is responsible for drug
The report stated that preapproval data are inher- approval and for initiating regulatory actions, and
ently limited in their ability to identify infrequent the Office of Drug Safety (ODS), which predomi-
adverse events and that existing approaches for nantly focuses on postmarketing safety. The GAO
data collection following drug approval are not described the ODS as serving in an advisory capac-
adequate to address this shortcoming. The report’s ity to the OND, based on its finding that the ODS
authors called for increased, proactive postmarket- had no authority to initiate a regulatory action.
ing surveillance by the FDA, as well as additional The report identified a lack of documented process-
authority for the FDA to control manufacturers’ es for decision making, including an absence of cri-
postapproval marketing activities. Many of the teria to determine the appropriate regulatory
IOM’s recommendations, including strengthened action when a safety concern is identified.
authority to require REMS, were included in Significant progress has been made to address
PDUFA IV. Strategies to better inform the public, shortcomings identified in the GAO report, such as
such as establishment of an advisory committee to better coordination and more frequent meetings
address communication of risks, have also been with the ODS risk-management advisory commit-
implemented. However, the IOM’s recommenda- tee and the OND’s disease-specific advisory com-
tion to prevent potential harm by restricting mittees. Other recommendations, including the
direct-to-consumer advertising for a period of 2 establishment of clearly defined processes to
years following drug approval, and require that resolve conflicts of opinion between the offices,
labeling and marketing materials for these prod- remain unresolved. The report describes a draft
ucts contain a symbol to designate the recent policy entitled “Process for Decision-making
approval status, were controversial and not Regarding Major Postmarketing Safety-related
addressed in the reauthorization of the legislation. Actions” that remains unavailable to the public at
Other IOM reports, including Preventing the time of this writing. While the GAO report
Medication Errors (2006) and Knowing What Works focuses on the lack of criteria and processes, it
in Health Care: A Roadmap for the Nation (2008) should be noted that risk assessment and decisions
have also addressed drug safety.30,31 While these about drug safety are not an exact science. It
reports focus on the broader context of avoidable requires careful balancing of the pros and cons of
harm from drug therapies and comparative effec- providing continued availability of a drug, and is
tiveness, respectively, they include components on based on evidence that, by nature, is constantly
drug-induced disease and postmarketing safety sur- evolving.
veillance.
FDA
Government Accountability Office (GAO) The FDA has also assessed existing processes and
In 2006, the GAO issued the report, Drug Safety: taken numerous steps to enhance drug safety. In late
Improvement Needed in FDA’s Postmarket Decision- 2007, the FDA’s Science Board Subcommittee on
Making and Oversight Process, which evaluated drug Science and Technology published, FDA Science and
safety processes based on an assessment of regula- Mission at Risk: Report of the Subcommittee on Science
tory actions for four drugs: leflunomide (Avara), and Technology.3 The report was requested by then
cerivastatin (Baycol), valdecoxib (Bextra), and cis- Commissioner Andrew von Eschenbach to review
apride (Propulsid).1 Leflunomide remains available, the adequacy of the agency’s science and technolo-
but the other drugs were voluntarily withdrawn gy resources to meet current and future challenges.
from the U.S. market following several safety The report concluded that the agency’s resources
assessments by FDA staff and subsequent regulato- had decreased, despite an increase in responsibilities
TisdaleC01_1-13 1/20/10 10:48 PM Page 10
that resulted from the speed of scientific discoveries, decrease the FDA’s reliance on user fees paid by
increased and more complex products, and the drug manufacturers.
increasingly global nature of the drug industry. The Other FDA efforts to enhance drug safety have
subcommittee recommended that the existing included improved guidance to industry on pre-
deficits in resources in scientific research programs; marketing risk assessment, development and use of
recruitment, development and retention of expert risk-minimization action plans, and pharmacovigi-
staff; and information technology must be corrected lance and pharmacoepidemiologic assessment.33-35
in order to meet these challenges. Consumer awareness and education has also been a
Among the report’s specific recommendations major focus, including new regulations that require
was the need to strengthen and coordinate the sci- inclusion of MedWatch reporting information on
ence program across the FDA’s centers. The need drug packaging and patient information leaflets for
for collaboration with external scientific and prescription and nonprescription drugs and in
research programs, including the Agency for direct-to-consumer television advertising.36-38
Healthcare Research and Quality’s Centers for
Education and Research on Therapeutics, the
Centers for Disease Control and Prevention, the
Improving Data Collection and Use
National Institutes of Health, and others when the At the core of efforts to improve drug safety, there
expertise is not available at the FDA was identified. is reliance on the extent and quality of informa-
It is anticipated that the Reagan–Udall Foundation, tion used to inform these decisions. Safety infor-
an independent organization mandated by PDUFA mation gained from premarketing as well as
IV, will assist in the development of these and postmarketing studies is often described as data
other public–private partnerships as part of its that are unreported, underreported, and unpub-
charge to assist the FDA in modernizing its activi- lished. The International Committee of Medical
ties to address the rapid pace of change in the sci- Journal Editors Uniform Requirements for
entific and regulatory environments. Manuscripts Submitted to Biomedical Journals
Other recommendations in the report include requirement that researchers register human sub-
broadening staff with the statistical and epidemio- jects research via www.clincialtrials.gov as a condi-
logic expertise needed to analyze collected data as tion of publication and the editor’s obligation to
well staff with expertise in risk assessment and its publish negative studies represent the combined
quantitative measurement. A major focus of the efforts of regulatory and private entities to address
report was the need to establish information stan- these shortcomings.39 Other efforts have focused
dards that permit sharing and aggregation of on developing standards for reporting drug-
information from public and private postmarket- induced diseases and other adverse drug events.
ing safety surveillance databases. The report noted The Consolidated Standards of Reporting Trials
that these standards were critical, especially with [CONSORT], in “Better Reporting of Harms in
the establishment of new sciences, including phar- Randomized Trials: An Extension of the CONSORT
macogenetics, nanotechnology, and cell-based Statement,” recommends the use of standardized
products, for which collection of the extent and terminology and inclusion of harms information
types of data will not be supported by current sys- in the publication abstract as mechanisms to assist
tems. clinicians, researchers, and patients in the critical
In terms of funding these improvements, the appraisal of clinical trial results.40
report stated that appropriation provided by Public and private collaborations to improve
PDUFA IV provided only a small portion of that active surveillance, including data mining in large
which is needed. The Science Board called for a population-based databases, are described in
2009 budget to address the identified shortcom- Chapter 4.
ings and directed the FDA Commissioner to devel-
op an action plan to implement the report’s
recommendations. Calls to increase FDA funding
are echoed by health care professional, research, DRUG SAFETY CHALLENGES
and consumer sectors through entities such as the AND OPPORTUNITIES
Alliance for a Stronger FDA.32 The Alliance, whose
members include former Secretaries of the As noted in the FDA Science Board report, the rapid
Department of Health and Human Services and rate of new-drug development, the evolving role of
Commissioners of the FDA, aims to build aware- evidence-based medicine, and advancing science
ness about current deficits in funding and advocate and technology will offer ongoing and new chal-
for increased federal appropriations in order to lenges to our nation’s drug safety system. Novel
TisdaleC01_1-13 1/20/10 10:48 PM Page 11
CHAPTER 1 • Drug Safety and Drug-Induced Diseases: The Regulatory, Legal, and Practice Environments 11
thrombolytic therapy was more in common in 3. Food and Drug Administration (FDA) FDA science and
black patients.44,45 While these and other studies mission at risk: report of the Subcommittee on Science and
Technology. Available at: http://www.fda.gov/ohrms/
give credence to ethnicity as a determinant of dockets/ac/07/briefing/2007-4329b_02_01_
adverse events, shortcomings in the data, includ- FDA%20Report%20on%20Science%20and%20Technolog
ing inconsistent definitions and reporting of eth- y.pdf. Accessed March 8, 2009.
nicity and adverse events, limit its application to 4. FDA. FDA media briefing on heparin; April 21, 2008
clinical practice. Most drug-induced diseases, (transcript). Available at:
http://www.fda.gov/bbs/transcripts/2008/heparin_transcr
including ACE-inhibitor–induced cough, have ipt_042108.pdf. Accessed April 27, 2009.
been theorized as a complex interaction of ethnic 5. Swann JP. History of the FDA. In: Kurian G, ed. The
and other factors such as age, sex, and comorbid Historical Guide to American Government. New York, NY:
disease.46 When considered in total, these predic- Oxford University Press; 1998.
tive factors can be used to improve drug safety by 6. 110th Congress. Food and Drug Administration
Amendments Act of 2007, Public law 110-85. September
guiding drug selection and monitoring. 27, 2007.
The inclusion of genetic biomarker informa- 7. FDA. PDUFA fact sheet. Available at:
tion, and its clinical application, in FDA-approved http://www.fda.gov/oc/pdufa4/factsheet011107.html.
drug labeling is becoming more common. Accessed March 8, 2009.
However, currently there is no requirement that 8. FDA. PDUFA IV five year plan, March 2008. Available at:
http://www.fda.gov/cder/pdufa/PDUFA_IV_5yr_plan_draf
pharmaceutical manufacturers complete genetic t.pdf. Accessed November 20, 2008.
studies. Whether these studies are voluntary or 9. FDA. Potential signals of serious risks/new safety
required, more research (including practical clini- information identified from the Adverse Event Reporting
cal trials) and better systems for collecting and ana- System (AERS). Available at
lyzing these data are needed. Even with improved http://www.fda.gov/cder/aers/potential_signals/default.ht
m. Accessed November 20, 2008.
data, uncertainties will remain about the extent to 10. Thalidomide prescribing information. Summit, NJ:
which genetics affects drug response and the inter- Celgene Corporation, 2007.
play of genetics with other variables, including 11. McEvoy GK, ed. AHFS drug information 2008. Bethesda,
concomitant therapies, diet, and other patient MD: American Society of Health-System Pharmacists;
variables. At present, the clinical significance of 2008.
12. FDA. Opioid Drugs and Risk Evaluation and Mitigation
genetic variation and genetic testing in drug safety Strategies (REMS): FDA to Meet with Drug Companies
and effectiveness are much debated. about REMS for Certain Opioid Drugs. Available at
As the regulatory and legal environments http://www.fda.gov/Drugs/DrugSafety/InformationbyDru
evolve, clinicians will continue to play a central gClass/ucm163647.htm. Accessed June 22, 2009.
role in improving drug safety and preventing drug- 13. American Society of Health-System Pharmacists (ASHP).
PDUFA reauthorization: opportunity to improve
induced disease. The identification and manage- continuity of care for patients treated with high risk
ment of adverse effects, participation in drugs. Available at:
spontaneous reporting efforts, and provision of http://www.ashp.org/s_ashp/docs/files/GAD_ASHP_RDDS
patient education that addresses both the risk and _IssueSumm0307.pdf. Accessed March 8, 2009.
benefit of therapies are critical and core clinician- 14. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of
new black box warnings and withdrawals for prescription
responsibilities. As illustrated by the example of medications. JAMA. 2002;287:2215-2220.
thalidomide, drugs with significant safety concerns 15. FDA News. FDA requests marketing suspension of
can provide great health benefits when properly Trasylol. Available at:
managed. Medication-therapy management and http://www.fda.gov/bbs/topics/NEWS/2007/NEW01738.h
other care provided by pharmacists are essential tml. Accessed January 28, 2009.
16. FDA. Maximizing the public health benefit of adverse
components of the drug-safety system. event collection throughout a product’s marketed life
cycle. FDA Public Workshop, January 29, 2008.
17. Medical and Public Health Law Site (MPHLS), Louisiana
State University. Feldman v Lederle Laboratories, 479 A.2d
374 (N.J. 1984). Available at:
References http://biotech.law.lsu.edu/cases/drugs/Feldman_v_Lederle
.htm. Accessed March 8, 2009.
1. General Accounting Office. Drug safety: improvement 18. MPHLS, Louisiana State University. Brown v American
needed in FDA’s postmarket decision-making and oversight Home Products Corporation Diet Drugs, No. 99-20593
process. GAO-06-402. Available at: (E.D.Pa. 08/28/2000). Available at:
http://www.gao.gov/new.items/d06402.pdf. Accessed http://biotech.law.lsu.edu/cases/Drugs/brown_v_AHPC_b
March 8, 2009. rief.htm. Accessed Xxxxx XX, 20XX.
2. Wysowski DK, Swartz L. Adverse drug event surveillance 19. Warner-Lambert Co. v. Kent . No 06-1498, 552 U.S., 2008
and drug withdrawals in the United States, 1969-2002: WL 552875 (2008)
the importance of reporting suspected reactions. Arch 20. Wyeth v. Levine 555 U.S. 06-1249 (2009).
Intern Med. 2005;165:1363-1369. 21. Alaska vs. Eli Lilly. 3AN-06-5630C1 (2008).
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CHAPTER 1 • Drug Safety and Drug-Induced Diseases: The Regulatory, Legal, and Practice Environments 13
CHAPTER 2
level whether an occurrence is due to chance important to remember that association does not
alone or to an association with a drug. For exam- imply causation. Simply put, this means that while
ple, during the past 5 years there has been sub- a reaction may appear to occur in tandem with a
stantial controversy regarding the administration particular drug, it does not necessarily imply that
of the measles, mump, and rubella (MMR) vaccine the drug caused the reaction. Indeed, the impor-
in the United Kingdom and the possible link of tance of determining causality was outlined by
the vaccination to autism. Biostatistics and epi- Professor Sir Austin Bradford Hill, from the London
demiology have been used to determine whether School of Hygiene and Tropical Medicine, in 1965.
autism is more or less likely to occur in vaccinat- In particular, Hill stated: “Our observations reveal
ed children as compared with the general popula- an association between two variables, perfectly
tion. The basic premise is that if autism is more clear-cut and beyond what we would care to attrib-
likely to develop in vaccinated children (as deter- ute to the play of chance. What aspects of that
mined statistically) than in children in the gener- association should we especially consider before
al population, then the association should be deciding that the most likely interpretation of it is
further explored to determine whether causality causation?”15 Hill suggested that the following
exists. That is, does the vaccine cause autism? Or aspects should be considered before causality can
is there some unaccounted factor that also occurs, occur, and these are presented with a specific
but is unrecognized, that causes autism in vacci- emphasis on drug-induced diseases:
nated children? Epidemiologic investigations sug-
gest that there is no evidence linking MMR • Strength of association: Is there a strong asso-
vaccination to autism, thus highlighting the ciation between a suspected drug-induced
importance of epidemiology.12 disease in people taking the drug versus
those not taking the drug? If the associa-
tion is strong (e.g., a relative risk >3), then
one would be more confident that a causal
EPIDEMIOLOGY OF effect exists. An example is the strength of
DRUG-INDUCED DISEASES association between pregnant women tak-
ing thalidomide and giving birth to a dis-
Epidemiology is important in the study of drug- figured child. Indeed, this association was
induced diseases. Among other things, epidemiol- so strong that thalidomide was withdrawn
ogy as applied to pharmaceuticals can be used to from the German market in November
investigate the therapeutic effects, risks, and use of 1961 and was not commercially available
drugs in society. Epidemiology is often used to help again until the U.S., in July 1998, intro-
explain morbidity and mortality questions associ- duced it to treat erythema nodosum lepro-
ated with particular medications. In August 2003, sum, but with specific safeguards to prevent
epidemiologists from the U.S. Department of it from being used by pregnant women.16
Defense were asked to determine whether there • Consistency: Does the suspected drug-
was a causal relationship between the antimalarial induced disease occur repeatedly in differ-
drug mefloquine and unexplained domestic ent persons, at different times, and in
killings among recently returned soldiers from different places? Indeed, consistency is a
Afghanistan.13 No causal link between mefloquine hallmark feature that must occur before
and the violence was established. causality can even be suggested.
A key obstacle in identifying the cause of drug- • Specificity: Is the suspected drug-induced
induced diseases is recognizing the reaction as a disease specific to that drug? For example,
drug-induced disease and being able to distinguish individuals who take excessive doses of
it from spontaneous (i.e., occurring without taking digitalis for heart failure often see “halos.”
the drug), yet similar, clinical manifestations that When they stop taking the drug and the
are not drug-related.14 Another obstacle is deter- plasma digitalis concentrations decrease,
mining the numerator (i.e., number of patients the halo effect disappears. Could there be
with a drug-induced disease) and denominator other causes for these patients seeing halos
(i.e., population who took the drug) necessary to or is it likely only due to digitalis over-
calculate the morbidity or mortality rate associated dose?
with a particular drug. • Temporality: Does the suspected drug-
In trying to determine causality of a potential induced disease manifest before or after
drug-induced disease by a particular drug, it is drug exposure? To even consider causality,
TisdaleC02_14-22 1/12/10 1:53 PM Page 17
An example is to determine the quantitative drug-induced disease during the same period. In
impact of a drug-induced disease of two alternative the general population, the denominator is the
therapies for the same condition. In 2004, the safe- number of people exposed to a particular medica-
ty and tolerability of two aerosolized antifungal tion and could be identified by using computerized
prophylaxis medications in lung transplant recipi- prescription data or medical records. In reality,
ents were assessed. Subjects receiving amphotericin however, numerous obstacles exist in determining
B deoxycholate were more likely to have experi- the denominator, because it is difficult to identify
enced an adverse event than subjects receiving the population of interest and to determine how
amphotericin B lipid complex (OR, 2.16; 95% con- many people in this population were exposed to
fidence interval, 1.10–4.24; P = 0.02).19 Using the the drug. Determining the numerator is also diffi-
equation above, the quantitative impact of adverse cult, because there is no systematic method of
events due to amphotericin B deoxycholate is: assessing the occurrence of drug-induced diseases
in individuals, unless the occurrence is serious
P = (2.16 – 1)/2.16 = 53.7%.
enough to warrant further medical attention.20
However, additional criteria (e.g., Hill’s causali- Data from hospital admission studies can be
ty criteria) must also be considered before making used as an appropriate measure of drug-induced
a definitive judgment on causality. disease incidence because: (1) medical record data
can be used to determine potential association, and
perhaps causation, between a particular drug and
disease; and (2) drug-induced events precipitating
PUBLIC HEALTH IMPACT OF hospitalization are deemed serious enough to be
DRUG-INDUCED DISEASES clinically significant and thus would seem to repre-
sent a higher burden to society. Indeed, Nelson and
Drug-induced diseases exert a considerable impact Talbert note that “the rate of drug-related admis-
on society. They are costly, result in considerable sions is a measure of a subset of the clinically sig-
morbidity, and may result in death. Some adverse nificant related morbidity. Determining this rate
drug effects are not clinically significant, yet “most could identify some of the cases of drug-related
[would] agree that any condition that results in morbidity.”20
hospitalization is significant.”20 In this book, a Another obstacle in determining the incidence
drug-induced disease is defined as an unintended of drug-induced diseases is that, in many cases,
effect of a drug that may result in mortality or mor- medications are not recognized as the cause of the
bidity, with symptoms sufficient to prompt a symptom or disease. Therefore, a particular med-
patient to seek medical attention and/or require ication may not be recorded or reported as a poten-
hospitalization. Costs associated with drug- tial cause. Clinicians may be slow in recognizing a
induced diseases have considerable implications drug-induced disease because not all adverse events
for public health policy and planning. For exam- are reported in the literature or necessarily known
ple, costs associated with drug-induced diseases to the FDA at the time of approval. For rare events
not only divert health care resources, but also have (e.g., a drug-induced disease occurring in 1 of every
measurable (e.g., hospitalization) and societal (e.g., 10,000 people), the likelihood of detection before
lost time from work) costs. From a clinical stand- approval and widespread use is low, because the
point, prevention of drug-induced diseases is clinical trial process, although rigorous, is not
preferable to treatment after the fact. Fortunately, designed to identify all drug-related adverse events.
many drug-induced diseases are preventable. This It is often only after a drug reaches the market, and
section explores issues related to the public health hence a much larger patient population, that rare
implication of drug-induced diseases. events are identified. Therefore, the importance of
postmarketing surveillance activities and signal-
detection activities cannot be overstated.
Determining the Incidence of
Drug-Induced Disease
Determining the incidence of drug-induced dis-
Drug-Related Hospital Admissions
eases can be a daunting task, chiefly because it is As noted earlier, drug-induced hospital admissions
difficult to determine the associated numerator are a sign of serious clinical events. Sometimes
and denominator. The numerator is defined as the these admissions are avoidable and other times
number of new drug-induced disease events occur- they are not. For example, a patient with a known
ring during a defined period, while the denomina- allergy to penicillin who is subsequently prescribed
tor is defined as the population at risk for the this drug and has anaphylactic shock is a case of an
TisdaleC02_14-22 1/12/10 1:53 PM Page 19
avoidable hospital admission. On the other hand, ty, or incidence rate.”22 However, there is some
a patient may receive a medication that causes a information that these studies can provide about
drug–drug, drug–food, or drug–laboratory interac- drug-related hospital admissions. For example,
tion with subsequent hospitalization that is reports can inform us about the types of drugs and
unavoidable, because these interactions were previ- drug classes frequently implicated in drug-related
ously undescribed, were previously unknown, or hospital admissions and about potential causes of
were idiosyncratic in nature. drug-related problems (e.g., drug–drug interaction,
In a 1993 review, the incidence of drug-related noncompliance, etc).
hospital admissions was reported to range from Many studies have identified drug types and
0.2% to 21.7%, with the median rate of drug-relat- drug classes frequently implicated in causing drug-
ed hospitalizations of 4.9%.21 The author defined induced hospital admissions. Although the results
drug-related hospitalizations as adverse events that of these studies vary in terms of drug classes impli-
could cause a side effect, excessive effect, idiosyn- cated and the number of adverse events associated
cratic effect, or hypersensitivity. All of the reviewed with each drug class, some general trends are
studies were conducted in large hospitals, with noted. For example, cardiovascular drugs are often
most located in urban areas. Sample sizes (or total implicated in drug-induced hospital admissions.
admission numbers) ranged from 41 to 11,891, Chiefly, among this group are digitalis, diuretics,
with a total patient population size of 69,187. Only and angiotensin-converting enzyme inhibitors. See
nine of these studies reported incidence rates Table 2–2 for a list of drug classes commonly asso-
above 7.0%, representing just 6.3% of the patient ciated with drug-induced hospital admissions.
population assessed (4,420/69,187). The highest
reported incident rate of 21.7% occurred in a
teaching hospital with oncology patients as the COSTS
predominant patient population. The major impli-
cated medications for drug-related admissions in Costs associated with drug-induced diseases can be
this group were theophylline, chemotherapy quite substantial. Unfortunately, because of
agents, and trimethoprim–sulfamethoxazole. In methodologic problems in determining causality
another review, covering the period from 1959 and because of the numerator/denominator prob-
through 1992, the rate of drug-related hospital lem, only a few attempts have been made to assess
admissions ranged from 0.3% to 16.8% of all hos- direct costs associated with drug-induced diseases.
pital admissions, with a median value of 5.6%.14 An attempt was made to estimate monetary costs
Determining the rate of drug-induced hospital associated with hospitalization due to drug-
admissions is dependent on the study population, induced diseases in Australia.23 However, this study
the ability to extract sufficient medical informa- simply calculated a mean average cost based on
tion, and the study method. Most studies of drug- average length of stay and average daily cost of
related admissions rely on a medical record review hospital care. The report did not include costs of
by a clinical pharmacist. Such a review typically outpatient visits, return visits to a physician’s
defines a drug-induced admission and establishes
criteria for objectively determining whether an
admission meets that definition. The definition of TABLE 2–2 Drug Classes Commonly Associated
drug-related admission can include an adverse drug with Drug-Related Hospital Admissions
reaction, dose-related therapeutic failures, improp-
• Antidiabetics/hypoglycemics
erly treated conditions, and drug interactions.
Among studies assessing drug-related admissions, • Cardiovascular agents (e.g., ACEa inhibitors,
wide ranging results are possible due to variation in diuretics, digoxin)
prescribing patterns, differences in patient popula- • Psychotropics
tions, and differences in defining drug-induced ill- • Gastrointestinal drugs
ness. • NSAIDsb
The true extent of drug-related hospital admis-
• Anticonvulsants
sions remains a mystery, because it is not possible
to make a collective determination of the overall • Antineoplastics
prevalence based on a collection of disparate stud- • Corticosteroids
ies. As Manasse pointed out, although published • Antibiotics
reports provided useful information about drug a
NSAIDs, non-steroidal anti-inflammatory drugs.
misadventuring, these reports were extremely lim- b ACE, Angiotensin-converting enzyme
ited “in establishing a national mortality, morbidi-
TisdaleC02_14-22 1/12/10 1:53 PM Page 20
office, pharmacy costs, or additional treatment ed diseases were $76.6 billion in 1995.24 A follow-
costs. Table 2–3 describes items that should be up study in 2001, using the same cost-of-illness
included in a comprehensive health economic model, reported annual drug-related morbidity
assessment. and mortality costs (in 2000 dollars) of $177.4 bil-
A more comprehensive cost-of-illness lion.25 By comparison, the cost of cardiovascular
approach associated with drug-related morbidity diseases and stroke were estimated to be $393.5 bil-
and mortality was conceived by researchers at the lion in 2005, and the 2004 cost for all cancers was
Center for Pharmaceutical Economics at the $190 billion.26
University of Arizona based on a probability path- When these figures are broken down by cost
way model.24 In this model, costs were determined center, hospitalization was the single highest cost
based on specific outcomes associated with treat- driver for drug-related morbidity and mortality,
ment. When a patient receives drug therapy, four with 1995 expenditures of $47.4 billion and 2000
possible outcomes are possible: (1) optimal thera- expenditures of $121.5 billion (Figure 2–1). In
peutic outcome, in which the patient recovers 1995, for example, 62% of the total cost was repre-
from the illness; (2) treatment failure; (3) a new sented by hospital admissions. In the 2001 study,
medical problem; and (4) a combination of treat- hospital admissions accounted for 69% of the total
ment failure and a new medical problem. costs. This increase is most likely due to higher
Therefore, this model went beyond addressing costs associated with hospitalizations rather than
drug-induced diseases, and included drug-related an increased incidence of drug-related diseases.
events including treatment failures. It stands to Costs associated with new medical problems due to
reason that attaining an optimal therapeutic out- a previously prescribed pharmacologic treatment
come is the desired end result. For patients who do are also expensive. Johnson and Bootman24 esti-
not reach this outcome, additional scenarios are mated that hospitalization costs associated with a
possible: no further treatment, an additional new medical problem were $5,504 in 1995, as com-
physician visit, additional treatment, an emer- pared with $12,797 in 2000.25
gency department visit, hospitalization, long-term However, it should be noted that the expendi-
care admission, or death. tures presented in this model are estimates. Indeed,
Based on this cost-of-illness model, total esti- hospitalization expenses from the 1995 study
mated morbidity and mortality costs for drug-relat- assume that 28.2% of all hospitalizations are due to
drug-related morbidity and mortality.24 This figure
is high and is at odds with reported estimates of
drug-related hospital admissions cited earlier in
this chapter.14,23 As previously discussed,
TABLE 2–3 Costs to Consider When Conducting Einarson21 reported an overall incidence of drug-
a Health Economic Evaluation related hospital admissions ranging from 0.2% to
Direct medical costs 21.7%, with a median value of 4.9%. Hallis14
• Hospitalization reported an incidence of drug-related hospital
admissions ranging from 0.3% to 16.8%, with a
• Outpatient service (including ancillary services)
median value of 5.8%. Johnson and Bootman24
• Pharmacy costs
acknowledge this discrepancy by noting that esti-
• Diagnostic procedures and tests (e.g., laboratory mates (such as by Einarson21) focused on hospital
tests, electrocardiography, and chest radiography) admissions due to noncompliance or adverse drug
• Surgery reactions. Johnson and Bootman24 further note
• Extended nursing or home health costs that estimates in their model included “negative
Direct nonmedical costs therapeutic outcomes owing to all types of drug-
• Transportation to and from the medical provider related problems” and, as such, the estimated num-
bers of hospital admissions “would be expected to
• Services (e.g., meals on wheels and social
be greater.” Despite this explanation, these num-
assistance)
bers appear to be high as compared with empirical
• Adopting devices and instruments evidence and should be judged cautiously in this
Indirect costs light. From a clinical perspective, the rate of drug-
• Sick leave related hospitalizations may be more appropriately
• Reduced productivity in line with the median estimates of 4.9% and
• Early retirement 5.6% reported by Einarson21 and Hallis,14 respec-
tively, because their studies represent wide reviews
• Premature death
of the published literature on the subject.
TisdaleC02_14-22 1/12/10 1:53 PM Page 21
$120 ⫹156.1%
$100
$80
$60
⫹127.7%
$40
⫹85.3%
$20
⫹8.3%
⫹81.9%
FIGURE 2–1 Health care costs for drug-related morbidity and mortality in the United
States in 1995 and 2000.
a
1995 data from: Johnson JA, Bootman JL. Drug-related morbidity and mortality. Archives of
Internal Medicine 1995;155:1949–1956.
2000 data from: Ernst FR, Grizzle AJ. Drug-related morbidity and mortality: updating the cost-of-ill-
ness model. Journal of the American Pharmaceutical Association 2001;41:192–199.
b
The percentage difference indicates the change in health care utilization costs for drug-related
morbidity and mortality from 1995 to 2000.
Mortality due to drug-induced diseases is related mortality due to a new medical problem
also a major concern for pharmacists, physi- that resulted in death had a total pathway cost
cians, and other health care providers. Mortality of $12 797.25
associated with drug-induced diseases presents Finally, it should be noted that although there
an emotional and economic burden to society, are morbidity, mortality, and economic costs asso-
especially in cases for which the cause is pre- ciated with adverse drug reactions, there are also
ventable. The mean death rate due to adverse significant opportunity costs to public health
drug reactions was reported to be 5% of all hos- when medications known to be safe and effective
pitalized patients admitted for a drug-related are not used. For example, childhood vaccination
problem.22 This is over 16 times higher than the rates have declined in some cities throughout the
mortality rate of 0.3% for all other hospital U.S. because of fears of autism. As such, there has
admissions.22 In addition, the cost of hospital- been an increase in the incidence of mumps and
ization with resultant mortality is one of the measles in some communities. This increase in pre-
most expensive costliest single pathways identi- ventable illnesses not only impacts the individual,
fied by Johnson and Bootman as a treatment but also exerts a concomitant effect on the com-
outcome.24 In 1995, for example, drug-related munity population, as herd immunity is reduced
mortality due to a new medical problem had a and individuals not previously susceptible to the
total pathway cost of $5,504.24 In 2001, drug- illness may become susceptible.
TisdaleC02_14-22 1/12/10 1:53 PM Page 22
CHAPTER 3
Factors Contributing to
Drug-Induced Diseases
23
TisdaleC03_23-30 1/12/10 2:26 PM Page 24
generally do not result in an altered clinical examples in Table 3–1. For instance, the incidence
response, however, because the concentration of of skin rashes and serious dermatologic adverse
unbound drug is unaffected. Nevertheless, misin- effects such as Stevens–Johnson syndrome is
terpretation of total serum drug concentrations of increased in patients with human immunodefi-
highly protein-bound drugs that are routinely ciency virus (HIV) infection who are taking
monitored may lead a clinician to inappropriately trimethoprim–sulfamethoxazole. Patients with
increase the dose, thus resulting in toxicity.8 cytomegalovirus infection who are taking ampi-
Concurrent diseases may also be associated cillin are also at increased risk for skin rashes.
with enhanced pharmacodynamic responses to Although the precise mechanisms are unknown,
drugs for a variety of reasons, as shown by the desensitization procedures generally reduce the
TisdaleC03_23-30 1/12/10 2:26 PM Page 25
severity of the adverse effect if rechallenge with the cells, biliary hepatocytes, and renal tubular cells,
drug is necessary.9 transports drug from within the cell to the intes-
tine, bile, or urine, respectively. Inhibition of P-gly-
coprotein can therefore increase the bioavailability
Physiologic Conditions and decrease renal and biliary excretion of affected
The pharmacokinetics of a drug may be affected by drugs, thus increasing their serum concentrations.
age, pregnancy, and sex.10 In general, the rate of Other interaction mechanisms that may result in
elimination of a drug is impaired in premature reduced renal excretion include reduction of the
newborns, increases in early childhood to more glomerular filtration rate and increased reabsorp-
efficient rates than those in adults, and then pro- tion of drug into blood from the renal tubule.
gressively declines with advancing age. In addi- Examples of drug-drug interactions involving
tion, elderly patients may also suffer from increased bioavailability, decreased metabolism,
decreased mental status or diminished physical and/or decreased biliary and renal excretion are
function. When these physiologic conditions are shown in Table 3–2.14,19-26
compounded by decreased elimination of some Drugs that displace other drugs from serum
drugs (e.g., benzodiazepines), the patient is more protein-binding sites without affecting their
susceptible to drug-induced falls or physical metabolism cause only transient increases in
injury.11 A variety of physiologic changes during unbound drug concentration, and hence do not
pregnancy may affect the pharmacokinetics of generally result in adverse effects. Displacement of
drugs, but no consistent patterns have been identi- drugs such as warfarin (long half-life, small volume
fied. The higher serum concentrations of digoxin of distribution, and narrow therapeutic range) can
reported in pregnant patients may be caused by be clinically important, however, and necessitate a
increased bioavailability resulting from decreased temporary reduction in the dose of the affected
gastric emptying time. Women have a higher risk drug.8
of drug-induced adverse events as compared with Serious drug–drug interactions may also occur
men, which has been attributed to the fact that when drugs produce additive effects through dif-
they take more drugs than men, have lower activi- ferent mechanisms. Examples include: (1) the com-
ty of drug-metabolizing enzymes, and have estro- bined blood-pressure–lowering effects of calcium
gen-related effects on drug receptors, as in the case channel-blockers and -blockers; (2) the increased
of drug-induced torsades de pointes.12,13 risk of gastrointestinal bleeding resulting from
nonsteroidal antiinflammatory drug (NSAID)–
induced gastric erosion in patients taking warfarin;
Drug–Drug Interactions and (3) exaggerated cyclic guanine monophos-
Drug–drug interactions may cause altered pharma- phate (cGMP)–mediated smooth-muscle relaxation
cokinetics (bioavailability, distribution, clearance) caused by the combination of sildenafil (which
or altered pharmacodynamics by additive or antag- inhibits cGMP degradation) and nitrates (which
onistic effects. Such interactions have been exten- increase GMP production), leading to potentially
sively reviewed and are often a predictable and serious hypotension.27 An example of a drug–drug
preventable cause of morbidity and mortality.14-17 interaction involving active or toxic metabolites is
By far the most frequent contributing factors to the potentiation of acetaminophen hepatotoxicity
drug-induced disease resulting from drug interac- in patients receiving enzyme inducers such as
tions are those that affect bioavailability and drug rifampin, presumably by increasing the formation
elimination. A large number of important interac- of toxic acetaminophen metabolites.28
tions occur in the liver and gastrointestinal tract
because of decreases in the rate of a drug’s metabo-
lism or transport caused by other drugs that are
Drug–Food Interactions
inhibitors of these systems.14-16 Most drug–drug Drug–food interactions have been extensively
interactions involving metabolism are attributable reviewed.15,29,30 One of the most serious drug–food
to enzymes in the cytochrome P-450 family which interactions occurs with first generation nonselec-
may be inhibited by other drugs. Tables listing the tive monoamine oxidase inhibitors and tyramine,
most common isozymes, their known substrates, an amino acid found in aged or fermented foods
and their inhibitors and inducers are designed to and beverages. The suppressed metabolism of large
help clinicians avoid or minimize serious conse- amounts of tyramine may result in hypertensive-
quences of particular drug combinations.14,18 crisis, the so-called cheese reaction.31 Components
P-glycoprotein, a transporter protein expressed of grapefruit juice are known to suppress the
on the luminal surfaces of intestinal epithelial presystemic elimination of certain drugs that are
TisdaleC03_23-30 1/12/10 2:26 PM Page 26
TABLE 3–2 Examples of Pharmacokinetic Drug–Drug Interactions That Can Result in Toxicity14,19-26
Mechanism Example
Bacterial inactivation of gut flora Approximately 10% of the population has bacteria in the gastrointestinal tract
that extensively inactivate digoxin prior to its absorption. Because these
patients require relatively high digoxin doses, inactivation of gut bacteria by an
antibiotic such as tetracycline can result in toxicity.
Inhibition of drug-metabolizing The atypical antipsychotic clozapine is a substrate for CYP1A2, while fluvoxe-
enzymes tine (and other serotonin reuptake inhibitors) are potent inhibitors of this
enzyme system. In one case, death was reported to be the result of a clozapine
overdose associated with fluoxetine coadministration.
Verapamil is a substrate of CYP3A4 and P-glycoprotein, while erythromycin is
an inhibitor of both. Coadministration of erythromycin or certain other
macrolide antibiotics increases verapamil bioavailability by minimizing intestin-
al and hepatic first-pass extraction and decreasing verapamil body clearance,
resulting in serious toxicity in at least one case.
Inhibition of drug transport Digoxin is a substrate for P-glycoprotein in enterocytes, biliary hepatocytes,
and renal tubular cells. Quinidine is a potent inhibitor of P-glycoprotein, and its
coadministration causes an increase in the bioavailability of digoxin, as well as
a decrease in digoxin renal and biliary clearances. Other P-glycoprotein
inhibitors that have similar effects on digoxin include amiodarone, verapamil,
cyclosporine, erythromycin, and several of the protease inhibitors.
Methotrexate excretion is reduced when a sulfonamide or sodium salicylate is
given concurrently, because of competition for the same drug transport
proteins in the proximal renal tubule.
Decreased organ blood flow NSAIDs decrease lithium clearance and increase lithium concentrations. The
probable mechanism is an NSAID-induced decrease in renal blood flow (result-
ing in decreased glomerular filtration rate) inhibition of prostaglandins.
Lidocaine clearance has been reported to be decreased by -blockers because
of a combination of hepatic blood flow–lowering and enzyme inhibition
effects.
Increased renal reabsorption Thiazide diuretics cause sodium and water depletion, which leads to increased
sodium reabsorption in the proximal tubule of the kidney as a compensatory
mechanism. Since lithium is reabsorbed by the same mechanisms as sodium,
lithium reabsorption increases and lithium clearance decreases during treat-
ment with thiazide diuretics.
Alkalinization of the urine in normal subjects has been shown to increase
serum concentrations of quinidine, presumably because of increased tubular
reabsorption. The increase in serum quinidine concentration was associated
with an increase in the QT interval.
NSAID = nonsteroidal antiinflammatory drug.
either metabolized in the intestinal wall by the In general, an increase in drug bioavailability
cytochrome P-450 isozyme CYP3A4, are substrates caused by food intake is not a problem if doses
for P-glycoprotein, or both, resulting in increased throughout the course of treatment are taken con-
bioavailability. Drugs for which bioavailability sistently at a fixed time relative to a meal.
increases dramatically when taken with grapefruit However, a clinically important drug–food interac-
juice include lovastatin, simvastatin, buspirone, tion was reported for a particular once-daily theo-
and amiodarone.14,29 If alternative, noninteracting phylline product, which has since been
drugs are not available, patients may need to avoid reformulated. When taken with high-fat meals, a
drinking grapefruit juice. sudden, rapid release of a large amount of theo-
TisdaleC03_23-30 1/12/10 2:26 PM Page 27
phylline occurred, leading to excessively high ants that produce low-activity enzymes for the
serum theophylline concentrations.29 metabolism of warfarin experience a higher risk of
The salt, protein, or vitamin content of the diet serious bleeding events.39 Severe and potentially
also may affect the renal excretion of drugs. For fatal hematologic toxicity occurs in the small per-
example, a patient taking lithium who initiates a centage of patients receiving azathioprine or mer-
low-salt diet for treatment of hypertension or heart captopurine who have a genetic deficiency in the
failure excretes less lithium, resulting in higher thiopurine methyltransferase enzyme.35
serum lithium concentrations and potential toxic- Polymorphisms in receptors, ion channels, or
ity, given this drug’s narrow therapeutic range.32 A other proteins involved in drug response also
low-protein diet is associated with decreased renal occur. These result in widely variable pharmacody-
clearance of oxypurinol, apparently through namic responses among patients despite similar
enhanced reabsorption efficiency by the uric acid concentrations of the drug at the site of action.
transporter system.29 Examples include the polymorphisms in: (1)
dopamine receptors, which affect the risk of drug-
induced tardive dyskinesia; (2) skeletal-muscle
Lifestyle Factors ryanodine receptors, which affect the risk of anes-
Alcohol and caffeine consumption can affect both thesia-induced malignant hyperthermia; (3) potas-
the pharmacokinetics and the pharmacodynamics sium or sodium channels, which affect the risk of
of other drugs, leading to serious drug-induced dis- potentially fatal torsades de pointes when certain
eases.15 There are many examples of alcohol exag- antiarrhythmic drugs are administered;34 (4) glu-
gerating the central nervous system depressant cose-6-phosphate dehydrogenase, which if defi-
effects of drugs, including benzodiazepines, phe- cient, leads to red-cell hemolysis in patients who
nothiazines, tricyclic antidepressants, opiates, and take drugs with a high redox potential, such as
antihistamines. Caffeine has an additive and aspirin, nitrofurantoin, sulfonamides, and quini-
potentially dangerous stimulant effect when taken dine; and (5) the major histocompatibility com-
with ephedrine in herbal weight-loss and athletic plex, which mediates hypersensitivity reactions to
performance–enhancing supplements.33 drugs such as abacavir and nevirapine.40
The future holds promise that drug-induced
adverse effects may be avoided by genetic screen-
Genetic Variability ing of patients prior to initiation of drug therapy. It
As a result of the rapidly evolving field of pharma- is becoming the standard of care to test patients for
cogenomics, interindividual differences in drug- the lack of thiopurine methyltransferase prior to
related toxicity and therapeutic response are not initiating azathioprine therapy to reduce the risk of
always considered to be “idiosyncratic” respons- severe and sometimes fatal toxicity, or the lack of
es.34 Rather, it is widely recognized that genetic glucose-6-phosphate dehydrogenase prior to dap-
makeup is responsible for a significant portion of sone therapy to avoid dapsone-induced hemolytic
drug-induced diseases. Many genes that encode anemia.41 In some cases, combinations of gene
metabolic enzymes or drug transporters are poly- variants have been better predictors of drug effects
morphic, meaning that some groups of patients than single gene variants. The presence of a combi-
with certain gene variants have relatively inactive nation of three gene variants in one Australian
enzymes or transporters, while others have unusu- population accurately predicted serious hypersen-
ally active forms. In addition, the proportion of sitivity to abacavir, a drug used to treat patients
patients with active or inactive forms may differ with HIV. Genotyping for this combination is now
among racial groups. routinely used in that population prior to initiat-
Polymorphisms in metabolizing enzymes have ing therapy.38 The use of pharmacogenetic diag-
been extensively reviewed.1,35-38 Patients with low nostic tests is slowly gaining acceptance by
N-acetyltransferase activities, known as “slow acety- clinicians and will undoubtedly become increas-
lators,” are more likely to suffer from peripheral ingly important for the safe use of a growing num-
nerve damage when administered standard isoni- ber of drugs.42,43
azid doses as compared with fast acetylators.
Likewise, slow acetylators of hydralazine are more
likely to suffer from hydralazine-induced lupus ery- ADHERENCE TO
thematosus. At least four of the major cytochrome PRESCRIBED THERAPY
P-450 isozymes (CYP2A6, CYP2C9, CYP2C19,
CYP2D6) responsible for oxidative drug metabolism The terms adherence and compliance are often used
are polymorphic in nature. Patients with gene vari- interchangeably. However, noncompliance implies
TisdaleC03_23-30 1/12/10 2:26 PM Page 28
that the patient is intentionally or willfully not fol- scribed medication regimen was the identified
lowing directions for medication use, which may cause of 33% of these admissions. Unfortunately,
or may not be the case. For this reason, some pre- health care providers typically are unable to identi-
fer the term nonadherence, because it places no fy patients at risk for nonadherence. Patient age,
blame on either the patient or the health care pro- sex, race, intelligence, and educational background
fessional. Common causes of nonadherence are have not been shown to be predictive of adherence
listed in Table 3–3. Regardless of the cause, nonad- or nonadherence to a prescribed drug regimen.48
herence can lead to drug-induced disease. Patients Many strategies have been used to improve
may take more or less drug than prescribed or rec- adherence to medication regimens, including ver-
ommended, modify medications in an inappropri- bal instruction, supplementary written instruction
ate fashion (e.g., crush a sustained-release tablet), sheets or videotaped instructions, phone call
or continue to take a prescribed drug even though reminders, supplementary educational programs
the underlying medical condition for which the for the patient and family caregivers, self-monitor-
drug was originally prescribed has resolved. Any of ing flow sheets, switching from multiple daily dos-
these actions can put patients at increased risk for ing of a medication to once-daily dosing, changing
drug-induced disease. the time of day that a medication is administered,
It is estimated that the prevalence of medica- special reminder packaging, and others. Until the
tion nonadherence is 40% to 70%.44-46 McDonnell most effective strategy or strategies to improve
and Jacobs analyzed the cause for hospital admis- adherence can be identified, it is recommended
sions from preventable adverse drug reactions.47 Of that health care professionals keep drug regimens
158 drug-related hospital admissions over an 11- simple, provide clear and complete instructions,
month period, patient nonadherence with a pre- encourage medication adherence by scheduling
regular appointments, respond clearly and prompt-
ly to patients’ questions and concerns, and rein-
force adherence with the prescribed regimen at
TABLE 3–3 Common Causes of Medication every opportunity.46
Nonadherence
Cultural beliefs of the patient MEDICATION ERRORS
Mistrust of health professional: patient does not agree
with health care management Medication errors contribute significantly to the
Patient wants to speed up response to treatment and problem of drug-induced disease. These errors can
takes more drug than is recommended include a variety of problems involving any step in
the drug-use process.49 One study of hospitalized
Patient is unable to read written materials provided by
patients reported that 49%, 26%, 14%, and 11% of
health care professional and is afraid to take
errors occur in the prescribing, administering, dis-
medication.
pensing, and transcribing stages, respectively, of
A long time passes between follow-up visits with the drug-use process.50 In another study, 67% of
health professional; patient begins to feel that treat- hospital admissions caused by adverse drug reac-
ment is not important. tions were attributed to inadequate patient moni-
Patient forgets to take medication during the day toring (e.g., failure to order appropriate laboratory
Patient has difficulty opening bottles that contain tests to monitor drug response or failure to respond
medications appropriately to abnormal laboratory-test results)
and 51% were caused by inappropriate drug
Patient has physical limitations and cannot administer
doses.47 In one study of more than 2,000 elderly
medication as prescribed (e.g., patient has severe
patients, it was estimated that 63% of elderly out-
arthritis and cannot administer insulin injection)
patients are receiving one or more medications
Patient cannot afford medication that are not necessary.51 This overuse can signifi-
Patient has psychological disorder and fails to compre- cantly increase the risk of drug-induced disease in
hend need to take medication. a very vulnerable population.
Health care professional fails to educate patient about Fortunately, not all medication errors result in
proper medication use, dose, and administration tech- clinically significant problems. In one study of hos-
niques. pitalized patients, only 7 of 100 medication errors
were thought to be serious enough to cause
Patient fails to understand proper prescribing direc-
harm.52 However, in view of the overall frequency
tions because of language barrier
of medication errors that occur each year, a 7%
TisdaleC03_23-30 1/12/10 2:26 PM Page 29
proportion of serious medication errors may result 12. Rademaker M. Do women have more adverse drug
in many affected lives. reactions? Am J Clin Dermatol. 2001;2:349-351.
13. Drici MD, Clement N. Is gender a risk factor for adverse
Medication errors and drug-induced diseases drug reactions? The example of drug-induced long QT
may result from the limitations of an individual syndrome. Drug Saf. 2001;24:575-585.
practitioner, from problems latent in the system or 14. Hansten PD, Horn JR. Drug Interactions: Analysis and
setting in which the practitioner operates, or from Management. 3rd ed. Baltimore, MD: Lippincott, Williams
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care settings to help reduce the incidence of med- digoxin by gut flora: reversal by antibiotic therapy. N Eng
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potentiation. Neurotoxicology. 2004;25:243-250. reactions in diagnostic and clinical practice. Clin Chem
32. Bettinger TL, Crismon ML. Lithium. In: Burton ME, Shaw Lab Med. 2007;45:801-814.
LM, Schentag JJ, et al., eds. Applied Pharmacokinetics and 44. Stewart RB, Caranasos G. Medication compliance in the
Pharmacodynamics: Principles of Therapeutic Drug elderly. Med Clin North Am. 1989;73:1551-1560
Monitoring. 4th ed. Baltimore, MD: Lippincott, Williams 45. Weintraub M. Compliance in the elderly. Clin Geriatr
& Wilkins; 2006:798-812. Med. 1990;6:445-452.
33. Haller CA, Jacob P, Benowitz NL. Enhanced stimulant 46. Haynes RB, McDonald HP, Garg AX. Helping patients
and metabolic effects of combined ephedrine and follow prescribed treatment. JAMA. 2002;288:2880-2883.
caffeine. Clin Pharmacol Ther. 2004;75:259-273. 47. McDonnell PJ, Jacobs MR. Hospital admissions resulting
34. Wilke RA, Lin DW, Roden DM, et al. Identifying genetic risk from preventable adverse drug reactions. Ann
factors for serious adverse drug reactions: current progress Pharmacother. 2002;36:1331-1336.
and challenges. Nat Rev Drug Discov. 2007;6:904-916. 48. McDonald HP, Garge AX, Haynes RB. Interventions to
35. Linder MW, Evans WE, McLeod HL. Application of enhance patient adherence to medication prescriptions.
pharmacogenetic principles to clinical pharmacology. In: JAMA. 2002;288:2868-2879.
Burton ME, Shaw LM, Schentag JJ, et al., eds. Applied 49. Krahenbuhl-Melcher A, Schlienger R, Lampert M, et al.
Pharmacokinetics and Pharmacodynamics: Principles of Drug-related problems in hospitals: a review of the recent
Therapeutic Drug Monitoring. 4th ed. Baltimore, MD: literature. Drug Saf. 2007;30:379-407.
Lippincott, Williams & Wilkins; 2006:165-185. 50. Bates DW, Cullen DJ, Laird N, et al. Incidence of adverse
36. Ma MK, Woo MH, McLeod HL. Genetic basis of drug drug events and potential adverse drug events:
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37. Humma LM, Terra SG. Pharmacogenetics and 51. Larouche ML, Charmes JP, Nouaille Y, et al. Is
cardiovascular disease: impact on drug response and inappropriate medication use a major cause of adverse
applications to disease management. Am J Health Syst drug reactions in the elderly? Br J Clin Pharmacol.
Pharm. 2002;59:1241-1252. 2007;63:177-186.
38. Güzey C, Spigset O. Genotyping of drug targets: a 52. Bates DW, Boyle DL, Vander Vliet MB, et al. Relationship
method to predict adverse drug reactions? Drug Saf. between medication errors and adverse drug events. J
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39. Higashi MK, Veenstra DL, Kondo LM, et al. Association 53. Vincent C. Understanding and responding to adverse
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diagnosing abacavir and nevirapine drug 55. Leape LL, Bates DW, Cullen DJ, et al. Systems analysis of
hypersensitivity: from bedside to bench and back again. adverse drug events. JAMA. 1995;274:35-43.
Pharmacogenomics. 2006;7:15-23. 56. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is
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42. Lanfear DE, McLeod HL. Pharmacogenetics: using DNA Crossing the Quality Chasm: A New Health System for the
to optimize drug therapy. Am Fam Physician. 21st Century. Washington, DC: National Academies Press;
2007;76:1179-1182. 2001.
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CHAPTER 4
Postmarketing Surveillance
for Drug-Induced Diseases
Hugh H. Tilson
erably severe adverse outcomes of treatment can The cornerstone of population-based surveil-
provide only statistical assurance that the likelihood lance for medication-induced illness, as with pub-
of such drug-induced illnesses, if they exist, is less lic health monitoring of many emerging problems,
than 1 in 1,000. Moreover, the duration of such is the technique of encouraging all practitioners to
preapproval studies is generally only as long as is participate in a system of spontaneous voluntary
needed to comply with FDA requirements. Thus, the reporting. Here, the logic is to invite a heightened
occurrence of an excess of heart attacks following 18 awareness, particularly regarding new drugs, that
months of therapy would be missed even in a rela- adverse outcomes following therapy—particularly
tively large preapproval database of shorter studies. those that are otherwise unexpected—may be
The hothouse environment of the well-con- attributable to the therapy. Therefore, if there is
trolled, blinded, and randomized study further any index of suspicion, any member of the treating
limits what we can know about the new drug’s per- team, as well as the patient or his or her family is
formance in wider clinical use following its encouraged to report, albeit on a voluntary basis.
approval. Naturally, preapproval studies are gener- Clinical detection of any single drug-induced
ally conducted under tightly controlled circum- disease or injury in a single patient is extremely dif-
stances, with carefully designed protocols that ficult. In professional training we are taught to
exclude patients who appear to present the threat “expect the unexpected.” In most cases, drug-
of confusing results. These can include patients induced illness does not manifest itself in dramati-
affected by concurrent illnesses, taking concomi- cally different ways from any illness that may be
tant medications, and with specific risk factors or treated in a physician’s office or pharmacist’s prac-
patients belonging to potentially risky population tice. Sudden death, liver or kidney failure,
strata, such as the poor, ethnic minorities, chil- encephalopathy, heart attack, and other events may
dren, pregnant women, and the elderly. occur for no particular reason. Even Stevens–
In summary, our understanding of the proba- Johnson syndrome, often thought of as a classic
bility (risk) of incurring a drug-induced disease drug-induced disease, has as its two most frequent
from a newly approved drug is limited by the causes “cause not apparent” and viral infection,
nature of the system for premarketing study and with drug-induced listed third.1 Thus, the experi-
the approval process. ences of the individual clinician, however impor-
tant in guiding continuing decision-making in
much of medicine, are inadequate for informing us
THE NEED FOR POPULATION- about drug-induced disease. On one hand, a clini-
BASED SURVEILLANCE cian witnessing one or two dramatic adverse events
FOLLOWING MARKETING following the use of a specific drug may consider
that drug a “bad actor,” when the events may have
Systematic approaches to detection, quantifica- been a rare coincidence or perhaps not drug-related
tion, and education concerning drug-induced dis- at all. On the other hand, having never had a prob-
ease following marketing have emerged only lem with the drug may simply be a function of the
relatively recently, with the advent of clinical trials rarity of the drug-induced illness, the luck of the
approximately 50 years ago. Then, as now, the draw, or failure to link, for example, the kidney fail-
medical community educated itself largely by ure in one or two patients with the drug or drugs
means of the published word, via clinical and sci- they were taking. There is, in short, no substitute for
entific journals. Before randomized, controlled population-level surveillance to determine the pres-
clinical trials were introduced, this “education by ence or absence of relatively rare problems or an
publication” typically took the form of anecdotal increase in the incidence of otherwise not-so-rare
case histories, describing incidents of illness fol- adverse events over baseline. Thus, as in other pub-
lowing drug therapy, in which the drug was lic health enterprises, the aggregate experience in a
blamed for the undesired outcome. As part of the population serves as the most effective sentinel or
reform of the Food, Drug and Cosmetic Act, volun- signaling tool for possible problems.
tary reporting of such experiences to the FDA or
the manufacturer was introduced as a fledgling sur-
veillance system. The logic for such a system is that THE SPONTANEOUS REPORTING
the only way to know of potential drug-induced SYSTEM IN AMERICA
problems that are unlikely to be detected in the
preapproval drug development process is to moni- In this book, we differentiate between adverse drug
tor real-world experience after introduction of reactions (ADRs), also referred to as adverse effects or
those products into the marketplace. side effects, and drug-induced disease. However, in
TisdaleC04_31-39 1/12/10 2:27 PM Page 33
every sense, the latter are a subset of the former. and generally unwanted has occurred and suspects
Thus, our primary system for detecting and tracking that the event is associated with a drug. (In princi-
drug-induced diseases at the national level is the ple, the SRS also could recognize unintended but
spontaneous adverse reactions reporting system positive effects such as the unexpected hair growth
(SRS), which is the nation’s system for tracking all observed with minoxidil, which led to the develop-
ADRs. Many have criticized the system as being a ment of Rogaine and the sustained penile erection
“nonsystem,” comprising a loosely administered observed as an unexpected side effect of an antihy-
chain of events in which those in positions to detect pertensive drug that eventually became Viagra). A
ADRs—the patients and the clinicians who work patient can introduce this information into the SRS
with them—are encouraged, voluntarily and without either by reporting it directly to the manufacturer
incentive, to call such incident to the attention of or a regulatory agency via a consumer report or by
those who are in a better position to assemble, ana- seeking medical care and calling it to the attention
lyze, and act upon the ADRs. Indeed, the activities of the provider who then reports it to one of these
constituting the SRS are not systematic and are not agencies. Most providers—physicians, nurses, den-
integrated into the rest of the nation’s systems of tists, and pharmacists—claim that they have not
public health and safety surveillance. As a result, the been trained sufficiently in the detection, manage-
protections that this component of the nation’s sur- ment, and reporting of ADRs to function effective-
veillance systems could provide are not guaranteed. ly as reporters in this system. Indeed, most indicate
For the system to effectively capture and apply that they have not reported a single ADR in the
data concerning ADRs, a certain chain of events past year, nor would they know how to report one
must transpire. Someone must detect that an had they wished to do so.2 Moreover, most
adverse event has happened and must suspect that providers suggest that they see very few ADRs in
the adverse event might be associated with a drug their practice, even though, given the nature and
exposure. This detection and interpretation must frequency of drug-associated adverse events, we
then be translated into action—the act of reporting know that they occur during the routine practice
the event, usually to an unseen, remote recipient. of all health care providers. Many health profes-
This event must be communicated to someone in sion educators attribute the lack of awareness of
the system who will decide to incorporate it with ADR prevalence on the failure of health curricula
information from other major sources—in the to educate emerging clinicians on the critical bal-
United States (U.S.), typically either a government ance between a systems-thinking sensibility and
agency such as the FDA’s MedWatch system or the the traditional art and science approach. The
Vaccine Adverse Event Reporting System or one or Association of American Medical Colleges has
more intermediaries. The primary such intermedi- acknowledged the lack of broad consensus around
ary in the U.S. is the research-based, brand-name the competencies required to be taught in profes-
pharmaceutical company. Pharmaceutical manu- sional education for effective participation in the
facturers receive, process, manage, analyze, and nation’s drug safety system. The result has been a
report well over 80% of all ADRs that eventually far-reaching comprehensive inventory of such
come to the attention of the FDA.2 For manufactur- competencies to be incorporated in all training
ers, further reporting of ADRs, reported sponta- programs.3
neously and voluntarily from the field, is It also must be noted that very few drug-induced
mandatory. diseases are unique clinical entities. Rather, drugs are
partially or broadly responsible for causing or aggra-
vating many common clinical conditions.
THE ACTORS AND THEIR ROLES Identifying drugs as a potential cause requires com-
plex clinical analysis. Furthermore, the drug may
It is worthwhile to examine the roles of each of the have been obtained through another prescriber, self-
personal “actors” and the processes involved in prescribed from the home medicine cabinet, or
postmarketing surveillance, and explore some of combined with an alternative or complementary
the challenges involved in linking them into an medicine (prescribed or otherwise) or an unusual or
effective system. unexpected dietary pattern. The patient may not
have adhered to the recommended regimen, result-
ing in overdosing, underdosing, or (most common-
The Clinician ly) episodic dosing, the latter two resulting in the
The point of departure for surveillance in the SRS is adverse outcome of unexpected or periodic treat-
the reporter—the person, usually a clinician, who ment failure. The patient may not recall fully or
recognizes that something untoward, unexpected, accurately which medications he or she has taken,
TisdaleC04_31-39 1/12/10 2:27 PM Page 34
or in what quantity, or in the case of illicit-drug use, ease. The SRS receives reports from patients or their
may not wish to disclose this information. And, of advocates every day; up to 20% of reports are from
course, the patient is generally taking medications patients/consumers.6 While good surveillance
to treat an underlying or intercurrent illness, the practice recommends that patients be referred to a
progression of which may be confused with the primary caregiver when making a report directly,
drug-attributable illness. Clearly, identifying (or, ide- the Council for International Organizations of
ally, preventing) drug-induced disease requires a Medical Sciences (CIOMS) working group conclud-
partnership between patient, physician, and phar- ed that it is the quality of the report and not the
macist based on full disclosure, open discussions, nature of the reporter that is essential.7 Thus, while
and awareness of potential risk factors. in Europe consumer reports are generally not
The clinician must not merely recognize the ill- included in the SRS, in the U.S. and Canada they
ness, but also must endure the complexities of clin- are. Thus, patient education regarding potential
ical attribution in differential diagnoses. This is no drug-induced illness and heightened awareness of
easy task, particularly given that the complexities reporting avenues and action all result in a
of clinical pharmacology are themselves rapidly stronger likelihood that the SRS will learn about
evolving. Having made a provisional association important drug-induced diseases directly from the
between drug and disease, the first concern of the patient.
treating provider is to remove or counter (or both)
the offending agent. Simply achieving this goal
easily can occupy the entirety of a 15-minute
The Manufacturer
patient visit, without the burdensome administra- A key factor in the SRS in the U.S., much misunder-
tive tasks of reporting to an invisible and remote stood and generally underestimated, is the role of
third party. No economic incentive exists to do so the entity marketing the drug (particularly in the
either, as voluntary reporting is expected to be per- early stages of marketing), the research-based phar-
formed pro bono. Indeed, ADR reporting likely will maceutical company. As an innovator, operating
generate subsequent questions and requests for under an Investigational New Drug Application,
more data from the agent receiving the report, cre- these companies also are referred to in the regula-
ating a potentially significant inconvenience, tory context as sponsors, since they sponsor New
which could discourage reporting. And, although Drug Applications. The sponsor is responsible,
in the wake of the Institute of Medicine’s (IOM) To under federal law, for compliance with all applica-
Err Is Human report,4 we are admonished not to ble federal regulations relating to the safety, effica-
“name, blame, or shame” those who report and cy, and purity of its products, including the
attempt to repair errors (in this case, in prescribing, conduct of regular ongoing product surveillance.8
warning, or monitoring), there nevertheless may Under these provisions, the sponsor is expected to
be fear that admitting to a decision that caused an maintain vigilance over the safety of its products,
adverse outcome could result in a lawsuit or other including receipt, management, and further
censure. Current tort law does little to allay this reporting of all ADRs from any source, including
anxiety. The extent to which these barriers con- the published literature, ongoing clinical trials,
tribute to underreporting is not known. Based on and, primarily, the reporters who use, manage, and
populations prospectively and objectively moni- prescribe their products, as described above. Under
tored, the underreporting ratio, even for severe or the applicable regulations, sponsors are expected
serious ADRs (actual illnesses induced by medica- to maintain a program that provides an immediate
tions) is estimated to be 10-fold or worse.5 review of any report, received from any source, and
can differentiate the serious event (as carefully
defined in FDA regulation and the subject of inter-
The Patient national consensus reports by CIOMS and interna-
The patient is the point of departure for the post- tional management agreements under the
marketing surveillance system. Preventing drug- International Conferences on Harmonization)
induced disease in the individual patient through from the nonserious.
awareness of the likely consequences of specific cir- Any report meeting the criteria for serious or
cumstances, such as risk factors and drug interac- potentially serious effects must be transmitted to
tions, requires a partnership between the FDA within 15 days of its initial receipt. This
physician, pharmacist, and patient and must requirement is not limited to the U.S., as the regu-
include full disclosure, open discussion, and aware- lations speak specifically to products sold any-
ness of potential risks. In addition, the patient may where in the world. Thus, any report documenting
be a direct reporter of potential drug-induced dis- an event that is serious and outside the product
TisdaleC04_31-39 1/12/10 2:27 PM Page 35
label (unexpected, unlabeled, or unlisted) that is healthy and active partnerships between govern-
received by the company, its affiliate, or its agent ment and the private sector, which in this case is
anywhere the drug is marketed requires immediate the regulated pharmaceutical industry.9 However,
transmittal to the FDA. Furthermore, such cases the FDA is the ultimate arbiter of a company’s ade-
also require sponsors to analyze the completeness quacy concerning compliance activities, both on a
of the description carefully and to follow up report-by-report level and overall as a partner in
regarding incomplete data and/or information public health protection. Each report receives
needed to ascertain both severity and outcome triage in the agency. Serious reports, such as those
associated with serious drug-related illness. Enough describing reactions most likely to result in drug-
information is needed to help with both causality induced disease or injury, receive priority atten-
assessments for the individual case and risk-factor tion, particularly those that also qualify as
assessment for evolving case series. This latter unexpected. Each sponsor also receives compliance
requirement results in the reporting practitioner oversight from the agency, including a program of
being pursued for more and better information. FDA site visits and compliance audits to ensure an
The CIOMS Working Group has outlined best prac- intact reporting system with full transparent dis-
tices for pharmacovigilance to provide guidance closure from sponsor to agency.
for sponsors in their vital roles in this public health Attribution of a problem being considered for
paradigm.7 These best practices include regular, an ADR report requires the clinician to consider
scheduled, comprehensive reviews of each of their the possibility of a causal relationship between an
products. For every drug under their responsibility, event and a drug, in the context of multiple other
the sponsor prepares a summary report, currently possible causal explanations for the same event.
known as a “Periodic Safety Update Report,” which Rarely is such a causal relationship unambiguous.
describes the overall experience over a particular Rather, the clinician must apply complex logic,
period of time and in the population under surveil- including consideration of the timing of the event,
lance. the presence of other possibly causal exposures, the
The modern scientific research-based pharma- natural history of the underlying disease, and so
ceutical company provides a broad spectrum of forth. The SRS operates on the fundamental
services to the treating community, including drug assumption that a report would not be submitted
information services that constitute a primary unless a reporter had some concern or suspicion
interface between the company and health care about a possible causal relationship to the drug.
practitioners. A physician, nurse, dentist, or phar- Thus, all SRS reports are considered possibly attrib-
macist may contact the company for information utable. The evolution of the system, however,
regarding its products and accumulated reported brings this assumption into question. For example,
clinical experiences or new information regarding more and more information comes to the atten-
their use. Typically, the purpose of the call is not tion of the system because of proactive study or
really to report anything, but to learn more about detailed information-seeking in association with
the drug product in question and its use. It is a an individual report. This challenges scientists and
requirement that the contact be viewed as sponta- practitioners involved in the science of surveil-
neous and that it be considered as a reportable pos- lance to differentiate between truly spontaneous
sible ADR. Thus, the better the drug information and possibly attributable reports and the reports
system, the more calls it receives, and the more that are elicited.
reports of potential ADRs are generated. This The pivotal role of the FDA in this public
process can create a significant artifact in the health system has made it particularly vulnerable
numerator as attempts are made to evaluate the rel- to public criticism. Concerns about unexpected
ative incidence of ADRs associated with a particu- serious drug-induced diseases being undetected for
lar drug. too long (e.g., cardiac events associated with rofe-
coxib or celecoxib, suicides associated with selec-
tive serotonin receptor inhibitors) resulted in the
The Regulatory Authority FDA Commissioner’s request to the IOM to con-
Ultimately, all ADR reports arrive at the responsible duct a thorough study of the system and the role
regulatory authority office, either by direct submis- and contributions of the FDA. In a landmark
sion (though this is growing less common) or report, the IOM calls for sweeping reforms in the
through the responsible intermediary, the sponsor manner in which the FDA approaches its roles, and
company. In the U.S. model of public health, the specifically defines the critical changes necessary
role of the government is to ensure conditions in to entail the creation of a new “culture of drug
which people can be healthy, a role that requires safety.”10 In this new culture, the public health
TisdaleC04_31-39 1/12/10 2:27 PM Page 36
public health approaches to spontaneous reports, Society has the responsibility to monitor for
has been designated “Pharmacoepidemiology.”11,12 those drug-induced diseases that are sufficiently
Intensive inpatient monitoring, the first such severe to create an unacceptable burden on indi-
scheme, was very productive in detecting increases viduals, as well as those that are serious and fre-
in the frequencies of otherwise expected diseases in quent enough to create a public health burden. For
association with drug use, permitting statistical the former, a system to detect the very rare but
associations to generate signals.13 However, such unacceptably severe reaction is needed. For this,
systems have proven expensive and limited with the SRS, with all of its faults, is the only existing
respect to the numbers of individuals exposed, par- tool that can be considered sufficient. But for the
ticularly with new drugs, and have fallen into dis- latter, monitoring and quantitating both the
use, except as ad hoc studies focused on specific occurrence of excess medical adversity risk and
new drugs, with an intense effort to discover the documenting excess morbidity, mortality, and cost
number of exposures nationwide. to society will permit us to accomplish society’s
public health surveillance tasks. With these objec-
tives clearly in mind, the IOM called for the aggres-
The Large Automated Multipurpose sive development of programs of automated
Population-Based Systems population based “active surveillance.”10 In
Contemporary health care operates within a con- response, Congress, in the Food and Drug
tinuing revolution in medical informatics, fueled Administration Authorization Act (FDAAA) of
by the advent of large automated databases that 2007, has mandated the FDA to develop a sentinel
support computerized medical records and pre- surveillance system based on such automated pop-
scribing, and wireless hand-held devices in ambu- ulation-based data systems with the objective of
latory medical practice. As a result, many large being able to monitor, prospectively, a population
components of the health care delivery system of 25 million by 2010 and 100 million by 2012.
have available to them automated data describing This mandate has, in turn, spawned major activity
every drug prescribed, every subsequent major across the breadth of the public health system,
diagnosis associated with a hospitalization (admis- with emerging LAMPs now recognized and har-
sion and discharge), and of course, longer-term nessed for drug safety surveillance as well as
monitoring for late or latent outcomes. These data research. Major health plans, including United
sets have been called “large automated multipur- Health Care, WellPoint (formerly Blue Cross/Blue
pose population-based systems” (LAMPS). They Shield), Aetna, and the collaborative HMO
clearly light the path to drug-use monitoring at the Research Network, among others, have made the
population level when examining increases in the data available to leading researchers for such explo-
frequencies of major illnesses, which might, in rations. Academia, in its critical role in the public
turn, signal possible drug-induced disease. health system, has organized centers of excellence,
Certainly, the LAMPS already have amply demon- notable among these under the Centers for
strated their value as tools for use by the pharma- Education and Research on Therapeutics program,
coepidemiologist when conducting formal to assist the FDA in this endeavor. Industry, as a
observational studies to test signals from other sys- key partner in the system, has organized and fund-
tems, such as the SRS. ed (through the National Institutes of Health
The LAMPS, however, have several critical limi- Foundation) an independent effort at testing new
tations as surveillance tools. The power of a signal methods for cross-system data summary and analy-
generator is tied directly to the size of the exposed sis for prospective (sentinel) development of sig-
population. Thus, a database owned by a health nals of potential drug-induced diseases (the
maintenance organization (HMO), even one reflect- Pharmaceutical Manufacturers’ Association
ing the medical transactions of millions of enrolled Observational Medical Outcomes Program). In
individuals, may not encompass enough exposure addition, the FDA has organized and initiated a
to any single drug, particularly a new drug in the vigorous process for exploring the path to respond-
early phases of marketing, to detect any but the ing to the FDAAA mandate for sentinel surveil-
most commonly associated drug-induced diseases. lance
This is true particularly in key population sub- The special situation of medication errors
groups in which a possible increased risk of medica- demands a third monitoring method. But what
tion-induced illness may occur. Understanding the system exists to monitor, compile, analyze, and
potential of LAMPS to contribute to our under- develop proper interventions regarding these
standing of drug-induced disease is important, as is errors? Part of the nation’s response has been
recognizing their limitations. developing institution-based reporting and contin-
TisdaleC04_31-39 1/12/10 2:27 PM Page 38
uous improvement systems. These are vital because public health–surveillance professionals, should
root causes can be locally identified and remedied undertake a thorough and systematic examination
in institutional systems and practices. They are of existing methods of population-based surveil-
inadequate, however, in detecting flaws in product lance to better align systems and the incentives to
presentation or design, name confusion, look-alike strengthen them. While the SRS may be the most
packaging, or confusing product information. For powerful generator of warnings of rare but unac-
these, integration into a more comprehensive ceptable toxicities, better-integrated and better-
national detection system is also required. aligned signal generators are needed for
Therefore, several key leadership organizations drug-induced diseases that, while possibly less
have taken decisive action, notably the MEDMARX severe, are occurring with greater frequency in the
system of the U.S. Pharmacopeia, which is a population at large. Certainly these include pre-
national database for medication errors. ventable errors in the use of medications and their
avoidable consequences. Can you imagine a truly
seamless and integrated system of surveillance for
THE WAY FORWARD: all problems of public health importance?
CAN YOU IMAGINE? Finally, those working in the field of informa-
tion technology to support medical practice, par-
Protecting society against preventable drug-induced ticularly (but not limited to) those involved in
diseases and device-associated injury, through early developing and promulgating the automated
detection of possible problems emerging from ther- medical record, personal digital assistant, and
apies, is the primary objective of a public other hand-held technologies, must work togeth-
health–oriented drug safety surveillance system. er to build data systems that are compatible with
Such protections require, at the population level, an efficient and accurate conduct of the medical pur-
affordable, effective system of monitoring for seri- poses for which they are intended. Equally critical
ous adverse events that occur in the population in is the development of data standards and refine-
excess of that which is expected in association with ments needed to provide the public health sur-
disease and natural causes alone. To achieve this veillance system (and, of course, the research
objective, we must make progress on three fronts. enterprise) with the data required to perform
First, the reporter must be more attuned both to these vital functions in a timely, effective, and
monitoring for possible drug-induced illness and to affordable way. Can you imagine a national sur-
reporting it effectively. Second, the system must be veillance system that does not require any busy
more efficient in retrieving and managing the therapy team members, including the patient, to
resulting data and more effective in harnessing data remember to report information and to recall
to existing systems of surveillance. Third, new tech- where to submit it, because the automated system
nologies, made available through the rapid dissem- that supports their transactions can do this for
ination of automation into medical practice, must them? Can you imagine a system that minimizes
be harnessed to the task effectively. the administrative tasks and maximizes patient
These goals, in turn, will require three ambitious well-being, perhaps even one which is capable of
sets of activity. First, medical, pharmacy, and other “finding” problems before they become clinically
health professionals must do a better job of reaching apparent and enabling us to prevent them from
the practitioner with salient messages about drug- becoming major public health problems? The
induced diseases and with convincing efforts to har- protection of the public health requires us to
ness the time and energy of the busy practitioner. imagine these things.
We must do a better job of incorporating these tasks,
and the competencies which underlie them, in
undergraduate and postgraduate professional train-
ing. Continuing education credit for participating in References
the SRS has been suggested as a promising device.
1. Strom BL, Carson JL, Halpern AC, et al. A population-
But an even more promising strategy is to make the based study of Stevens-Johnson syndrome: incidence and
act of reporting one that reaps rewards in terms of antecedent drug exposures. Arch Dermatol. 1991;127:831-
useful information that makes a direct contribution 838.
to patient care. Can you imagine a truly easy, user- 2. Ahmad SR. Adverse drug event monitoring at the Food
and Drug Administration. J Gen Intern Med. 2003;18:57-60.
friendly, and useful system populated by truly pub-
3. American Association of Medical Colleges. Report X:
lic health–oriented satisfied reporters? contemporary issues in medicine: education in safe and
Secondly, public health agencies, notably the effective prescribing practices. Available at:
CDC and the FDA, working with state and local https://services.aamc.org/publications/showfile.cfm?file=
TisdaleC04_31-39 1/12/10 2:27 PM Page 39
CHAPTER 5
is easier in some situations and with some drugs possible to rely solely on information the patient
and reaction types than others. provides. Discussions with a spouse or caregiver or
a phone call to the patient’s pharmacy to check the
refill history can sometimes yield additional help-
PATIENT EVALUATION ful information.
It is also important to collect a careful history
Perhaps the most important tool for evaluating a of the suspected adverse drug event. What did the
possible drug-induced disease is the medication patient notice, and when did it start? How did the
history. Taking a careful history can yield many problem progress? Was there a temporal relation-
clues that will help the clinician rule in or rule ship between the onset of symptoms and the
out a drug-induced disease. Information that addition or discontinuation of any medications
should be collected as part of the medication his- and, if so, was the timing of the event similar to
tory is listed in Table 5–1. Information may be that reported previously for a specific drug or
gathered from many sources, including the drugs for that disease? Has the patient experi-
patient, medication containers, a spouse or care- enced similar reactions in the past? Can the
giver, the patient’s medical records, or another patient provide any insight into what he or she
health care provider, such as the patient’s primary suspects may be causing the problem? Did the
care physician or pharmacist. The accuracy of the patient attempt to self-medicate to treat the prob-
medication history depends not only on the accu- lem? If so, what treatment was tried, and was it
racy of the source data but also on the skill and effective? Do any treatments or activities seem to
knowledge of the health care provider who col- make the problem better? Does anything seem to
lects the information and puts it all together. make it worse?
Asking the right questions in the right way can A careful physical exam focusing on the organ
elicit information regarding a patient’s medica- system(s) involved and the collection of laborato-
tion use that otherwise might be overlooked. ry data can provide objective information that is
Table 5–2 lists suggestions for obtaining an accu- helpful in determining whether or not a drug-
rate medication history. Information available to induced disease is present. Depending on the reac-
a physician at the time of admission may be inac- tion type and organ system(s) involved,
curate and could result in an incomplete or inac- evaluation of renal function (blood urea nitrogen,
curate medication history.4,5 Because of more serum creatinine, and estimated creatinine clear-
extensive knowledge of various drugs and drug ance), hepatic function (alanine aminotransferase,
products, greater focus on medication therapy aspartate aminotransferase, alkaline phosphatase,
issues and access to more information sources, total and direct bilirubin, total protein, albumin,
pharmacists often are able to perform more com- international normalized ratio), blood counts,
plete medication histories.6,7 and/or urinalysis may be helpful and necessary.
Information regarding prescription drugs Special laboratory tests (e.g., antinuclear antibod-
(including any sample medications, inhalers, ies, histamine metabolites, complement concen-
creams, ointments, patches, medications adminis- tration, patch tests) are available and helpful in
tered in a doctor’s office or clinic), over-the-count- some situations. Noninvasive procedures (e.g.,
er (OTC; nonprescription) drugs, vitamins, herbals electrocardiography, computed tomography) and
(nutraceuticals, health supplements), and illicit even invasive procedures (e.g., kidney or lung
drugs should be collected. Smoking history and biopsy) may be required for some patients.
alcohol use should also be documented. The name Specific elements of the physical exam and labora-
of each medication, its strength, formulation tory evaluation important in the differential diag-
(tablet, capsule, liquid, extended-release), dose, nosis of drug-induced diseases are discussed in
route, and frequency should be recorded. The Chapters 6 to 55.
objective is to determine how a medication has The patient’s history and physical exam should
actually been used rather than how it was pre- be carefully reviewed for the presence of risk fac-
scribed. A precise history of when therapy with the tors known to be associated with the drug-induced
medication was started and stopped and when the disease suspected. Race, sex, age, genetic and envi-
last dose was taken is critical to the investigation of ronmental factors, concomitant drug therapy,
a possible drug-induced disease. In some cases, it is comorbidities, immune status, alcohol and tobacco
important to know not only about current medica- use, and a host of other factors may impact
tions but also about medications that were taken in patients’ relative risk for a drug-induced disease.
the past and recently discontinued. Although some Specific risk factors for the various drug-induced
patients are very good historians, it is not always diseases are included in Chapters 6 to 55.
TisdaleC05_40-48 1/12/10 2:28 PM Page 42
TABLE 5–1 Information That Should Be Included in the Medication History (Continued)
• Current and/or past use of alcohol
• Type (liquor, wine, beer)
• Amount and frequency
• Date started
• Last use
• Current and/or past use of illicit drugs
• Drug name
• Method of administration (oral, inhaled, smoked, injected)
• Frequency
• Date started
• Last use
• Financial issues
• Approximate monthly out-of-pocket medication costs
• Financial burden created by medication purchase
• Allergies
• Name of medication or type of food causing allergic reaction
• Type of reaction
• Date of reaction
• Treatment and outcome
• Similar reactions to related drugs or similar foods
• Exposure to common drug allergens (penicillin and sulfa-containing compounds)
• Adverse drug reactions
• Name of the medication
• Dosage and frequency
• Reason the medication was being taken
• Nature of the reaction experienced
• How the reaction was treated or managed
TABLE 5–3 The Naranjo Scale for Estimating the Probability of Adverse Drug Reactions
Question Points
Are there previous conclusive reports on this reaction?
Yes (+1) No (0) Don’t know (0)
Did the adverse event appear after the suspected drug was administered?
Yes (+2) No (–1) Don’t know (0)
Did the adverse reaction improve when the drug was discontinued, or a specific antagonist
was administered?
Yes (+1) No (0) Don’t know (0)
Did the adverse reaction reappear when the drug was readministered?
Yes (+2) No (–1) Don’t know (0)
Are there alternative causes (other than the drug) that could on their own have caused the reaction?
Yes (–1) No (+2) Don’t know (0)
Did the reaction reappear when a placebo was given?
Yes (–1) No (+1) Don’t know (0)
Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?
Yes (+1) No (0) Don’t know (0)
Was the reaction more severe when the dose was increased, or less severe when dose was decreased?
Yes (+1) No (0) Don’t know (0)
Did the patient have a similar reaction to the same or similar drug in any previous exposure?
Yes (+1) No (0) Don’t know (0)
Was the adverse event confirmed by any objective evidence?
Yes (+1) No (0) Don’t know (0)
Total Points:
Probability that adverse drug event has occurred:
≥9 highly probable
≥5 probable
≥1 possible
0 doubtful
From Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther.
1981;30:239-245.
spondence with admitting or referring physicians. ous adverse events” as those that are fatal, life-
Depending on the severity and acuity of the reac- threatening, permanently or significantly dis-
tion, patients should be advised to obtain and wear abling, require or prolong hospitalization, cause a
a medical alert bracelet. congenital anomaly, or require intervention to pre-
vent permanent impairment or damage.
Notwithstanding these definitions, the FDA
Reporting Drug-Induced Diseases encourages health professionals to report any
Proper reporting can also be important in efforts to adverse event judged to be clinically significant.
help prevent drug-induced diseases in others who The adverse event does not have to be previously
will be exposed to the drug in the future. Some unreported or uncommon. Suspicion that a med-
adverse drug effects and their associated drug- ical product may be related to a serious event is suf-
induced diseases have been well documented and ficient reason to submit a report, and proof of
are well known to health care providers. Because causality is not necessary.
they are well known, these adverse events can Reports can be filed online (www.fda.gov/med-
sometimes be prevented with careful drug use watch), via a toll-free phone line (1-800-FDA-
and/or patient monitoring. Unfortunately, some 1088), by fax (1-800-FDA-0178), or by prepaid
adverse drug effects and drug-induced diseases mail. The core elements of the report include the
have not yet been recognized or characterized. reporter’s name, the suspect drug or device, a nar-
These are unexpected and therefore not yet pre- rative report of the adverse event or problem, and
ventable. Identifying and characterizing these patient information (identifier, sex, age, weight).
events, and therefore increasing the likelihood that The FDA holds patient identity information in
they can be prevented in the future, is the focus of strict confidence. Reporting does not violate provi-
the voluntary “MedWatch” program operated by sions of the Health Insurance Portability and
the FDA.14 Accountability Act (HIPAA), which specifically per-
MedWatch was established by the FDA in 1993 mits covered entities (such as pharmacists, physi-
as a method to stimulate voluntary reporting of cians, or hospitals) to report adverse events and
serious adverse events by health care professionals other information related to the quality, effective-
and patients. The system collects spontaneous ness, and safety of FDA-regulated products both to
reports of adverse events involving drugs (prescrip- the manufacturers and directly to the FDA.
tion and OTC), biologics, devices, and special Once received by the FDA, reports of adverse
nutritional products, including dietary supple- events are entered into a postmarketing surveillance
ments, medical foods, and infant formulas. database that can be examined for similar reports
Adverse reactions associated with vaccines are and used to develop case series. When a report or a
reported to FDA through the Vaccine Adverse series of reports define a previously unrecognized
Event Reporting System (VAERS), rather than safety issue, the FDA can order a formal epidemio-
through MedWatch. A spontaneous report is an logic evaluation, require labeling changes (including
observation of an adverse event that is made dur- boxed warnings), place restrictions on prescribing or
ing direct patient care and subsequently reported dispensing of the drug, or if necessary, order that the
either directly to the FDA or indirectly to the FDA product be withdrawn from the market.
through the drug’s manufacturer. Observations Heath care providers can obtain information
made during clinical trials are not included as part generated through the FDA MedWatch program by
of this spontaneous reporting system. The accessing their Web site at www.fda.gov/med-
MedWatch system is also used to collect informa- watch. Information is also disseminated via e-mail
tion regarding product quality problems, reports of to those who subscribe online and through a large
suspected counterfeit products, and reports of number of professional organizations that partner
medication- and device-use errors that may have with FDA for that purpose.
been caused by either product-name confusion or
confusion resulting from packaging and labeling.
The FDA encourages health care providers and
patients to use MedWatch to submit reports of seri- CONCLUSION
ous adverse events. For the purpose of this report-
ing system, an “adverse event” is defined as any Morbidity and mortality associated with drug-
unfavorable and unintended sign, symptom, or induced diseases continue to be a major concern for
disease temporally associated with the use of a all health care practitioners and add significantly to
medicinal product, whether or not it is considered health care costs. Although some drug-induced dis-
to be related to the product. The FDA defines “seri- eases are identified during clinical trials and the
TisdaleC05_40-48 1/12/10 2:28 PM Page 47
drug-approval process, others are not recognized admission to hospital: a systematic review. CMAJ.
until long after the drug is marketed and available 2005;173:510-515.
6. Walchle RD, McKercher PL, Cooper JW. Physician-,
for routine use. Although all drugs have the poten- nurse-, and pharmacist-conducted patient drug histories.
tial to cause drug-induced diseases, it is easy to over- Contemp Pharm Pract. 1980;3:75-78.
look a drug as a possible cause of a patient’s illness. 7. Reeder TA, Mutnick A. Pharmacist- versus physician-
All health care providers would be well advised obtained medication histories. Am J Health-Syst Pharm.
to always ask themselves, “Could this be drug-relat- 2008;65:857-860.
8. Naranjo CA, Busto U, Sellers EM, et al. A method for
ed?” whenever confronted with a patient experi- estimating the probability of adverse drug reactions. Clin
encing new or worsening symptoms. Pharmacol Ther. 1981;30:239-245.
9. Kramer MS, Leventhal JM, Hutchinson TA, et al. An
algorithm for the operational assessment of adverse drug
reactions. I. Background, description, and instructions
References for use. JAMA. 1979;242:623-632.
10. Karch FE, Lasagna L. Toward the operational
1. Kaufman DW, Kelly JP, Rosenberg L, et al. Recent identification of adverse drug reactions. Clin Pharmacol
patterns of medication use in the ambulatory adult Ther. 1977;21:247-254.
population of the United States: the Slone Survey. JAMA. 11. Koh Y, Li SC. A new algorithm to identify the causality
2002;287:337-344. of adverse drug reactions. Drug Saf. 2005;28:1159-1161.
2. Rawlins M, Thompson W. Mechanisms of adverse drug 12. Berry LL, Segal R, Sherrin TP, et al. Sensitivity and
reactions. In: Davies D, ed. Textbook of Adverse Drug specificity of three methods of detecting adverse drug
Reactions. New York: Oxford University Press; 1991:18-45. reactions. Am J Hosp Pharm. 1988;45:1534-1539.
3. deShazo R, Kemp S. Allergic reactions to drugs and 13. Michel DJ, Knodel LC. Comparison of three algorithms
biologic agents. JAMA. 1997;278:1895-1906. used to evaluate adverse drug reactions. Am J Hosp
4. Gonski PN, Stahters GM, Freiman JS, et al. A critical review Pharm. 1986;43:1709-1714.
of admission and discharge medications in an elderly 14. Food and Drug Administration MedWatch: The FDA
Australian population. Drugs Aging. 1993;3:358-362. Safety Information and Adverse Event Reporting
5. Tam VC, Knowles SR, Cornish PL, et al. Frequency, type Program. Available from: http://www.fda.gov/medwatch.
and clinical importance of medication history errors at Accessed January 31, 2009.
TisdaleC05_40-48 1/12/10 2:28 PM Page 48
TisdaleC06_49-97 1/20/10 10:54 PM Page 49
SECTION II
DRUG-INDUCED
DERMATOLOGIC DISEASES
CHAPTER 8 Photosensitivity
CHAPTER 6
Lynne M. Sylvia
properties should be considered. First, the molecu- gen.125 Identifying a drug’s reactive metabolites
lar weight of a drug can influence its antigenicity. and the potential of these metabolites to bind to
Drugs of molecular weight >4,000 Da such as carrier proteins is not readily achieved in premar-
erythropoietin, insulin, or other polypeptide keting studies126; thus, the allergic potential of
hormones, are more capable of serving as com- many low-molecular-weight drugs is not deter-
plete antigens than are low-molecular- mined until the postmarketing phase of study.
weight drugs (<1,000 Da).124 Biologic agents (e.g., Drugs that are commonly associated with
antisera, antithymocyte globulin, intravenous pseudoallergic reactions are listed in Table 6–3.127-
146
immunoglobulin) also fit in this category of large A drug’s ability to cause a pseudoallergic reac-
polypeptides. Second, drugs containing foreign tion can often be determined by a review of the
proteins or large polypeptides of nonhuman origin drug’s chemical and/or pharmacologic properties.
(e.g., streptokinase, beef or pork insulin, Classic examples of pseudoallergy are anaphylac-
chimeric/murine-derived monoclonal antibodies, toid reactions to radiocontrast media, opiate-
L-asparaginase) have the ability to serve as com- induced urticaria or generalized pruritus, and
plete antigens.2,124 The most common antigenic “red–man” syndrome with vancomycin.4,5
drugs (e.g., penicillins, sulfonamides) are of low When reviewing Tables 6–2 and 6–3, it should
molecular weight (<1,000 Da) and do not contain be noted that some drugs are listed as causing both
a foreign protein. These agents possess a third hypersensitivity and pseudoallergic reactions. For
drug-related property related to conferring anti- example, vancomycin-induced red man syndrome
genic potential, which is the ability of the parent is thought to be due to a pseudoallergic reaction,
drug or its reactive metabolite to bind covalently to whereas vancomycin-associated blood dyscrasias
a carrier protein in vivo, thereby forming a com- and anaphylaxis are attributed to more rare hyper-
plete antigen. The term hapten is used to describe a sensitivity reactions.53,110,111 Captopril,127,147
30,133-135
drug (or a metabolite) that must bind to a tissue or ciprofloxacin, and protamine2,3 have also
cell protein in order to serve as a complete anti- been reported to cause both true hypersensitivity
TisdaleC06_49-97 1/20/10 10:54 PM Page 53
and anaphylactoid reactions. Intravenous adminis- skin testing or other in vitro testing methods to
tration of immunoglobulin G (IVIG) is most com- determine the presence of drug-specific antibod-
monly associated with infusion-related reactions ies.149
such as fever and arthralgias. However, IVIG can The epidemiology of anaphylaxis, including
also cause an IgE-mediated reaction in patients drug-induced anaphylaxis, has been reevaluated by
with selective IgA deficiency.2 In situations in a working group composed of experts in allergy
which a drug can cause both types of reactions, it and immunology.150 The expert panel estimated
is often difficult to distinguish between true hyper- the frequency of anaphylaxis at 50 to 2,000
sensitivity and the more predictable pseudoallergic episodes per 100,000 persons, or a lifetime preva-
response. The features listed in Table 6–1 can be lence of 0.05% to 2%.150 Neugut et al.151 reported
helpful in differentiating these events. Most impor- that the most serious cases of drug-induced ana-
tantly, the signs, symptoms, and severity of the phylaxis have been associated with the use of peni-
reaction, rather than its mechanism, should drive cillin and radiocontrast media. Penicillin is
clinicians’ decision making. recognized as the most common cause of anaphy-
laxis and is estimated to account for approximate-
ly 75% of fatal cases in the United States (U.S.)
EPIDEMIOLOGY annually.1 Nonfatal anaphylaxis attributed to peni-
cillin has been reported in 0.7% to 10% of the gen-
The combination of drug hypersensitivity, intoler- eral population, whereas fatal cases have occurred
ance, and pseudoallergic reactions has been esti- in 0.002% of the general population.151 Non-IgE-
mated to comprise 25% of all adverse drug events.1 mediated anaphylaxis (i.e., anaphylactoid reac-
Hypersensitivity reactions are considered to be tions) associated with radiocontrast media have
rare, representing 6% to 10% of all adverse drug occurred in 0.22% to 1% of patients, particularly in
reactions.1,126,148 In 2002, Hunziker et al.149 provid- those receiving an agent with high osmolarity.151
ed an analysis of 12,785 adverse drug reactions of Angioedema is estimated to occur in only 0.1%
probable or definite association occurring in inpa- to 1.2% of patients treated with angiotensin-con-
tients between 1974 and 1993. Drug allergy or verting–enzyme (ACE) inhibitors. However, 25% to
pseudoallergy accounted for 13% of the adverse 38% of cases of angioedema seen in the emergency
drug reactions. Differentiation between allergy and department (ED) have been attributed to ACE
pseu- doallergy as the cause of the adverse event inhibitor therapy.152,153 In an 8-year retrospective
could not be achieved because of the lack of valid study, 12 of 49 patients (24.5%) presenting to the
TisdaleC06_49-97 1/20/10 10:54 PM Page 57
Adrenocorticotropic hormone NK C
Angiotensin-converting-enzyme inhibitors1,4,127,128 0.1–0.2% B
Angiotensin receptor blockers129-132 NK C
Acetylsalicylic acid (aspirin)1,3 NK C
Ciprofloxacin133-135 NK C
Corticosteroids136 NK C
Cremophor (polyethoxyethylated castor oil)-containing products9,11 NK C
Enoxaparin137 NK C
Infliximab138,139 NK C
Levofloxacin140 NK C
Midazolam141 NK C
Muromonab142 NK C
N-acetylcysteine143 NK C
Nonsteroidal antiinflammatory drugs1,3 NK C
144,145
Ondansetron NK C
Opiates1,3,146 NK C
Paclitaxel9 NK C
Pentamidine5 NK C
Polymyxin B4,5 NK C
Protamine1-4 NK C
Radiocontrast media1,3,4 1.7% B
Rituximab NK C
Somatostatin NK C
Urokinase NK C
Vaccines123 NK C
Vancomycin NK C
NK = not known.
ED with angioedema reported concomitant thera- pseudoallergic reactions associated with some
py with an ACE inhibitor.152 A second retrospective implicated drugs are presented in Tables 6–2 and
case–control study revealed an association between 6–3.
ACE inhibitors and angioedema in 15 of 40
patients (38%) presenting to the ED.153 Compared
with a control group of patients without angioede-
ma, patients presenting to the ED with angioede-
MECHANISMS
ma were 5 times more likely to be taking an ACE
inhibitor (odds ratio [OR], 5.1; 95% confidence
Hypersensitivity Reactions
interval [CI], 2.03–12.89).153 The exact mechanisms by which drugs serve as
The incidences of hypersensitivity and allergens and elicit immune responses are not
pseudoallergic reactions associated with the completely understood. Gaps in our understand-
majority of implicated drugs are unknown. The ing of these mechanisms can be attributed, in part,
estimated incidences of hypersensitivity and to the lack of a validated animal model of drug
TisdaleC06_49-97 1/20/10 10:54 PM Page 58
(i.e., hemolysis, thrombocytopenia, neutropenia). throughout the bloodstream and activate the com-
Cell-bound antibody can also activate comple- plement cascade before depositing on targeted cells
ment, a series of 25 plasma proteins that, when or tissues.163 Complement-mediated migration of
activated, assist in cell lysis.94,95,161 Activated com- phagocytes and the release of pyrogens manifests
plement proteins possess a variety of properties, as a fluid phase or serum sickness–like reaction
including the ability to degranulate mast cells consisting of fever, malaise, and lymphadenopa-
(C3a, C5a), the ability to form a membrane attack thy.166
complex (C5a and C9a), and the ability to stimu- Activation of complement proteins C3a and
late opsonization to amplify the immune C5a can also result in degranulation of mast cells
response.161 with the release of histamine. Eventually, the
Type III reactions, commonly referred to as immune complex may deposit in a variety of tis-
immune complex reactions, are usually mediated sues, including the walls of blood vessels, glomeru-
by IgG. During these events, the drug hapten typi- lar cells, joint tissue, alveoli, and cells in the skin.
cally forms a complete antigen by binding cova- After deposition on the targeted tissue, the
lently with an amino acid component (such as the immune complex can mediate cell destruction
lysine or cysteine residues) of a plasma protein. with the assistance of complement.166
The hapten–protein complex then stimulates the Type IV reactions, commonly referred to as
production of IgG. Binding between IgG and the delayed or cellular immune responses, are mediat-
circulating complete antigen results in the forma- ed by sensitized CD4 and CD8 T lymphocytes.
tion of immune complexes, which often circulate Upon activation, T lymphocytes secrete cytokines
TisdaleC06_49-97 1/20/10 10:54 PM Page 61
(e.g., IL-5, IL-8) that recruit monocytes, neu- chospasm, inflammation, and increased mucus
trophils, and eosinophils to mediate the hypersen- production.169
sitivity reaction.167 Type IV reactions involve a
wide range of clinical events including contact der-
matitis from a topically applied medication and CLINICAL PRESENTATION AND
more systemic conditions involving lymphoid DIFFERENTIAL DIAGNOSIS
organs. The presence of lymphocytic infiltrates
often suggests a type IV hypersensitivity reaction. The signs and symptoms of a number of specific
A complete review of the mechanisms by which allergic syndromes are provided in Table 6–5. The
drugs cause type IV reactions has been pub- clinical presentation of drug hypersensitivity is
lished.167 highly variable and dependent on the responding
antibody and the targeted tissues. Hypersensitivity
syndromes may include anaphylaxis; angioedema;
Pseudoallergic Reactions urticaria; immune complex diseases manifesting as
Drugs cause pseudoallergic reactions by a number a serum sickness–like illness, lupus-like reaction,
of mechanisms, including: (1) direct stimulation hypersensitivity vasculitis, or DRESS; and mucocu-
of mast cells resulting in the release of histamine taneous syndromes such as Stevens–Johnson syn-
(e.g., opiates, polymyxin, protamine, diamines drome (SJS) and toxic epidermal necrolysis (TEN).
such as pentamidine, polyethoxylated castor oil), In addition, allergic drug reactions may be the
(2) nonimmunologic activation of the comple- cause of disorders of the blood, kidney, liver, and
ment cascade (e.g., radiocontrast media, prota- pulmonary system. Conditions to consider in the
mine), and (3) alteration of the metabolism or differential diagnoses of these syndromes are listed
production of inflammatory mediators (e.g., ACE in Table 6–6. The mucocutaneous syndromes and
inhibitors, aspirin, and nonsteroidal antiinflam- DRESS are discussed in the section on “Cutaneous
matory drugs [NSAIDs]).3-5 The direct stimulatory Diseases.”
effects of drugs on mast cells appear to be dose- Anaphylaxis, the most severe form of a type I,
related and tend to predominate on mast cells in or IgE-mediated, reaction, constitutes a medical
the skin. Ciprofloxacin, vancomycin, and muscle emergency. The onset of anaphylaxis is usually
relaxants such as succinylcholine and opiates (e.g., within minutes to 2 hours after exposure to the
codeine, morphine) have been shown to elicit causative drug.170 In rare cases, the onset can be
urticarial reactions in normal skin at concentra- delayed for up to 48 hours after exposure. No
tions of ≥100 g/mL.3 The mechanism by which standardized definition of anaphylaxis
the ACE inhibitors cause angioedema is not com- exists.151,164,170 Using some definitions, involve-
pletely understood; however, inhibition of the ment of a shock organ, either the lungs or heart,
breakdown of bradykinin and substance P may is a requirement for a diagnosis of anaphylaxis.164
partially explain this adverse event. Angiotensin- Most recently, anaphylaxis has been described as
converting enzyme, a nonspecific dipeptidase a life-threatening reaction that results from the
enzyme, not only converts angiotensin I to sudden systemic release of mast cell and basophil
angiotensin II but is also involved in the inactiva- mediators.170 In the majority of patients, the ini-
tion of bradykinin, substance P, and neurokinin tial sign of anaphylaxis is generalized urticaria
A.168 Elevations in the concentrations of with or without angioedema; however, in some
bradykinin and substance P can lead to inflamma- patients, urticaria may be delayed or absent.164,170
tion, increased vascular permeability, and vasodi- On the basis of a review of two retrospective series
lation. Aspirin-induced asthma, also known as of a total of 835 patients with anaphylaxis, respi-
aspirin-exacerbated respiratory disease (AERD), is ratory symptoms are the second most commonly
believed to result from an imbalance between the occurring manifestations of anaphylaxis, fol-
production of prostaglandins and leukotrienes lowed by dizziness, unconsciousness, and gas-
from arachidonic acids.169 Inhibition of cyclooxy- trointestinal symptoms.164 An elevated serum
genase-1 (COX-1) leads to decreased production of tryptase concentration is indicative of the release
prostaglandin E2, a modulating prostaglandin in of stored mediators from mast cells.
bronchial tissue, and an increased propensity for Concentrations of tryptase, an enzyme that is
arachidonic acids to be synthesized via the lipoxy- stored in the secretory granules of the mast cell,
genase pathway. Increased production of become elevated in the serum within 1 to 2 hours
leukotrienes C4, D4, and E4 is associated with after the onset of anaphylaxis and persist for as
smooth-muscle contraction manifesting as bron- long as 6 hours after the event.164,170 -Tryptase is
TisdaleC06_49-97 1/20/10 10:54 PM Page 62
TABLE 6–5 Signs and Symptoms Associated with Drug-Induced Allergic Syndromes
Anaphylaxis1,164,165,170
• Diffuse urticaria
• Facial flushing
• Angioedema
• Bronchospasm (wheezing, chest tightness, hoarseness)
• Laryngeal edema
• Stridor
• Hypotension
• Cardiac arrhythmias (atrial or ventricular)
• Nausea, vomiting, abdominal cramping, diarrhea
• Light-headedness, feeling of impending doom
• Eosinophila
• Elevated tryptase concentrations
Urticaria248
• Asymmetric, circumscribed erythematous (pink) papular lesions of variable shape ranging from small to geographic in
size; lesions have raised borders and areas of central clearing
• Pruritus
• ociated with angioedema
• ociated with eosinophilia
Angioedema172,248
• Asymmetric, nonpitting edema of the face (tongue, lips, eyelids)
• Periorbital edema
• Laryngeal edema
• Tingling of the lips
• Hoarseness, difficulty speaking
• Difficulty swallowing
• Diarrhea, nausea, abdominal pain (if visceral involvement)
• Edema of the extremities, genitalia
Allergic-mediated blood disorders94-96
• Hemolytic anemia with positive direct or indirect Coombs test
• Thrombocytopenia, with peripheral count <100,000 mm3
• Granulocytopenia (agranulocytosis, neutropenia)
• Decreased concentrations of C3, C4
• Evidence of antiplatelet or antineutrophil antibodies
Serum sickness or serum sickness–like reaction55,124,166
• Fever and malaise
• Skin rash—urticaria, maculopapular rash or mixed presentation of urticarial plaques and maculopapular usually
starting on the extremities (hands, fingers, toes)
• Arthralgias
• Lymphadenopathy
• Glomerulonephritis
• Elevated erythrocyte sedimentation rate (nonspecific marker)
• Reduced concentrations of C4 and C3; possible elevations in C3a
Vasculitis72-74,175
• Skin manifestations—purpura, maculopapular rash, hemorrhagic blisters; skin biopsy revealing leukocytoclastic vasculi-
tis with fibrinoid necrosis and lymphocytic infiltrate
• General—fever, nausea, abdominal pain, polyarthritis, joint swelling
• Renal—urinalysis revealing proteinuria, granular casts, and red cells; kidney biopsy may reveal deposition of IgG, IgM,
or activated complement (C3)
• Pulmonary—hemoptysis, wheezing, pleuritic pain, presence of infiltrate on chest x-ray
• Sore throat, hoarseness
• Synovitis
• Elevated erythrocyte sedimentation rate, presence of antinuclear antibodies or antineutrophilic cytoplasmic autoanti-
bodies
TisdaleC06_49-97 1/20/10 10:54 PM Page 63
released only during episodes of mast-cell degran- inant feature of an SSLD is a cutaneous eruption
ulation, whereas concentrations of ␣-tryptase are that manifests within 5 to 21 days after drug ini-
elevated in patients with a large mast-cell burden tiation.166 Approximately 90% of patients have
(e.g., mastocytosis).170 Anaphylaxis is most sug- either an urticarial reaction due to complement-
gestive when the ratio of total (␣ + ) tryptase to mediated activation of the mast cells (one third of
-tryptase is 10 or less.170 Serum platelet-activat- patients) or a maculopapular rash on the
ing factor may also be a biomarker of anaphylax- abdomen and extremities with possible extension
is.171 A late phase of anaphylaxis, characterized by to the palms and soles (two thirds of
erythema, edema, and excess mucus production patients).55,166,175 The rash is usually preceded by a
with mucus plug formation, occurs 8 to 12 hours prodromal phase consisting of fever and malaise,
after the initial attack and can last for up to 32 arthralgias, and lymphadenopathy. In rare
hours.170 The late-phase reaction is attributed to instances, the reaction can extend to involve the
the effects of leukotrienes, such as leukotriene B4, kidney (i.e., glomerulonephritis). SSLD has been
which stimulate the migration of macrophages to reported in association with a number of drugs,
the sites of tissue damage.164,165 including -lactam antibiotics,55 bupropion,56-58
Urticaria with pruritis, a common manifesta- cefaclor,59-61 ciprofloxacin,62 minocycline,66-68 and
tion of anaphylaxis, can also occur as a sole mani- sulfonamides. 55 Drug-induced SSLD is often
festation of a type I reaction. On subsequent described as a mild condition that is self-limiting
exposure to the causative agent, urticaria may after discontinuation of the causative agent.
progress to include an anaphylactic presentation. However, in some cases, it progresses to a more
Drug-induced angioedema can also occur as a sole serious vasculitis. Any evidence of mucous mem-
manifestation of allergy, or it can occur with brane involvement (i.e., mucocutaneous lesions
urticaria or as part of an anaphylactic event.172 of the mouth, genitalia, naries) may suggest the
Angioedema, also known as giant urticaria, or development of a more progressive condition,
angioneurotic edema, presents as nonpitting such as SJS.
edema that extends beyond the epidermis to Drug-induced vasculitides are associated with
involve the deep dermis, mucous membranes, and acute inflammatory and necrotic lesions of the
subcutaneous tissues.172 Angioedema secondary to arteries, arterioles, venules, and capillaries.
ACE inhibitors is typically confined to the head Consistent with other immune complex diseases,
and neck, presenting as localized swelling of the an initial prodromal period is noted within 1 to 3
face (tongue, lips, and eyelids) with edema of the weeks after drug initiation and usually consists of
mucous membranes of the mouth, throat, and fever, arthralgias, and sore throat.72,175 Cutaneous
nose.127,173,174 Rarely, the edematous reaction can vasculitis, described as either a purpuric or macu-
extend to the gastrointestinal tract, hands, feet, lopapular rash of the lower extremities, is the most
and genitalia. common presenting manifestation.73 The purpuric
The presentation of drug-induced allergic lesions can progress to necrotic ulcerations, and
blood disorders is included in Table 6–5. the vasculitic process can extend to include the
Depending on the causative drug, the patient may kidneys, lungs, nasal mucosa, and ears. A number
present with hemolytic anemia, thrombocytope- of drugs, such as propylthiouracil, hydralazine,
nia, or granulocytopenia.94,95 These peripherally- minocycline, phenytoin, and allopurinol, can
mediated blood disorders typically occur within 5 induce vasculitis through the production of anti-
to 21 days after drug initiation.94,95 The affected neutrophil cytoplasmic autoantibodies.72 Other
blood-cell counts decline rapidly as compared with terms used to describe this condition include
the relatively slow decline in the counts observed leukocytoclastic vasculitis, polyarteritis nodosa,
with bone-marrow mediated blood disorders. In and Churg–Strauss syndrome.
some patients, drug-specific antibodies (IgM or
IgG) and reduced serum concentrations of C3 and
C4 can be observed.94,95
The immune complex diseases consist of a RISK FACTORS
group of conditions including serum sickness–like
disease (SSLD), hypersensitivity vasculitis, and The rarity of drug hypersensitivity reactions sug-
lupus-like reaction.166 SSLD is a mild and tran- gests a reliance on contributory or predisposing
sient form of the serum sickness that originally factors. Risk factors for drug hypersensitivity reac-
occurred with the administration of horse serum tions have been categorized as either drug-related
in the form of diphtheria antitoxin. The predom- or patient (host)-related. Many extensive reviews
TisdaleC06_49-97 1/20/10 10:54 PM Page 65
ages of 20 and 49 years than in children.180 This convulsant hypersensitivity syndrome because of a
finding relates less to the specific age of the patient lesser ability to detoxify the arene oxide metabolite
than to the number of potential exposures to the of the aromatic anticonvulsants.187,188 In addition
specific allergenic drug. Within the age of 20 to 49 to encoding for drug metabolic activity, genes also
years, a greater likelihood exists that a patient has encode for the type of T cell receptor and costimu-
been previously exposed and possibly sensitized to latory molecules/cytokines involved in the signal-
a penicillin, thereby increasing the risk of reactivi- ing of allergic reactions.
ty on subsequent exposure. Allergic drug reactions Although often implicated as a predisposing
do occur in children, particularly in those who factor, atopy has not been found to increase the
receive frequent courses of antibiotics for chronic risk of drug allergy.176,178 Patients who are atopic
otitis media, chronic bouts of bronchitis, or infec- have high IgE responsiveness to environmental
tions associated with cystic fibrosis. Therefore, the allergens, manifesting as allergic rhinitis, allergic
frequency and number of exposures, rather than asthma, and atopic dermatitis. Originally, it was
age, are more likely to increase risk. For unknown theorized that the high IgE responsiveness report-
reasons, drug allergy occurs more frequently in ed in atopic patients could increase the risk of IgE
female than male patients. Bigby et al.179 reported sensitization to drugs. Studies have shown that a
a 35% higher incidence of drug-induced allergic history of atopy does not influence the likelihood
cutaneous reactions in women than in men. More of a patient being sensitized to a drug. However, if
recently, in a study of penicillin allergy, Macy et an atopic patient becomes sensitized to a drug, evi-
al.181 also found that women were at higher risk. dence suggests that the reaction will be more
Genetic factors may influence a patient’s risk of severe than that observed in nonatopic
drug allergy. In order for T-helper cells to recognize patients.1,177
a drug as an antigen, the drug hapten–protein Concomitant viral infections may also predis-
complex must be co-presented with MHC class pose a patient to an allergic drug reaction. Pullen et
molecules on the surface of antigen-presenting al.189 reported ampicillin-associated morbilliform
cells.155,156,159 In this regard, patients with certain rash in 18 of 19 (95%) patients with acute
MHC characteristics (or human leukocyte antigens Epstein–Barr virus (EBV) infection. In comparison,
[HLA]) may be at higher risk of reacting to a given a morbilliform skin rash develops in approximate-
antigenic compound as compared with patients ly 5% to 10% of the general population exposed to
without the specific MHC molecules. For example, an aminopenicillin (e.g., ampicillin, amoxicillin).41
in patients infected with human immunodeficien- Patients infected with other viral pathogens, such
cy virus (HIV), susceptibility to abacavir-induced as human herpes-virus 6 (HHV-6) and HIV, have
hypersensitivity has been found to be associated also exhibited an increased risk of drug allergy. In
with the presence of HLA-B*5701, HLA DR7, and HIV-infected patients, 29% to 65% of those treated
HLA-DQ3.182,183 HLA-DR4 was present in 19 of 26 with sulfamethoxazole exhibited an allergic or
patients (73%) with hydralazine-associated lupus, allergic-like reaction and the risk of reactivity to a
as compared with 4 of 16 hydralazine-treated number of other drugs (e.g., ciprofloxacin, dap-
patients without lupus (25%).184 With further sone, foscarnet, penicillins, phenytoin, rifampin)
research in pharmacogenomics, the risk of reacting has also been shown to be increased.190 Most
to additional antigenic compounds may be found recently, HHV-6 has been linked to an increased
to be associated with certain histocompatibility risk of DRESS.191,192 The mechanism by which viral
types. infections increase the risk of drug reactivity is not
In addition to encoding for histocompatibility completely understood. Proposed mechanisms
phenotypes, genetic factors can influence the include virally mediated alterations in drug metab-
metabolic deactivation of drugs via phase 1 or olism, upregulation of MHC class II molecules on
phase 2 metabolism. For example, severe reactions APCs, and the increased release of cytokines such
to sulfamethoxazole have been noted in patients as interferon-, which amplify the immune
with hereditary deficiency in N-acetyltransferase response.154,159,160
(slow acetylators).185 Rieder et al.186 reported that Cystic fibrosis is a risk factor for allergic reac-
19 of 21 (90%) patients with sulfonamide hyper- tions to -lactam antibiotics. At least 20% of
sensitivity were slow acetylators, as compared with patients with cystic fibrosis have an allergic reac-
a 55% frequency of slow acetylators in a race- tion during an antibiotic treatment course, and the
matched control group (P<0.008). It has also been risk increases with the number of treatment cours-
suggested that patients with a hereditary deficien- es.193 The most commonly reported allergenic -
cy in epoxide hydrolase are at higher risk of anti- lactam antibiotic in these patients is piperacillin194;
TisdaleC06_49-97 1/20/10 10:54 PM Page 67
however, increased rates of reactivity have also system.126 On the basis of the assumption that 6%
been demonstrated with other antipseudomonal to 10% of adverse drug reactions are related to
penicillins and cephalosporins.195,196 Current evi- hypersensitivity, it was estimated that 137,000 to
dence suggests that these reactions are not typical- 230,000 hospital admissions in 1998 in the U.S.
ly mediated by the -lactam ring, but are more were attributed to drug hypersensitivity reactions.
likely to be reactions to the side chains of the Using cost estimates determined in 1997 for the
agents. treatment of adverse drug reactions in hospitalized
Risk factors for pseudoallergy are highly patients, the task force estimated that the annual
dependent on the specific causative drug. For exam- cost of hospital-based management of drug hyper-
ple, the risk of an anaphylactoid reaction to a radio- sensitivity reactions is $275 million to $600 mil-
contrast agent is higher in women,197 patients with lion.126 It was further hypothesized that the total
atopy or asthma,198 and patients receiving -adren- annual cost for management of both inpatient-
ergic blocker therapy with either a nonselective or and outpatient-related drug hypersensitivity reac-
selective agent.198,199 Patients at increased risk of tions could approach $1 billion.
ACE inhibitor–induced angioedema include black
Americans,200,201 patients with a history of idiopath-
ic angioedema secondary to a deficiency in comple-
ment-1-esterase inhibitor,127 and those receiving
PREVENTION
longer acting agents (i.e., enalapril, lisinopril).200
Aspirin intolerance manifesting as aspirin-induced
Hypersensitivity Reactions
asthma is more commonly observed in patients Drug hypersensitivity reactions have consistently
with history of asthma with or without allergic been considered to be unpredictable in nature and
rhinitis or nasal polys.202 Aspirin- or NSAID- largely unpreventable. However, continuing
induced exacerbations of urticaria or angioedema advances in pharmacogenomic research may alter
are more common in atopic patients with history of the level of preventability of these events.
idiopathic urticaria or angioedema.203 Prospective screening for the presence of the HLA-
The most reliable risk factor for hypersensitivi- B*5701 allele has been shown to lower the risk of
ty and most pseudoallergic reactions is history of a hypersensitivity to abacavir.183 In a double-blind,
prior reaction to the drug. For example, a patient controlled study, 1,956 HIV-infected patients were
with a history of an anaphylactoid reaction to a randomly assigned to receive either prospective
radiocontrast agent has a 16% to 44% risk of hav- screening for HLA-B*5701 prior to the initiation of
ing a reaction on reexposure, particularly to a high- abacavir or a standard-of-care approach to aba-
osmolarity agent.204 For the penicillins, a reliable cavir therapy.183 Prospective screening for HLA-
skin testing method with a high negative predic- B*5701 with subsequent avoidance of abacavir in
tive value has allowed for more accurate determi- identified carriers prevented the occurrence of
nations of the risk of reactivity on reexposure. In a immunologically confirmed hypersensitivity reac-
patient with a positive history of an IgE-mediated tions. All patients in whom an immunologically
reaction to a penicillin, a positive skin-prick test confirmed hypersensitivity reaction to abacavir
reveals a 50% to 70% risk of an IgE-mediated reac- developed during the 6-week study were in the
tion on reexposure.1,205 In contrast, a negative skin control group and were later determined to be car-
test indicates only a 2% to 3% risk of an IgE-medi- riers of HLA-B*5701.183 Screening was associated
ated reaction on reexposure.205 Unfortunately, reli- with a negative predictive value of 100% and a
able skin-test reagents for other highly allergenic positive predictive value of 47.9% in this primari-
drugs have not been produced, thereby limiting ly white population.183 The investigators calculat-
the ability to accurately assess the risk of reactivity ed that only 14 patients would have to be screened
to other allergenic drugs. to prevent one case of abacavir hypersensitivity.
Screening for the HLA-B*5701 allele is currently
available.
MORBIDITY AND MORTALITY Once a patient has had an allergic reaction to a
drug, a number of measures can be taken to pre-
In 2002, a task force assembled by the vent a subsequent reaction. The most important
Immunotoxicology Technical Committee, part of preventive measure is patient education. In partic-
the nonprofit Health and Environmental Sciences ular, patients should be educated regarding avoid-
Institute, provided an estimate of the impact of ance of the causative drug and any cross-reactive
drug hypersensitivity reactions on the health care drugs in the future. Guidelines for the avoidance of
TisdaleC06_49-97 1/20/10 10:54 PM Page 68
H H
S
R-CONH CH3
N CH3
O
H COOH
R⫺ R⫺
CH CH
Ticarcillin
COOH NH
S
Azlocillin O
N
O
Oxacillin N
N
O CH3
CH
Cl
NH
Mezlocillin O
Cloxacillin
N
N
O CH3 O
N
Cl SO2CH3
Dicloxacillin
N CH
Cl O CH3
NH
Piperacillin O
Cl O
N
Flucloxacillin
N
N O
F O CH3 CH2CH3
patient may be challenged with a penicillin with a ness of the patient’s allergy history. In addition to
structurally different side chain. In the absence of causing side-chain–mediated allergic reactions,
Pre-Pen, assessing the risk of a -lactam–mediated some penicillins have been associated with the
allergy versus a side-chain–mediated reaction is development of nonimmunologically mediated
highly dependent on the accuracy and complete- drug eruptions. Maculopapular rash with an
TisdaleC06_49-97 1/20/10 10:54 PM Page 70
H H
S
R1-CONH
N
O R2
COOH
Cephalexin Ceftizoxime N C
CH CH3 H2N H
S N⫺OCH3
NH2
Cefaclor Cefotoxime N C
CH Cl CH2OCOCH3
H2N
S N⫺OCH3
NH2
Cefadroxil
Cefpodoxime N C
HO CH CH3 CH2OCH3
H2N
NH2 S N⫺OCH3
Cephaloglycin H3C Na
CH CH2OCOCH3 Ceftriaxone N C N N
H2N CH2S O
NH2 N⫺OCH3
S N
O
Ceftazidime N C CH3
Cephalothin ⫹
H2N
N⫺O⫺C⫺COOH CH2⫺N
CH2 CH2OCOCH3 S
S CH3
Cefoxitin1
Cefamandole CH3
CH2 CH2OCONH2
S N
CH N
CH2⫺S
OH N
N
Cefuroxime
C CH2OCONH2 CH3
O Cefmetazole1
N
N⫺OCH3 N
CH2⫺S
N
N
Cefotetan1
CH3
Cefazolin N N N
N H2NCO S
N CH2 CH2S CH3 N
N C N
S CH2⫺S
HOOC S N
N
FIGURE 6–3 Similarities and Differences in the Structures of Various Cephalosporins
Reprinted with permission from Baldo BA. Penicillins and cephalosporins as allergens—structural
aspects of recognition and cross-reactions. Clin Exp Allergy. 1999;29:744-749.
the cephalosporin. In such a patient, examination and cefotaxime have similar side chains at the R2
of the cephalosporin’s side chains may aid in the position.22 Ceftazidime shares a common side
determination of potential cross-reactive agents. chain with aztreonam.22,23 Overall, the risk of cross
For example, cefaclor and cephalexin have identi- reactivity between cephalosporin antibiotics is
cal side chains at the R1 position and cephalothin believed to be greater than the risk of cross reactiv-
TisdaleC06_49-97 1/20/10 10:54 PM Page 72
ity between the cephalosporins and the penicillins. glycemic agents, carbonic anhydrase inhibitors
In patients with selective allergy to a cephalo- (e.g., acetazolamide, dorzolamide), celecoxib,
sporin, decisions regarding the use of alternative metolazone, sumatriptan, and zonisamide. Sulfa
cephalosporins should be based on the severity of drugs can be further categorized based on the pres-
the allergic reaction, the availability of equally ence or absence of an aromatic amine group in the
effective non–-lactam antibiotics, and the struc- N4 position. Sulfonamide antibiotics (e.g., sulfadi-
ture-specific feature (i.e., R1 and R2 substitutions) azine, sulfamethoxazole, sulfapyridine) have an
of the cephalosporin. arylamine at the N4 position, whereas the sulfon-
amide nonantibiotics (as listed above) do not.157
Presence of an arylamine at the N4 position may
Sulfa Drugs influence the type of reactivity to a sulfa drug and
In a patient with a documented or reported sulfa the potential for the sulfa drug to be reactive.157,225
allergy, the first step to prevention of a subsequent Compared with nonantibiotic sulfonamides, the
reaction is accurate and complete history taking. sulfonamide antibiotics are associated with a high-
Clarification is needed as to the specific sulfa drug er frequency of severe allergic reactions such as SJS.
to which the patient reacted in the past, and Sulfonamide antibiotics also have an N1 sub-
whether he or she has taken other sulfa drugs with- stituent consisting of a 5- to 6-member hetero-
out incident. Sulfa drugs, by definition, possess a cyclic ring containing ≥1 nitrogen, which has been
sulfamoyl (SO2NH2) moiety. Sulfate salts (e.g., mor- linked to the development of IgE-mediated reac-
phine sulfate, atropine sulfate), sulfites, and sul- tions.157 The structural differences between the sul-
fides are not members of the “sulfa” drug class. fonamide antibiotics and the nonantibiotic
Sulfa drugs include sulfonamide antibiotics, thi- sulfonamides are illustrated in Figure 6–4.
azide diuretics, loop diuretics (e.g., bumetanide, Although sulfa drugs are well recognized as
furosemide, torsemide), oral sulfonylurea hypo- allergenic, the risk of reactivity to a specific sulfa
NH3
O S Celecoxib
O
N
N
CF3 Furosemide
Cl N
O
NH2
H3C Chlorothiazide O
Cl H S
N
O O
O
NH2
NH
S S
O
O O O
FIGURE 6–4 Structural Differences between the Sulfonamide Antibiotics and the
Nonantibiotic Sulfonamides
Reprinted with permission from Shapiro LE, Knowles SR, Weber E, et al. Safety of celecoxib in indi-
viduals allergic to sulfonamide: a pilot study. Drug Saf. 2003;26:187-95.
TisdaleC06_49-97 1/20/10 10:54 PM Page 73
drug and the risk of cross reactivity to other sulfa pected cross reactions between sulfonamide
drugs are not completely known. The lack of a antibiotics and nonantibiotics have been report-
commercially available, reliable reagent for skin ed.228,229 If therapy with a sulfa drug is deemed
testing limits the value of such testing for deter- necessary in a patient with history of sulfa allergy,
mination of sulfa allergy. Arndt and Jick,226 as part consideration may also be given to the administra-
of the Boston Collaborative Drug Surveillance tion of graded challenge doses. At least two cases
program, compared the frequency with which dif- have been published describing the successful
ferent sulfa drugs caused allergic reactions in a administration of graded challenge doses of loop
cohort of prospectively monitored inpatients. The diuretics in patients with a history of sulfa aller-
risk of reactivity to sulfamethoxazole was the gy.230,231
highest at 6% (10 of 169), followed by sulfisoxa-
zole (1.7%, or 8 of 462), chlorothiazide (0.28%, or Tetracyclines
2 of 707), hydrochlorothiazide (0%, or 0 of
The risk of cross reactivity between the tetracyclines
1,263), and tolbutamide (0%, or 0 of 702).226 On
is unknown. Serum sickness–like reactions have
the basis of this study, sulfamethoxazole is fre-
been reported in association with tetracycline,
quently cited as the most reactive of the sulfa
doxycycline, and minocycline.232 Minocycline is
class. Strom et al.227 studied the risk of cross reac-
considered to be the most antigenic agent in the
tivity between a sulfonamide antibiotic (e.g., sul-
tetracycline class, based on the number and severi-
famethoxazole) and nonantibiotic sulfonamides
ty of the reported cases (i.e., lupus-like, serum
(e.g., acetazolamide, loop diuretic, sulfonylurea,
sickness-like reaction).68 The antigenicity of
thiazide) in a retrospective cohort. Study patients
minocycline has been attributed to its unique
received a nonantibiotic sulfonamide at least 60
amino acid side chain.232 Until more is known
days after having experienced an allergic reaction
about the antigenic properties of this drug class, it
to a sulfonamide antibiotic. The risk of an allergic
may be best to avoid the use of all tetracyclines in
reaction in these patients within 30 days of
patients with a history of a severe reaction to any
receipt of the nonantibiotic sulfonamide was
specific tetracycline.
compared with that of a control group of patients
without history of sulfa allergy. Of the 969
Aromatic Anticonvulsants
patients with history of sulfa allergy, 96 (9.9%)
had a reaction to the nonantibiotic sulfonamide A high degree of cross reactivity exists between
as compared with 315 (1.6%) of the 19,257 the aromatic anticonvulsants (e.g., carba-
patients without a history of sulfa allergy.227 mazepine, phenobarbital, phenytoin). In vitro
Based on the results of this study, the risk of a lymphocyte testing has revealed cross reactivity
cross reaction between the sulfa subclasses is con- between all three of these anticonvulsants in 40
sidered low. In fact, patients in this study with a of 50 patients (80%) with anticonvulsant hyper-
history of sulfonamide antibiotic allergy exhibit- sensitivity syndrome (AHS).187 Thus, patients with
ed a higher risk of subsequent reactivity to a peni- AHS associated with one aromatic anticonvulsant
cillin (14%) than to a nonantibiotic sulfonamide should be advised to avoid the others. Moreover,
(9.9%). When interpreting the findings of this the family members of patients with AHS may be
study, consideration should be given to study at increased risk of AHS.233 In patients in whom
design (i.e., retrospective cohort), and the broad AHS develops, underlying seizure disorders can be
definition for drug allergy that included eczema- safely treated with benzodiazepines, gabapentin,
tous reactions. or valproic acid. Oxcarbazepine, the 10-keto
In a patient who is allergic to a specific sulfa derivative of carbamazepine, has exhibited both
drug (e.g., sulfamethoxazole) and requires treat- in vitro and in vivo cross reactivity with carba-
ment with another sulfa agent (e.g., a loop diuret- mazepine. Some patients with AHS induced by
ic), consideration should be given to the severity carbamazepine have been subsequently treated
of the patient’s previous allergic reaction. Sulfas with oxcarbazepine without incident,234 while
can cause serious mucocutaneous events such as others have had severe cross reactions. 235
SJS and TEN, and they can also cause relatively Lamotrigine, a structurally dissimilar anticonvul-
mild maculopapular rash or other isolated skin sant, has also been reported to cause an anticon-
rash. The severity of the reaction should largely vulsant hypersensitivity syndrome due to an
influence the decision as to whether the causative unknown mechanism.91 For information on pre-
sulfa drug or other sulfa drugs should be adminis- vention of DRESS and SJS due to anticonvulsants,
tered in the future. Although the structures of the see the section on “Cutaneous Diseases” in this
sulfa agents may influence reactivity, cases of sus- chapter.
TisdaleC06_49-97 1/20/10 10:54 PM Page 74
TABLE 6–8 Approaches to Help Prevent Drug-Induced Hypersensitivity and Pseudoallergic Reactions
Hypersensitivity Reactions (in general)
• With high-risk drugs, monitor for signs and symptoms of allergy during the first 7–30 days of therapy.
• Be vigilant in monitoring patients who are frequently exposed to allergenic drugs (e.g., patients with cystic fibrosis,
patients with frequent bouts of bronchitis, pneumonia, or otitis media).
• Educate patients about high-risk drugs and the signs of an allergic reaction.
• Obtain detailed histories of allergies, with attention to the causative agent(s) and the severity of the reaction(s).
• Educate patients with a documented allergy to avoid the causative drug in the future (depending on the severity of
the reaction).
• Educate patients to avoid drugs structurally similar to the causative agent (depending on the severity of the reaction).
• Educate patients to read drug labels, particularly if the patient is reactive to excipients.
Anaphylactoid Reaction to Radiocontrast Media (high- or low osmolarity agent)
• Pretreat using prednisone 50 mg orally, administered at 13 hr, 7 hr, and 1 hr before administration of the contrast
agent; diphenhydramine 50 mg orally/IV/IM 1 hr before the procedure and ephedrine 25 mg orally 1 hr before the
procedure (avoid ephedrine in patients with unstable angina, hypertension, arrhythmias).245
• In an emergency situation, the following pretreatment regimen has been used: hydrocortisone 200 mg IV immediately
upon determination of need of the radiocontrast study and every 4 hr until the procedure is completed; diphenhy-
dramine 50 mg IV/IM 1 hr before the procedure.249
Anaphylactoid Reaction to Paclitaxel
A number of different pretreatment regimens have been used with success:
• Pretreat with dexamethasone 20 mg orally at 12 hr, 6 hr, and 1 hr before paclitaxel infusion; diphenhydramine 50 mg IV
30 to 60 min before the infusion; cimetidine 300 mg IV (or ranitidine 50 mg IV, famotidine 20 mg IV) before the pacli-
taxel infusion.250
• Diphenhydramine 50 mg IV, famotidine 20 mg IV and dexamethasone 20 mg IV, each given 30 min before the
paclitaxel infusion.251
Vancomycin Red Man Syndrome
• Administer each 1-g dose over at least 1 hr; each 1.5-g dose over at least 90 min; each 2-g dose over 2 hr.
• Pretreat using diphenhydramine 25–50 mg IV, acetaminophen 650 mg orally, hydrocortisone 100 mg IV.
IM = intramuscularly; IV = intravenously.
TisdaleC06_49-97 1/20/10 10:54 PM Page 75
urticaria, angioedema). In this setting, it is crucial (AAAI) and the American College of Allergy,
to obtain an accurate allergy history. If a patient’s Asthma, and Allergy (ACAAA) updated the
history suggests reactivity to a specific NSAID and Practice Parameter on the Diagnosis and
lack of reactivity to NSAIDs of other chemically Management of Anaphylaxis.170 On the basis of
dissimilar classes, a true hypersensitivity reaction these guidelines, patients with stridor, respiratory
should be suspected.12 Such patients should be distress, wheezing, hypotension, cardiac arrhyth-
advised to avoid the specific NSAID and any struc- mias, shock, or loss of consciousness require
turally similar agent (e.g., all propionic acid deriv- immediate treatment. Life-threatening conditions
atives) because of the risk of cross reactivity. In may also develop in patients with non-life-threat-
patients with asthma who describe an exacerbation ening symptoms on initial presentation (e.g.,
after the administration of aspirin or another COX- localized urticaria) .170 Table 6–9 summarizes the
1 inhibitor, a pseudoallergic reaction should be sus- Joint Task Force’s guidelines for treatment of ana-
pected.12 These patients are at risk of severe asthma phylaxis. The mainstays of therapy are epineph-
exacerbations resulting from the pharmacologic rine 1:1,000 dilution administered subcutaneously
effects of aspirin and other potent COX-1 or intramuscularly, a histamine H1-receptor block-
inhibitors on prostaglandin and leukotriene syn- er administered intravenously, and aggressive
thesis.169 Patients with aspirin- or NSAID-induced intravenous fluid replacement. In studies of adults
asthma should be advised to avoid all COX-1 and children not experiencing anaphylaxis, epi-
inhibitors.12,169 Studies of short duration involving nephrine has been shown to be most efficiently
small numbers of patients with aspirin-induced absorbed when administered intramuscularly,
asthma have shown that the COX-2 inhibitors, rather than subcutaneously.246 In adults, the pre-
celecoxib and rofecoxib, do not exacerbate asth- ferred intramuscular site of injection is the antero-
ma.240-242 In addition, acetaminophen at a dose of lateral thigh, because of a higher rate of
less than 1g, sodium salicylate, choline salicy- absorption.247 In patients with hypotension that is
lamide, and magnesium trisalicylate have not been refractory to epinephrine and intravenous fluid
shown to exacerbate asthma because of their lack replacement, the addition of a histamine H2-recep-
of effect on the COX-1 enzyme. In some patients tor blocker is advised. Patients receiving long-term
with NSAID-induced asthma, desensitization to -blocker therapy by either oral or topical routes
aspirin or other NSAIDs has been achieved.243 usually require higher doses of epinephrine.170 In
Rapid desensitization protocols for patients with these patients, anaphylaxis is often severe and
cardiovascular disease requiring aspirin have also associated with profound hypotension or brady-
been described.244 cardia that are unresponsive to epinephrine.
Glucagon may be used in these patients for its
Radiocontrast Media inotropic and chronotropic effects that occur
independently of -receptor responsiveness.
Pseudoallergic reactions associated with radiocon-
Corticosteroids have no role in the acute treat-
trast agents are largely prevented by the use of pre-
ment of anaphylaxis, except for patients with a
treatment regimens, as noted in Table 6–8. In
history of asthma or idiopathic angioedema; how-
addition, administration of a low-osmolarity agent
ever, they are used adjunctively to prevent the
in conjunction with pretreatment has been shown to
late-phase reaction. Patients treated long term
lower the risk of reactivity to approximately 1%.245
with ACE inhibitors may also require aggressive
treatment for hypotension associated with ana-
phylaxis. In these patients, the release of
MANAGEMENT angiotensin II as a normal compensatory mecha-
nism will be blunted.
Recommended treatment regimens for drug allergy Treatment of immune complex diseases is high-
vary based on the signs and symptoms of the reac- ly variable and dependent on the patient’s presen-
tion and the type of allergic syndrome. Reactions tation. In many cases, discontinuation of the
mediated by pseudoallergic mechanisms are treat- causative drug is the only treatment required.
ed in a manner similar to those of true hypersensi- Supportive therapy may include a mild
tivity reactions, with the choice of therapy based analgesic/antipyretic, such as acetaminophen, for
on the patient’s signs and symptoms. Table 6–9 flu-like symptoms. An oral antihistamine should be
provides a summary of recommended treatments considered in patients with pruritus associated with
for a variety of allergic syndromes. an urticarial, maculopapular, or mixed skin rash. In
In 2005, the Joint Task Force of the American some patients, a short course of a low-dose oral cor-
Academy of Allergy, Asthma and Immunology ticosteroid such as methylprednisolone may be
TisdaleC06_49-97 1/20/10 10:54 PM Page 76
used for treatment of a diffuse erythematous, mac- thematous reactions, fixed drug eruptions, psoria-
ulopapular skin rash. High-dose corticosteroids (i.e., sis, and the SCARs (DRESS, SJS, TEN, warfarin tissue
prednisone 40 to 60 mg/day) should be reserved for necrosis). The previous section provides discussion
patients with systemic events involving the kidney of urticaria, angioedema, and skin reactions associ-
or liver, patients with drug hypersensitivity syn- ated with immune complex diseases. Chapter 8
dromes, or patients with vasculitis.175 The presence provides a review of drug-induced photosensitivity.
of mucosal involvement (i.e., SJS or TEN) often pre- Standard terms are used to describe the mani-
cludes the use of systemic corticosteroids because of festations of drug-induced cutaneous reactions. A
the risk of infectious complications.175 listing of these terms and their definitions is pro-
vided in Table 6–10.252,253
ACNE
Androgenic steroids (methyltestosterone, testosterone, nandrolone)258 NK C
Azathioprine NK C
Corticosteroids258-260 NK C
Cyclosporine NK C
Danazol NK C
Epidermal growth factor receptor inhibitors261,262
Cetuximab 88–90% B
Erlotinib 75% B
Gefitinib 25–33% B
Panitumumab 70–100% B
Granulocyte colony-stimulating factor267 NK C
Infliximab265 NK C
Iodides257 NK C
Lamotrigine266 NK C
Lithium263 NK C
Tacrolimus264 NK C
FIXED DRUG ERUPTION
Acetaminophen268 NK C
Allopurinol268 NK C
Barbiturates257 NK C
Carbamazepine257 NK C
Celecoxib268 NK C
Dipyrone268 NK C
Erythromycin268 NK C
Griseofulvin268 NK C
Ibuprofen268 NK C
Metronidazole268 NK C
Paclitaxel268 NK C
Penicillins268 NK C
Phenophthalein268 NK C
Pseudoephedrine268 NK C
Rifampin268 NK C
Sulfamethoxazole257,268 NK C
Tetracyclines257 NK C
DRESS
Allopurinol175 NK C
Captopril147 NK C
Carbamazepine175 NK C
Dapsone175,253 NK C
Lamotrigine175,253 NK C
(Continued)
TisdaleC06_49-97 1/20/10 10:54 PM Page 80
compared to surgical patients (0.01%).255 Thirty- angioedema, serum sickness–like syndrome with
four percent of cases were deemed serious on the maculopapular rash, fixed drug eruptions, vasculi-
basis of being responsible for the hospitalization tis, and the SCARs, including DRESS, SJS, and TEN.
(18%), increasing the duration of hospital stay The skin is a target for immunologically mediated
(14%), or being life-threatening (2%).255 Compared reactions because it possesses APCs such as the cuta-
to other studies reporting an incidence of cuta- neous Langerhans’ cells. The presence of monooxy-
neous drug reactions of 2% in hospitalized genases, cytochromes, and transport-associated
patients, the lower prevalence determined in this proteins in the keratinocytes allow for transforma-
study can be attributed to the restricted focus on tion of low-molecular-weight drug haptens into
allergic-mediated skin reactions and on systemic reactive, immunogenic metabolites.284
drug exposures.255 T cells play a major role in the pathophysiology
TEN is estimated to occur in 0.4 to 1.3 cases per of drug-related cutaneous reactions. An extensive
million person-years, while SJS occurs in 1 to 6 review of the role of the T lymphocyte in the medi-
cases per million person-years.253,275 The variability ation of a variety of drug-induced eruptions
in these estimates of incidence can be attributed to has been provided by Naisbett.285 Based on
differences in the diagnostic criteria for SJS and immunohistologic studies, allergy-mediated macu-
TEN. The prevalence or incidence of other cuta- lopapular rashes have been shown to involve the
neous skin disorders is less well described. The inci- recruitment of CD4 cells and co-presentation of the
dence of DRESS is highly variable, occurring in 1 of drug hapten with MHC class II molecule HLA-
1,000 to 1 of 10,000 patients exposed to anticon- DR.285 Maculopapular rashes are also associated
vulsants and sulfonamides, and the mortality rate with the secretion of high levels of IL-5 and eotax-
has been estimated to be approximately 10%.253 in, two cytokines involved in the recruitment and
The wide variability in the reported incidence of differentiation of eosinophils. Bullous reactions are
DRESS can be attributed to the variable presenta- more likely to be associated with the recruitment of
tion of the condition. Fixed drug eruptions occur CD8+ cells and co-presentation of the haptenic
more frequently, with reported incidences of 2.5% drug or reactive metabolite with MHC class I mole-
to 22%.268 Tissue necrosis has been reported in 1 of cules.285 Cell studies of blister fluid from patients
10,000 patients treated with warfarin and in 0.01% who survived TEN also support a dominant role for
to 0.12 % of patients treated with all oral anticoag- T lymphocytes, particularly CD8+ cells, in the
ulants including the coumarin products.175,281 pathogenesis of this SCAR. In patients with TEN,
activation of cytotoxic T lymphocytes ultimately
results in dermal-cell apoptosis, which is believed to
MECHANISMS be triggered via activation of the perforin/granzyme
or the Fas–Fas ligand pathways. In addition to cyto-
Cutaneous reactions to drugs can result from both toxic T lymphocytes, other mediators of TEN
allergic and nonallergic mechanisms (i.e., direct include monocytes, macrophages, and tumor
pharmacologic effects, pseudoallergy, idiosyncrasy). necrosis factor  (TNF-). Overexpression of TNF-,
Hypersensitivity is the underlying mechanism in interferon-, IL-2, and IL-5 has been reported in
50% of the events, including most cases of urticaria, skin lesions of patients with SJS and TEN.253
TisdaleC06_49-97 1/20/10 10:54 PM Page 82
Mechanisms by which many drugs cause skin upper and lower extremities, and potentially the
eruptions are not known. Pharmacologic effects face.257,286 The rash is often described as “dot-like”
may be the underlying mechanism by which most in appearance, or measles (morbilliform)-like, and
drugs cause acneiform eruptions and provocation may or may not be associated with fever and pruri-
of psoriasis. Androgenic drugs (e.g., anabolic tis. The discrete lesions typically coalesce over days
steroids, danazol, methyltestosterone) aggravate into patches with large areas of confluence. The
preexisting acne or cause acneiform eruptions by rash usually occurs within 4 to 14 days after the
activating sebaceous-gland hypertrophy and initiation of therapy with the causative drug or
increasing sebum production. The high incidence within 1 to 2 days after drug discontinuation.286
of acneiform eruptions associated with the use of This reaction is usually self-limited, with resolution
epidermal growth factor receptor (EGFR) inhibitors in 1 to 2 weeks after drug discontinuation. Upon
may also be explained in part by the known phar- reexposure to the drug, the rash may reappear
macology of these agents. EGFRs are overexpressed within hours. In rare instances, a maculopapular
in many solid tumors, explaining the effectiveness rash may be the initial sign of a severe cutaneous
of EGFR inhibitors in the treatment of refractory event such as SJS. Therefore, all patients who pres-
colorectal and lung cancers. EGFRs are also ent with a maculopapular rash should be assessed
expressed in the basal layer of the epidermis and in for hallmark signs of a more severe, progressive
the hair follicle.261,262 Although the mechanism by reaction. Lesions in the mucous membranes (e.g.,
which EGFR inhibitors cause acne-like rashes is not conjunctiva, oral cavity, naries, genitalia) are evi-
entirely known, the dose-related incidence may be dent in more than 90% of serious cutaneous events
related to inhibition of EGFR signaling on epider- and extension of the rash to the palms and soles
mal epithelium leading to impaired cell growth often portends a more protracted course.175,253
and differentiation.261 Provocation of psoriasis by A commonly encountered clinical challenge is
nonselective -blockers such as propranolol may differentiation of a maculopapular rash from an
be explained in part by blockade of epidermal 2- urticarial lesion. Unlike maculopapular lesions,
receptors, resulting in a decrease in intraepidermal urticarial lesions are typically asymmetrical, pink
cyclic adenosine monophosphate and an increase rather than red, and irregular in shape. These
in epidermal-cell turnover.270 Cyclooxygenase superficial wheals, largely confined to the epider-
inhibitors such as indomethacin may induce psori- mis, are often described as geographic in shape
asis by inhibiting prostaglandin synthesis, thereby (i.e., similar in shape to the continent of Africa or
shunting the metabolism of arachidonic acids to Asia). Urticarial lesions are highly pruritic, vary in
the lipoxygenase pathway. The resultant increase size from 1 mm to several centimeters in diameter,
in leukotriene concentrations may contribute to and typically develop on the chest, face or neck
the exacerbation of psoriasis in patients treated within minutes to 48 hours after drug exposure.257
with COX inhibitors.271 Studies support that Differentiation of a maculopapular rash from
leukotriene concentrations are 7 to 11 times high- urticaria is important, because the latter often indi-
er in psoriatic lesions as compared with normal cates IgE-mediated mast-cell degranulation. In a
skin.270 patient with drug-related IgE-mediated urticaria,
continuation of the causative drug may lead to a
more severe reaction, including angioedema or
CLINICAL PRESENTATION AND anaphylaxis. Urticaria may also be caused by foods,
DIFFERENTIAL DIAGNOSIS insect bites/stings, and environmental factors such
as sunlight, cold, and heat.257
The discriminating features of specific drug erup- Fixed drug eruptions (FDEs) are the second
tions are provided in Table 6–12 and the condi- most commonly occurring drug- related cutaneous
tions to consider in the differential diagnoses are reaction.252 FDEs present as solitary lesions or mul-
provided in Table 6–13. tiple well-demarcated lesions occurring anywhere
The most common type of drug-induced skin on the body, but favoring the face, lips, hands, feet,
eruption is the exanthematous or maculopapular and genitalia. The lesions are round or oval in
rash. This red, inflamed cutaneous reaction usually shape and range in size from 1 to 20 cm in diame-
appears as a mixture of discrete macules and ter.252,257 The color of the lesions may vary from
papules on the trunk or dependent areas of the dusky red, to blue-gray or violaceous. Patients typ-
body (e.g., lower extremities of an ambulating ically describe a burning sensation or itching, or
patient, middle to lower back of a bedridden both, associated with the development of lesions.
patient). The lesions typically spread outward in a In some patients, the center of the lesion may
bilateral, symmetrical pattern to involve the neck, become bullous and result in denuding of skin. The
TisdaleC06_49-97 1/20/10 10:54 PM Page 83
TABLE 6–13 Conditions to Consider in the Differential Diagnosis of Drug-Induced Cutaneous Disorders
Erythematous rash257
• Viral exanthema (Epstein–Barr virus, human herpesvirus-6, parvovirus B19)
• Acute graft-versus-host disease
• Bacterial toxin eruption
• Kawasaki disease
• Stills disease
Fixed drug eruption252,268
• Bullous pemphigoid
• Herpes (simplex) labialis
• Discoid lupus erythematosus
• Insect bite (if a single lesion)
DRESS175
• Cutaneous lymphoma
• Psoriasis (aggravation of)270,271
• Alcohol consumption
• Physical trauma
• Psychological stress
• Streptococcal infection
• Viral infection
SJS175,288
• Postinfectious erythema multiforme (secondary to herpes simplex or mycoplasma infection)
• Kawasaki disease
TEN175
• Exfoliative dermatitis
• Staphylococcal scalded-skin syndrome
• Paraneoplastic pemphigus
• Thermal burns
Warfarin-Induced Skin Necrosis281
• Disseminated intravascular coagulation
• Purple toe syndrome
• Pyoderma gangrenosum
• Microembolization
• Leukocytoclastic vasculitis
• Necrotizing fasciitis
• Purpura fulminans
• Venous gangrene
• Heparin-induced thrombocytopenia
• Septicemia
DRESS = drug rash with eosinophilia and systemic symptoms; HHV-6 = human herpesvirus-6; SJS = Stevens–Johnson syndrome; TEN =
toxic epidermal necrolysis.
diagnostic hallmark of FDE is recurrence of the history with attention to prescription, nonpre-
lesion in the same anatomical location after drug scription and herbal remedies must be obtained to
rechallenge.268 Both topical and oral provocation identify the causative agent. Drugs most common-
tests have been performed to confirm the diagno- ly associated with FDE are listed in Table 6–11.
sis. However, oral challenge is more likely to lead Acneiform eruptions are an infrequent drug-
to the development of generalized bullous induced adverse event, accounting for only 1% of
lesions.268 Following resolution of lesions, the all drug-related cutaneous reactions.257 Unlike acne
affected tissue may remain hyperpigmented for an vulgaris, drug-related acneiform eruptions consist
extended period. As the name implies, the sole primarily of papules and pustules with limited to
cause of FDE are drugs. Therefore, a complete drug no comedones. Similar to those associated with
TisdaleC06_49-97 1/20/10 10:54 PM Page 85
acne vulgaris, the eruptions are typically confined disease or a transformation to the pustular form of
to the face and upper trunk.257 The classic drug psoriasis.270 The latency period from initiation of
offenders are corticosteroids, adrenocorticotropic therapy with the offending drug to the exacerba-
hormone, anabolic steroids, combination oral con- tion or appearance of psoriatic lesions varies wide-
traceptives, danazol, bromides, iodides, isoniazid, ly. Mean latency periods of 3 weeks, 6 weeks, and
lithium, and azathioprine. Corticosteroids admin- 33 weeks have been described for psoriasis induced
istered orally, parenterally, topically, or by inhala- by the synthetic antimalarial drugs, ACE
tion have been shown to provoke acneiform inhibitors, and lithium, respectively.270 -Blockers
eruptions or exacerbate underlying conditions of have been associated with a latency period ranging
acne.258,259,260 Steroid-induced acne is common and from days to weeks after initiation of therapy.
usually appears within 14 days after initiation of Drugs used to treat psoriasis, including topically
systemic or topical therapy. An acne-like reaction applied agents (e.g., coal tar) and systemically
has also been described in association with the use administered agents (e.g., etretinate, etanercept,
of the EGFR inhibitors (e.g., cetuximab, panitu- infliximab) can also aggravate the condition. The
mumab, erlotinib, gefitinib) used in the treatment tumor necrosis factor ␣ agents infliximab and etan-
of colorectal and non-small-cell lung cancer. The ercept have aggravated psoriasis in patients under-
acne-like rash is pruritic, with a predominance of going treatment for psoriatic arthritis and have
pustules and an absence of open or closed come- provoked psoriasis in patients treated for Crohn’s
dones.261,262 The rash is typically mild to moderate disease, ankylosing spondylitis, rheumatoid arthri-
in severity, occurs most frequently on the face and tis, and ulcerative colitis.273 In patients treated with
V-shaped areas of the chest, back, or both and infliximab or etanercept, new psoriatic lesions
appears within 10 to 14 days after drug therapy ini- developed as soon as after the second injection.273
tiation. The severity of the rash has been shown to Serious cutaneous adverse reactions include
correlate with both increasing drug dose and the DRESS, SJS, TEN, and warfarin tissue necrosis.
antitumor activity of the agent.262 Some data sup- DRESS is a distinct clinical syndrome previously
port a relationship between the occurrence of rash described by the more general term, drug hyper-
and the increased likelihood of patient survival.261 sensitivity syndrome.84,92,287 DRESS is characterized
In patients with severe rashes, particularly those by the triad of high fever, rash, and internal organ
involving more than 50% of the body-surface area, involvement.175,287 Compared with immune com-
dose modification or interruption of EGFR plex diseases such as SSLD, DRESS is associated
inhibitor therapy is recommended.261,262 The rash with a more delayed onset of symptoms, ranging
is typically reversible following discontinuation of from 3 to 8 weeks after drug initiation, and a more
therapy. consistent pattern of internal-organ involve-
Psoriasis is a chronic, immunologically mediat- ment.84,287 The initial manifestation of DRESS is dif-
ed skin disease that is characterized by red or fuse, symmetrical maculopapular eruptions on the
salmon-pink plaques covered by silvery or white upper trunk and face. This rash can extend to
scales surrounded by normal skin.270 The plaques include the lower extremities and is typically asso-
are symmetrically distributed on the elbows, knees, ciated with facial and periorbital edema. The
scalp and lumbosacral region. Several clinical phe- edema may lead to gross distortion of the patient’s
notypes of psoriasis exist, including pustular, ery- features.253 Organs affected by this syndrome
throdermic, and nail psoriasis. However, 90% of include the kidney, liver, pancreas, lungs, and
cases present as plaque psoriasis (psoriasis vul- hematologic system. A high degree of interpatient
garis). This chronic condition involves the activa- variability exists with regard to the targeted organ
tion of T lymphocytes with overexpression of a and the severity of organ involvement. Both the
number of cytokines, including tumor necrosis fac- anticonvulsant hypersensitivity syndrome and the
tor , interferon-, IL-6, IL-2, and IL-8. Drugs can allopurinol hypersensitivity syndrome are classic
exacerbate preexisting lesions (e.g., -blockers, examples of DRESS. Anticonvulsant hypersensitivi-
lithium, synthetic antimalarial drugs), provoke the ty syndrome, associated with the aromatic anticon-
development of new plaques on the normal skin of vulsants (e.g., phenytoin, phenobarbital,
patients with psoriasis (e.g., -blockers, lithium), carbamazepine) is characterized by the triad of
and cause psoriasis in patients with no history or fever (38–40°C), rash (papular, pruritic, often asso-
familial predisposition (e.g., growth hormone).270- ciated with facial or periorbital edema), and lym-
273
Most cases of drug-induced psoriasis are clinical- phadenopathy occurring within 3 months after the
ly indistinguishable from psoriasis from initiation of therapy.87,233 Other diagnostic criteria
non-drug-induced causes. In some cases, the include hematologic abnormalities (leukocytosis,
offending drug can cause a lichenoid pattern of eosinophilia), myalgias, pharyngitis, and hepatitis
TisdaleC06_49-97 1/20/10 10:54 PM Page 86
or other multisystem involvement (e.g., interstitial involves widespread purpuric macules and epider-
nephritis, rhabdomyolysis, pneumonitis).87,233 mal detachment of >30% of body-surface
Allopurinol hypersensitivity syndrome is associat- area.288,291 The term SJS–TEN overlap is used to
ed with a mean (±SD) onset of 47±109 days92 and describe cases in which evidence of epidermal
also presents with high fever, eosinophilia, and detachment is present on 10% to 30% of the body-
skin rash that may be severe (e.g., SJS or TEN). surface area.288,291 Although regrowth of the epider-
Kidney failure, hepatomegaly, and abnormalities in mis begins within days after the onset of epidermal
liver-function tests are also frequently noted. This loss, TEN is often complicated by the development
reaction, attributed to the active metabolite oxy- of acute kidney disease, respiratory failure, neu-
purinol, has been described as a vasculitic immune tropenia, electrolyte abnormalities, and sepsis.
complex disease.91,92 Long-term sequelae of SJS and TEN may include
SJS and TEN are related mucocutaneous disor- temporary nail loss, permanent visual impairment,
ders that are considered by many as severe variants cutaneous scarring, and irregular pigmentation. A
of erythema multiforme. Like erythema multi- severity-of-illness scoring system for TEN, known
forme, both SJS and TEN are associated with the as SCORTEN, has been described and evaluated as
widespread development of multiple types of skin a prognostic indicator.292 With the use of this sys-
lesions, including macules, blisters, purpuric tem, seven independent risk factors, determined
lesions, and the hallmark target iris lesions. The within 24 hours of patient presentation with TEN,
target lesion is discrete, round, <3 cm in diameter, are used as patient outcome indicators.292
and identified by its central zone of epidermal Warfarin-induced skin necrosis (WISN) is a
necrosis surrounded by two concentric rings of severe cutaneous reaction that typically begins
edema and erythema.288 SJS and TEN are progres- within 10 days after initiation of warfarin therapy,
sive bullous disorders that are considered dermato- with a peak occurrence between days 3 and 6.257
logic emergencies.288 Unlike erythema multiforme, WISN initially presents with red, poorly demarcat-
which is usually self-limiting and related to recur- ed painful plaques usually in areas of high adipose
rent herpes simplex viral infections, both SJS and tissue (e.g., breasts, hips, buttocks). The plaques
TEN are usually drug-related and extend from dif- can progress to hemorrhagic blisters and eventual-
fuse erythematous reactions to include mucous ly become necrotic, requiring surgical debride-
membrane erosion and epidermal detachment. ment.175,257 WISN occurs as a result of an
Drugs are the cause of SJS and TEN in 50% and imbalance between the concentrations of the
80% of cases, respectively.252,289 endogenous vitamin K–dependent anticoagulant,
Both SJS and TEN typically occur within the protein C, and the vitamin K–dependent clotting
first 4 weeks of drug therapy. Before skin lesions factors.175,257 The half-life of protein C is much
become evident, both SJS and TEN are associated shorter (8 hours) as compared with those of clot-
with a prodromal syndrome of nausea, vomiting, ting factors II, IX, and X (24 to 48 hours). After
sore throat, diarrhea, myalgias, and arthralgias. In warfarin initiation, a rapid decline in the concen-
patients with TEN, high fevers and a burning sen- tration of protein C may lead to a hypercoagulable
sation of the skin are also frequently reported prior state, resulting in WISN. This theory is supported
to the eruption of skin lesions. Mucous membrane by the fact that WISN is more likely to occur in
involvement, typically of the mouth and lips, nasal patients who receive excessive starting doses of
cavity, and conjunctivae, tends to precede the warfarin and have an underlying protein C defi-
development of skin lesions by 1 to 3 days.252,290 ciency. Patients with a deficiency of protein S, the
The initial lesions are erythematous and appear on cofactor for protein C activity, may also be at
the face and upper trunk, after which they rapidly greater risk of WISN. WISN can be fatal if not
evolve into blisters and target lesions on the face, treated.
trunk, and limbs.290 Full-thickness epidermal
detachment occurs within days after the onset of
skin lesions. Rather than being thought of as two RISK FACTORS
distinctly different syndromes, SJS and TEN are
often described as a continuous spectrum of a dis- Female sex,179 concomitant viral infection with
ease, with TEN as the more severe form.288 The HIV190 or EBV,189 and the presence of autoim-
extent of epidermal detachment has been used to mune disease have routinely been identified as
distinguish between SJS and TEN. SJS is described risk factors for cutaneous drug eruptions. In a
by the presence of mucosal erosions with wide- prospective study of 48 patients with allergic-
spread purpuric macules and epidermal detach- mediated skin reactions, identified risk factors
ment of <10% of body-surface area, whereas TEN were HIV (19% of patients), connective-tissue
TisdaleC06_49-97 1/20/10 10:54 PM Page 87
and TEN associated with sulfonamides and the name of the specific offending drug, the terminol-
potential for cross reactivity with sulfadiazine.252 ogy used to describe the rash, and the likelihood of
The use of systemic corticosteroids remains con- the occurrence of a similar or more severe reaction
troversial.175,252,288 To date, there are no large ran- following reexposure to the drug. If the reaction
domized, controlled studies to support the was allergic-mediated, the patient should be
concept that systemic corticosteroids either instructed to question all newly prescribed medica-
reduce the time to recovery or prevent the devel- tions regarding similarity to the offending agent in
opment of complications. High dose intravenous chemical structure or chemical class. Patients with
immunoglobulin (IVIG), administered as 0.4 to underlying skin conditions such as acne or psoria-
1.0 g/kg/day for 3 to 4 consecutive days, has sis should be instructed to question whether any
emerged as a potential treatment of SJS and TEN newly prescribed medication may aggravate the
in children and adults.300-303 IVIG is postulated to condition.
inhibit dermal-cell apoptosis triggered via the
Fas–Fas ligand pathway.290 When administered
early in the course of the disease, IVIG has shown
promising effects on wound healing, progression
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CHAPTER 7
98
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Most common
Chlorpromazine6-20 1% C
Hydralazine6,14-27 2–21% C
Isoniazid6,16,18-20,28-31 NK C
Methyldopa16,32-34 NK C
Minocycline16,35-49 NK B
Procainamide6,14-20,50-60 15–35% C
Quinidine16,20,61-66 NK C
Anticonvulsants
Carbamazepine16,67-70 1% C
Ethosuximide6,16,67,71-73 NK C
Lamotrigine74 NK C
Mephenytoin72 NK C
Phenytoin16,18,67,72 NK C
Primidone6,16,67 NK C
Trimethadione16,67,71,72 NK C
Troxidone6 NK C
Antithyroid drugs
Methimazole6,75 NK C
Methylthiouracil6,75 NK C
Propythiouracil6,16,34,75-80 NK C
Thiamazole75 NK C
Cardiovascular agents
Acebutolol6,16,81,82 NK C
Amiodarone83 NK C
Atenolol6,16,84 NK C
Calcium-channel blockers85 NK C
Captopril6,16,86-89 NK C
Chlorthalidone16,84 NK C
Clonidine6,16,90 NK C
Disopyramide16,84 NK C
Enalapril16,91 NK C
Gemfibrozil92,93 NK C
Guanoxan6 NK C
HMG-CoA reductase inhibitors6,16,92,94-100 NK C
Hydrochlorothiazide16,101,102,108 NK C
Labetalol6,16,103 NK C
Lisinopril91 NK C
Minoxidil6,16,84 NK C
(Continued)
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Molecular mimicry involves the interaction methylation, which may be an important compo-
between an implicated medication and a nucleic nent of the development of drug-induced lupus
acid. Drugs or drug metabolites with structures that associated with these drugs.
are similar to the structure of a particular nucleic The immunoregulatory alteration hypo-
acid may stimulate the production of autoantibod- thesis suggests that drug or drug metabolites may
ies to that nucleic acid, the drug, or its metabolite. alter the function of immunoregulatory cells via
This hypothesis has been supported by several direct cytotoxicity. Studies examining this
studies showing structural similarities between hypothesis have produced inconsistent results.210
hydralazine and the nucleic acid adenosine.17,196 Procainamide alters the function of T lymphocytes
The nucleic acid alteration hypothesis suggests in vitro, enhancing or suppressing the prolifera-
that the offending drug or its metabolite may tive response in a concentration-dependent
somehow alter the immune process, increasing the fashion; high concentrations of procainamide
immunogenicity of nuclear antigens. Alternatively, suppress lymphocyte response, whereas low
the drug or metabolite may couple with an antigen concentrations enhance this response.202
to form a hapten, triggering the formation of Macrophages and mononuclear cells may also be
autoantibodies. The drug or its metabolites may involved in immunoregulation. It is proposed that
also damage deoxyribonucleic acid (DNA), which during drug metabolism, these cells may release a
also may result in the formation of autoantibod- variety of oxygen free radicals, which may be
ies.17,75,208 For drugs that undergo hepatic acetyla- directly cytotoxic to lymphocytes. This cytotoxic-
tion, acetylator phenotype may affect response to ity may lead to the loss of T suppressor cells, stim-
this damage. Fast acetylators require less DNA ulation of B cells, and increased antibody
repair, suggesting that less damage to DNA occurs production.17,197 Drugs or drug metabolites may
in patients with this phenotype.17,75,208 bind to the major histocompatibility antigens on
Defective methylation of DNA in T cells has monocytes, rendering them immunogenic.17,211
been suggested in the pathogenesis of idiopathic The drug or the metabolite may also bind to his-
SLE and may also contribute to the development of tone antibodies, stimulating the production of
drug-induced lupus. Hypomethylation of DNA in T antihistone antibodies.17,212 Anti–tumor necrosis
cells alters T-cell gene expression and function.193 factor ␣ (anti-TNF␣) therapies have been shown to
Both procainamide and hydralazine inhibit DNA down regulate a mechanism involved in control-
TisdaleC07_98-116 1/12/10 2:30 PM Page 102
ling B-cell hyperactivity, which may induce lupus plexes and possibly stimulating autoimmune
in some patients.207 processes. Isoniazid, hydralazine, and the hydroxy-
Another immunoregulatory alteration hypoth- lamine metabolite of procainamide have been
esis involves the interference of T-cell maturation shown to inhibit covalent binding reactions
in the thymus by a reactive metabolite of pro- between C3 and C4.17,198
cainamide—procainamide-hydroxylamine. These It has been proposed that genetic factors may
T cells are then exported to the periphery and are play a role in the development of drug-induced
reactive to chromatin. The T cells help autoreactive lupus. The term lupus diathesis refers to a predispo-
B cells already in the periphery to stimulate an sition to idiopathic lupus. Patients with lupus
autoantibody response.203-206 diathesis are those with a personal or family histo-
It is well established that hereditary deficien- ry of arthritis, myalgia, drug reaction, pleuritic
cies in complements 1, 2, and 4 (C1, C2, and C4) pain, epilepsy, or leukopenia.197,214 In patients with
predispose patients to idiopathic lupus and other lupus diathesis, certain drugs may cause the clini-
autoimmune diseases.17 One of the roles of the cal expression of the disease; in contrast, medica-
complement system is to scavenge immune com- tions known to cause drug-induced lupus may be
plexes, promoting their clearance from the body.213 used in patients with idiopathic SLE without exac-
Drug-induced lupus may occur as a result of inter- erbating disease.197,214 Other genetic factors may be
ference in the complement pathway. Some drugs important in the development of drug-induced
or drug metabolites may inhibit C3 activation, pre- lupus. The incidence of lupus induced by
venting complement from clearing immune com- hydralazine and, to a lesser extent, procainamide is
TisdaleC07_98-116 1/12/10 2:30 PM Page 105
TABLE 7-4 Comparison of Signs and Symptoms Associated with Drug-Induced Lupus and Idiopathic
SLE1,2,17,19,50,84,194,195,217,220,222,237,245-249
Lupus Conditions (% of patients experiencing sign/symptom)
Drug-induced Lupus
Manifestations Idiopathic SLE All Drugs Procainamide Hydralazine
% of patients experiencing sign/symptom
Fever 75–85 25–50 45 14–50
Malaise 75 25–50 NK NK
Myalgia 48 NK 20–50 2–34
Arthralgia 92–95 75 74–95 84–95
Arthritis 86–95 75 18 50
Pleuritis 42–60 NK 52 14–25
Pericarditis 18–50 50 14–18 0–2
Pleural effusion 16–33 NK 33 10
Pulmonary infiltrate 0–10 NK 5–20 3–25
Hepatosplenomegaly 9–46 25 20–41 3–75
Skin manifestations 50–75 0–10 5–18 2–39
Alopecia 42 Unusual 0 0
Discoid lesions 23 Unusual 0 0
Mucosal ulcers 42 Unusual 0 0
CNS involvement 25–70 0 0–2 0
Renal involvement 38–75 5 0–5 0–20
Antinuclear antibodies 95 95 100 100
Lupus erythematosus cells Up to 70 90 NK NK
Antihistone antibodies 20–60 70–95 90–95 90–95
Anti-ssDNA 50–90 30–48 70–80 70–80
Anti-dsDNA 25–80 5 Rare Rare
Anti-Sm antibodies 40–50 5 10–20 10–20
Erythrocyte sedimentation rate Elevated Elevated (80) Elevated Elevated
Complement levels Reduced Normal/reduced NK NK
Anemia (hemoglobin <11.5 g/dl) 57 0 –46 9–21 30-35
Leukopenia (white-cell count <4000/mm3) 43–50 2–33 2–32 26
Thrombocytopenia NK Unusual NK NK
Hypergammaglobulinemia NK 10–50 NK NK
Positive Coombs’ test 18–25 0–33 33 0–5
CNS = central nervous system; DNA = deoxyribonucleic acid; dsDNA = double-stranded DNA; NK = not known; SLE = systemic lupus
erythematosus; Sm = Smith nuclear antigen; ssDNA, single-stranded DNA.
metics), tartrazine (i.e., food colorant), insecti- including terbinafine, hydrochlorothiazide, acebu-
cide, and heavy metals (e.g., mercury, cadmi- tolol, bupropion, and certain calcium-channel
um).5,17,251 blockers have been associated with drug-induced
Two other forms of drug-induced lupus include SCLE, in addition to 3-hydroxy-3-methylglutaryl
drug-induced subacute cutaneous lupus erythe- coenzyme A reductase inhibitors (statins) and
matosus (SCLE) and drug-induced chronic cuta- interferons alfa and beta. 82,99,133,146,252,253 This con-
neous lupus erythematosus (CCLE). Drugs dition appears to be more common in females than
TisdaleC07_98-116 1/12/10 2:30 PM Page 108
ner.5,17,19,117 This dose relationship may correlate to lupus.5 For example, in one study, 73% of patients
the accumulation of unacetylated drug in the with hydralazine-induced lupus had HLA-DR4.213
body.17,19 Hydralazine doses greater than 200 The presence of a null allele for C4 is also a risk fac-
mg/day or cumulative doses of more than 100 g tor for drug-induced lupus.193,215
have been associated with lupus-like syn-
drome.20,255,258
Certain drugs undergo acetylation to be inacti- MORBIDITY AND MORTALITY
vated. Patients who are slow acetylators often are
at a higher risk of adverse effects from these drugs Drug-induced lupus usually resolves within weeks
because of the potential for accumulation of the to months after discontinuation of the offending
active drug. For instance, sulfasalazine is metabo- drug, although the ANA test may remain positive
lized into sulfapyridine and 5-aminosalicylic acid; for months to years.5,20 It is fatal only in extremely
the sulfapyridine component is typically acetylated rare circumstances, usually as a result of kidney
in the liver by the enzyme N-acetyltransferase 2 failure.5
(NAT2). Individuals with a mutation on the NAT2
gene have impaired enzyme function and are thus
known as slow acetylators,119 and will present with PREVENTION
higher concentrations of the active sulfapyridine
component rather than its inactivated form.259 Monitoring parameters for prevention and detec-
Slow acetylators of procainamide experience lupus- tion of drug-induced lupus are presented in Table
like symptoms four times faster than fast acetyla- 7–7. Drug-induced lupus is an idiosyncratic drug
tors, and positive ANA tests develop at lower reaction that may not be explained by the known
cumulative drug doses in slow acetylators than in pharmacologic actions of the specific drug. To pre-
fast acetylators.217,260 Other drugs that are acetylat- vent drug-induced lupus, the drug known to cause
ed in the liver through NAT2 include hydralazine, the lupus-like syndrome should be avoided.
isoniazid, and sulfonamides.5,17,20,212,217 However, avoidance of certain drugs may not be an
The severity of lupus induced by hydralazine is option in many medical circumstances. The lupus-
greatly influenced by acetylator phenotype. One inducing potential of only a select number of drugs
study reported that 60% of slow acetylators taking has been substantiated with results from prospec-
less than 400 mg of hydralazine had a positive tive studies. The potential for other drugs to cause
ANA test, whereas 0% of fast acetylators taking the lupus is supported only by spontaneous, and often
same dose of hydralazine showed positive serum single, case reports. As a routine screening process,
ANA titers.259 On the other hand, although the baseline serum ANA concentrations should be
incidence of procainamide-induced lupus is higher determined when initiating a medication docu-
in slow acetylators, the severity of procainamide- mented to induce lupus.34 Periodic ANA testing
induced lupus is influenced minimally by acetyla- should be initiated based on clinical judgment,
tor type.201,259 Because both fast and slow remembering that serum ANA concentrations
acetylators may experience procainamide-induced alone are not diagnostic of drug-induced lupus. A
lupus, it has been hypothesized that a reactive, common recommendation is to obtain a complete
nonacetylated metabolite of procainamide may be blood count, ANA concentration, and ESR every 3
responsible for the syndrome.260 The influence of months in a patient receiving a drug with the
the acetylator phenotype is supported by the evi- potential to cause lupus.20 Periodic assessment of
dence that no cases of drug-induced lupus associat- constitutional signs and symptoms associated with
ed with the administration of the acetylated form the syndrome helps guide the clinical decision to
of procainamide, N-acetylprocainamide, have been
reported.17,19 Acetylator phenotype is not necessar-
ily a risk factor for lupus induced by all drugs
reported to induce this disease; this risk factor is TABLE 7–7 Approaches to Help Prevent
exclusive to certain drugs (see Table 7–2). It is also Drug-Induced Lupus
important to note that acetylator status does not Monitor the following at baseline and every
influence idiopathic SLE.261 3 months during therapy:
Various human leukocyte antigen (HLA) types,
• Serum antinuclear antibody titers
especially HLA-DR2 and DR4, are associated with
• Complete blood count
SLE.20 However, only HLA-DR4, which is associated
• Erythrocyte sedimentation rate
with slow acetylation, has been shown to be
• Signs and symptoms of drug-induced lupus
strongly associated with hydralazine-induced
TisdaleC07_98-116 1/12/10 2:30 PM Page 110
continue or discontinue the implicated drug. There teroidal antiinflammatory drugs if there are no
are no data to support cross-sensitivity between contraindications to their use.17,19,20,218,222
medications implicated in drug-induced lupus; However, patients presenting with more severe
therefore, it is not possible to say with certainty symptoms (e.g., pleurisy, pericarditis, renal
that patients experiencing drug-induced lupus involvement) require treatment with empirical,
after taking a certain medication will have the short-term low-dose systemic corticosteroids (e.g.,
same reaction to another medication implicated in prednisone 0.5–1.0 mg/kgd) tapered over 1 week
the disease. However, careful clinical decision mak- to several months.5,16-17,19-20,217,246-247,253 Patients
ing is necessary when considering treatment with presenting with lupus-induced skin manifesta-
such medications. Patients should be followed tions have been treated with antimalarial agents
carefully and appropriate baseline testing should (i.e., chloroquine–hydroxychloroquine). 5,221
be done to ensure patient safety during the course Several case reports describe rechallenge of the
of treatment. offending agent in the patient; lupus symptoms
promptly reappeared on reinitiation of the
drug.38,217
MANAGEMENT
Strategies for managing drug-induced lupus are INFORMATION FOR PATIENTS
presented in Table 7–8. Symptoms of drug-induced
lupus do not subside with continued administra- When patients are initiated on a drug that is
tion of the offending agent, although they are strongly associated with drug-induced lupus, the
reversible on discontinuation of the drug.19,217,221 health care professional should counsel the patient
Therefore, discontinuation of the offending drug is regarding the fact that symptoms of arthralgia or
required. Clinical and laboratory findings associat- arthritis may occur at any time during the thera-
ed with drug-induced lupus typically disappear py—up to and including 2 years after the first dose.
within weeks. Rarely, clinical and laboratory find- Regardless of whether or not the patient has an
ings may take years to resolve after the termination arthritis-related medical condition before the initi-
of the lupus-inducing drug.5,19,20,118,253 Although ation of the drug, symptoms of fever, malaise, and
symptoms often resolve quickly, serum ANA con- skin manifestations of unknown origin should be
centrations may fall gradually over several months reported promptly. The patient should also be
to 2 years.5,34,193 Clinical symptoms of lupus never counseled regarding other specific symptoms asso-
develop in most asymptomatic patients with posi- ciated with the implicated drugs (e.g., pulmonary
tive ANA serum concentrations, and drug discon- symptoms with procainamide, symptoms of hepa-
tinuation is not required in these cases.8,193 totoxicity with minocycline). The health care pro-
Patients often improve dramatically without fessional must educate the patient regarding the
treatment. Patients experiencing musculoskeletal importance of reporting symptoms because of: (1)
and mild constitutional symptoms (e.g., pyrexia, the progression of the syndrome if ignored and (2)
arthralgia, myalgia) may be treated with antiin- the reversibility of the syndrome on cessation of
flammatory agents such as aspirin and nons- the implicated drug.
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CHAPTER 8
Photosensitivity
Julie M. Koehler
Acebutolol4 NK C
Acetazolamide5 NK C
Alfalfa6 NK C
Alitretinoin7 NK C
Alprazolam8,9 NK C
Amantadine10 NK C
Aminolevulinic acid11 NK C
Amiodarone12-19 3–10% B
Amitriptyline20,21 NK C
Amlodipine22,23 NK C
Aripiprazole3,24 0.1–1% A
Atovaquone/proguanil25 NK C
Azathioprine26 NK B
Benzocaine27 NK C
Bergamot oil28 NK B
Bexarotene29 NK C
Bishop’s weed30 NK C
Bitter orange28 NK B
Calcipotriene31 NK C
Captopril32 NK C
Carbamazepine33 NK C
Carvedilol34 0.1–1% A
Cefazolin35 NK C
Ceftazidime36 NK C
Cetirizine3 <2% A
Chlordiazepoxide37,38 NK C
Chlorella39 NK C
Chloroquine40 NK C
Chlorothiazide41-43 NK C
Chlorpromazine44-47 NK C
Chlorpropamide48 NK C
Chlorthalidone49 NK C
Chrysanthemum50-55 NK B
Ciprofloxacin3,56-59 <1% A
Clioquinol60 NK C
Clofazimine61 <1% B
Clomipramine62 NK C
Clopidogrel63 NK C
Clozapine64 NK C
Coal tar65-67 NK B
Cyproheptadine68 NK C
(Continued)
TisdaleC08_117-134 1/15/10 9:43 AM Page 119
Ultraviolet
Radiation
Reactive
Phototoxin
Excited State Oxygen Tissue Damage
(Drug/Chromophore)
Energy Energy Intermediates
Absorption Transfer
FIGURE 8–1 Mechanism of Drug-Induced Phototoxicity319
Subsequent
Ultraviolet Protein Drug
Radiation (tissue antigen) Exposure
Excited Hapten-Protein
Phototallergen Hypersensitivity
Photoallergen Complex
(drug or drug’s Response
(hapten) (complete
metabolites)
antigen)
skin only. Occasionally, the nails may also be lous, or purpuric lesions. Histopathologic findings
affected. This phototoxic effect is a well-known in cases of drug-induced photoallergy are typically
phenomenon known as photoonycholysis.2,325 similar to those found in cases of contact dermati-
Histologically, dermal edema, dyskeratosis, and tis.1 In general, photoallergic reactions involve only
keratinocytic necrosis may be observed.325 areas directly exposed to the sun, but in severe
Cases of drug-induced photoallergic reactions cases, these reactions may also affect areas that are
are typically associated with an onset ranging from normally protected from UV light. It is important
24 to 48 hours to up to 14 days after initial expo- to note that after discontinuation of therapy with
sure to the sun. The initial eruption is usually the offending agent, the clinical effects of drug-
described as a papulovesicular, intensely pruritic, induced photoallergy may persist for some time.
eczematous rash.323,325 In some cases, the rash has Over time, the eruptions may even become hyper-
been reported to involve lichenoid, urticarial, bul- pigmented or hypopigmented.319
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Semin Oncol. 1994;21:4-10. Ayerst Laboratories; 1998.
309. Visudyne [package insert]. Duluth, GA: Novartis 331. Layton AM, Cunliffe WJ. Phototoxic eruptions due to
Ophthalmics; 2001. doxycycline–a dose-related phenomenon. Clin Exp
310. Velban [package insert]. Indianapolis, IN: Eli Lilly and Dermatol. 1993;18:425-427.
Company; 1997. 332. Wainwright NJ, Collins P, Ferguson J. Photosensitivity
311. Tolland JP, McKeown PP, Corbett JR. Voriconazole- associated with antibacterial agents. Drug Saf.
induced pseudoporphyria. Photodermatol Photoimmunol 1993;9:437-440.
Photomed. 2007;23:29-31. 333. Johnson BE, Ferguson J. Drug and chemical
312. McCarthy KL, Playford EG, Looke DF, et al. Severe photosensitivity. Semin Dermatol. 1990;9:39-46.
photosensitivity causing multifocal squamous cell 334. Toback AC, Longley J, Cardullo AC, et al. Severe chronic
carcinoma secondary to prolonged voriconazole therapy. photosensitivity in association with acquired
Clin Infect Dis. 2007;44:e55-56. immunodeficiency syndrome. J Am Acad Dermatol.
313. Racette AJ, Roenigk HH Jr, Hansen R, et al. Photoaging 1986;15:1056-1057.
and phototoxicity from long-term voriconazole 335. Thami GP, Kaur S, Kanwar AJ. Delayed reactivation of
treatment in a 15-year-old girl. J Am Acad Dermatol. haloperidol induced photosensitive dermatitis by
2005;52(5 Suppl 1):581-585. methotrexate. Postgrad Med J. 2002;78:116-117.
314. Rubenstein M, Levy ML, Metry D. Voriconazole-induced 336. Wolverton SE. Update on cutaneous reactions. In:
retinoid-like photosensitivity in children. Pediatr James WD, Cockerell CJ, eds. Comprehensive
Dermatol. 2004;21:675-678. Dermatologic Drug Therapy. St. Louis, MO: Mosby-
315. VFEND(r) [package insert]. New York, NY: Pfizer, Inc; 2002. Yearbook; 1997:65-83.
316. Sonata [package insert]. Philadelphia, PA: Wyeth 337. Mirensky YM, Parish LC. Photosensitivity and the
Laboratories Inc; 2007. quinolones. J Eur Acad Dermatol Venereol. 1995;4:1-4.
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CHAPTER 9
Kristine E. Keplar
135
TisdaleC09_135-176 1/12/10 2:33 PM Page 136
AMPHETAMINES12-14,A
Amphetamine aspartate <1% C
Benzphetamine NK C
Dextroamphetamine NK C
Dexmethylphenidate NK C
Lisdexamfetamine NK C
Methamphetamine NK C
ANABOLIC STEROIDS/ANDROGENS6,11,14-16
Fluoxymesterone NKb C
Danazol NKb C
Dehydroepiandrosterone (DHEA) NKb C
Methyltestosterone NKb C
Nandrolone NKb C
Oxandrolone NKb C
Oxymetholone NK C
Progesterone17 NKb A
Stanozolol NKb C
Testolactone18 Up to 66% A
Testosterone NKb C
ANESTHETICS
Halothane13 NK C
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
Benazepril19 <1% C
Captopril19 1–5% C
Enalopril19 NK C
Lisinopril19 NK C
Quinapril19 NK C
Ramipril9 NK C
ANTIARRHYTHMICS
Amiodarone20 1 –4% C
ANTICOAGULANTS
Heparin21 0–50% C
Enoxaparin22 NKc C
Dalteparin23 NKc C
Nidroparin24 NKc C
Warfarin9,25,26,27 >5% C
ANTICONVULSANTSd
Carbamazepine28,29 0.01–6% C
Felbamate19 NK C
Gabapentin19,30 0.1–1% A
(Continued)
TisdaleC09_135-176 1/12/10 2:33 PM Page 137
after the initiation of therapy. Most cases of hair occurs after 3 to 8 weeks of therapy. Alopecia may
loss secondary to warfarin or heparinoid drugs go occur after exposure to lower doses, but the onset
unnoticed by the patient. Only 20% of those who is longer than 8 weeks. Alopecia is diffuse and
experience hair loss associated with these drugs involves not only the scalp, but also eyelashes, eye-
exhibit clinically evident alopecia. Scalp hair is the brows, and pubic and axillary hair.13 Alopecia is
primary target, but eyebrows, axillary, and pubic quickly reversible when the dose is decreased or
hair also may be affected. Total alopecia is extreme- vitamin A supplementation is discontinued. Hair
ly rare.13 regrowth occurs in approximately 2 to 3
months.6,13 Lightening of hair color and hair kink-
ing can also occur in association with retinoids.12
Retinoids
Vitamin A, or retinol, is often prescribed for the
treatment of hair disorders. However, alopecia of
Immunosuppressants
the telogen effluvium type can occur in association Medications used for rheumatoid arthritis, notably
with ingestion of vitamin A in doses greater than disease-modifying antirheumatic drugs (DMARDs),
50,000 IU daily (whether dietary, such as cod liver have been associated with mild, reversible alope-
oil, or pharmaceutical) over a period of several cia.9,19,133 Gold therapy may cause exfoliative der-
months.12 Other retinoids such as acitretin, etreti- matitis leading to alopecia. There is a case report of
nate, and isotretinoin also cause hair loss.19 scarring alopecia following gold therapy.9,19,133
Alopecia associated with these agents usually Methotrexate-induced alopecia is thought to be
TisdaleC09_135-176 1/12/10 2:33 PM Page 142
dose-dependent.77,92 Other DMARDs that may of the telogen effluvium type. The hair loss is usual-
cause alopecia include leflunamide and sul- ly transient and may terminate even if the medica-
fasalazine. Cyclosporine, tacrolimus, and tion is continued.13 Valproic acid can also affect hair
mycophenolate, which are often used following by causing a “perming” effect or “diffuse curliness of
organ transplantation, have also been associated the hair.” One report stated that this curliness
with hair loss.12,137 occurred while taking valproic acid for approximate-
ly 1 year. The curliness persisted for approximately
30 months of therapy and subsided within approxi-
Dopamine Agonists mately 6 months after discontinuation of the thera-
Dopamine agonists implicated in alopecia include py.36 Carbamazepine may also cause hair loss.6,28,29,34
bromocriptine, levodopa, pergolide, pramipexole, Other antiepileptic medications that have been
and ropinirole. Alopecia caused by these agents is associated with hair loss have all been implicated via
considered to be a rare side effect. Hair loss is case reports. In one case, alopecia developed after 2
reversible following discontinuation of thera- months of topiramate therapy in a 15-year-old
py.12,154 female. Hair loss resolved after discontinuation of
therapy and recurred upon reinitiation of topira-
mate treatment.34
Interferons
No correlation has been established between inter-
Psychotropics
feron dose and the onset or severity of hair loss. In
some patients, alopecia resolves despite continued Psychotropic drug–induced alopecia tends to be
treatment.6 Transient localized alopecia has been associated with transient mild to moderate hair
noted at the injection site in patients treated with loss and is reversible upon discontinuation of ther-
interferon alfa. There are also reports of hair-shape apy.3 In some cases, improvement has occurred
and hair-color changes associated with interferon spontaneously despite continuation of lithium
use.12 therapy. Lithium has been associated with dry and
limp hair as well as texture changes. There have
been some rare reports of loss of body hair associ-
Thyroid Agents ated with lithium use. This effect reversed upon
Antithyroid medications, including iodine, propy- discontinuation of lithium therapy.29 Lithium-
lthiouracil, carbimazole, and methimazole can induced hair loss may be a result of lithium-
cause iatrogenic hypothyroidism leading to alope- induced hypothyroidism; resolution of the
cia. Papadopoulos and Harden149 reported that hypothyroid state may reverse the hair loss.142
carbimazole, an agent similar in structure to Antidepressant agents such as the tricyclic antide-
methimazole, induced alopecia in a small percent- pressants, selective serotonin reuptake inhibitors,
age of patients. However hair regrowth occurred in new-generation antidepressants and the antianxi-
all cases after carbimazole therapy was discontin- ety agent buspirone have all been implicated as
ued.149 This reversible type of hair loss is telogen causing alopecia, although this occurs rarely.29
effluvium and is associated with dry scalp and dry Atypical and typical antipsychotic agents have also
and brittle hair.4,6 In a few case reports, carbima- been reported to induce hair loss, which usually
zole-induced alopecia occurred in euthyroid occurs several months after the initiation of thera-
patients.149 Sometimes the hair loss terminates py and is characterized as nonscarring, diffuse
despite continuation of therapy with carbimazole alopecia with generalized or localized hair loss
and methimazole.13 Thyroid replacement medica- commonly affecting the scalp. The alopecia is
tions can also cause drug-induced alopecia.155,156 reversible, usually within 2 to 5 months after dis-
In general, maintaining patients’ euthyroid status continuation of therapy.157
will aid in preventing antithyroid-induced alope-
cia.156
Hormones/Androgens
Two types of oral contraceptive–induced hair loss
Antiepileptics have been identified. In the first type, hair loss
Several antiepileptic drugs have been associated occurs 3 months after discontinuation of therapy
with alopecia.13 Of these, valproic acid is associated with oral contraceptives. This type of alopecia is
with the highest incidence of hair loss, reported to similar to postpartum hair loss, in which increased
be between 2.6% and 12%. Alopecia occurs within 3 telogen loss is a consequence of the higher percent-
months after initiating therapy, and is believed to be age of anagen hair maintained during pregnancy.
TisdaleC09_135-176 1/12/10 2:33 PM Page 143
eral aspects), arms, and legs. Total epilation may causative agent. It may be equally difficult to deter-
occur approximately 1 month after the initiation mine whether it was drug treatment or another
of therapy.4,6 Severe hair shedding usually occurs event that was the cause of the hair loss.6,163-165
only in association with the cytotoxic agents.
Noncytotoxic drug-induced hair loss rarely results
in total hair loss, and is normally reversible upon MECHANISMS
discontinuation of the offending drug.12
Mechanisms of drug-induced alopecia are listed in
Table 9–2.5,6,166 Drugs that induce alopecia can be
EPIDEMIOLOGY classified according to their effects on the phases of
the hair growth cycle (Figure 9–2).1,63 There are two
Drug-induced alopecia is not uncommon, patterns of drug-induced alopecia; anagen effluvi-
although the exact incidence is not known. The um and telogen effluvium.5,163
incidence of alopecia associated with specific During anagen effluvium, drugs may partially
drugs, where known, is presented in Table 9–1.13-151 or completely suppress mitosis and cause metabol-
Alopecia associated with chemotherapy and ic impairment of hair growth. This leads to failure
cytotoxic drugs, whether noticed or unnoticed, to form a hair shaft or the formation of a thinned,
occurs nearly in 100% of patients who do not weakened hair shaft.5,166 Eighty-five percent of hair
undergo prophylaxis against the hair loss. The follicles on the scalp are in the anagen phase.
prevalence and severity depend on the drug as well Therefore, this is a major target for drugs that cause
as on individual predisposition. Hair loss can occur alopecia. Hair loss also can be manifested in axil-
in association with some drugs when administered lary, pubic, and other body regions. Cytotoxic
in usual doses, while other drugs are unpredictable agents such as cancer chemotherapy drugs and
and produce drug-induced alopecia only occasion- toxic plasma concentrations of certain metals
ally.6,9,12,60 Heparin and heparinoid drugs can lead cause drug-induced alopecia by affecting follicles
to telogen effluvium, with an incidence that varies during the anagen phase of hair growth. Since the
from 0 to >50%.21 Vitamin A (retinol)–induced anagen phase duration is the main determinant of
alopecia has been reported in approximately 20% the length of the hair, the maximum length of the
to 30% of patients.6,13 The incidence of DMARD- new anagen hair is shorter than that of the hair it
induced alopecia ranges from 1% to 10%.11,20,21 is replacing. Eventually, the anagen phase is short-
Alopecia caused by dopamine agonists occurs rarely ened to the point at which the hair cannot reach
and is more common in females.12,154 Nearly 20% to the skin surface. At this point, the only visible part
30% of patients receiving interferon experience of the hair cycle on the skin is the pore, as the hair
alopecia of the telogen effluvium type.6 One review follicle can no longer be seen.7 In patients with
of case reports found the incidence of alopecia anagen alopecia, hair loss is almost always
induced by carbimazole to be low, ranging from reversible when therapy with the offending agent
3.5% to 10%.149 The overall incidence of hair loss is terminated. However, since hair grows at a rate
induced by antiepileptic medications is 0.01% to of only about 1 cm per month, several months is
12%, with valproic acid therapy leading to the required for complete reversal of the hair loss.6 The
highest incidence (2.6% to 12%).13,34 Alopecia asso- medications most commonly associated with ana-
ciated with carbamazepine has been reported to be gen effluvium are cancer chemotherapy agents.5
a very rare adverse event in some case reports, while Drug-induced hair loss is primarily considered
others have documented it as “common.”6,28,29,34 telogen effluvium hair loss, since the majority of
The incidence of lithium-induced hair loss has been drugs that induce hair loss disrupt the telogen efflu-
reported to be 12% to 17%.3 Hormone-replacement vium growth phase. In telogen effluvium, drugs
therapy with esterified estrogen 1.25 mg with induce hair loss by causing premature termination
methyltestosterone 2.5 mg or with esterified estro- of the anagen, or growing, phase of the hair cycle,
gen 0.625 mg and methyltestosterone 1.25 mg resulting in an increased number of shed hairs. This
induces alopecia with a reported incidence of type of hair loss often can be identified by the pres-
8.8%.140 Cytostatic agents have been reported to ence of a clubbed root on shed hair. Hair loss is typ-
cause total scalp-hair loss in roughly 10% of ically diffuse rather than patchy, and patients often
patients. Hair loss was reversed after therapy with are asymptomatic. Telogen effluvium is primarily
the agent was discontinued.4,13,126,163 noted on the scalp; however, it sometimes may be
The onset of drug-induced hair loss occurring detected in other locations.1,5,6,28
in telogen effluvium is delayed by several months; Alopecia in patients with telogen effluvium is
consequently, it may be difficult to determine the usually subclinical and rarely involves more than
TisdaleC09_135-176 1/12/10 2:33 PM Page 145
Drug Mechanism
BENZODIAZEPINES
Clonazepam Telogen effluvium
-BLOCKERS:
Acebutolol Telogen effluvium
Atenolol
Betaxolol
Carvedilol
Metoprolol
Nadolol
Propranolol
Timolol
CALCIUM-CHANNEL BLOCKERS
Nifedipine Telogen effluvium
Verapamil
CANCER CHEMOTHERAPY AGENTS
Altretamine Anagen effluvium
Amsacrine
Anastrozole
Bleomycin
Busulfan
Carboplatin
Cetuximab
Cisplatin
Cyclophosphamide
Dactinomycin
Dasatinib
Daunorubicin
Docetaxel
Doxifluridine
Doxorubicin
Edatrexate
Efaproxiral
Epirubicin
Erlotinib
Etoposide
Exemestane
Fluorouracil
Gemcitabine
Gefitinib
Idarubicin
Ifosfamide
Imatinib
Irinotecan
Ixabepilone
Lobaplatin
Methotrexate
Mitomycin
Mitoxantrone
Nilotinib
Oxaliplatin
(Continued)
TisdaleC09_135-176 1/12/10 2:33 PM Page 147
Drug Mechanism
CANCER CHEMOTHERAPY AGENTS (Continued)
Paclitaxel
Panitumumab
Pirarubicin
Pemetrexed
Sorafenib
Sunitinib
Tamoxifen
Temozolomide
Teniposide
Thiotepa
Topotecan
Vinblastin
Vincristine
Vindesine
Vinorelbine
CHOLESTEROL-LOWERING AGENTS
Atorvastatin Telogen effluvium
Cholestyramine
Clofibrate
Lovastatin
Pravastatin
DOPAMINE AGONISTS
Bromocriptine Telogen effluvium
Cabergoline
Dopamine
Levodopa
Pergolide
Ropinirole
GONADOTROPIN-RELEASING HORMONE–RELEASING AGONISTS
Goserelin Androgen alopecia
GOUT MEDICATIONS
Allopurinol Telogen effluvium
Colchicine
HISTAMINE2-RECEPTOR ANTAGONISTS
Cimetidine Telogen effluvium
HEAVY METALS/TOXINS
Arsenic, bismuth, lead, mercury, thallium Anagen effluvium
IMMUNOSUPPRESSANTS
Azathioprine Telogen effluvium
Cyclosporine
Gold
Leflunomide
Methotrexate
Mycophenolate
Sulfasalazine
Tacrolimus
(Continued)
TisdaleC09_135-176 1/12/10 2:33 PM Page 148
Drug Mechanism
INTERFERONS
All agents implicated Telogen effluvium
ORAL CONTRACEPTIVES
All agents with high progesterone content Androgenic alopecia
ANTIANXIETY/PSYCHIATRIC MEDICATIONS
Aripiprazole Telogen effluvium
Buspirone
Haloperidol
Lithium
Olanzapine
Quetiapine
Risperidone
Ziprasidone
RETINOIDS
Acitretin Telogen effluvium
Etretinate
Isotretinoin
Retinoic acid
THYROID MEDICATIONS
Carbimazole Telogen effluvium
Methimazole
Propylthiouracil
All thyroid replacement agents implicated since hyperthyroidism and
hypothyroidism are associated with hair loss
MISCELLANEOUS AGENTS
Aminoglutethimide Telogen effluvium
Cetirizine Telogen effluvium
Naproxen Telogen effluvium
Vasopressin Telogen effluvium
50% of the hairs. The onset of this type of drug- anism is termed “androgenic alopecia” or “androge-
induced alopecia is often delayed for months.21 As netic alopecia,” also known as “male pattern bald-
the hair loss is mild and often occurs long after ness.” Women with androgenic alopecia have
therapy with the offending agent is initiated, this higher plasma concentrations of 5␣-reductase
condition can be easily overlooked. In telogen (which converts testosterone to dihydrotestos-
effluvium, the hair root is not damaged and hair terone), lower plasma concentrations of cytochrome
will spontaneously regrows once therapy with the P-450 (which converts testosterone to estrogen), and
offending drug is discontinued. The condition also greater density of androgen receptors. However,
may be reversed following a reduction in the dose these patients do not have higher plasma concentra-
of the causative agent.6,163-165 tions of androgens and tend to have normal fertili-
Telogen hair loss often occurs secondary to events ty, menses, and endocrine function.167 Androgenic
such as severe illness, childbirth, fever, and hemor- alopecia often presents as a bitemporal recession of
rhage. It can be caused by drugs including heparin, the hairline, as thinning of the frontal and vertex
warfarin, low-molecular-weight heparins, lithium, areas of the scalp, or as complete baldness and loss
certain -blockers (metoprolol, nadolol, propranolol), of all hair except the occipital and temporal
and alpha- and gamma-interferon. A few cytotoxic fringes.1,5,63,168 In women, androgenic alopecia often
agents also may cause telogen effluvium by shifting manifests as a diffuse thinning over the top of the
the hair follicles into a premature resting cycle.166 scalp with preservation of the anterior hairline.
Drugs also may induce hair loss by increasing Drugs implicated in androgenic alopecia include
androgen activity. Hair loss occurring by this mech- danazol, metyrapone, estrogen receptor antagonists,
TisdaleC09_135-176 1/12/10 2:33 PM Page 149
FIGURE 9–2 Diagrammatic representation of the scalp hair cycle. During the normal hair cycle, the active growth phase
(anagen) can last from 2 years up to 6 years. This is followed by a short transition phase (catagen), which lasts 1 to 2 weeks,
and then by a resting phase (telogen), lasting 5 to 6 weeks. The hair is then shed, the anagen phase begins again, and a new
hair is grown. In the altered hair cycle of the balding scalp (not shown), the phases of the cycle remain unchanged.
However, the anagen growth phase becomes shorter and telogen resting phase becomes longer with each passage through
the hair cycle, resulting in diminishing hair length.7 Reproduced with permission from Cambridge University Press and BMJ
Publishing Group from Ellis JA, Sinclair R, Harrap SB. Androgenetic alopecia: pathogenesis and potential for therapy. Expert
Rev Mol Med. 2002;4:1-11; and Sinclair R. Male pattern alopecia. BMJ. 1998;317:865-9.
and anabolic steroids.5,11,63 In many cases, hair loss licles involved, hair loss in patients with drug-
is not reversible upon discontinuation of therapy induced telogen alopecia often does not become evi-
with the offending agent.5 dent until 2 to 4 months after the initiation of
therapy with the offending drug.50 Examination
reveals patterned, nonpatchy hair loss. Progressive
miniaturization of the hair follicles is noted. With
CLINICAL PRESENTATION AND each successive growth cycle, hair follicles become
DIFFERENTIAL DIAGNOSIS smaller and produce shorter, finer hairs that poorly
cover the scalp. Miniaturization of hairs with vari-
Signs and symptoms associated with drug-induced ous lengths and diameters is a classic sign of andro-
alopecia are listed in Table 9–3.4-6,10,11,12,63,167,169 genic alopecia.5,168 Evaluation of plasma
Features of different types of drug-induced alopecia testosterone concentrations is of value in these
are compared in Table 9–4.6,9,10,12,63,167,169 Patients patients; testing for drug-induced alopecia is expect-
with drug-induced anagen alopecia present with ed to yield normal or low results in the absence of
hair that is thin and fragile, and shed hairs are nar- other features consistent with androgen excess (e.g.,
row, broken, and have no roots.5 Hair loss usually hirsutism, acne, or irregular menses).9,167,171 Biopsy
occurs within days to weeks after the initiation of of the scalp in women with androgenic alopecia
therapy with the offending medication and often shows increased aromatase activity as compared to
is very severe. Microscopic examination of hair that in men with androgenic alopecia.158
from patients with cancer chemotherapy–induced Patients should be evaluated for the presence
alopecia reveals fragmentation, trichorrhexis, of shedding or fragile hair (or both), slowed rate of
decreased diameter, and depigmentation of the hair growth, inability to regenerate new hair, and
hair shaft. Hair is fragile, thin, and breaks off near- any related local or systemic disorders. In addition
ly as quickly as it issues from the hair follicle.166,170 to a visual inspection, specific diagnostic proce-
Patients with drug-induced telogen alopecia typ- dures such as the hair-pull test, hair plucks, micro-
ically present with mild, diffuse hair loss. Shed hair scopic examination of hair and scalp, as well as
is typically found to have clubbed roots; miniatur- cultures and biopsies may be used.1 The hair-pull
ized hairs are generally not found.1,5,6,28,165 Although test is one of the easiest tests used to evaluate
presentation depends on the percentage of hair fol- alopecia. Patients are advised not to shampoo the
TisdaleC09_135-176 1/12/10 2:33 PM Page 150
hair for 24 hours prior to the test.167 The clinician area, which provides a more definitive analysis of
grasps approximately 60 hairs using the thumb the hair loss. A scalp biopsy leaves a small scar on
and index and middle fingers. The hairs are gently the patient’s scalp, as it is an invasive procedure.
but firmly pulled. The test is considered positive Patients may refuse the biopsy because of the scar
for active shedding when more than six hairs are if the hair loss is potentially irreversible. A scalp
pulled free. If on microscopic exam a white bulb is biopsy is usually not necessary for routine diagno-
found on the shaft of extracted hair, the test is con- sis of hair loss.10
sidered positive for telogen effluvium.8 Drug-induced androgenic alopecia may be sus-
When a definitive diagnosis is needed or if the pected in patients taking an androgenic drug and
routine testing is inconclusive, a scalp biopsy can in whom the hair loss is mediated by the presence
be performed. The scalp biopsy provides histologic of androgen dihydrotestosterone, the hair loss is
features, the number of anagen and telogen hairs, male-pattern type (no effects on nonscalp hair),
and the number of terminal and vellus hairs per the shedding is usually not severe, and the hair
TisdaleC09_135-176 1/12/10 2:33 PM Page 151
TABLE 9–5 Conditions to Consider in the TABLE 9–6 Risk Factors for Drug-Induced
Differential Diagnosis of Drug-Induced Alopecia4,8 Alopecia148,152,155
Alopecia areata, cicatricial alopecia, telogen Risk factors related to drug administration:
effluvium: • Higher doses
• Systemic/chronic illness (e.g., autoimmune disorder, • Intravenous route of administration
cancer) • Longer duration of exposure
Cicatricial alopecia, telogen effluvium, tinea • Combination therapy
capitis: Disease states:
• Infection (systemic or local) • Endocrine abnormalities
Telogen effluvium; anagen effluvium: • Autoimmune disease
• Serious illness within previous 3– 4 mo • Polycystic ovary disease
• Inflammatory diseases (i.e., seborrheic dermatitis,
Trichotillomania:
psoriasis)
• If taking psychoactive medication, also consider
• Hyperandrogenic disorders
telogen effluvium, as both types of alopecia could
• Hypothyroidism or hyperthyroidism
be occurring simultaneously
• Illness/fevers/infection
• Psychiatric disorder (e.g., psychosis, anxiety, obses-
• Iron deficiency anemia
sive–compulsive disorder)
• Parturition; increased blood loss
Telogen effluvium: • Poor nutritional status/crash diets (low serum iron
• Physical stress (e.g., surgery, pregnancy, malnutrition) or ferritin concentrations or deficiency of protein,
• Life-threatening psychological stress zinc, selenium)
Traction alopecia: • Family history of androgenic alopecia
• Tight braids • Recent surgery
• “Pulled-back” hairstyle • Stress
Androgenic alopecia (women):
• Hirsutism (combined hirsutism/alopecia in polycys-
tic ovary disease) droepiandrosterone (DHEA) should be avoided in
• Amenorrhea women with androgen alopecia because of the
• Infertility increased risk for worsening the condition.168
Alopecia areata, telogen effluvium: Postoperative alopecia is the temporary or per-
• Hypothyroidism manent loss of hair that occurs following pro-
• Other endocrinopathies longed immobilization during general anesthesia
and intubation.172 Localized pressure-induced
ischemia is the likely cause. Patients at highest risk
mon in women than in men.12,154 Vitamin A for permanent hair loss include those undergoing
(retinol)–induced alopecia occurs more frequently cardiac or gynecologic surgical procedures for
in women receiving higher doses. Vitamin E, taken which the combined intraoperative and postopera-
concurrently with vitamin A, may potentiate vita- tive intubation time exceeds 24 hours.
min A toxicity.6,13 Patients with preexisting thyroid
disease, polycystic ovary disease, inflammatory dis-
eases such as seborrheic dermatitis, psoriasis, mal- MORBIDITY AND MORTALITY
nutrition, or certain metabolic disorders are at risk
for alopecia.1 Concomitant systemic and chronic Although drug-induced hair loss is usually
illness such as autoimmune disorders and cancer reversible, it can be quite traumatic for both men
may also increase the risk. Stress, crash dieting, and women.77 In one study, cancer chemothera-
infection, fever, and childbirth are other factors py–induced alopecia ranked third on patients’ lists
that can lead to telogen effluvium.4,8 Women with of distressing symptoms, behind nausea and vom-
androgen alopecia who take a progestin with high iting.173 Patients sometimes refuse cancer
androgenic activity for oral contraception or hor- chemotherapy for fear of hair loss.77 It is important
mone-replacement therapy are at increased risk for that clinicians appreciate their patients’ views
further hair loss. Consequently, a progestin with regarding the social impact of hair loss, even in
little or no androgenic activity such as norgesti- cases in which patients experience only hair thin-
mate or ethynodiol diacetate is preferable. ning. Understanding patients’ feelings regarding
Testosterone and related substances such as dehy- hair loss and openly discussing the matter may
TisdaleC09_135-176 1/12/10 2:33 PM Page 153
Patients with a family history of androgenic agent with proven efficacy for androgenic alopecia
alopecia are at high risk for androgen-induced and is the only drug that is approved by the Food
alopecia associated with certain oral contracep- and Drug Administration (FDA) for hair loss for
tives. In these patients, selection of an oral contra- both men and women. The drug works by affecting
ceptive with little to no androgenic effects may the hair cycle, causing premature termination of
reduce the risk of alopecia.148 Prophylactic therapy the telogen phase, and may also prolong the ana-
with topical minoxidil can be prescribed when a gen phase.183 A 2% strength is available for both
patient with a family history of androgenic alope- men and women and a 5% strength is approved
cia requires long-term therapy with a medication only for men.9,10 For women who do not respond
known to induce androgenic alopecia. However, to the 2% strength, the 5% strength can be used, as
minoxidil is not effective for prevention of cancer it has been shown to provide greater patient satis-
chemotherapy–induced alopecia.178 faction in one study.9 However, the incidence of
Scalp cooling and hypothermia are of question- hypertrichosis and scalp contact dermatitis were
able efficacy for the prevention of cancer higher in association with the 5% strength as com-
chemotherapy-induced alopecia. Scalp cooling pared with the 2% strength.9 Minoxidil solution or
involves applying a cooling turban around the minoxidil foam should be applied twice daily to a
scalp with a tourniquet pressure ranging from 30 to dry scalp. If the solution is used, a dropper or
50 mm Hg above systolic blood pressure 10 minutes extended-spray applicator must be used to apply
prior to drug administration, followed by removal the solution directly to the scalp.168 A capful of the
30 minutes after drug administration application. foam product should be applied directly to the
Hypothermia involves cooling the scalp to at least scalp with the hands. Patients should be told that
24°C for 5 minutes before, during, and 20 minutes at least 4 to 6 months of treatment is necessary
after the infusion of cancer chemotherapy.6,56 Some before the effects of minoxidil become evident,
investigators have raised concerns that, in some and maximum effects may not occur for approxi-
cases, these methods may be detrimental because of mately 1 year.10,152 Adverse effects of tachycardia
a possible reduction of delivery of chemotherapy and low blood pressure are very rare (0.001%).10
drugs to intended areas, or when chemotherapy is Minoxidil treatment may be required indefi-
being used for generalized hematogenic metastases nitely, unless therapy with the alopecia-inducing
or there is a high likelihood of metastasis to the drug is discontinued. However, if minoxidil treat-
scalp, such as in patients with breast cancer or lym- ment is discontinued, all of the regained hairs are
phoproliferative disorders.56,174 Liver dysfunction shed within 3 months.10,165 Minoxidil has been
may also impair the potential efficacy of these pre- reported to cause scalp irritation, although the
ventive measures, as it inhibits the metabolism of incidence is lower in association with the new
some chemotherapy agents, thereby allowing drug foam product. In addition, the foam product con-
concentrations to persist beyond the protective tains much less propylene glycol, which is thought
time frame of induced scalp hypothermia.175-177 to be the cause of the contact dermatitis.150
Oral medications are also available for andro-
gen-induced alopecia. However, these drugs have
MANAGEMENT not been studied for the management of drug-
induced alopecia. Finasteride and dutasteride work
For patients with drug-induced telogen alopecia, by inhibiting 5␣-reductase type 2, which results in
hair growth returns when the causative agent is a decrease in plasma dihydrotesterone (DHT) con-
discontinued or the dose is decreased. centrations. Finasteride has been documented to
Consequently, additional treatment is usually not decrease plasma prostate-specific antigen (PSA) con-
necessary.6,162,164,165 When discontinuation or dose centrations by 50% in older men. Consequently,
adjustment is not possible, a trial with topical when monitoring older men for prostate dysfunc-
minoxidil is suggested (Table 9–8).1,6-9,11,56,152, tion, the serum PSA concentration range may need
165,167,168,174-177,179-181
Use of minoxidil for the pre- to be doubled.184 Finasteride has been on the mar-
vention and treatment of chemotherapy-induced ket for years and has been widely used for the man-
alopecia has been found to reduce the severity or agement of androgenic alopecia in men, whereas,
shorten the duration of the disorder. Minoxidil can dutasteride, a newer agent, is relatively new for the
be used for the management of any type of drug- treatment of androgenic alopecia. A study by Olsen
induced hair loss; the American Academy of et al.185 found that dutasteride 2.5 mg daily was
Dermatology guidelines recommend minoxidil as superior to finasteride 5 mg daily in increasing scalp
first-line treatment for androgenetic alopecia in hair growth in men. The difference may be that
men or women.182 Minoxidil is the only topical finasteride inhibits only one isoenzyme of 5␣-
TisdaleC09_135-176 1/12/10 2:33 PM Page 155
reductase, which results in a reduction of serum age, pregnancy should be ruled out prior to use and
DHT concentrations by approximately 70%, while oral contraceptive therapy or other methods of con-
dutasteride inhibits both type 1 and type 2 isoen- traception should be prescribed concomitantly, as
zymes and can reduce serum DHT concentrations these agents are known teratogens.9,11 Oral antian-
by 94% to 95%.186 Despite initial failures of finas- drogens have been used alone or in combination
teride for treatment of women with androgen with topical minoxidil in men and women.8,10,187
alopecia, more recent data have demonstrated clin- Some trials in men have shown superior efficacy
ical efficacy of finasteride in women. One case when minoxidil is combined with finasteride.10
found that dutasteride 0.5 mg orally daily provided Newer oral contraceptives with antiandrogenic
clinical improvement, accompanied by an increase effects such as ethanyl estradiol in combination
in mean hair diameter, reduction in variability of with drospirenone, norgestimate, or ethynodiol are
hair diameter, and normalization of trichogram potential treatments for female alopecia.188 Some
results in a 46-year-old female.186 Dutasteride was premenopausal female patients taking antiandro-
noted to also be well tolerated.186 Dutasteride may gens are using these newer low-dose progesterone
have the potential for efficacy in the management oral contraceptives to prevent pregnancy (since
of androgen alopecia in women as well as men if antiandrogens are teratogenic) while benefiting
large, long-term studies provide similar results. from their antiandrogenic effects. Unfortunately,
For women, other oral antiandrogens that can the use of topical and oral antiandrogens such as
be used to treat androgen-induced alopecia include progestins and estrogens for the treatment of
spironolactone, cyproterone acetate (which is not alopecia has not been studied in large trials, and
available in the United States), and flutamide. the safety and efficacy of these agents are
However, flutamide is associated with hepatic toxi- unknown. These agents are not used in men
city and is rarely used.8,9 Spironolactone, an aldos- because of the potential for sexual side effects.19
terone antagonist with antiandrogenic effects, is Cosmetic treatments are also available for
commonly used in females with androgenic alope- addressing drug-induced alopecia and are applica-
cia at doses of 100 to 300 mg daily.11 In patients tak- ble to both men and women. Common cosmetic
ing spironolactone, periodic serum potassium treatment options for temporary or permanent
concentrations should be determined, as the drug drug-induced alopecia include wigs, hair pieces,
can cause hyperkalemia. In an open-label trial of 80 hair extensions, and hair weaves. There are also
women taking spironolactone 200 mg daily or dyes now available that can be sprayed or applied
cyproterone acetate either 50 mg daily (or 100 mg onto the scalp that aid in camouflaging balding
for 10 days/mo in women who were pre- areas. Special hairstyling techniques also can be of
menopausal), 85% of women in both groups expe- benefit. These cosmetic measures often can pro-
rienced no worsening of female pattern hair loss. duce satisfactory results.8
If oral antiandrogens such as finasteride or spiro- Surgical procedures are rarely needed for patients
nolactone are prescribed to females of reproductive with drug-induced alopecia, but are an option for
TisdaleC09_135-176 1/12/10 2:33 PM Page 157
patients with alopecia that is either permanent or soft. Avoiding sun exposure helps protect the
severe or in situations in which therapy with the scalp.77
offending drug cannot be discontinued. Hair restora- Patients should be educated regarding the risk
tion is a permanent and successful treatment for of alopecia when a potentially causative agent is
qualifying candidates.10 There are several surgical prescribed. A study by Edelstyn et al.77,189 demon-
options for patients with baldness, and these proce- strated that although patients found hair loss to be
dures currently are performed routinely and provide disturbing, the alopecia was tolerable, provided that
a definitive correction of the alopecia. The degree of wigs were available and advance warning regarding
alopecia often dictates the surgical technique to be hair loss was provided. Patients should also be
used. If the baldness is extensive, more than one informed that hair regrowth following chemother-
method is usually required.152 Table 9–81,6- apy may involve new hair that is coarse and has a
9,11,56,152,165,167,168,174-177,178-180
provides a list of the var- changed color. Hair also may be thinner than it was
ious treatment options for drug-induced alopecia. prior to the chemotherapy.77,166 Patients should be
counseled regarding proper nutrition, such as
dietary protein intake, and should avoid fad or
INFORMATION FOR PATIENTS crash dieting while receiving medications with the
potential to induce alopecia.158
Patients experiencing hair loss, whether perma- Patients using topical minoxidil should be
nent or temporary, should be informed that it is warned of its primary adverse effect, which is hyper-
safe for them to style, blow dry, and tease the hair trichosis or excessive hair growth. Hypertrichosis
and use hair spray, hair color, and permanents. primarily occurs above the eyebrows, in the malar
This helps patients deal with the cosmetic effects of region, and on the lateral cheek area. Occasionally,
alopecia.167-168 Patients with alopecia often hair growth is also noted above the lip and on the
decrease the frequency of shampooing because chin.167 Some rare hair growth on the limbs has
they associate it with increased hair shedding. been noted in association with the 5% solution.
Patients should be taught about the hair growth Local adverse effects from irritation and contact der-
cycle and should understand the cumulative matitis also have been reported with continued
nature of hair loss. With once-weekly shampooing, use.165 Switching to the foam product may help
patients may experience 7 days’ cumulative hair minimize the risk of these adverse effects. Patients
loss at one time, while daily shampooing allows a should be told that an increase in scalp hair shed-
more realistic assessment of the actual daily hair ding may occur during the first months of therapy
loss and improves scalp health.152,158 as the follicles cycle from the telogen to the anagen
If significant alopecia occurs, head coverings, phase. Patients should be informed that 4 to 6
wigs, and hairpieces should be encouraged and months may be required before the effects of
patients should be assured that these cosmetic minoxidil become evident, and up to 1 year may be
devices will not interfere with hair regrowth. Use required for maximum effects.10 Patients should be
of these cosmetic aids may improve patients’ warned that if minoxidil treatment is discontinued
morale.5 Patients also may benefit from use of a and the alopecia-inducing agent is still present, that
wide-toothed comb or soft-bristled brush and the hair loss will return.10,11,155 After each use of the
should be instructed to comb hair gently and to topical solution, the hands should be washed to
avoid excessive brushing, especially if undergoing avoid getting solution on other parts of the body.
cancer chemotherapy. Baby shampoo or a protein- The topical product should stay on the scalp for at
enriched shampoo may be optimal in patients with least 4 hours before showering or shampooing.10
alopecia, and use of a satin pillowcase will mini- When appropriate, it is important to assure patients
mize friction. If alopecia is excessive, short hair- that once the drug causing alopecia is discontinued,
styles tend to disguise hair thinning, but enough the alopecia tends to resolve.
length should be left to possibly allow for arrange- Patients taking 5␣-reductase inhibitor therapy
ment of hair to cover areas of baldness. If hair loss may experience decreased libido or impotence during
becomes pronounced, some patients prefer to therapy. To prevent pregnancy in a partner of child-
shave the head, which may promote regrowth bearing age, men should use barrier contraceptives
once the treatment is stopped. If a wig is worn, care (even though the risk is negligible) and women of
should be taken to ensure that the lining is com- childbearing age should be told to use contraception,
fortable and not irritating. Applying baby oil, min- since these medications can lead to fetal abnormali-
eral oil, or ointment containing petrolatum and ties.10,11,184 Women who are prescribed antiandro-
lanolin with some mineral oil and cod liver oil genic medications should be warned, if applicable,
(which contain vitamins A and D) and massaging not to become pregnant, since these medications are
the scalp may reducing itching and keep the skin teratogenic.9 Effects on libido and changes in men-
TisdaleC09_135-176 1/12/10 2:33 PM Page 158
strual patterns may occur. Patients with heart failure the body, particularly in nonsexual areas. Unlike
should be instructed to have their serum potassium hirsutism, hypertrichosis can occur in both men
concentrations and kidney function measured at 3 and women. Hirsutism can be induced by drugs
days and 1 week after initiating therapy with spirono- that lead to an interaction between the serum
lactone and with every increase in dose, then every 2 androgen concentration and the sensitivity of
to 4 weeks for 3 months, then every 3 months for a the hair follicle to androgen. Unlike drug-
year, then every 6 months thereafter.23 induced hirsutism, drug-induced hypertrichosis
usually is not associated with androgen produc-
tion.1,6,148,190,191
HIRSUTISM AND HYPERTRICHOSIS
Both hirsutism and hypertrichosis are patterns
of excessive hair growth that may be highly dis-
CAUSATIVE AGENTS
tressing to patients. Hirsutism occurs only in
women and involves excessive growth of hair
Hirsutism
with masculine characteristics or “male-like” By definition, hirsutism is induced by androgenic
pattern of hair growth on the body and face. agents (Table 9–9).12,17,18,158,179,180,191-199 Androgenic
This usually occurs as a result of excessive andro- agents such as danazol, testosterone, adrenocorti-
genic stimulation. In contrast, hypertrichosis is cotropic hormones, and glucocorticoids are com-
excessive hair growth that is independent of mon agents associated with hirsutism.6,179
androgen influence. Hypertrichosis describes Anabolic steroids and medications containing
hair growth on any part of the body that is in androgens or that can directly or indirectly cause
excess of the amount that is usually present in an increase in androgen activity or serum andro-
persons of the same race, sex, and age. The hair gen concentrations may induce hirsutism.160
growth is manifested by the uniform and super- Hirsutism has been reported in 0.1% of women
fluous growth of vellus (nonterminal) hair over taking oral contraceptives. Hair growth has been
reported on the face and is most likely caused by 2 years.6,218 Erythropoietin, when used in patients
the progestin component.200 Using an agent with a with chronic kidney disease, can induce hypertri-
lower progestin content may be of benefit. It may chosis. Erythropoietin-induced hypertrichosis is
take some time for the hair growth to resolve fol- reversible upon discontinuation of therapy.6
lowing discontinuation. Hormone-replacement Ophthalmic agents used to treat glaucoma that
therapies containing moderate to high amounts of contain prostaglandin F analogs such as latano-
progestin are more likely to induce hirsutism.158 prost, bimatoprost, and travoprost can induce tri-
Valproic acid has been shown in one prospec- chomegaly of the eyelashes and can also darken
tive trial in Indian women to increase serum testos- the eyelashes. In one case report, latanoprost pro-
terone concentrations and lead to polycystic moted the regrowth of eyelashes in a patient suffer-
ovarian syndrome. The incidence of hirsutism was ing eyelash loss due to alopecia.211
20% in this longitudinal trial.180,199 Phenytoin is
also associated with drug-induced hypertrichosis of
the face and arms.201 See Table 9–912,17,18,158,179,180,191-
199
EPIDEMIOLOGY
for a list of drugs reported to induced hirsutism.
The overall incidence of drug-induced hirsutism
Hypertrichosis and hypertrichosis is unknown. The incidence of
hirsutism and hypertrichosis associated with specif-
Drugs associated with hypertrichosis are listed in ic drugs, when known, is presented in Tables
Table 9–10.12-14,132,164,191,194,201-216 The primary drugs 9–912,17,18,158,179,180,191-199 and 9–10.12-14,132,164,191,194,
known to cause hypertrichosis are cyclosporine, 201-216
Although neither is considered to be a com-
phenytoin, and oral minoxidil. Other agents report- mon event, they are well-recognized complications
ed to induce hypertrichosis include diazoxide, oral associated with drugs such as anabolic steroids,
chlorobenzene, erythropoietin, penicillamine, and cyclosporine, and minoxidil.218 When minoxidil is
psoralens.12,191 Ophthalmic prosta- glandin analogs taken orally for at least 1 month, over 80% of
and topical minoxidil have been well documented patients experience reversible hypertrichosis.6
to cause hypertrichosis.211 Drug-induced hyperpro- Topical minoxidil has been reported to cause hyper-
lactinemia can induce unwanted hair growth.217 trichosis in 3% to 5% of women using the 2% solu-
Cyclosporine-induced hypertrichosis usually tion and more than 5% of those using the 5%
occurs within the first 3 months of therapy and solution. Erythropoietin has been reported to cause
involves excessive hair growth on the trunk, back, hypertrichosis in 13% of patients with chronic kid-
neck, shoulders, nose, and fingers. The hair growth ney disease. With the lower cyclosporine doses used
may worsen over the first 6 months and then in the treatment of dermatologic diseases, the risk
remain constant. The condition is reversible upon of hypertrichosis declines to approximately 3%.6
discontinuation of therapy, with hair growth ceas- Hirsutism is known to affect 5% to 15% of women,
ing over 1 or more months.6,218 but drugs are not a frequent cause of that disor-
Long-term phenytoin therapy has been well der.179 The incidence of drug-induced hypertri-
documented as a cause of hypertrichosis (Figure chosis associated with diazoxide in children treated
9–3),13 which typically occurs approximately 2 to 3 for idiopathic hypoglycemia is nearly 100%. Two
months after the initiation of therapy. The limbs investigators reported incidences of hypertrichosis
and sometimes the face and trunk are the most com- of 2% and 6% in children receiving phenytoin.
monly affected areas. Hypertrichosis is reversible Another study found that 35% of children experi-
upon discontinuation of the drug. Dose reduction, enced hair growth; however, this report included
when possible, may stop abnormal hair growth.218 cases in which only moderate hypertrichosis
Both oral and topical minoxidil cause hypertri- occurred.219 Drug-induced hypertrichosis appears to
chosis that primarily affects the malar areas, forehead, be less common than hirsutism except in the treat-
and sides of the face. Facial hypertrichosis is believed ment of organ transplantation, during which hir-
to be due to a systemic effect or via the transfer of the sutism is manifested in 30% to 60% of patients.
drug.12 Hypertrichosis may disappear after approxi-
mately 1 year, even if the medication is continued,
and usually resolves in 1 to 6 months if minoxidil
application is discontinued.167 Diazoxide can also
MECHANISMS
lead to hypertrichosis that is often is observed within
a few weeks of initiating therapy and is more severe
Hirsutism
on the face and limbs. Diazoxide-induced hypertri- Terminal hair (coarse, longer, pigmented hair) is
chosis is reversible, but resolution can take as long as found primarily on the scalp and eyebrows. Vellus
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ANTIHYPERTENSIVES
Diltiazem12 NK C
Minoxidil13,191 >90% C
ANTICONVULSANTS
Phenytoin12,201-206 8.5–12% A
ANTIVIRAL AGENTS
Acyclovir207 NK C
Zidovudine12 NK C
CHELATING AGENT
Penicillamine12,13,191 NK C
CANCER CHEMOTHERAPY AGENTS
Erlotinib208 (eyelash trichomegaly; hypertrichosis) NK C
Cetuximab NK C
Sorafenib209 NK C
CORTICOSTEROIDS12,191,210,a
Budesonide NK C
Butamethasone NK C
Corticotropin NK C
Cortisone NK C
Dexamethasone NK C
Fludrocortisone NK C
Hydrocortisone NK C
Methylprednisolone NK C
Prednisone NK C
Prednisolone NK C
Triamcinolone NK C
ERYTHROPOIESIS-STIMULATING AGENTS
Erythropoietin12 NK C
IMMUNOSUPPRESSANTS
Cyclosporine12,191,194 50–60% for high doses C
3% for doses >5 mg/kg/day C
INTERFERONS191,b
Interferon alfa-N3 NK C
Interferon alfacon-1 NK C
Interferon alfa-2a, recombinant NK C
Interferon alba-2b NK C
Peginterferon alfa-2a and alfa-2b NK C
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
Benoxaprofen12 NK C
(Continued)
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hair is the short fine, unpigmented hair found in Valproic acid can cause hirsutism as a result of
all other areas. As androgen concentrations inducing hyperinsulinemia.220
increase during puberty, the vellus hair of andro-
gen-sensitive follicles is converted to terminal hair.
Exposure to exogenous androgens such as testos-
Hypertrichosis
terone can also cause vellus hair to be converted to Although the mechanism of hypertrichosis is not
terminal hair. Excessive growth of terminal hair well understood, it is, by definition, not associated
induced by androgenic drugs is known as “drug- with androgen excess or exposure to androgenic
induced hirsutism”199 (Table 9–1112,158,179,180,191- agents. The disorder is not common and describes
194,196,197,199
). Hirsutism is commonly associated an increase in nonsexual hair. Hypertrichosis may
with hormonal abnormalities associated with poly- be congenital (e.g., Hurler’s syndrome, fetal alco-
cystic ovary syndrome. Hirsutism involving viril- hol syndrome, or trisomy 18 syndrome), or associ-
ization, especially in women over 25 years of age, ated with anorexia nervosa, malnutrition,
is commonly associated with an androgen-produc- hypothyroidism, porphyria, epidermolysis bullosa,
ing tumor. Drugs that induce androgenic stimula- dermatomyositis, or following skin trauma. It also
tion of hair follicles are a less common cause of can be caused by drugs that stimulate hair
hirsutism.32,63,220-223 Hyperinsulinemia can also growth.217,218 Hair growth induced by erythropoi-
lead to hirsutism via inhibition of aromatase, the etin may be caused by a decrease in plasma cortisol
enzyme that converts testosterone to estrogen. concentrations. At higher serum concentrations,
TisdaleC09_135-176 1/12/10 2:33 PM Page 162
PREVENTION
TABLE 9–13 Conditions to Consider in the Drug-induced hair growth is best prevented by
Differential Diagnosis of Drug-Induced Hirsutism avoiding the use of agents known to cause hir-
or Drug-Induced Hypertrichosis217,225,226 sutism or hypertrichosis, especially in patients
• Congenital adrenal hyperplasia with preexisting risk factors. Patients should not be
exposed to two or more drugs with a known poten-
• Polycystic ovary syndrome
tial to cause abnormal hair growth. Lower doses
• Ovarian tumor and shorter periods of exposure to potentially
• Adrenal tumor causative drugs are also advised.218 The potential
• Idiopathic for minoxidil-associated hypertrichosis is increased
if the topical solution is accidentally transferred to
• Familial
the face from the hands or from residual minoxidil
TisdaleC09_135-176 1/12/10 2:33 PM Page 165
TABLE 9–18 Cosmetic Measures for Management of Hypertrichosis and Hirsutism180,191,227,228 (Continued)
gestrel, ethynodiol diacetate, gestrodene, and hepatotoxicity, and liver function should be
norethindrone acetate) are preferable for the man- monitored in patients receiving this agent.
agement of mild-to-moderate hirsutism. This Cyproterone is not available in the United States.
treatment should reduce the need for shaving by The use of spironolactone or cyproterone often
50% and can usually stop the progression of hir- provides significant attenuation of hirsutism
sutism, but will not reverse it.180 Women with clin- within 6 months and maximum benefit within 9
ically significant hirsutism may require therapy to 12 months.180
with an androgen-inhibiting agent either as Other hormonal therapies include finas-
monotherapy or in addition to oral contraceptive teride—a 5␣-reductase inhibitor that has been
treatment.180,219,222,227 The addition of the oral shown to be effective for the treatment of hir-
contraceptive will help ensure menstrual cycling sutism. However, finasteride is teratogenic, causing
and minimize the risk of pregnancy, as antiandro- feminization in male infants, and is therefore con-
gens and ␣2-reductase inhibitors are teratero- traindicated in many women. Like oral antiandro-
genic.180 It has been reported that combined gens, finasteride therapy should be reserved for
therapy with an oral contraceptive and an andro- severe or refractory cases of hirsutism. Once initiat-
gen-receptor inhibitor may produce clinical ed, treatment should be continued for at least 2
improvement in up to 75% of women with hir- years for maximum benefit.217,221 Combination
sutism.217 therapy with spironolactone and finasteride is an
Antiandrogenic drugs include spironolac- option for some patients.226 Dutasteride, also a 5␣-
tone, flutamine, and cyproterone. Spironolac- reductase inhibitor, has not been extensively stud-
tone and flutamine are the most widely used and ied for the management of hirsutism. Other
are equally effective. Spironolactone is an aldos- hormonal therapies include glucocorticoids and
terone antagonist and appears to be the safest gonadotropin-releasing hormone agonists. The
androgen-receptor blocker. Flutamide may cause efficacy of glucocorticoids for drug-induced hir-
TisdaleC09_135-176 1/12/10 2:33 PM Page 169
sutism is unknown. Gonadotropin-releasing hor- sometimes an issue, since most patients require
mone agonists are considered alternatives to oral repeated treatments.158,219,222
contraceptives.180
Treatment with eflornithine, a topical hair
growth inhibitor, has been shown to reduce rates INFORMATION FOR PATIENTS
of hair growth. Eflornithine therapy results in the
reduction of the frequency of use of other methods Patients should have realistic expectations regard-
of hair removal. Eflornithine is indicated for facial ing the time frame for the resolution of drug-
hirsutism and is marketed as an 11.5% topical induced hirsutism and hypertrichosis, and must
cream that is applied twice daily. The cream is understand that it may take a long time for these
effective for slowing excessive hair growth, but not conditions to resolve even after the causative agent
for removing excess hair. The cream must remain is discontinued. When certain medications are
on the skin for at least 4 hours. Unfortunately, if used to treat hirsutism, hormonal suppression for 6
therapy is discontinued, hair growth will likely months or longer may be necessary before reduc-
return.158,191,227 tion of hair growth becomes evident.222 When oral
Information regarding cosmetic procedures for drug therapy is used to manage hirsutism, patients
hair removal for patients with either hirsutism or should be instructed that treatment must continue
hypertrichosis is provided in the next section. during therapy with the causative agent. For
patients with drug-induced hypertrichosis, when
the offending drug is discontinued, resolution of
Hypertrichosis excess hair growth may require several months to
Although drug-induced hypertrichosis nearly 1 year, depending on the hair-cycling characteris-
always resolves after discontinuation of therapy tics of the site of hypertrichosis. For example, it
with the causative agent, reversal of hair growth takes an average of 3 months for hypertrichosis res-
takes time. During that period, cosmetic methods olution if the excess hair growth is on the face, but
for hair removal are suggested and are effec- an average of 1 year if the excessive hair growth is
tive.191,219,222 Consequently, the management of on the arms.191
drug-induced hypertrichosis includes discontinua- Patients with drug-induced hirsutism or hyper-
tion of the offending agent, if possible; cosmetic trichosis should be counseled regarding the poten-
procedures for removal of excess hair; hair removal tial benefit of cosmetic measures, and these can be
using light sources and lasers; and only topical encouraged even if oral therapy is prescribed.
pharmacologic treatment.191 Systemic agents such Patients should be informed of the cosmetic
as antiandrogens or oral contraceptives should not options available, their adverse effects, duration,
be used. Treatment with eflornithine may be effec- effectiveness, and cost. Patients should be
tive for hypertrichosis. informed that although shaving can lead to a stub-
Treatment options for drug-induced hypertri- ble-like hair, it does not worsen hirsutism.
chosis are provided in Table 9–18.180,191,227,228 Depilating agents, though effective, can cause
Cosmetic measures include bleaching, wax strip- chronic skin irritation and may even worsen hair
ping, shaving, plucking (tweezing), using hair- growth if used excessively or indiscriminately.
removal creams (depilatories), and electrolysis. Waxing or plucking in androgenized skin may lead
The FDA has approved electrolysis as a permanent to folliculitis and trauma to the hair shaft, and
option for hair removal, because it has been asso- does not kill the hair follicles. Methods that can
ciated with a 30% reduction in the number of hair permanently destroy the hair follicle, such as elec-
follicles. Laser therapy is a newer development, trolysis and laser, often work well, but require time
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SECTION III
DRUG-INDUCED
NEUROLOGICAL DISEASES
CHAPTER 10 Seizures
CHAPTER 11 Stroke
CHAPTER 15 Delirium
CHAPTER 10
Seizures
Timothy E. Welty
ANALGESICS
Hydromorphone1 NK C
Meperidine2,3 2.1% B
Morphine1 NK B
Naloxone1 NK B
Nefopam1 NK B
Tramadol4,5 13–50% B
ANESTHETICS
Propofol1 23–40% B
Sevoflurane6-8 50–100% A
ANTIBIOTICS
Carbapenems9 0.9%a B
2–3%b
Cephalosporins1 NK B
Fluoroquinolones1 NK B
Penicillins1 NK B
ANTIDEPRESSANTS
Bupropion10,11 0.5%–4% A
Tricyclic/tetracyclic antidepressants11,12 0.25%–2% B
ANTIEPILEPTIC DRUGS
Benzodiazepines1 NK B
Carbamazepine13-15 NK B
Felbamate16 NK B
Oxcarbazepine13,17 NK C
Phenobarbital1 NK B
Phenytoin1 NK B
Topiramate1 NK B
ANTIMALARIAL DRUGS
Hydroxychloroquine18 NK B
ANTINEOPLASTIC DRUGS
5-Fluorouracil19,20 NK C
Busulfan21 1.8%–40% B
Chlorambucil19 NK B
Interferon-alfa1 NK B
Methotrexate19 NK B
ANTIPSYCHOTIC DRUGS
Phenothiazines22-24 2.1% B
Clozapine25,26 1 –4% B
(Continued)
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seizures that occur outside these settings. Most this group of patients to a seizure. Most cases are
likely, the incidence of drug-induced seizures is associated with toxic doses or prolonged chronic
greater than is reflected in these reports. Even so, use, but seizures are possible at therapeutic doses,
drug-induced seizures are relatively rare events that especially in patients with underlying epilepsy.4,5
typically occur as a single, isolated seizure.
Anesthetics
Analgesics While propofol is used in the treatment of refractory
Tramadol, a non-narcotic analgesic, is associated status epilepticus, it is also associated with drug-
with drug-induced seizures. In a review of 190 cases induced seizures. Several case series have suggested
of tramadol toxicity reported to a poison control that 24% to 40% of patients receiving propofol expe-
center, 13.7% of patients experienced a seizure.4 A rience seizures or epileptiform electroencephalogram
similar study reported that 55% of patients with (EEG) activity during induction, emergence, and
tramadol intoxication experienced a seizure.5 recovery from anesthesia.1
Ninety percent of these seizures were single events, Sevoflurane is associated with a high incidence
and 84% occurred within 24 hours of ingesting a of drug-induced seizures. Studies of EEG activity
toxic dose. Chronic use of tramadol predisposed during the induction of anesthesia have shown
TisdaleC10_177-189 1/20/10 11:00 PM Page 182
epileptiform activity in 50% to 60% of children and seizures, with an incidence of 2.1%.22 At chlorpro-
adults,6,7 and this increases to nearly 100% of mazine doses <200 mg/day, the incidence of
patients when combined with hyperventilation and seizures is 0.3%, at doses of 200 to 900 mg/day
hypocapnia.7 Additional study of EEGs in patients 0.7%, and at doses >900 mg/day 9%.23
receiving sevoflurane has demonstrated a dose- Concomitant treatment with other psychoactive
dependent relationship in the EEG change.8 At a 1.5 agents increases the risk of seizures caused by
minimum alveolar concentration, epileptiform EEG chlorpromazine.23 Other older antipsychotic
discharges were present in 100% of patients. agents are associated with a much lower risk of
seizures than chlorpromazine.24
Of the newer, atypical antipsychotic agents,
Antibiotics
clozapine is associated with the greatest risk of
Carbapenems have been reported to cause seizures. seizures. The cumulative risk of seizures with cloza-
Approximately 0.9% of patients taking imipenem pine over nearly 4 years of treatment has been esti-
as monotherapy experience a seizure.9 The inci- mated at 10%.25 At clozapine doses <300 mg/day,
dence of seizures in patients taking imipenem in the incidence of seizures is approximately 1%,
combination with other antibiotics is 2% to 3%. In which increases to 4% at doses >600 mg/day.26
one study, 28% of children treated with imipenem
for bacterial meningitis experienced a seizure.37 In
contrast, meropenem caused no seizures in a study
Antineoplastic Agents
of adult patients with bacterial meningitis.38 In Seizures are common among patients undergoing
another study, 12% of children receiving therapy treatment for cancer. Approximately 13% of
with meropenem experienced a seizure.39 patients with cancer experience a seizure, and
seizures account for 5% of neurologic complica-
tions.42 Children with cancer are especially suscep-
Antidepressants
tible to seizures, which occur with a much higher
Overdose with tricyclic antidepressants is responsi- incidence than that in adults.43 The causes of
ble for over 40% of seizures encountered in the seizures among patients with cancer vary greatly
emergency department.12 Most of these seizures are and include primary brain tumors, brain metas-
generalized tonic–clonic seizures, but partial tases, metabolic derangements, and medications.19
seizures may occur in individuals with a history of Drug-induced seizures are more common during
epilepsy.36,40 intensive cancer chemotherapy, in patients with
Other antidepressant agents can cause seizures liver or kidney disease, or when high doses of anti-
in the setting of an overdose. Approximately 2% of neoplastic agents are used, such as those recom-
patients with an overdose of a selective serotonin mended in protocols for bone marrow
reuptake inhibitors experience a seizure.41 transplantation.
Overdose of bupropion is also associated with a
high incidence of seizures.10
Antidepressant drugs may also cause seizures at
Stimulant Drugs for Attention
therapeutic doses. The incidence varies from
Deficit/Hyperactivity Disorder (ADHD)
approximately 0.1%, with lower doses of Drugs such as methylphenidate and atomoxetine
imipramine, to over 2%, with higher doses of have been implicated as a cause of seizures in
bupropion.11 The risk of seizures appears lowest cases of overdose and abuse.30,31 Early reports of
with trazadone, fluoxetine, and fluvoxamine. In seizures associated with drugs for ADHD in chil-
contrast, the risk of seizures is highest in associa- dren were complicated by the fact that children
tion with maprotiline, amoxapine, and bupropion, with ADHD are at a higher risk for seizures. Two
and these drugs should be avoided in patients with studies indicate that these drugs do not increase
epilepsy. The risk of antidepressant-associated the risk of seizures for children with ADHD.44,45
seizures is dose-dependent; for example, the inci- In one of these studies, children with epilepti-
dence of seizures associated with bupropion at form discharges on EEG were studied separately
doses above 400 mg/day is 2% to 4%, while at from those with normal EEG recordings. 44
lower doses the incidence is 0.5% to 1.0%. Stimulant medications did not increase the risk
of seizures in children with normal EEGs. A
greater risk of seizures was seen in children with
Antipsychotics epileptiform discharges, but this could not be
Among older antipsychotic agents, chlorpro- attributed to stimulant use. These data indicate
mazine is associated with the greatest risk of that stimulant medications may be safely used in
TisdaleC10_177-189 1/20/10 11:00 PM Page 183
children with ADHD with little added risk of ly as a result of accumulation of the active metabo-
seizures. lite normeperidine. Penicillin is a direct neurotox-
in that results in seizures. The mechanism of
carbapenem-induced seizures is believed to be inhi-
MECHANISMS bition of the inhibitory neurotransmitter gamma-
aminobutyric acid,48 which is also the likely
Seizures are acute neurologic events resulting from mechanisms of seizures induced by tricyclic antide-
hypersynchronous and hyperactive discharges of pressants.12 Seizures caused by theophylline over-
neurons. The precise mechanisms that result in dose in children, adults, and the elderly may occur
this type of neuronal activity are poorly under- as a result of saturation of hepatic metabolism of
stood, partly because there are multiple causes of the drug, resulting in progressive theophylline
hypersynchronous activity. Proposed mechanisms accumulation. Premature infants may be some-
of action of antiepileptic drugs involve excitatory what protected from theophylline-induced seizures
neurotransmitters, ion channels (sodium, potassi- because of the different metabolic pathways for
um, and calcium), and inhibitory neurotransmit- theophylline in immature hepatic enzyme sys-
ters, providing limited understanding of the tems.59
pathophysiology of seizures. However, other mech-
anisms are likely involved in the genesis of seizures
due to toxicity and overdoses of medications.
Even though specific mechanisms are not fully CLINICAL PRESENTATION AND
understood, there is some limited insight regarding DIFFERENTIAL DIAGNOSIS
potential mechanisms of seizures induced by some
drugs. Proposed mechanisms by which specific A major problem with drug-induced seizures is
drugs induce seizures are summarized in Table accurate detection and diagnosis. The clinical pres-
10–2.1,46-58 Meperidine is a well-documented entation of seizures may be variable, ranging from
causative agent in drug-induced seizures, most like- decreased levels of consciousness to a major gener-
be helpful in preventing seizures due to drug However, if the risk for another acute seizure is
effects on serum chemistry and homeostasis. high, then seizures should be treated aggressively.
Premedication and combination anesthesia In either case, there is no evidence that drug-
may reduce the risk of seizures associated with induced seizures produce epilepsy. The focus of
sevoflurane. To minimize the risk of seizures, pre- treatment is prevention of additional acute
treatment with benzodiazepines and/or narcotics seizures.
and concomitant use of nitrous oxide have been Some drugs induce seizures by altering metab-
suggested.65 In addition, hypocapnia should be olism leading to disorders such as hypoglycemia or
avoided and a maximum of 1.5 minimum alveolar hyponatremia. In these cases, the underlying meta-
concentration should be used during anesthesia to bolic problem should be identified and corrected
prevent sevoflurane-induced seizures. before the initiation of therapy with drugs com-
To reduce the risk of withdrawal seizures, ther- monly used to treat seizures. Antiepileptic drugs
apy with antiepileptic drugs should be withdrawn are associated with numerous adverse drug reac-
over 1 to 2 months, unless potentially life-threat- tions, and indiscriminate use should be avoided.
ening adverse effects are occurring, in which case Management of drug-induced seizures is some-
more rapid discontinuation of therapy is warrant- what dependent on the causative agent. For some
ed. Care should be taken to ensure proper doses drugs that induce seizures, there are specific treat-
and laboratory monitoring of antiepileptic drug ment guidelines or recommendations regarding
therapy, including serum antiepileptic drug con- drugs to avoid. With other causative drugs, a gen-
centrations, serum electrolyte concentrations, and eral treatment approach to seizures can be used. In
kidney and liver function tests. either case, the key to treatment and prevention of
Appropriate dose adjustment of penicillins additional seizures is rapid identification of the
and carbapenems in patients with kidney disease causative agent, and rapid implementation of the
or a compromised blood–brain barrier is the best appropriate treatment plan. When the likelihood
method of preventing seizures associated with of repeated acute seizures is low, more time is avail-
these agents. These drugs and fluoroquinolone able to discontinue the offending agent or take
antibiotics should be used with caution in alternative actions.
patients with a history of seizures. Similarly, The acute treatment of seizures typically
other drugs, such as hydroxychloroquine66 and involves the use of a drug to immediately control
antipsychotic agents,67 should be used with cau- the seizures and a drug to provide sustained control
tion in patients with a history of epilepsy. Some of seizures. Usually a benzodiazepine, such as
have suggested initiating therapy with an lorazepam or diazepam, is administered to provide
antiepileptic drug in patients in whom therapy rapid control of seizures. This should be followed by
with clozapine is initiated in an attempt to pre- the administration of an antiepileptic drug, usually
vent seizures.22 phenytoin, to provide sustained control of seizures.
Many of the reported cases of seizures associat- Most patients respond to these measures. If seizures
ed with ephedra or ma huang occurred in patients are not controlled or recur, administration of a ben-
without a history of epilepsy, and often occurred zodiazepine can be repeated and additional pheny-
with the co-administration of other stimulant toin may be administered. In the very rare
drugs, like phenylpropanolamine or caffeine.27 situations in which patients do not respond to addi-
Clearly, stimulant drugs should not be adminis- tional doses of a benzodiazepine and phenytoin,
tered in combination with ephedra. phenobarbital or other agents, such as short-acting
barbiturates, general anesthetics, exceptionally
high doses of a benzodiazepine, or other antiepilep-
tic drugs may be used. Special treatment plans for
MANAGEMENT specific drugs should be used in the place of this
general treatment approach to seizures.
Because drug-induced seizures can occur through a Benzodiazepines are usually effective in treat-
variety of mechanisms, treatment strategies should ing and preventing carbapenem-induced seizures,
be approached carefully and individualized. The because of the benzodiazepine-associated enhance-
first step is to immediately discontinue the ment of gamma-aminobutyric acid activity.68 For
causative agent, or in the case of abrupt discontin- patients with seizures induced by tricyclic antide-
uation, to initiate therapy with the discontinued pressants, benzodiazepines are the preferred drugs
medication. If the risk of a second acute seizure for treatment.12 In this situation, phenytoin should
appears to be low, then pharmacologic interven- be avoided, because of its lack of efficacy and the
tions to treat seizures are probably not necessary. possibility of enhancing the arrhythmogenic
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CHAPTER 11
Stroke
Denise H. Rhoney
has added a “black box” warning to the labeling. In ing the risk of stroke in patients who have previ-
addition, the NIH halted a trial conducted in ously been exposed to rofecoxib.50
patients with Alzheimer’s disease, which showed The results of the Rotterdam Study indicated
an increased risk of cardiovascular events in that in the general population the risk of stroke
patients receiving naproxen, but not in those was greater in association with the use of nonse-
receiving celecoxib.51 The extended follow-up data lective NSAIDS (e.g., naproxen, ibuprofen) and
from the Adenomatous Polyps Prevention with COX-2 selective NSAIDs (e.g., celecoxib), with the
VIOXX (APPROVe) study revealed an increased risk most pronounced risk of stroke related to the use
of ischemic stroke with rofecoxib as compared of COX-2 selective NSAIDs.52 The public health
with placebo, and found that 7 of the 18 ischemic advisory issued by the FDA is as follows49: (1)
strokes occurred after rofecoxib therapy had been Physicians prescribing COX-2 selective agents
discontinued. This finding raised concern regard- should consider this emerging information when
TisdaleC011_190-210 1/12/10 2:35 PM Page 192
weighing the benefits against risks for individual botic, with the remainder cardioembolic in origin.
patients. Patients who are at a high risk of gas- The overall incidence of drug-induced stroke is
trointestinal bleeding, have a history of intoler- unknown, but is generally considered to be low. In
ance to non-selective NSAIDs, or are not doing young adults (<50 years of age) drug-related etiolo-
well on non-selective NSAIDs may be appropriate gies can be identified in 15–38% of ischemic
candidates for COX-2 selective agents. (2) strokes.2,56 Use of illicit drugs, particularly cocaine,
Individual patient risk for cardiovascular events is commonly implicated in younger patients who
and other risks commonly associated with NSAIDs lack other known vascular risk factors. Since the
should be taken into account for each prescribing emergence of the more potent alkaloidal cocaine
situation. (3) Consumers are advised that all non- (“crack”) there has been a significant increase in
prescription pain medications, including NSAIDs, case reports of cocaine-induced stroke.57 The inci-
should be used in strict accordance with the label dence of all drug-induced stroke may be on the
directions. If an NSAID is needed for longer than rise.2 See Table 11–1 for the incidence of stroke
10 days, a physician should be consulted. The associated with specific agents.
American Heart Association (AHA) has recom-
mended a stepped-care approach for the manage-
ment of musculoskeletal symptoms in patients
MECHANISMS
with risk factors or known cardiovascular dis-
There are many proposed mechanisms for drug-
ease.51
induced strokes. Mechanisms by which drugs
result in stroke may be multifactorial, and are pre-
sented in Table 11–2.
EPIDEMIOLOGY
The most common type of non-drug-induced
Embolic Mechanisms
stroke is ischemic, which accounts for 85% of all Embolism can result in a stroke when a clot,
cases. Of ischemic strokes, 65% are atherothrom- plaque, platelet aggregate, or foreign body
breaks off into the circulation and obstructs an bral and internal carotid arteries within 30 min-
artery. Intravenous drugs of abuse (e.g., heroin) utes.63 There have been case reports of stroke
can be associated with infarction due to embolic associated with triptan use. However, patients
vessel occlusion, infective endocarditis, or hem- with migraine are also at increased risk of
orrhage caused by the rupture of a septic stroke.18
(mycotic) aneurysm. Stroke is a complication in
about 20% of patients with infective endocardi-
tis. Cocaine and other drugs may cause heart dis-
Acute Hypertension
ease resulting in release of emboli to the brain. The primary mechanism of drug-induced acute
Foreign body emboli, primarily from talc fillers, hypertension is related to the effects of drugs on
have been reported after the injection of agents neurotransmitters. Many drugs increase cate-
intended for oral administration (i.e., cholamine release from central noradrenergic
methylphenidate).58 Foreign substances injected nerve terminals (e.g., amphetamines, ephedra,
into the systemic circulation may embed in the nonprescription sympathomimetics), inhibit
lung, resulting in granulomatous reactions that reuptake of catecholamines into adrenergic
ultimately provide a path for this foreign materi- nerve terminals (e.g., cocaine), or increase plas-
al to reach the brain. Tamoxifen may be associ- ma catecholamine concentrations (e.g., ethanol,
ated with a paradoxical embolism (emboli cocaine). Hypertension related to drug use may
originating in the venous system migrating to disrupt cerebral autoregulation, promote reper-
the arterial system as a result of abnormal com- fusion of brain tissue, or damage cerebral arteri-
munication within the heart) and subsequent oles, which may eventually rupture. Cigarette
cerebral venous thrombosis.59-60 smoking acutely elevates blood pressure and
reduces cerebral blood flow.64-66 Alcohol acutely
and chronically increases blood pressure because
Vasoconstriction/Vasospasm of the increased adrenergic activity and the
Systemic vasoconstriction can lead to hyperten- increased plasma concentrations of cortisol,
sion and intracerebral hemorrhage (ICH), where- renin, aldosterone, and vasopressin.67-69
as cerebral vasoconstriction can lead to
infarction. Vasoconstriction may be transient or
prolonged. Vasospasm with subsequent cerebral
Vasculitis
infarction may occur in association with Inflammation of small, medium, and large
cocaine, amphetamines, phenylpropanolamine, intracranial arteries and subsequent develop-
ephedrine, and methylphenidate. 61 Cocaine ment of arteritis is another reported mechanism
temporarily causes vasoconstriction, thus reduc- of stroke induced by drugs such as heroin,
ing blood supply to various brain regions. It also amphetamines, cocaine, ephedra, and pseu-
may potentiate the effects of serotonin by block- doephedrine.70 These agents are associated with
ing its reuptake, resulting in vasoconstriction.62 an inflammatory vasculopathy and vessel-wall
In addition, cocaine exerts direct effects on cal- necrosis.71
cium channels, leading to the release of intracel-
lular calcium in cerebral vascular smooth-muscle
cells.57 Other possible mechanisms of cocaine-
Clotting Derangements
induced vasospasm are via endothelin-1 and Platelets play an important role in the develop-
reuptake of dopamine at presynaptic nerve ter- ment of thrombosis. With endothelial damage,
minals. There appears to be a cumulative effect vessel collagen can be exposed to blood and acts as
of cocaine exposure and the risk of stroke.57 The a triggering mechanism for platelet activation,
use of selective serotonin reuptake inhibitors resulting in release of adenosine diphosphate from
and serotonin–norepinephrine reuptake the platelets, which causes platelets to aggregate.
inhibitors can cause vasoconstrictive stroke Thromboxane A2 is produced, which also pro-
(Call–Fleming syndrome) or vasospasm. 37,39 motes platelet aggregation and vasoconstriction.
Underlying atherosclerosis may augment this Cocaine may stimulate platelet aggregation and
vasoconstriction. Sumatriptan binds to a partic- inhibit prostacyclin.72 Cigarette smoking aggra-
ular subpopulation of 5-hydroxytryptamine (5- vates atherosclerosis and increases arterial wall
HT1) receptors in the pia and dural vessels, stiffness, ultimately increasing the likelihood of
leading to vasconstriction. 14 Subcutaneous plaque formation. Cigarette smoking increases
administration of sumatriptan has been shown platelet reactivity and inhibits prostacyclin forma-
to result in vasoconstriction of the middle cere- tion.73 Alcohol consumption may elevate blood
TisdaleC011_190-210 1/12/10 2:35 PM Page 194
pressure and cause thrombocytopenia and platelet- drug-induced ischemic stroke are presented in
function defects, and long-term use may result in Table 11–3.
coagulation abnormalities due to liver impairment. Drug-induced stroke must be distinguished
Nonsteroidal antiinflammatory agents act primari- from stroke due to other etiologies. Conditions to
ly via inhibition of COX, which consists of 2 major consider in the differential diagnosis of drug-
isoenzymes—COX-1 and COX-2. Experimental induced stroke are presented in Table 11–4. It is dif-
evidence suggests that inhibition of COX-2 results ficult to distinguish between drug-induced and
in a shift in the prothombotic/antithrombotic bal- non-drug-induced causes of stroke unless symp-
ance toward thrombosis. The differential biologic toms are temporally related to the ingestion of sub-
effects of these agents are a result of the degree of stances of abuse or agents with surrogate
selectivity for COX-2 versus COX-1.51 Cisplatin monitoring parameters (e.g., drug screen) that can
induces direct endovascular damage and also indi- be quantitatively assessed.
rect damage via free radical–induced lipid peroxi- The diagnosis of stroke consists of a thorough
dation. Direct endovascular damage can lead to the evaluation of patient history, clinical examina-
accumulation of mediators that promote platelet tion, laboratory evaluation, and imaging studies,
aggregation and vasoconstriction.74 In addition, including computed tomography (CT) scan, cere-
cisplatin may reduce the activity of the anticoagu- bral angiography, and magnetic resonance imag-
lant protein C and may elevate plasma concentra- ing (MRI). Laboratory studies should consist of
tions of von Willebrand factor.44 serum electrolyte and glucose concentrations,
complete blood count, coagulation parameters,
Orthostatic Hypotension and drug screen evaluation. A CT scan is essential
to differentiate between ischemic and hemor-
A potential mechanism for atypical antipsychotic rhagic stroke.
agent–associated stroke is orthostatic hypotension
leading to “watershed” (areas of the brain furthest
from direct perfusion of the major cerebral arteries)
strokes. In addition, hyperprolactinemia induced TABLE 11–3 Signs and Symptoms Associated with
by these agents may also result in the promotion of Drug-Induced Ischemic Stroke
platelet aggregation.75
Anterior cerebral artery blockage
• Contralateral hemiparesis
CLINICAL PRESENTATION AND • Confusion
• Gait apraxia
DIFFERENTIAL DIAGNOSIS
Middle cerebral artery blockage
Clinically, it is difficult to distinguish drug-induced • Contralateral hemiparesis
stroke from non-drug-induced stroke. The diagno- • Dysarthria
sis of drug-induced stroke is often made by exclu- • Hemianesthesia
sion of other causes, or through serum or urine • Contralateral homonymous hemianopia
testing for drugs. The typical stroke patient pres- • Aphasia
ents with an abrupt onset of neurologic deficits, • Apraxia
which can include hemiparesis, speech distur- Posterior cerebral artery blockage
bance, hemisensory loss, monocular or visual field • Unilateral cortical blindness
loss, and/or ataxia. The clinical presentation of • Memory loss
both ischemic stroke and ICH is dependent on the • Contralateral homonymous hemianopia
anatomical location of the stroke. It is not possible • Unilateral third-cranial-nerve palsy
to distinguish an ischemic stroke from ICH based Ophthalmic artery blockage
on clinical examination alone, although several • Monocular loss of vision
characteristics are more indicative of ICH:
Vertebrobasilar system blockage
headache, impaired level of consciousness, nausea
• Unilateral or bilateral cranial-nerve deficits
and vomiting, and extreme elevations of blood
(e.g. nystagmus, vertigo, dysphagia, dysarthria,
pressure. Subarachnoid hemorrhage must be sus-
diplopia, blindness)
pected in a patient who experiences a sudden new
• Coma
severe headache. Drug-induced stroke can occur at
• Ataxia
any time during therapy with a potentially
• Impaired consciousness
causative agent. Common signs and symptoms of
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TABLE 11–4 Conditions to Consider in the TABLE 11–5 Risk Factors for Drug-Induced
Differential Diagnosis of Drug-Induced Ischemic Ischemic Stroke54
Stroke
• Elderly
• Seizure disorder (with postictal paralysis) • Previous stroke
• Migraine headache • Polydrug use
• Metabolic encephalopathy (hypoglycemia, diabetic • Hypertension
ketoacidosis, hyperosmolar coma, hepatic • Migraine headaches with aura
encephalopathy, kidney disease, hypercapnia, sepsis) • Pregnancy
• Syncope • Diabetes
• Peripheral neuropathy • Concurrent caffeine use
• Malingering/somatization • Dementia
• Brain tumor • Concurrent tobacco use
• Cerebral abscess • Use of higher than recommended doses of potentially
• Encephalitis causative agents
• Meningitis • Exposure to drugs of abuse
• Psychiatric symptoms • Physical inactivity
• Post–cardiac arrest ischemia • History of vascular events
• Cerebral hemorrhage
• Cranial trauma
• Antiphospholipid syndromes
• Genetic factors (i.e., deficiencies in protein ing cause of death in the U.S. and a leading cause
factors C and S, factor V Leiden, Moya moya, Fabry’s of disability in hospitalized patients. Long-term
disease, CADASIL [cerebral autosomal dominant sequelae of a stroke, whether induced by drugs or
arteriopathy with subcortical infarcts and other etiologies, include memory loss, depression,
leukoencephalopathy]) behavioral changes, emotional lability, difficulty
performing activities of daily living, communica-
tion problems, paralysis, and neglect (lack of
awareness) on the side of the body corresponding
to the location of the stroke.
RISK FACTORS
Risk factors for drug-induced stroke have been
identified and are presented in Table 11–5. An
PREVENTION
underlying history of hypertension is one of the The most effective means of preventing drug-
most common risk factors. In addition, any patient induced stroke is avoidance of agents known to
with risk factors for stroke is at a higher risk for be associated with stroke, especially in high-risk
drug-induced stroke. The Framingham study iden- patients. Strategies for prevention of drug-
tified five factors that placed the general popula- induced ischemic stroke are listed in Table
tion at increased risk of ischemic stroke: elevated 11–6.54 Drug-induced stroke may also be prevent-
systolic blood pressure, elevated serum cholesterol ed by minimizing other ischemic stroke risk fac-
concentration, glucose intolerance, cigarette smok- tors (e.g., hypertension, hyperlipidemia,
ing, and left ventricular hypertrophy as shown on smoking, diabetes). However, the mainstay of
an electrocardiogram.76 Risk factors for ischemic prevention is patient education and identifica-
stroke have been outlined in recent guidelines tion of risk factors, particularly in patients who
from the American Stroke Association (ASA) and are at high risk.
the AHA.54
MANAGEMENT
MORBIDITY AND MORTALITY
The treatment of any patient has many phases:
Stroke is one of the most devastating diseases, yet prevention of additional strokes or other vascular
one of the most preventable. The overall direct and disease, supportive and medical management dur-
indirect economic impact of stroke is approximate- ing the acute phase, measures to mitigate the
ly $40.9 billion annually.77 Stroke is the third lead- ongoing pathologic process, and rehabilitation. In
TisdaleC011_190-210 1/12/10 2:35 PM Page 196
addition, discontinuation of the offending agent (rt-PA). In appropriately selected patients, rt-PA sig-
(if identified) is essential. nificantly increases the likelihood of a good neuro-
Approaches to treatment of drug-induced acute logic recovery.79 To be eligible for rt-PA therapy,
ischemic stroke are similar to those of stroke due to patients should have a well-described time of
other etiologies (refer to treatment guidelines pub- symptom onset within 3-4.5 hours before the initi-
lished for the acute management of ischemic ation of treatment. The dose of rt-PA for stroke is
stroke78). Hospital admission is indicated for any 0.9 mg/kg IV over 1 hour, 10% as an initial bolus.
patient presenting with an acute stroke. Neurologic The maximum total dose is 90 mg. During the first
progression and cardiac sequelae are common in 24 hours after treatment, therapy with antithrom-
the early stages of a stroke. Preventing and recog- botic agents such as heparin and aspirin should be
nizing secondary complications such as aspiration withheld, blood pressure should be strictly main-
pneumonia and pulmonary embolism are essen- tained at <180/105 mm Hg, and neurologic and
tial. The only proven specific treatment for acute cardiac function should be closely monitored in an
ischemic stroke at present is the thrombolytic intensive care unit or stroke unit. Some evidence
agent recombinant tissue plasminogen activator suggests that continuous 2-MHz transcranial
TisdaleC011_190-210 1/12/10 2:35 PM Page 197
Doppler ultrasonography for 2 hours with or with- infarction, or dilated cardiomyopathy. The stan-
out intravenous galactose-based microbubbles aug- dard target range for the international normalized
ments intravenous rt-PA recanalization. This ratio (INR) is 2.0–3.0. Patients with mechanical
technique is currently being tested in clinical tri- prosthetic valves require a higher INR (2.5–3.5),
als.80 Therapy with intraarterial thrombolysis for but this places them at increased risk for ICH. In
patients with middle cerebral artery occlusions pre- addition, any other risk factor that may be present
senting within 6 hours of the onset of stroke symp- (e.g., hyperlipidemia, hypertension, diabetes)
toms appears promising.81 Angioplasty and should be managed aggressively. Refer to second-
stenting of cerebral arteries may also have a thera- ary prevention guidelines for specific recommen-
peutic role for patients with acute ischemic strokes. dations.82
In 2004 the FDA approved the MERCI (mechanical
embolus removal in cerebral ischemia) Retrieval
System. This “corkscrew-type” device is designed to INFORMATION FOR PATIENTS
restore blood flow by engaging, capturing, and
removing blood clots. Most recently (2008), anoth- Risk factor assessment of patients is essential in the
er mechanical device, the Penumbra System, prevention of drug-induced stroke. Because many
designed to reduce clot burden, was approved by of the drugs that are known to cause stroke are not
the FDA. These might represent treatment options obtained by patients at pharmacies, it is extremely
for patients who do not present within the 3-4.5 important that patients at risk are counseled to
hour time window necessary for administration of consult health care professionals before purchasing
thrombolysis, as the clinical trials enrolled patients nonprescription drug products. For example,
within 8 hours of symptom onset.80 patients with hypertension should be advised that
Fever and hyperglycemia should be treated cough and cold products or herbal products might
aggressively in patients with acute stroke, because contain sympathomimetic drugs that could place
both conditions exacerbate cerebral ischemia and them at increased risk for drug-induced stroke.
may worsen neurologic outcome. The appropriate- Patients should be instructed to inform their
ness of treating acute hypertension is less clear, health professionals of all medications and herbal
except in the patient who has undergone throm- products that they are taking, to facilitate a full
bolysis. In fact, lowering blood pressure excessive- evaluation of potential agents that may be associ-
ly may contribute to cerebral ischemia. In most ated with drug-induced stroke. Since a large num-
patients, blood pressure probably should not be ber of recreational drugs of abuse may cause stroke,
lowered during the first 24–48 hours after the appropriate counseling on the risk of these agents
stroke unless blood pressure exceeds 220/120 mm should be performed, and referral to rehabilitation
Hg.78 programs should be considered. In addition, all
If antihypertensive therapy is needed in the patients should be counseled regarding the signs
acute stage, intravenous agents should be used, and symptoms of ischemic stroke and risk factors,
particularly those for which doses can be easily and should be instructed to seek medical attention
titrated. Current ASA/AHA guidelines suggest the at the onset of symptoms.
use of either labetalol or nicardipine. Labetalol
may be administered initially as intravenous bolus-
es of 10–20 mg until the desired blood pressure is INTRACEREBRAL
achieved. Labetalol should be avoided in patients
with contraindications to -blockers. Nicardipine HEMORRHAGE (ICH)
therapy may be initiated as an intravenous infu-
sion of 5 mg/hr, and the infusion rate can be CAUSATIVE AGENTS
adjusted to achieve the desired blood pressure.78
After the acute phase of a stroke, risk-factor Drugs that have been reported to cause hemorrhag-
management is essential.82 The appropriate specif- ic stroke are listed in Table 11–7.2-3,8,25,38,79,81,83-136
ic preventive agent in patients with other risk fac- Many of the agents that are associated with ICH
tors may be aspirin, clopidogrel, ticlopidine, or are used as therapeutic agents for other disease
warfarin. Of these, aspirin is the most frequently states. Symptomatic ICH is one of the most feared
prescribed. There is a lack of consensus regarding complications associated with the use of rt-PA for
the optimal dose for stroke prevention. Doses of ischemic stroke and occurs in approximately 6% of
50–325 mg have been shown to be effective. treated patients. It is estimated that for every 100
Warfarin is indicated for stroke prevention in most patients treated with rt-PA, 1 will experience severe
patients with atrial fibrillation, acute myocardial disability or death associated with symptomatic
TisdaleC011_190-210 1/12/10 2:35 PM Page 198
ICH.137 Most of the patients who experience this study found underutilization of warfarin, primarily
devastating complication have more severe base- due to the perceived bleeding risk.139 An estimated
line infarcts.137,138 Other risk factors for sympto- 3,000 of the 60,000 ICH cases occurring annually
matic ICH associated with rt-PA will be discussed in the U.S. are caused by warfarin, with an associ-
later in the chapter. ated mortality rate as high as 67%.90,105 Warfarin
Warfarin is highly effective therapy for the pre- increases the risk of progressive bleeding and sub-
vention of ischemic stroke among patients with sequent clinical deterioration in these patients.
atrial fibrillation. Despite its proven efficacy, one The overall risk of ICH in patients treated with war-
TisdaleC011_190-210 1/12/10 2:35 PM Page 199
farin is between 0.3% and 3.7% when the INR is heparin.145 However, clinicians should be aware of
2.0–4.5. The incidence of ICH increases by a factor the possibility of ICH associated with these agents,
of 1.37 for each 0.5-unit increase in the INR. especially when used in combination with other
Unfortunately, the prevalence of atrial fibrillation antiplatelet drugs such as the glycoprotein IIb/IIIa
is expected to triple by the year 2050, so the inci- receptor antagonists. Activated protein C
dence of warfarin-associated ICH is expected to (drotrecogin alfa activated) promotes fibrinolysis
increase.90,105,140-141 and inhibits thrombosis and inflammation and has
Alcohol abuse remains an important risk factor been associated with serious bleeding events in
for ICH, with the risk related to the quantity con- clinical trials involving severe sepsis.135-136
sumed. Consumption of 41–120 g is associated However, these trials have not found an increased
with a 4.6 times higher risk of ICH as compared intracranial bleeding rate. One analysis of four
with that in nondrinkers, and the risk is 11.3-fold clinical studies found a higher rate of ICH in
higher in those who consume 121 g or more.142 patients with severe sepsis presenting with purpu-
Other drugs of abuse have also been implicated in ra fulminans, meningitis, or meningococcal dis-
causing ICH. Cocaine and other sympathomimet- ease who received drotrecogin alfa.134 Intracranial
ics have been implicated in both ischemic stroke bleeding events have been reported in association
and ICH.71 with glycoprotein IIb/IIIa receptor antagonists,
Both epidemiologic and clinical trials have especially when used in combination with heparin,
suggested that very low cholesterol concentrations and these events are associated with increased mor-
(total cholesterol <160 mg/dL) achieved with tality.123 The Abciximab in Emergency Treatment
high-dose statin therapy is associated with ICH.129- of Stroke Trial (AbESTT-II), which was prematurely
133
It has been suggested that adequate plasma halted, was designed to evaluate the impact of
cholesterol concentrations are necessary to main- abciximab on outcome following ischemic stroke.
tain the integrity of the small vessels to prevent This study found an increased rate of symptomatic
rupture.143 In the Heart Protection Study, patients or fatal ICH, without improved efficacy, in patients
who had a previous history of stroke or transient who were treated with abciximab.122 Conflicting
ischemic attack showed a trend toward a higher information has been reported regarding the risk of
incidence of ICH after treatment with simvastatin bleeding complications associated with the use of
as compared with placebo.144 The Stroke enoxaparin for the prevention of venous throm-
Prevention by Aggressive Reduction in Cholesterol boembolism in patients undergoing neurosurgery,
Levels (SPARCL) trial was the first study to specifi- but concern has been expressed regarding the use
cally evaluate the effect of high-dose statin (ator- of low-molecular-weight heparins in this popula-
vastatin) in patients with prior stroke or transient tion.118-119 There has also been concern regarding
ischemic attacks but without a history of coronary the risk of ICH associated with the use of non-
artery disease or hypercholesterolemia. Patients aspirin nonsteroidal antiinflammatory drugs
randomly assigned to atorvastatin had a higher (NANSAIDs). However, one multicenter case–con-
rate of ICH as compared with those who received trol study did not find an increase in the risk of
placebo (hazard ratio, 1.66; 95% confidence inter- ICH associated with NANSAIDs.146
val, 1.08–2.55).129 However, the overall net vascu-
lar benefit (16% reduction in nonfatal or fatal
stroke) observed in this trial outweighs the risk of EPIDEMIOLOGY
ICH, so it is reasonable to conclude that the
majority of patients with ischemic stroke are like- Intracerebral hemorrhage is defined as bleeding
ly to receive benefit from statin therapy. The effect into the brain parenchyma with possible extension
of cholesterol concentrations or the use of statins into the ventricular system or subarachnoid space.
and incidence of ICH is unclear; this observation Approximately 37,000–52,000 people suffer from
needs to be further evaluated in larger prospective ICH annually (approximately 8–13% of all strokes)
studies. in the U.S.147 Although ICH accounts for only a
There are many drugs that may theoretically small proportion of all strokes, it is associated with
increase the risk of hemorrhagic stroke, although, the highest mortality rate. Drug-related etiologies
for some, such an association has not been report- can be identified in 14–27% of intracerebral hem-
ed in the literature. Direct thrombin inhibitors orrhages.2,56 The incidence of drug-induced stroke
such as hirudin or bivalirudin have not been may be on the rise.2 Anticoagulant therapy is
shown to increase the risk of hemorrhagic stroke in implicated in about 10% of all cases of ICH. The
clinical trials, and the risk of bleeding associated incidence of stroke associated with specific agents
with these drugs is lower than that associated with is presented in Table 11–7.
TisdaleC011_190-210 1/12/10 2:35 PM Page 200
of diabetes mellitus and cardiac disease, increas- tion management should focus on maintaining the
ing stroke severity, advancing age, use of INR between 2.0 and 3.0.91 The risk of anticoagu-
antiplatelet agents other than aspirin, elevated lant-related bleeding is highest during the first
pretreatment mean blood pressure, and lower month of therapy.161 Other factors that increase the
platelet counts.138,154 In addition, the use of r-tPA risk of anticoagulant-induced ICH include atrial fib-
in patients who do not meet the inclusion criteria rillation, diabetes, concomitant use of antiplatelet
or meet exclusion criteria detailed in the National agents, amyloid angiopathy, fibrinoid degeneration
Institutes of Neurological Diseases Study (espe- of arterioles, head trauma, acute alcohol intoxica-
cially administration of r-tPA to patients that tion, and migraine headaches.89 There is an
present >3 hours from the onset of symptoms) or increased rate of cerebral bleeding associated with
both increases the risk of ICH in patients with intermittent intravenous heparin therapy as com-
acute ischemic stroke.156-157 pared with that associated with continuous intra-
Phenylpropanolamine was marketed in combi- venous infusion. Subcutaneous heparin is
nation with caffeine as a weight-loss aid and was associated with bleeding rates similar to those due
banned by the FDA after the occurrence of numer- to continuous intravenous infusion.91,93 Increased
ous cardiovascular and central nervous system bleeding incidences (cerebral and noncerebral)
adverse events.112 Used in combination, these have been reported in patients who have an aPTT
drugs have an additive effect on blood pressure.158 that is prolonged to more than twice the upper
Women between the ages of 18 and 49 years who limit of the therapeutic range in at least 50% of the
use phenylpropanolamine as an appetite suppres- tested samples. For every 10-second increase in the
sant are 17 times more likely to experience an ICH aPTT, major bleeding complications increase by
as compared with women of that age group who 7%.91
do not take this medication.110 The risks associated Patients with kidney disease (serum creatinine,
with cough and cold preparations are less clear. >2.0 mg/dL) are at greater risk of bleeding associat-
The risks in men taking phenylpropanolamine are ed with low-molecular-heparins or glycoprotein
also unclear, because the case–control study IIb/IIIa receptor antagonists than patients with
included too few men from which to make conclu- normal kidney function.162,163 Many of these
sions.112 The association between sympathomimet- agents are excreted renally and may accumulate in
ic drugs and ICH appears to be dose-related and patients with kidney disease, and therefore dose
additive when used in combination with other adjustments are necessary. Patients ≥75 years of age
agents with similar activity. ICH was three times have a higher rate of ICH after treatment with gly-
more likely to develop in patients receiving coprotein IIb/IIIa receptor antagonists.125
phenylpropanolamine in cough and cold prod- The use of aspirin for both primary and sec-
ucts.112,159 Herbal preparations that contain ondary prevention of vascular events, including
ephedra or ma huang also increase the risk of ICH ischemic stroke, has been associated with increased
in a dose-related fashion. The risk of ICH is four- risk of ICH (relative risk, 1.35).103 Since significant
fold greater in patients receiving ephedra doses >32 benefit is achieved with the use of aspirin, evalua-
mg/day.107-108,160 This is an important issue with tion of possible risk factors for ICH may assist in
respect to counseling patients regarding the use of assessing whether the risk exceeds the benefit. Risk
nonprescription drugs or herbal supplements/ener- factors for ICH include age >75 years, African-
gy drinks that may have sympathomimetic effects. American race, hypertension, amyloid accumula-
Anticoagulant therapy is used commonly to tion, history of epistaxis, dose ⱖ650 mg/day,
treat many thromboembolic disorders, particularly bleeding disorders, and neoplasm.103
in the elderly population. Patients with an INR >3.0 Use of combinations of agents, such as
or an activated partial thromboplastin time (aPTT) antiplatelet drugs, anticoagulants, and throm-
>80–90 seconds are at increased risk of ICH associ- bolytics, may provide additive beneficial effects in
ated with warfarin and heparin, respectively. patients with heart disease or stroke, but these
Factors that increase the risk of anticoagulant-relat- combinations also increase the risk of ICH.
ed ICH includes older age, level of anticoagulation, Concomitant use of aspirin with warfarin or
prior stroke, and hypertenson.89,91,153 The risk for heparin and glycoprotein IIb/IIIa antagonists is
ICH with warfarin therapy particularly increases at associated with an increased incidence of bleed-
ages ≥85 years. An INR <2.0 is not associated a with ing.91 The use of combinations of oral antiplatelet
lower risk of ICH as compared with an INR of agents for secondary prevention of stroke or acute
2.0–3.0, but the risk is increased with an INR >3.5, coronary syndromes has become a common prac-
which should be avoided.88,91,153 Therefore, for pre- tice. However, a study that evaluated the combina-
vention of recurrent ischemic stroke, anticoagula- tion of aspirin and clopidogrel for prevention of
TisdaleC011_190-210 1/12/10 2:35 PM Page 204
recurrent stroke or transient ischemic attack All patients with acute drug-induced ICH
reported an absolute increased risk of life-threaten- should be hospitalized, and most will require care
ing bleeding of 1.3%. The combination therapy in an intensive care unit. Guidelines for the man-
was not associated with a reduction in vascular agement of patients with ICH have been pub-
events, so the risks of the combination therapy lished previously.166 Patients with ICH often
appeared to outweigh the benefits.164 In addition, present with severe acute hypertension. There is
the Prevention Regimen for Effectively avoiding no consensus regarding the ideal target range for
Second Strokes (PRoFESS) trial showed similar blood pressure control. The decision regarding
recurrent ischemic stroke rates with extended the appropriate target lower blood pressure is a
release dipyridamole plus aspirin as compared with balance between limiting an increase in
clopidogrel. However, major bleeding events and hematoma volume and preventing ischemic
intracranial bleeds were more frequently observed changes. Surgical evacuation of the hematoma
in those who received extended-release dipyri- may be necessary in some patients. General med-
damole plus aspirin. The overall risk:benefit was ical management and supportive care are indicat-
not significantly different between the two regi- ed in all patients to prevent complications (i.e.,
mens.165 intracranial hypertension).
If ICH occurs in association with thrombolytic,
anticoagulant, or antiplatelet therapy, immediate
MORBIDITY AND MORTALITY cessation of the causative agent is indicated, with
rapid reversal of the impaired clotting profile.
ICH accounts for only a small percentage of all Patients with ICH who are receiving unfractionat-
stroke cases but is associated with the highest inci- ed heparin or low-molecular-weight heparin
dence of mortality. Therefore, although the mortal- should receive protamine sulfate (1 mg/100 units
ity rates associated with drug-induced ICH are of heparin or 1 mg of enoxaparin). The dose of pro-
unknown, it is reasonable to assume that they may tamine should be adjusted according to the time
be high. elapsed from last heparin dose. For example, if
heparin is discontinued for 30–60 minutes, the
protamine dose is 0.5–0.75 mg/100 units of
heparin; if the heparin infusion is discontinued for
PREVENTION 60–120 minutes, the protamine dose should be
0.375–0.5 mg/100 units of heparin; finally, if the
The most effective means of prevention of drug- heparin infusion is discontinued for more than 120
induced stroke is avoidance of agents known to be minutes, the protamine dose should be 0.25–0.375
associated with ICH, especially in high-risk mg/100 units of heparin. Protamine sulfate should
patients. Strategies for the prevention of drug- be administered intravenously over 10 minutes in
induced stroke are listed in Table 11–12. Patients doses not to exceed 50 mg, because of the potential
receiving anticoagulant therapy should be closely risk of severe systemic hypotension.166 Patients
monitored for intensity of anticoagulation and the with bleeding caused by platelet dysfunction
possibility of drug interactions. Careful selection of should receive platelet transfusions (6 units)
patients with ischemic stroke who receive intra- and/or a single dose of desmopressin (0.3 mcg/kg).
venous rt-PA is also important. However, the main- For treatment of ICH related to thrombolysis, the
stay of prevention is patient education and currently recommended therapy is platelet infu-
identification of risk factors, particularly in sion (6–8 units) and cryoprecipitate that contains
patients who are at high risk. factor VIII.166
The clotting factor inhibition in patients who
are receiving warfarin and experiencing ICH
MANAGEMENT should be reversed immediately with fresh frozen
plasma (15 mL/kg) or prothrombin-complex con-
The treatment of any patient with ICH includes centrates (15–30 units/kg) and vitamin K (5–10
many phases: prevention of additional ICH, sup- mg). Therapy should never be withheld to check
portive and medical management during the acute coagulation profiles because normalization of the
phase, measures to mitigate the ongoing patholog- INR with some of these approaches may take sev-
ic process, and rehabilitation. In addition, discon- eral hours. Administration of prothrombin-com-
tinuation of the offending agent (if identified) is plex concentrate normalizes the INR more
essential. rapidly than fresh-frozen plasma and can be
TisdaleC011_190-210 1/12/10 2:35 PM Page 205
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CHAPTER 12
Movement Disorders
ent EPS. Risperidone at doses >6 mg daily or extensively to describe the restlessness and pacing
administered concurrently with cytochrome P-450 behavior induced by neuroleptics and other drugs.
2D6 or 3A4 inhibitors, which can result in accumu- Akathisia induced by psychotropic agents can be a
lation of risperidone’s active moiety (9-hydrox- distressing adverse effect, resulting in poor treat-
yrisperidone or paliperidone), predispose to ment adherence and, consequently, an increased
occurrence of DIMDs. EPS induction occurs more risk of relapse or exacerbation of the underlying
frequently at paliperidone doses >9 mg daily. psychiatric disorder.
Movement disorders are also associated with
other psychotropic drugs, such as lithium, selective
serotonin reuptake inhibitors (SSRIs), psychostim-
ulants, and tricyclic antidepressants (TCAs).
CAUSATIVE AGENTS
Tremor commonly occurs with lithium treatment,
Agents implicated in drug-induced akathisia are
which also occasionally causes chorea.14 Treatment
listed in Table 12–1.24,25,33-43 Conventional neu-
with SSRIs may cause akathisia and tremor, but
roleptics and antidopaminergic antiemetics are the
rarely induces dyskinesia, dystonia, or parkinson-
most commonly implicated drugs in acute and tar-
ism.15,16 Psychostimulants (e.g., amphetamine,
dive akathisia. Several atypical antipsychotics also
methylphenidate, pemoline) have occasionally
induce akathisia, albeit at lower rates as compared
been reported to produce a variety of movement
with conventional neuroleptics. The SSRIs and the
disorders such as dyskinesias, dystonia, stereotypic
serotonin–norepinephrine reuptake inhibitor mir-
behavior, and tics.17 The most common movement
tazapine are also commonly implicated in acute
disorders associated with TCAs are akathisia,
akathisia, but rarely in tardive akathisia.
myoclonus, and tremor.18,19 Antiepileptic agents
rarely induce movement disorders, with the excep-
tion of valproate, which is frequently associated
with tremor and, to a lesser extent, parkinsonism. EPIDEMIOLOGY
Carbamazepine, ethosuximide, felbamate, gaba-
pentin, phenobarbital, and phenytoin have rarely Acute akathisia occurs in 8% to 76% of patients tak-
been associated with dyskinesia or dystonic reac- ing conventional neuroleptics.33,34 However, the
tions.20 For many years, chorea has been recog- most consistently reported incidence of acute
nized as a complication of estrogen- and pro- akathisia associated with conventional neuroleptics
gesterone-containing products (e.g., oral contra- is 20% to 30%,35 and the incidence of tardive
ceptives).21 Antiemetics that block central dopa- akathisia is approximately 30%. The atypical
mine receptors (i.e., droperidol, metoclopramide, antipsychotics (i.e., aripiprazole, clozapine, iloperi-
prochlorperazine) are also commonly implicated done, olanzapine, paliperidone, quetiapine, risperi-
in the various DIMDs.22-25 done, ziprasidone) also induce akathisia, although
Drug-induced tremor, although not uncom- the risk is lower than that associated with conven-
mon, will not be discussed in this chapter, and tional neuroleptics. In one study, the point preva-
readers are referred elsewhere for further reading.26 lences of akathisia associated with clozapine,
Readers are also referred elsewhere for discussions risperidone, and conventional neuroleptics were
on drug-induced myoclonus (abrupt, brief, and 7.3%, 13%, and 23.8%, respectively.36 However, at
sudden “shock-like” involuntary movements), lev- daily doses >6 mg, the frequency of risperidone-
odopa-induced dyskinesias, neuroleptic malignant induced akathisia increases significantly. The inci-
syndrome, restless legs syndrome, and motor dence of akathisia in iloperidone-treated patients is
tics.27-32 The primary topics that will be covered in low and similar to that of placebo.37,38
this chapter are drug-induced akathisias, tardive Akathisia is also induced by SSRIs and TCAs.
dyskinesia, dystonias, and parkinsonism. Although the incidence of SSRI- and TCA-induced
akathisia has not been systematically studied, it
appears to occur in at least 5% of patients treated
with SSRIs,39 with higher rates associated with stim-
AKATHISIA (ACUTE AND TARDIVE) ulating SSRIs (e.g., fluoxetine, paroxetine).
The term akathisia is derived from Greek (“not sit- Treatment-emergent anxiety, agitation, and restless-
ting still”), and was initially used at the turn of the ness are commonly reported in association with
20th century to describe the restlessness and pac- antidepressants (especially within the first 2 weeks
ing observed in patients diagnosed with hysteria of initiating treatment) and it is possible that a sub-
and neuroses. The term akathisia is now used set of these patients are experiencing akathisia.
TisdaleC012_211-235 1/12/10 2:36 PM Page 213
Akathisia also frequently occurs in association observation that akathisia may be caused by sero-
with antidopaminergic antiemetics. In one study, toninergic agents, such as SSRIs, and the positive
acute, transient akathisia occurred in 71.4%, 25%, therapeutic response to 5-hydroxytryptophan
35.3%, and 11.1% of patients treated with droperi- (serotonin) type 2 (5-HT2) receptor blockers (e.g.,
dol, metoclopramide, prochlorperazine, and place- cyproheptadine) and the noradrenergic -receptor
bo, respectively.24 Bolus intravenous infusion of blocker propranolol (which also possess antisero-
metoclopramide is associated with higher rates of tonergic activity). In addition, the atypical antipsy-
akathisa as compared with slow infusion.25 chotics, which possess more potent 5-HT2 receptor
blockade relative to dopamine type 2 (D2) recep-
tors, are associated with rates of akathisia as com-
MECHANISMS pared to those of conventional neuroleptics. Iron
deficiency has been implicated as a component of
The pathophysiologic mechanism of drug-induced the pathophysiologic mechanism for akathisia, but
acute akathisia is not well understood, but involves the data are inconsistent.45 The mechanism under-
altered dopaminergic and serotoninergic activity lying the tardive form of akathisia is less well
(Table 12–2). This model is supported by the obser- understood, but is probably distinct from that of
vation that akathisia is a well-recognized effect of acute akathisa.
central-acting dopamine-receptor–blocking agents
(DRBAs). The dopaminergic pathway of the
mesolimbic tract appears to be affected, and the
stronger the antidopaminergic effect of a drug, the CLINICAL PRESENTATION AND
higher the incidence of akathisia.44 Serotoninergic DIFFERENTIAL DIAGNOSIS
and noradrenergic input in the ventral tegmental
area exerts an inhibitory effect on mesocortical According to the Diagnostic and Statistical Manual of
dopamine transmission. This is supported by the Mental Disorders (DSM-IV), neuroleptic-induced
TisdaleC012_211-235 1/12/10 2:36 PM Page 214
akathisia is comprised of both a subjective and an roleptic therapy cessation or dose reduction (i.e.,
objective component.46 The core features are sub- withdrawal akathisia). Occasionally, the discon-
jective symptoms of restlessness (commonly refer- tinuation of therapy with a concurrent anti-
able to the legs) and at least one of the following akathisia agent (e.g., propranolol) may unmask
objective findings: fidgety movements or leg akathisia. Although the temporal criteria for tar-
swinging while seated, marching on the spot while dive akathisia are debatable, an onset of symp-
standing, rocking from one foot to another, pacing toms after 3 months of stable drug therapy is
to relieve subjective restlessness, or an inability to considered tardive. Tardive akathisia can also
sit or stand still for several minutes (Table 12–3). occur several months after drug therapy discon-
Subjective dysphoria is a major component of neu- tinuation or dose reduction. Concurrent symp-
roleptic-induced akathisia and includes apprehen- toms of parkinsonism, TDk, dystonia, or tremor
sion, an inner sense of restlessness (often in the are not uncommon.
legs), anxiety, and the urge to move. Significant Drug-induced akathisia may resemble agitation
mental distress is experienced if the patient is and anxiety presenting as a component of a psy-
asked to not move or is restrained from moving. chiatric disorder or from drug withdrawal syn-
Drug-induced akathisia can easily be mistaken for dromes. Acute drug-induced akathisia should be
anxiety, psychotic agitation, or restless legs syn- suspected if symptoms develop soon after the initi-
drome (Table 12–4). Unlike most movement disor- ation of therapy with potentially causative drugs
ders, which are involuntary, the movements and in the absence of other conditions associated
associated with akathisia (e.g., fidgeting, leg or with restlessness. In contrast to restless legs syn-
body shifting, toe tapping, walking) are voluntary, drome, patients with akathisia may report
and occur in response to the subjective feeling of improvement when lying down or sleeping,
restlessness or discomfort. As with other move- absence of lower extremity paresthesias, absence of
ment disorders, anxiety or stress exacerbates preex- diurnal pattern, and absence of periodic leg move-
isting akathisia. ments in sleep. Tardive akathisia may be suspected
Symptoms of acute akathisia may occur with- in the absence of other conditions associated with
in an hour (as with intravenously administered restlessness. The symptoms of tardive akathisia are
antidopaminergic antiemetics) to within several similar to those of acute akathisia, except that
weeks of initiating or increasing the dose of the patients with tardive akathisia tend to report less
offending drug, and may also develop after neu- distressing subjective symptoms and are able to
TisdaleC012_211-235 1/12/10 2:36 PM Page 215
TABLE 12–3 Signs and Symptoms Associated with TABLE 12–4 Conditions to Consider in the
Drug-Induced Movement Disorders Differential Diagnosis of Drug-Induced Movement
Disorders
Akathisia
• Subjective feeling of restlessness and need to move Akathisia
• Objective symptoms of pacing, walking in place, foot • Alcohol or drug withdrawal
or toe tapping, rocking while seated • Anxiety disorder
• Distress if restrained or unable to move • Psychic agitation
• Symptoms may improve during sleep or in a supine • Restless legs syndrome
position. Tardive Dyskinesia
Tardive dyskinesia • Edentulism
• Abnormal involuntary choreoathetoid movements • Huntington’s disease
affecting the orofacial region, tongue, upper and • Hyperthyroidism
lower extremities, and trunk • Levodopa-induced dyskinesia
• Symptoms are not painful but may result in embar- • Neuroacanthocytosis (choreoacanthocytosis)
rassment in social settings and difficulty with chew- • Sydenham’s chorea
ing, speaking, and swallowing. • Wilson’s disease
• Lip smacking, chewing movements, and tongue pro- Dystonia
trusion are common.
• Arthritis
Dystonia • Atlantoaxial rotary subluxation
• Sustained involuntary muscle contractions or spasms • Catatonia
resulting in abnormal postures or twisting and repeti- • Conversion reaction
tive movements • Dopa-responsive dystonia
• Affected body parts include the neck, upper and • Huntington’s disease
lower extremities, jaw, larynx, and trunk. • Idiopathic dystonia
• Symptoms associated with distress, pain, and disability • Inherited dystonias
• Difficulty with walking, breathing, head turning, • Neuroleptic malignant syndrome
speech, and swallowing • Orthopedic disorder
Parkinsonism • Tetanus
• Wilson’s disease
• Tremor, rigidity, slowness of movement affecting bilat-
eral upper and lower extremities, and truncal regions Parkinsonism
• Masked facies, micrographia, slow shuffling gait, and • Essential tremor
stooped posture • Hypothyroidism
• Idiopathic parkinsonism
• Severe depression
• Wilson’s disease
TABLE 12–5 Risk Factors for Drug-Induced TABLE 12–6 Approaches to Help Prevent Drug-
Akathisia Induced Akathisia
• Advanced age Amoxapine, atypical antipsychotics, conventional neu-
• Affective disorder roleptics, lithium, metoclopramide
• Cognitive impairment • Use lowest effective dose,
• Female sex • Use standardized dose titration to avoid excessive
• High dose neuroleptic therapy dose escalation.
• High potency neuroleptic therapy • Correct underlying iron deficiency .
• History of akathisia • If high risk for akathisia (e.g., prior history of akathisia)
• Iron deficiency exists, concurrent administration of an antimuscarinic
• Mental retardation agent or -blocker is recommended.
• Presence of negative symptoms of schizophrenia Droperidol, prochlorperazine, promethazine, selective
• Rapid neuroleptic dose escalation serotonin reuptake inhibitors, tricyclic antidepressants
• Use lowest effective dose.
Carbamazepine, reserpine
months or years. Acute akathisia has been associat-
• None known
ed with promoting aggression, suicidal behavior,
and treatment nonadherence in patients with
schizophrenia.48-50 Worsening of anxiety and
aggressive behavior may result in an increase in
neuroleptic dose, which in turn may exacerbate MANAGEMENT
the underlying akathisia. Although tardive
akathisia may slowly remit upon drug discontinu- Early detection is a key factor in the probability of
ation, it often persists. eventual remission of drug-induced akathisia. If
treatment with an implicated agent has been
extended for 3 months or longer, the patient
PREVENTION should be periodically examined to determine the
presence of subjective and objective features of
Approaches to help prevent drug-induced akathisia akathisia. When akathisia is detected, several
are summarized in Table 12–6. As with most drug- management approaches can be initiated (Table
induced adverse effects, prevention is very impor- 12–7).
tant. Primary prevention aided by knowledge and For patients with acute akathisia, the
recognition of risk factors is a key factor for mini- causative agent should be discontinued, if possi-
mizing the burden of akathisia. The necessity of ble. For neuroleptic-treated patients, a switch to
short- or long term use of potentially causative an atypical antipsychotic or alternative agent
agents should be carefully evaluated. If indicated, should be considered. In patients in whom
the lowest effective dose should be used and causative agents have been discontinued, the
patients should undergo regular evaluations for akathisia may promptly resolve, only to be
emergence of akathisia. Standardized titration of replaced with increased agitation and anxiety.
doses of antipsychotic agents to avoid excessive Care should be taken to differentiate these symp-
dose escalation and the use of atypical antipsy- toms from those of persistent akathisia.
chotics are successful means of prevention. Administration of a lipophilic -blocker, such as
Although iron deficiency has been associated with propranolol, is effective and well-tolerated.52 2-
acute and tardive akathisia, routine iron supple- receptor inhibition appears to be crucial for effica-
mentation as a preventive or treatment interven- cy, as 1-receptor selective agents are less
tion is not supported by the available evidence.51 effective.53 However, a trial of a cardioselective,
However, it is reasonable to correct an underlying 1-receptor blocker is reasonable if 2-blockade is
iron deficiency or to administer oral iron supple- undesirable. The hydrophilic -blockers (e.g.,
mentation to patients with akathisia that is unre- atenolol, nadolol) do not appear to be effective. -
sponsive to standard measures. In patients at high blockers should be avoided in patients with a his-
risk of akathisia (e.g., history of akathisia), concur- tory of cardiac conduction blocks, orthostatic
rent administration of an antimuscarinic agent or hypotension, or reactive airway disease.
-blocker is reasonable. Administration of antimuscarinic agents (e.g.,
TisdaleC012_211-235 1/12/10 2:36 PM Page 217
EPIDEMIOLOGY
benztropine, diphenhydramine), benzodi-
azepines, or antiserotoninergic agents (cyprohep- Since the initial reports in the late 1950s and early
tadine) is also effective and may be preferable if 1960s, TDk has become one of the most recognized
sedation is desired.52,54-56 However, these agents DIMDs.64-66 In the early 1970s, product labeling for
should be used with caution in elderly patients all antipsychotic drugs was revised to include
with cognitive impairment. Less commonly used information regarding TDk. Although symptoms
agents include amantadine, amitriptyline, cloni- may initially be mild, many patients develop pro-
dine, mianserin, mirtazapine, and mild opioids gressively severe TDk, resulting in meaningful dis-
(e.g., codeine or propoxyphene).57-62 ability. In a study of antipsychotic-naive patients
Treatment of drug-induced tardive akathisia is with first-episode schizophrenia, the incidence of
difficult, as no pharmacologic intervention consis- persistent TDk increased with longer duration of
tently provides benefit. If possible, therapy with treatment.67 The cumulative incidence of TDk was
the suspected agent should be discontinued, or 4.8% after 1 year, 7.2% after 2 years, and 15.6%
modification of therapy from a conventional neu- after 4 years. Increasing antipsychotic drug dose
roleptic to an atypical antipsychotic should be per- was associated with a modestly increased risk of
formed. Antimuscarinic agents and -blockers may TDk, with each 100-mg chlorpromazine equivalent
be considered. However, as compared with their unit increase associated with a 5% increase in the
use in patients with acute akathisia, improvement risk of TDk. In the Hillside Hospital TDk study,
is less likely to occur. young patients (mean age, 29.4 years) were fol-
lowed prospectively for several years.68 The inci-
dence of TDk associated with neuroleptic
treatment was 5.3% per year, similar to the rate in
INFORMATION FOR PATIENTS other prospective studies.12 The authors concluded
that, at the end of 5 years, approximately one in
Before initiating therapy with antipsychotic four patients treated with neuroleptics were at risk
agents, clinicians should inform patients regard- for TDk. It is important to note that peculiar, chor-
ing the potential risk of DIMDs. It is important to eiform orofacial movements were observed in
inform patients about the purpose of antipsychot- patients with schizophrenia before the advent of
ic treatment and the potential risk of movement conventional neuroleptic therapy and that dyski-
disorders, such as akathisia, and to document that nesias may be an intrinsic motor feature of schizo-
this counseling has been performed. Informed phrenia.69 Although spontaneous dyskinesias
consent is recommended by some clinicians, and occur, the data provide strong evidence demon-
should be updated yearly or when there is a strating an increased incidence of TDk associated
change in antipsychotic therapy. The patient’s with neuroleptic drug exposure.
family members or caregivers can play a role in The incidence of TDk associated with neu-
monitoring and reporting any abnormal move- roleptic drug therapy has been extensively studied
ments. Patients and caregivers should be educated and ranges from 0.5% to 70%.70,71 This range
regarding the symptoms of akathisia and the reflects differences in diagnostic criteria, duration
importance of timely reporting, because early of follow-up, sampled population, and study
detection reduces the risk of irreversible abnormal design. Overall, TDk develops in approximately
movements. 20% to 30% of patients treated with conventional
TisdaleC012_211-235 1/12/10 2:36 PM Page 218
ANTIEMETICS/GASTRIC-MOTILITY AGENTS
Metoclopramide23 12–40% B
Prochlorperazine23 NK C
PSYCHOTROPICS
Amoxapine63 NK C
Atypical antipsychotics9-11,13 5–15% A
Conventional neuroleptics12,13 20–30% A
NK = not known.
particularly if TDk is recognized early. However, antimuscarinic agent may be attempted. This con-
complete and long-lasting resolution is uncom- trasts with orofacial TDk, for which addition of an
mon. 120 The most consistent predictor of antimuscarinic agent tends to exacerbate the
improvement after discontinuation of neurolep- movements.
tic therapy is younger age, with an inverse corre-
lation between rates of remission and age.120
Remissions are less likely in patients with severe INFORMATION FOR PATIENTS
TDk and the elderly. In patients on stable neu-
roleptic maintenance therapy, a modification to Before initiating therapy with antipsychotics,
a low or intermittent dose regimen may occa- clinicians should inform patients about the
sionally provide relief, but is associated with a potential risk of TDk. 125 It is important to
risk of relapse and potential exacerbation of inform patients about the purpose of antipsy-
TDk. Modifying therapy to an atypical antipsy- chotic treatment and the potential risk of TDk
chotic often results in significant improvement, and to document that this counseling has been
and is the most appropriate approach if mainte- performed. Some clinicians believe that such
nance antipsychotic treatment is indicated for discussion concerning the risk of TDk should
an underlying psychiatric disorder. Increasing occur after the patient’s acute psychiatric condi-
the neuroleptic dose may suppress the dyskine- tion has been stabilized, and at the time that
sias but, with the advent of atypical antipsy- treatment for longer than 3 months is being
chotics, is considered inappropriate. For mild considered.126 Informed consent is recommend-
cases of drug-induced TDk, therapy with benzo- ed and should be updated yearly or when there
diazepines may be helpful, and may also reduce is a change in antipsychotic medication.127 The
concomitant anxiety. Vitamin E 1,600 IU daily benefits and need for long term treatment with
has also been found to be effective, particularly antipsychotics should be discussed, and patients
in patients with mild TDk for a duration of less should be informed that long term treatment
than 5 years.121,122 Dopamine-depleting drugs, can result in TDk, especially with the conven-
such as reserpine and tetrabenazine, are also tional neuroleptics. Patients should under-
effective. In young patients, tetrabenazine tends stand that movement disorders may also occur
to induce depression, whereas older patients in association with the atypical antipsychotics,
tend to experience parkinsonism. The use of but are much less common. Patients should also
reserpine for TDk is limited by the development understand that early detection of any antipsy-
of depression and dose-related hypotension. chotic movement disorder is important and
Trials of several other agents, including amanta- reduces the risk of irreversible abnormal move-
dine, baclofen, branched-chain amino acids, cal- ments. The patient’s family members or care-
cium-channel blockers (e.g., verapamil), givers can play a role in monitoring and
donepezil, gabapentin, levetiracetam, mela- reporting any abnormal movements.
tonin, methyldopa, ondansetron, pregabalin,
and vitamin B6 (pyridoxine), may be attempted.
For patients with severe and refractory TDk,
deep brain stimulation of the globus pallidus or
DYSTONIA (ACUTE AND TARDIVE)
a pallidotomy may be considered.123,124
Occasionally, discontinuation of DRBA thera- CAUSATIVE AGENTS
py results in emergence of dyskinesia (i.e., with-
drawal dyskinesia), particularly if therapy with Agents implicated in drug-induced dystonia are
the DRBA is withdrawn abruptly. Withdrawal listed in Table 12–12.11,13,36,128-132,134-137
dyskinesias are generally self-limiting within 3
months. In general, reintroduction of the
causative agent followed by a slow taper alleviates EPIDEMIOLOGY
the dyskinesias.
Treatment of rabbit syndrome involves reduc- The reported incidence of drug-induced acute dys-
tion of the neuroleptic dose as much as possible. tonia (DIAD) varies widely, from 2% to 94% of
However, in most cases, complete discontinuation patients treated with conventional neuroleptics.128-
130
of neuroleptic therapy may not be possible because This variance may be attributed to the study
of the risk of relapse or worsening of the underly- method, the study setting (e.g., inpatient or outpa-
ing psychiatric condition. Therapy with an tient), and the characteristics of the study popula-
TisdaleC012_211-235 1/12/10 2:36 PM Page 223
ANTIEMETICS/GASTRIC-MOTILITY AGENTS
Metoclopramide132 1–5% B
Prochlorperazine131 1–5% B
PSYCHOTROPICS
Atypical antipsychotics11,13,36 1–5% A
Conventional neuroleptics13,36,128-130,134-137 1–50% A
subtype of tardive dystonia. Rarely, patients with had acute dystonia as compared with those with
tardive dystonia may experience “status dyston- schizophrenia (5.9%).146 However, subsequent
icus,” a life-threatening condition associated studies failed to find a significant difference
with severe dystonic spasms resulting in rhab- between manic and schizophrenic patients in
domyolysis, myoglobinuria, and kidney failure. the prevalence of DIAD. In a prospective study
In addition to idiopathic dystonia, other con- of 31 patients, neuroleptic-induced dystonia
ditions, such as atlantoaxial rotary subluxation, occurred in 62.5% of the patients with mania
conversion reaction, dopa-responsive dystonia, and 66.7% of the patients with schizophrenia.147
inherited dystonias (e.g., DYT1), Huntington’s In another prospective study of 83 male patients,
disease, and Wilson’s disease must be ruled out neuroleptic-induced acute dystonia was reported
(Table 12–4). Other conditions that cause a twist- in 24% of patients with mania and 15% of
ed neck, such as orthopedic or congenital prob- patients with schizophrenia.148 Manic patients
lems of the neck, ophthalmologic conditions received higher peak doses of neuroleptics dur-
resulting in head tilt to compensate for double ing the risk period for dystonia, and analysis
vision, stiff neck, arthritis, or wry neck should revealed that peak neuroleptic dose and younger
also be considered. age were strongly related to the occurrence of
dystonia.
Risk factors for tardive dystonia overlap with
RISK FACTORS some of the risk factors for DIAD and include
young age, male sex, and the presence of TDk.
Risk factors for the development of acute dysto- Children are at particularly high risk for drug-
nia include young age,136 previous electroconvul- induced tardive dystonia. Duration of therapy is
sive therapy, male sex, mental retardation, and not consistently correlated with the risk of drug-
use of high-potency neuroleptics (Table 12–13). induced tardive dystonia, which may develop
As with other DIMDs, the presence of multiple after a relatively short duration of therapy or after
risk factors exerts an additive effective on risk; for years of treatment. In some cases, drug-induced
example, young men are very susceptible to dys- tardive dystonia may develop following a dose
tonic reactions.133 An inverse relationship exists increase despite a long stable period of treat-
between the incidence of DIAD and age. In con- ment.16
trast to TDk, dystonia is uncommon in older
patients. In one retrospective study, antipsychot-
ic-induced acute dystonia was 15 times more MORBIDITY AND MORTALITY
common in patients under 35 years of age as
compared with patients older than 35 years (31% Although drug-induced dystonia generally does
vs. 2%, respectively).136 The highest risk popula- not affect mortality, except in rare cases of laryn-
tion is young male patients receiving high-poten- geal spasm or status dystonicus, patients are at
cy neuroleptics.145 higher risk for medication nonadherence or refusal
Patients with affective disorders may be at because of the discomfort that accompanies a dys-
greater risk of DIAD. In a study of 181 male tonic reaction. In moderate to severe cases of tar-
patients with mania or schizophrenia treated dive dystonia, task-specific impairment can occur,
with conventional neuroleptics, a significantly the likelihood of which depends on the affected
higher proportion of the manic patients (26.1%) body part. For example, blepharospasm may
impair driving abilities, anterocollis or retrocollis
can interfere with maintaining an appropriate line
of vision that is required for walking and other
sight-directed activities, and jaw-closing dystonia
TABLE 12–13 Risk Factors for Drug-Induced
can damage dentition.
Dystonia
• Affective symptomatology
• High-potency neuroleptics
• History of electroconvulsive therapy
PREVENTION
• Male sex
Approaches to help prevent drug-induced dysto-
• Mental retardation
nia are summarized in Table 12–14. Primary pre-
• Young age
vention aided by knowledge and recognition of
TisdaleC012_211-235 1/12/10 2:36 PM Page 226
administered orally, intramuscularly, or intra- second most common form. DIP is associated
venously. If drug-induced dystonia is life-threat- with up to 15% of all cases of parkinsonism
ening (e.g., stridor due to laryngospasm), worldwide. In one study of elderly patients, 51%
intravenous administration of antimuscarinic of newly referred cases of parkinsonism were
drugs is warranted and supportive measures such believed to be caused by drugs.154 Agents impli-
as tracheostomy may be required. cated in drug-induced parkinsonism are listed in
Benzodiazepines may be administered (to relieve Table 12–16.6,36,155-165 The DRBAs are the most
anxiety) in conjunction with antimuscarinic commonly implicated agents, and are responsi-
therapy. ble for 70% to 80% of DIP cases worldwide.
Symptoms of tardive dystonia also may be Valproate is a common cause of DIP. 159
improved with antimuscarinic therapy. In addi- Valproate-induced parkinsonism is often charac-
tion, atypical antipsychotics (e.g., clozapine, queti- terized by concurrent cognitive and hearing
apine), benzodiazepines, muscle relaxants (e.g., impairments and is underreported because of its
baclofen), and dopamine-depleting drugs, such as insidious onset. The SSRIs are rarely associated
tetrabenazine, are also effective. Less commonly with DIP, although SSRI-induced tremor is com-
used drugs include amantadine, -blockers, benzo- mon.
diazepines, clonidine, dantrolene, levodopa, and
antiepileptics such as levetiracetam, pregabalin,
tiagabine, and zonisamide.
For patients with symptoms of focal dystonia
EPIDEMIOLOGY
(e.g., cervical, mandibular), local injections of bot-
In patients treated with conventional neuroleptics,
ulinum toxin are highly effective and are preferred
the prevalence of DIP ranges from 20% to
because of a low incidence of systemic adverse
66%.6,155,156 The prevalence of parkinsonism associ-
effects. In refractory and severe cases, intrathecal
ated with atypical antipsychotics is much lower. In
baclofen and deep brain stimulation of the globus
one study, the prevalence of parkinsonian rigidity
pallidus or ablative pallidotomy should be consid-
associated with clozapine, risperidone, and con-
ered.124,152,153
ventional neuroleptics was 4.9%, 17.4%, and
35.7%, respectively.36
ANTIEMETICS/GASTRIC-MOTILITY AGENTS
Metoclopramide157 1–5% B
Prochlorperazine158 1–5% B
ANTIEPILEPTICS
Valproate159 5% B
CARDIOVASCULAR DRUGS
Methyldopa160 NK C
Reserpine161 NK C
PSYCHOTROPICS
Amoxapine162 NK C
Atypical antipsychotics36 5–20% A
Conventional neuroleptics6,155,156 20–60% A
VESTIBULAR SEDATIVES
Cinnarizine163,a 30% A
Flunarizine163,a 30% A
MISCELLANEOUS
Tetrabenazine164,165 15% A
NK = not known.
a
Not marketed in the United States.
bradykinesia and rigidity often result in masked older age, dementia, or preexisting parkinsonism),
facies, shuffling gait, slowness of movement, and female sex, and use of central DRBAs (e.g., meto-
difficulty with daily tasks (e.g., walking, dressing, clopramide, phenothiazine, and butyrophenone
eating, grooming, writing). Some investigators antipsychotics) (Table 12–18). Patients with
define classic DIP as characterized by symmetrical acquired immunodeficiency syndrome (AIDS)
distribution of symptoms, the additional presence appear to be very susceptible to DIP. In one study,
of a chin or jaw tremor, and greater postural insta- the likelihood of EPS was 2.4 times higher among
bility (balance problems and falling) upon initial patients with AIDS as compared with patients with
presentation.172,173 Single-photon emission com- psychiatric disorders who did not have AIDS.175
puted tomography using a dopamine transporter
ligand can be used to differentiate DIP from idio-
pathic Parkinson’s disease, as results should be nor-
mal in patients with DIP. In the majority of cases,
MORBIDITY AND MORTALITY
DIP is a subacute process that develops within 3
Discontinuation of therapy with the offending
months of initiating therapy with the causative
agent often results in some improvement of
agent or, in some cases, after a dose increase, and is
parkinsonian features within 2 weeks. However,
reversible upon drug discontinuation. Occasionally,
complete improvement is often not achieved for
the onset may be acute. Generally, DIP remits (over
months or a year. In a subset of patients, features of
a period of several months) following discontinua-
parkinsonism remain indefinitely, despite discon-
tion of therapy. However, some patients may have
tinuation of therapy with the offending agent. Of
persistent DIP. The Simpson–Angus Scale is a 10-
the motor features, tremor typically confers the
item rating scale that has been used widely for
assessment of DIP in both clinical practice and
research settings.174 The scale consists of one item
measuring gait (hypokinesia), six items measuring
rigidity, and three items measuring glabella tap, TABLE 12–18 Risk Factors for Drug-Induced
tremor, and salivation, respectively. Parkinsonism
• Acquired immunodeficiency syndrome
• Advanced age
RISK FACTORS • Dementia
• Female sex
Risk factors for the development of DRBA-induced
• Underlying Parkinson’s disease
parkinsonism include vulnerability to EPS (e.g.,
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CHAPTER 13
Peripheral Neuropathy
EPIDEMIOLOGY
MECHANISMS
The exact incidence of drug-induced peripheral
neuropathy is unknown. Despite few epidemiolog- Peripheral neuropathy is associated with damage
ic data, it seems likely that, although many agents to the peripheral nervous system, namely the dor-
have been implicated, the overall occurrence of sal-root ganglia and dorsal roots. The cell bodies of
drug-induced peripheral neuropathy is low.98 The sensory neurons lie in the dorsal-root ganglia,
incidence varies depending on the agent in ques- which also give rise to the dorsal roots (axons). It is
tion, as well as its duration of use and dose, and postulated that drugs may affect the peripheral
patient-specific factors. The risk of peripheral neu- nervous system selectively because these anatomi-
ropathy is notably high in association with certain cal structures have a somewhat porous
drug classes. Cancer chemotherapeutic agents blood–nerve barrier, thus allowing access of harm-
(platinum derivatives, taxanes, vinca alkaloids) ful toxins.98,104 Others have pointed out that
and antiretroviral drugs (nucleoside reverse-tran- increased access to sensory neurons alone could
scriptase inhibitors) are commonly associated with not explain susceptibility, as autonomic neurons
peripheral neuropathy. The incidence of peripher- also lack a blood–brain barrier but autonomic dys-
al neuropathy has been reported to be as high as function is commonly absent in patients with
85% to 100% in patients receiving higher doses of drug-induced peripheral neuropathy.37
236
TisdaleC013_236-249 1/12/10 2:38 PM Page 237
ANTI-INFECTIVES
Chloramphenicol1,2 NK C
Chloroquine3-5 NK C
Ciprofloxacin6 NK C
Dapsone7,8 NK C
Didanosine9,10 up to 23% B
Ethambutol11,12 NK C
Isoniazid13-15 1-2 % B
Lamivudine16 NK C
Levofloxacin6 NK C
Linezolid17 NK C
Lomefloxacin6 NK C
Mefloquine18 NK C
Metronidazole19-21 NK C
22
Nitrofurantoin NK C
Ofloxacin6 NK C
Podophyllin23 NK C
Stavudine24,25 6–31% A
Trovafloxacin6 NK C
Zalcitabine26-28 >30% A
ANTINEOPLASTICS
Fluorouracil29 1% C
Bortezomib30 30–47% A
Capecitabine31 NK C
Carboplatin32-34 15–85% A
Chlorambucil32 NK C
Cisplatin32,35-37 15–85% A
Cytarabine38 NK C
Docetaxel39,40 50% A
Etoposide41 NK B
Ifosfamide42 NK B
Oxaliplatin43-45 85% A
Paclitaxel46-48 50% A
Procarbazine49 10–20% C
Suramin50 NK C
Thalidomide51-54 50% A
Vincristine55,56 50% A
CARDIOVASCULAR DRUGS
Amiodarone57,58 NK C
Atorvastatin59,60 NK C
(Continued)
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Although mechanisms by which drugs induce also associated with detrimental consequences to
peripheral neuropathy have not been fully eluci- sensory neurons. Nucleoside reverse-transcriptase
dated, the general pathogenesis of drug-induced inhibitors cause peripheral neuropathy by deplet-
peripheral neuropathy involves primarily axonal ing mitochondrial deoxyribonucleic acid (DNA) in
or cell-body degeneration, demyelination, or both. neurons. These agents exert a therapeutic effect on
Axonal degeneration is often associated with the HIV reverse-transcriptase DNA but are also sub-
“dying back” phenomenon, in which the most dis- strates for gamma DNA polymerase, which is
tal portion of the axon degenerates and the myelin responsible for replication of mitochondrial DNA
sheath begins to break down more proximally in neurons.99 Vinca alkaloids destroy cancer cells
toward the cell body.105 by binding with tubulin to prevent microtubular
For some drugs with well-established associa- formation, which disrupts mitosis. Axonal trans-
tions with peripheral neuropathy, several cellular port is dependent on microtubular function.
pathways have been identified using in vitro meth- Dysfunction of axoplasmic transport has been
ods and animal models (Table 13–2).106-109 The demonstrated in animal models.36,110,111 Other
therapeutic mechanism of action of some drugs is drugs can affect important mediators of metabolic
TisdaleC013_236-249 1/12/10 2:38 PM Page 239
Conditions to consider in the differential diag- can cause complications of neuropathy. Therefore,
nosis of drug-induced peripheral neuropathy are this technique is reserved for patients for whom
listed in Table 13–4. A wide variety of systemic dis- the diagnosis of neuropathy cannot be determined
eases, particularly diabetes mellitus, kidney disease, by other means.104,105,119
and thyroid disease may play a role in producing
neuropathy. Therefore, complete blood count,
fasting blood glucose, blood urea nitrogen and cre- RISK FACTORS
atinine, and thyroid-stimulating hormone concen-
trations should be evaluated. Serum vitamin B12 Risk factors for the development of drug-induced
concentrations can also be easily obtained and peripheral neuropathy are listed in Table 13–5. For
should be included in the patient evaluation. A the most part, cumulative drug exposure increases
serum concentration of 100 pg/mL or less with the risk of peripheral neuropathy, and repeated
symptoms is usually indicative of vitamin B12 defi- exposure to an agent that has caused peripheral
ciency. Malignancy has also been associated with neuropathy places patients at a higher risk.
peripheral neuropathy, which is a common pre- However, some data demonstrate that some
senting feature in patients with small-cell lung can- patients can be safely rechallenged with cisplatin.120
cer.104 In these patients, symptoms of sensory For many anticancer drugs, the risk of neurotoxici-
neuropathy often occur rather abruptly, a presenta- ty appears to be related to both the amount of drug
tion that differs from the more common subacute given in each individual dose and the cumulative
presentation of drug-induced peripheral neuropa- dose. Postma et al.121 studied the effect of dose-
thy. Therefore, a routine cancer evaluation includ- dependent neurotoxicity in 227 patients with can-
ing chest radiography and measurement of anti-Hu cer receiving paclitaxel in doses ranging from 135
antibodies should be performed in any patient pre- to 300 mg/m2 every 3 weeks. The incidence of neu-
senting with acute symptoms of neuropathy. ropathy was higher in patients who had received
Cerebrospinal fluid evaluation may be useful in both a higher cumulative dose and a higher dose
screening patients for immune-related causes such per cycle. Similar effects have been noted in
as Guillain–Barré syndrome and chronic inflamma- patients receiving high doses of oxaliplatin, cis-
tory demyelinating polyradiculoneuropathy platin, and vincristine. Therefore, it appears that
(CIDP), as elevated plasma protein concentrations both total drug exposure and dose intensity can
may be found in patients with these illnesses. influence chemotherapy-induced neuropathy.122
Nerve biopsy, which involves removing and exam- Infusion time appears to affect the incidence of
ining nerve tissue, is generally poorly tolerated and peripheral neuropathy associated with some agents.
In patients receiving paclitaxel, doses administered
slowly (over 24 hours) produce less neurotoxicity
than doses administered over 3 hours.123
TABLE 13–4 Conditions to Consider in the Combinations of neurotoxic HIV medications
Differential Diagnosis of Drug-Induced may result in a substantial increase in the risk of
Peripheral Neuropathy
• Immune-related disorders
• Guillain–Barré syndrome TABLE 13–5 Risk Factors for Drug-Induced
• Sjögren’s syndrome Peripheral Neuropathy
• Chronic inflammatory demyelinating polyradicu-
loneuropathy • High drug doses
• Prolonged drug administration
• Infectious diseases
• Human immunodeficiency virus
• Human immunodeficiency virus
• Diabetes mellitus
• Herpes simplex
• Alcohol abuse
• Metabolic/systemic diseases • Hypothyroidism
• Nutritional deficiency • Preexisting neuropathy
• Diabetic neuropathy • Concomitant administration of agents known to
• Hypothyroidism cause neuropathy
• Traumatic injury • Possible genetic predisposition
• Hereditary sensory neuropathies • Impaired hepatic or renal drug metabolism/elimina-
• Idiopathic sensory neuropathy tion
• Paraneoplastic neuropathy • Rapid infusion of some antitumor agents
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CHAPTER 14
Visual Disturbances
IOP = intraocular pressure; NAION = nonarteritic anterior ischemic optic neuropathy; NK = not known; RPE = retinal pigment epitheli-
um.
aAcute myopia may last 24–48 hr. Probably caused by an increase in anteroposterior diameter of the lens, which may be reversible
even if drug use is continued.
b Only 30 reported cases of mydriasis; 1 case of bilateral narrow-angle glaucoma precipitated by use of albuterol.
c Diffuse, white punctate subepithelial corneal opacities have been reported, occasionally associated with superficial punctate kerati-
tis. Onset has been 1-2 weeks after initiation of therapy with doses of 200-400 mg/day. Resolves with drug discontinuation.
d Dose-dependent ocular effect.
e Corneal deposits are dose- and duration-related; resembles chloroquine keratopathy. Deposits are bilateral, reversible, and unassoci-
ated with visual symptoms. Patients taking 100–200 mg/day have only minimal deposits. Deposits occur in ~100% patients receiving
400 mg/day. In addition, anterior subcapsular lens opacities have been reported. Rarely, such opacities may progress, increasing in den-
sity and in the diffuse distribution of the deposits. Because of amiodarone’s photosensitizing properties, it is thought that light expo-
sure may result in lens changes.
f Ocular effects reported with high doses; can induce or exacerbate narrow-angle glaucoma.
gSystemic and transdermal anticholinergic agents may cause mydriasis and, less frequently, cycloplegia. Mydriasis may precipitate
angle-closure glaucoma. Photophobia is related to the mydriasis. Accommodation is decreased for near objects.
h Most significant ocular side effects occur in long-term users or in toxic states. Pupillary responses are variable; miosis occurs most
frequently–except in toxicity, when mydriasis predominates. Nystagmus and weakness in extraocular muscles may be seen. Chronic
abusers exhibit a characteristic ptosis.
i Reported with high doses.
j Primarily blurred vision; transient blindness at peak concentrations has been observed in several patients.
k Ocular adverse effects when dose >1–2 g/day; disappears when dose decreased.
lThese ocular effects are not well established. Evidence of delayed bilateral ocular toxicity in 2 of 50 patients treated with high-dose
intravenous carmustine (800 mg/m2). Symptoms of ocular toxicity became evident 4 wk after intravenous treatment. Evidence of
delayed ocular toxicity (mean onset, 6 wk) ipsilateral to the site of infusion developed in 7 of 10 patients treated with intraarterial
carotid doses of carmustine to a cumulative minimum of 450 mg/m2 in two treatments.
m Optic neuritis occurs more frequently than retrobulbar neuritis. Rare unless a total dose of 100 g and duration >6 wk are exceeded.
Vision usually improves after drug discontinuation.
n Patients using ordinary doses may have white-yellow corneal deposits in as little as 3 wk; little effect on visual function. Serious
retinopathy when total dose >100 g; usually develops after 1–3 years, but can occur in 6 mo. Visual loss may progress from peripheral
to central and be associated with changes in color vision. Blurred vision is rare and usually associated with high doses (500–700
mg/day). Macular changes may progress even after the drug is discontinued.
o Blurred vision occurs rarely (~1% of patients taking 12–14 mg/day). Decreased lacrimation may lead to contact lens intolerance or
aggravate keratoconjunctivitis sicca. Mydriasis is rare, but may precipitate angle-closure glaucoma.
pDeposits rare when total dose <500 g. Visible after a total dose of 1 kg in most cases; incidence may increase to 90% after ≥2.5 kg.
Usually, deposits do not affect vision. The cornea and conjunctiva may be affected after the lens shows pigment changes. Minimal reti-
nal pigment deposits; further documentation is necessary.
q Ocular adverse effects occur in 5–10% of patients. Blurred vision is the most common effect, although visual sensations such as flash-
ing lights, distortion of images, and various colored lights (primarily silver) may occur.
r Dry eyes are rare; reversible upon discontinuation of therapy. Miosis may occur in overdose.
s Posterior subcapsular cataracts have been associated with systemic administration. Risk is increased in patients who have received >15
mg/day of prednisone or its equivalent for periods >1 yr. Bilateral posterior subcapsular cataracts associated with nasal or inhalation of
beclomethasone diproprionate have been reported rarely. Most patients have received therapy for >5 yr, often at higher-than-recom-
mended dosages. About 40% of patients also were receiving systemic corticosteroids. An elevation in IOP is more common with top-
ical corticosteroids than with systemic therapy, but this is of little consequence in patients without preexisting glaucoma. Patients with
glaucoma should be monitored routinely if receiving systemic corticosteroids. Papilledema is primarily associated with long-term ther-
apy, and the incidence appears to be greater in children than in adults. Intracranial hypertension or pseudotumor cerebri associated
with systemic corticosteroids has been well documented.
t Blurred vision is common; onset within 24 hr of receiving high-dose intravenous cyclophosphamide; resolves within 1 hr to 2 wk.
Conjunctivitis is a well-established adverse effect of therapy. Miosis occurs secondary to parasympathomimetic effects. In addition,
cyclophosphamide has been reported to potentiate cataract formation when used in combination with corticosteroids. However, more
information is needed before a causal relationship can be confirmed.
(Continued)
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Ocular adverse effects associated with the and increasing in incidence to 11% and 40% to
antiepileptic medications are not uncommon. 50% in association with the 100-mg and 200-mg
Blurred vision, diplopia, and nystagmus are well- doses, respectively. There are also reports of nonar-
documented adverse effects of carbamazepine and teritic anterior ischemic optic neuropathy (NAION)
phenytoin.109 Downbeat nystagmus has been in patients using selective phosphodiesterase-5
described as a consequence of lamotrigine therapy inhibitors. However, a causal relationship cannot
in two patients. In both cases, plasma lamotrigine yet be confirmed, as other risk factors may have
concentrations were supratherapeutic and the nys- been involved.5,119,121,123
tagmus was reversible upon correction of plasma Other drug classes associated with ocular
concentrations.108 There have also been numerous adverse effects include analgesics, anticoagulants,
case reports linking topiramate with acute, second- antidepressants, antiinfectives, antihyperlipi-
ary bilateral angle-closure glaucoma.140 demics, antineoplastic agents, barbiturates, benzo-
The bisphosphonates have been linked to a diazepines, -adrenergic blockers, calcium-channel
number of ocular inflammatory side effects, blockers, corticosteroids, hypouricemics, immune
including nonspecific conjunctivitis and anterior modulators, and oral contraceptives.1,2 Numerous
uveitis. They are currently the only drugs reported visual disturbances have also been reported in asso-
to cause scleritis.6,7,113 While this is a rare occur- ciation with the use of herbal products and nutri-
rence, scleritis is a serious condition associated tional supplements.3,5,12,41-43,48
with ocular pain and may lead to vision loss.6
Selective phosphodiesterase-5 inhibitors, such as
sildenafil, tadalafil, and vardenafil, are commonly EPIDEMIOLOGY
associated with transient visual disturbances,
namely changes in color perception, blurred The exact incidence of drug-induced visual distur-
vision, and photophobia. These effects are largely bances is not known. Numerous factors including
dose-dependent. Sildenafil appears to carry the the specific medication, frequency of administra-
greatest dose-dependency, with impaired color per- tion, cumulative dose, genetics, and route of
ception observed at the standard 50 mg dose (3%), administration may influence the occurrence of
TisdaleC14_250-274 1/12/10 2:39 PM Page 266
visual disturbances. For example, 5% of the popu- cells, resulting in retinotoxicity. For example, the
lation receiving therapy with topical corticos- antimalarial drugs chloroquine and hydroxychloro-
teroids experience an increase in intraocular quine have high affinity for melanin in RPE and
pressure of 16 mm Hg or greater, while 30% of the may induce photoreceptor degradation, leading to
population experiences an increase of 6 to 15 mm the development of a “bulls-eye” maculopathy.33,154
Hg following 4 weeks or more of treatment.151,152 Amphophilic compounds, such as amiodarone,
Further assessment documented that primary accumulate in lysosomes and cannot be eliminated
open-angle glaucoma developed in 13% of high effectively. This leads to the accumulation of the
corticosteroid responders (defined as >15-mm-Hg drug in intracytoplasmic lamellar bodies in the eye.
increase) and ocular hypertension occurred in The resulting complex with cellular phospholipids
63.8%. Open-angle glaucoma developed in no low- on the epithelium cannot be metabolized by lysoso-
responders (<5-mm-Hg increase) and ocular hyper- mal phospholipids, and corneal deposits occur.
tension occurred in only 2.4%.153 These deposits are dose- and duration-related and
Corneal opacities occur in 70 to 100% of resemble chloroquine-induced keratopathy.32,33,154
patients receiving amiodarone, while optic neu- Amiodarone also causes optic neuropathy, although
ropathy develops in approximately 2%. The anti- the mechanism is less clear. It is thought that a vas-
convulsant lamotrigine causes diplopia and cular occlusion from a decrease in axoplasmic flow
blurred vision with incidences of 22% and 15%, may be involved. This may result in optic disk edema
respectively.1 Agents used for erectile dysfunction that progresses to optic neuropathy.30,32
(sildenafil, vardenafil, tadalafil) are associated with Amiodarone-induced optic neuropathy is sometimes
dose-dependent changes in color vision, blurred difficult to distinguish from NAION, since patients
vision, increased light perception, and visualiza- may already have underlying vascular disease.5
tion of flashing lights in 3% to 50% of patients.1 The mechanism of ethambutol-induced optic
High-dose cytarabine has been associated with neuropathy remains incompletely understood. It is
blurred vision and keratitis in 100% of treated postulated that ethambutol chelates retinal-cell
patients. Decreased visual acuity, diplopia, and copper, which acts as a cofactor for mitochondrial
color vision defects have been reported with nons- functioning in the optic nerve. As a result, axonal
teroidal antiinflammatory drugs even in patients transport in the optic nerve may be compromised,
taking small doses infrequently.1 The known inci- leading to optic neuropathy. These effects appear
dences of visual disturbances associated with spe- to be dose- and time-dependent.12
cific drugs are provided in Table 14–1. An increase in intraocular pressure, caused by
certain medications such as corticosteroids, can
exacerbate open-angle glaucoma. Mydriatics and
MECHANISMS mydriatic/cycloplegics could exacerbate angle-clo-
sure glaucoma, because this is an anatomical event.
The pathogenesis of drug-induced visual distur- Drugs that cause mydriasis also have the potential
bances appears to be multifactorial. Cumulative or to exacerbate angle-closure glaucoma. Secretion of
daily dose, duration of therapy, properties of spe- medications through the lacrimal gland can lead to
cific medications, and site of drug action all appear blurred vision, eye and contact-lens discomfort,
to play a role. While we are knowledgeable about dry eye symptoms, and conjunctivitis.
mechanisms of visual disturbances associated with Drug-induced ocular effects are time-depend-
some drugs, mechanisms have yet to be described ent, suggesting that tissue accumulation likely plays
for the majority of medications. Known mecha- a role in the pathophysiology.32 Visual disturbances
nisms can be divided into direct and indirect drug can also result from the indirect actions of certain
effects on the ocular structures (Table 14–2). medications on nonocular structures. Blurred
The blood aqueous barrier and posterior vision is a common side effect of anticholinergic
blood–retinal barrier serve to naturally defend the medications and benzodiazepines. Phenytoin may
intraocular structures of the eye from exogenous cause cerebellar degeneration and eventually lead
compounds or toxins. However, some compounds to irreversible cerebellar deficits. Vision changes
may penetrate the tight junctional areas between may be an indication of toxic plasma drug concen-
retinal pigment epithelium (RPE) cells and within trations.1 Drugs that lead to hypertension, metabol-
the retinal capillary endothelium. Over time, this ic abnormalities, sedation, or dehydration may also
can lead to a number of ocular problems, such as lead to visual problems. Nystagmus induced by car-
epithelial keratopathy or pigmentary deposition. bamazepine and phenytoin may be due to cere-
Medications may also interact directly with RPE bellovestibular dysfunction.49
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Effect Mechanisms
Periorbital edema Allergic reaction. With imatinib, it is presumed that inhibition of platelet-derived
growth factor in dermal dendrocytes of the perior-bital skin may result in a
decrease in interstitial fluid pressure, which may lead to localized edema.
Ptosis Cranial nerve palsy, which may lead to dysfunction in one or both upper eyelid
elevator muscles
Retrobulbar neuritis Drug chelates retinal-cell copper, which acts as a cofactor for mitochondrial
functioning in the optic nerve. Consequentially, axonal transport in the optic
nerve may be compromised and progress to optic neuropathy.
Superficial punctate keratitis Unknown
TABLE 14–3 Signs and Symptoms Associated TABLE 14–4 Conditions to Consider in the
with Drug-Induced Visual Disturbances155 Differential Diagnosis of Drug-Induced Visual
Disturbances30,33,155
• Blepharitis
• Blindness • scular accident
• Blurred vision • Concussion
• Cataracts • Dehydration
• Color vision alterations • Encephalopathy
• Conjunctivitis • Exposure to environmental toxins
• Decreased vision (miosis, mydriasis) • Drug intoxication
• Diplopia • Glaucoma
• Glaucoma • Head trauma
• Halos around lights • Hypertension
• Hallucinations • Intracranial lesions/infarction
• Hazy vision • Macular degeneration
• Increased intraocular pressure • Medication history
• Keratopathy • Migraine
• Night blindness • Metabolic disorders
• Optic neuropathy • Neoplasm
• Photophobia • Psychiatric disease
• Pseudotumor cerebri • Retinal disease /detachment
• Scleritis • Seizures
• Tunnel vision • Trauma
• Vertigo • Vitreous detachment
• Visual field constriction
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CHAPTER 15
Delirium
ANTIPSYCHOTICS
Clozapine7 10% B
Fluphenazine13 NK C
Haloperidol12 NK C
Loxapine16 NK C
Olanzapine11 NK C
Perphenazine14 NK C
Quetiapine9 NK C
Risperidone10 NK C
Thioridazine15 NK C
Ziprasidone8 NK C
OPIOIDS27
Fentanyl18,19 OR, 1.5, 95% CI 0.6– 4.2 B
Meperidine19 RR, 2.4; 95% CI 1.3– 4.5 B
17,19
Morphine OR, 1.2; 95% CI, 0.6–2.4 B
CORTICOSTEROIDS
Prednisone20,21,27 NK C
ANTIARRHYTHMICS
Amiodarone25 NK C
Lidocaine23 NK C
Quinidine26 NK C
Tocainide24 NK C
ANTIASTHMATICS
Theophylline NK C
ANTICONVULSANTS
Phenytoin28 NK C
Acetazolamide29 NK C
Lamotrigine30 NK C
Pregabalin31 NK C
Tiagabine32 NK C
Valproic acid33,57 4.1/100 person-years B
ANTIDEPRESSANTS
Protriptyline34 NK C
Desipramine35,36 NK B
Clomipramine37 NK C
Amitriptyline38 NK C
Imipramine39 NK C
Lithium57 2.8/100 person-years B
(Continued)
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appears to be the final common pathway involved cantly larger number of anticholinergic medica-
in delirium.100 This is consistent with the acetyl- tions than the control group with dementia. It is
choline hypothesis of cognitive impairment in unlikely that acetylcholine is the sole neurotrans-
dementias such as Alzheimer’s disease. An age- mitter involved in the development of delirium,
related decrease in acetylcholine reserve develops given its interaction with dopamine transmis-
in elderly patients, making them more vulner- sion.101 Dopamine exerts an inhibitory effect on
able to acute changes in plasma acetylcholine con- the release of acetylcholine.
centrations. Further support for this theory is the Glucocorticoid excess also has been implicated
relationship between the administration of anti- in the development of delirium.102 Preclinical and
cholinergic drugs and cognitive deficits, particular- clinical data support the hypothesis that increases
ly reduction in the ability to focus or maintain in plasma glucocorticoid concentrations associated
attention and short-term memory deficits. Tune with various disorders, including depression,
and Egeli100 studied 91 patients meeting criteria for dementia, and Cushing’s disease, lead to cognitive
delirium (n = 47) or dementia (n = 41) and found impairment. Even modest increases in plasma glu-
that patients with delirium were taking a signifi- cocorticoid concentrations over a period of 5 to 6
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 280
to the potential for delirium, which may occur in extended period of time with continuous drug use,
association with drug or alcohol withdrawal.2,105 In or during drug or alcohol withdrawal. Delirium
the majority of cases, a multitude of causes exists, during acute intoxication presents within minutes
including drugs, and all possibilities must be to hours after ingestion of the substance (e.g.,
explored. cocaine, hallucinogens).111 The potential for
The diagnosis of drug-induced delirium is pure- delirium is increased if additional agents with
ly clinical, as there are no laboratory tests that can anticholinergic activity also are ingested. Drug-
definitively diagnose the disorder. Along with the induced delirium also may develop secondary to
medical history and clinical observation, the use of the accumulation of a drug or its metabolite over
rating scales may assist in confirming the diagno- an extended period (e.g., barbiturates, alcohol)
sis. A simple screening tool for delirium, the or as a result of a combination of a suspect medi-
Confusion Assessment Method,106 can be complet- cation and a preexisting medical condition.1,112
ed by clinicians in just a few minutes and has been Withdrawal delirium may last a few hours to sever-
adapted to other settings, such as the ICU.107 The al weeks, depending on the half-life of the
Mini–Mental State Examination (MMSE) may also causative agent. This type of delirium results from
be used to screen patients for delirium. Other lower tissue and body fluid concentrations than
scales, such as the Delirium Rating scale108 and the those to which the body has become accustomed.
Memorial Delirium Assessment Scale,109 are used to Withdrawal delirium may also be precipitated by a
monitor symptoms over time. Differentiating delir- drug interaction, lowering the dose of a medica-
ium from other disorders may be difficult as symp- tion, or increased drug clearance.113
toms may overlap considerably. Delirium is also Most underlying causes of delirium often can
frequently underdiagnosed. Studies report that be easily ruled out. However, the diagnosis of
delirium occurring in patients on general medical dementia is often confused with that of deliri-
units is not diagnosed in 32% to 67% of cases.110 It um.1,5,112 Although memory impairment is com-
may also be difficult to distinguish drug-induced mon to both delirium and dementia, delirium is
delirium from delirium occurring as a result of associated with impairment in consciousness dur-
other causes. Conditions to consider in the differ- ing which patients are not alert or oriented to time
ential diagnosis of drug-induced delirium are listed or place. In addition, symptoms that develop rap-
in Table 15–4. idly and fluctuate throughout the day are more
Patients with drug-induced delirium usually consistent with delirium than dementia.
have symptoms during intoxication, over an Differentiation between the two disorders is impor-
tant and may require a more complete history
from family or caregivers (Table 15–5).114
A number of medical conditions are recognized Cancer increases the risk of delirium, possibly
as potential risk factors for delirium and may pos- because of associated hepatic or renal failure, prer-
sibly increase the risk of drug-induced delirium. A enal azotemia, hyperosmolality, dehydration, med-
diagnosis of dementia or cognitive impairment has ications (e.g., opioids), hypoxia, disseminated
been identified as a risk factor for delirium.5,115 intravascular coagulation, recent surgery, metasta-
Disorders that affect neuronal functioning may sis to the brain or other areas of the central nerv-
cause delirium, including cerebral infarction, ous system, and infection.119,120 In addition,
seizures, head trauma, vascular disease, Parkinson’s patients undergoing treatment for cancer are often
disease, and dementia.2,5,115 Various metabolic receiving therapy with complex medication regi-
abnormalities may contribute to the development mens associated with drug interactions that
of delirium, including electrolyte disturbances, kid- increase the potential for delirium.
ney disease, hepatic insufficiency, edema from The increased risk of delirium in postoperative
heart failure, thiamine deficiency, and acid–base patients appears to be linked to common occur-
imbalance.2,111 Conditions that lead to a change in rences such as infection, hypoxia, myocardial
the delivery of oxygen or nutrients to the central ischemia, metabolic derangement, decreased
nervous system—myocardial infarction, cardiac mobility, and exposure to anticholinergic
arrhythmias, heart failure, respiratory failure, drugs.113,121 The increased risk in this population
chronic obstructive pulmonary disease, anemia, does not correlate with the number of previous sur-
hypoxia, or shock—also may predispose patients to geries, the duration of the surgical procedure, the
delirium. Patients with a history of alcohol abuse, type of anesthesia used, or the surgical technique
hypertension, and higher Acute Physiology and used.
Chronic Health Evaluation (also known as Conditions of deprivation, including both
APACHE) II scores have been identified as being at sleep and sensory deprivation (hearing loss, visual
an increased risk for delirium.116 impairment, immobility) such as that which
Infection and fever also are risk factors for occurs in an ICU have been found to be risk factors
delirium. Hyperthermia causes a central release of for delirium.122 An interventional study of patients
norepinephrine, glutamate, and dopamine, which with deprivation as a risk factor for delirium found
may predispose the patient to a delirious that nonpharmacologic interventions such as pro-
episode.111 Patients with the human immunodefi- viding a relaxing nighttime environment, hearing
ciency virus infection may have delirium caused by aids, glasses or magnifying glasses, large-print
viral infection of neuronal tissue, opportunistic materials, other forms of communication, and
infection of the central nervous system, or meta- exercise all may lower the incidence of delirium.122
bolic encephalopathy.117,118 Antibiotics, antivirals, Advanced age is considered to be a risk factor
or antifungals may be involved in drug interac- for delirium, because elderly patients are more like-
tions contributing to the potential for delirium. ly to have multiple predisposing risk fac-
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 283
accounts for an estimated $38 billion to $152 bil- The incidence of delirium was not different in the
lion in annual health care expenditures.134 Mean haloperidol (15.1%) or placebo-treated groups
(±SD) daily costs were 2.5 times higher in delirium (16.5%); (RR, 0.91; 95% CI, 0.59–1.44). Delirium in
survivors as compared with those in whom deliri- haloperidol-treated patients was less severe, of
um did not develop ($461±$570 vs. $166±$570; shorter duration, and associated with a shorter
P<0.001). Prolonged hospital stays account for a duration of hospital stay as compared with those in
portion of these costs, but expenses are compound- the placebo group.
ed by the need for rehabilitation, long-term care, Nursing staff on an orthopedic unit were edu-
and home health care.122,134 cated regarding the appropriate use of pharmaco-
logic and nonpharmacologic interventions to
prevent and treat delirium.137 Suggestions regard-
PREVENTION ing medication use included avoiding or minimiz-
ing the routine use of anticholinergics to prevent
There are few studies of the primary prevention of or treat nausea, prescribing morphine in the lowest
drug-induced delirium.122,135 However, methods of doses for the shortest possible duration after sur-
prevention of delirium in general may also be gery, and using antipsychotic agents for manage-
effective for prevention of drug-induced delirium ment of psychotic symptoms of delirium.
(Table 15–7). A prospective, controlled trial was Medication use was evaluated in the 6 months
conducted in which standardized protocols were before and after the education session. There was a
implemented for managing specific risk factors for significant decrease in the use of anticholinergic
delirium, such as cognitive impairment, sleep dep- medications, but the use of opiates and antipsy-
rivation, immobility, visual and hearing impair- chotics did not change significantly. Data regard-
ments, and dehydration in a group of hospitalized ing the rates of delirium were incomplete. Effective
patients.122 Risk-factor management in the treat- treatment of pain with opiates led to a decreased
ment group reduced the incidence of delirium as risk of delirium (OR, 0.4; 95% CI, 0.2–0.7).95
compared with that in the control (usual-care) Since delirium is likely the result of multiple
group (9.9% vs. 15%; P = 0.02). Risk-factor manage- issues, including drugs, management of nondrug
ment was also associated with significantly fewer risk factors is important for the prevention of drug-
days of delirium and a smaller number of delirium induced delirium. Anticholinergic, hypnotic/seda-
episodes. Those in the risk-factor management tive, and opioid medications should be avoided
group who were most adherent to the prevention whenever possible in elderly patients.6 A careful
protocol carried a significantly lower risk of deliri- medication history should be obtained from
um (adjusted OR, 0.69; 95% CI, 0.56–0.87).135 patients at risk and periodic reviews of all drug
These techniques for the prevention of delirium therapy should be performed. All elderly patients
may also be applied to those at risk for drug- who present with an acute illness should be
induced delirium. screened for the presence of drug-induced deliri-
Prophylactic low-dose haloperidol (1.5 um.
mg/day) has been studied in elderly patients
undergoing hip surgery who were at risk for deliri-
um.136 Haloperidol therapy was initiated on admis- MANAGEMENT
sion and continued for up to 3 days after surgery.
Principles of management of drug-induced delirium
are presented in Table 15–8. Management of drug-
induced delirium requires that clinicians recognize
TABLE 15–7 Approaches to Help Prevent Drug- the presence of delirium and consider that it may
Induced Delirium be caused by drugs.5,6 This can be extremely diffi-
cult, particularly in intubated patients in the ICU or
• Avoid anticholinergic, sedative/hypnotic, and opioid
in those with underlying dementia.138,139 The most
medications in the elderly.
critical step in the diagnosis is a careful medication
• Obtain a careful medication history and perform
history. The clinician must carefully consider any
periodic reviews of all drug therapy.
new medications that the patient is taking and the
• Perform a brief mental status exam on acutely ill
time to onset of signs and symptoms. Other steps in
patients at admission to assist in the detection of
diagnosis include a physical exam and a toxicology
drug-induced delirium.
screen, which may help in identifying the drug(s)
• Avoid medications known to cause drug-induced
involved. Determination of serum concentrations
delirium.
of suspected drugs may be helpful, although some
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 285
Lorazepam can be administered orally, intramuscu- venously (IV).140 Doses vary greatly, from as low as
larly, or intravenously in doses ranging from 0.5 to 0.25 mg intramuscularly or as high as 10 mg in a
2 mg.143 This dose also can be repeated or doubled single IV dose. A continuous IV infusion of
every 30 to 60 minutes, depending on the patient’s haloperidol may be administered at rates ranging
degree of agitation and sedation. Diazepam is rec- from 2 to 10 mg per hour.148 Intravenous adminis-
ommended as an alternative to physostigmine in tration of haloperidol has been shown to produce
patients with anticholinergic toxicity because of its a lower incidence of extrapyramidal adverse
longer duration of action and more favorable effects, presumably due to lower concentrations of
adverse effect profile.6 Haloperidol and phenoth- the pyridium metabolite. However, intravenous
iazines should be avoided in this situation. haloperidol is associated with a risk of prolonga-
When benzodiazepines are administered par- tion of the corrected QT (QTc) interval and, in
enterally, they may cause respiratory depression some cases, torsades de pointes.140,149 Patients
and arrhythmias, and therefore cardiopulmonary receiving treatment with IV haloperidol should
function must be monitored.140 There also is the undergo baseline electrocardiography to determine
potential for the occurrence of a paradoxical reac- the QTc interval. Prolongation of the QTc interval
tion, in which the patient becomes more agitated to longer than 0.45 second or more than 25%
with continued benzodiazepine administration. above baseline is cause for concern, and the rela-
Paradoxical reactions tend to occur more often in tive risks and benefits of continued therapy must
the elderly, in those with liver dysfunction, and in be carefully considered.
patients with low plasma albumin concentrations. The use of high-dose haloperidol for the treat-
Caution should be exercised when using benzodi- ment of delirium is not without controversy.
azepines as they may worsen delirium and cause Dopamine-D2 receptor blockade in the mesolimbic
excessive sedation in some patients.144 region is believed to be the main mechanism of
In a small case series study, melatonin 2 mg action; a threshold of 60% of D2 receptor blockade
was administered to two postoperative patients for is necessary for antipsychotic effects. Some argue
3 to 4 nights. One patient received melatonin for that very high doses of haloperidol are unlikely to
the prevention of delirium and the other for the be more effective than lower doses, since 53% to
treatment of delirium. In both cases, melatonin 85% of D2 receptors are occupied by haloperidol at
effectively reduced the severity of delirium symp- doses of 2 to 20 mg/day.150 Therefore, large doses
toms or prevented delirium. No adverse events should offer no additional benefit, with the poten-
were reported.145 tial for a higher incidence of adverse effects. In fact,
Haloperidol is the most widely used antipsy- there are numerous reports of extrapyramidal
chotic medication for the symptomatic manage- symptoms (EPS), including pseudoparkinsonism,
ment of delirium, despite few prospective studies of acute or tardive dystonia, dyskinesias, and
its effectiveness for agitation and hallucinations in akathisia associated with high-dose IV haloperidol
this setting. Haloperidol offers several advantages or withdrawal from haloperidol therapy.151,152
over the low-potency antipsychotics, including a Worsening symptoms may be the result of EPS,
relative absence of anticholinergic activity, ␣-adren- especially akathisia, which often goes unrecog-
ergic blockade, and sedation.6,141 In nonelderly nized and is sometimes inappropriately managed
patients, haloperidol oral doses of 2 mg may be by increasing haloperidol doses.
given for mild agitation, 5 mg for moderate agita- Some clinicians prefer to use droperidol in the
tion, and 10 mg for severe agitation.146 In elderly critical care setting, as it is a more potent, fast-act-
patients, recommended haloperidol doses are 0.5 ing antipsychotic that is more sedating than
mg for mild agitation, 1 mg for moderate agitation, haloperidol and is reportedly associated with a
and 2 mg for severe agitation.147 Response may lower incidence of extrapyramidal effects.153 Bolus
occur in 10 to 30 minutes. The dose may be repeat- IV injections of droperidol have been associated
ed every 30 to 60 minutes until the patient is sedat- with hypotension, tachycardia, and torsades de
ed or calm. In some cases, the dose may be doubled pointes.153 Baseline QTc-interval assessment and
until the agitation is controlled. Haloperidol thera- cardiac monitoring are necessary when administer-
py can be continued on a tapering schedule for 3 to ing high doses of droperidol, since prolongation of
5 days.146 The goal is to use the lowest possible the QTc interval can occur. This drug should be
haloperidol dose for the shortest possible duration. reserved for use only in the ICU setting, where
In cases in which agitation is severe, the patients are closely monitored and resuscitation
patient is at serious risk of self-injury or is unable equipment is immediately available.
or unwilling to take medications orally, haloperi- Newer antipsychotic agents including aripipra-
dol may be administered intramuscularly or intra- zole, olanzapine, quetiapine, risperidone, and
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 287
ziprasidone have been reported to be effective for EPS. In another study, the efficacy of therapy with
the management of delirium. The use of aripipra- quetiapine at doses of 25 to 100 mg daily for 7 days
zole for the management of delirium was reported was assessed in 22 patients with delirium.165 The
in a small case series of two patients.154 One DRS and Clinical Global Improvement (CGI) scores
patient’s MMSE score improved from 5 to 28, while on days 2 to 7 were significantly lower than those
his Delirium Rating Scale (DRS) score decreased on day 0. Mild tremor developed in 2 patients
from 28 to 6. The second patient’s MMSE score (9.1%).
improved from 7 to 27, while her DRS score Risperidone at mean doses of 0.75 to 1.7 mg
decreased from 18 to 6. In another series of 14 daily has been reported to be effective for the man-
patients with delirium treated with aripiprazole, 12 agement of delirium.166,167 In an unblinded study, 64
had a reduction of greater than 50 percent in the medically ill hospitalized patients with delirium
DRS score and 13 showed improvement on the received oral risperidone in daily doses of 1.85 to
Clinical Global Impressions scale scores.155 There 2.97 mg (mean daily dose, 2.6±3.3 mg).168
was a low incidence of adverse effects. Olanzapine Risperidone was effective in 58 of 64 patients and
has been reported to be effective for delirium in significantly improved all symptoms measured by
several clinical trials. One study enrolled medically DRS, Positive and Negative Symptom Scale, MMSE,
ill patients whose mean age was 46 years.156 The and CGI during a period of 7 days. The comparative
mean maximum dose of olanzapine was 8.8 mg per efficacy of risperidone and haloperidol for treatment
day, and the mean time to response was 3.8 days. of delirium was assessed in a prospective, random-
In another study, patients with cancer (mean age, ized, double-blind study of acutely ill inpatients.169
61 years) were enrolled.157 The mean maximum The Memorial Delirium Assessment Scale improved
dose was only 6.3 mg per day. Approximately 76% significantly in both groups at 7 days, and there was
of patients responded within 4 to 7 days. However, no significant difference in efficacy between the
patients older than 70 years had a lower response groups. In another study, the relationship between
rate (42%). Sipahimalania and Masand conducted response and genetic polymorphisms in the
a retrospective medical record review of 22 mixed dopamine transporter was studied in 42 patients
medical–surgical patients.158 Five of 11 patients receiving either haloperidol or risperidone for the
treated with olanzapine (mean dose, 8.2 mg daily) management of delirium.170 There was no difference
showed a significant improvement in their DRS in efficacy between the groups. Interestingly,
score as compared with 6 of 11 patients in the dopamine transporter polymorphisms did not play
haloperidol group. In a prospective, randomized, a significant role in the effects of the antipsychotics.
single-blind study, the efficacy of therapy with In a randomized, double-blind study of 126 patients
olanzapine (n = 28) was compared with that of undergoing cardiac surgery with cardiopulmonary
haloperidol (n = 45) in a mixed group of critically bypass,171 patients were randomly assigned to
ill medical–surgical patients.159 Delirium index receive risperidone 1 mg or placebo sublingually.
scores improved similarly in both groups and the The incidence of postoperative delirium was signifi-
need for rescue therapy did not differ between cantly lower in the risperidone group. Miyaji et al.
groups. Six patients receiving haloperidol experi- compared the adverse effects of risperidone with
enced mild EPS, as compared with no patients in those of haloperidol in a retrospective study of 266
the olanzapine group. Japanese inpatients treated for delirium. The inci-
Several case reports indicate that quetiapine dence of adverse effects was significantly lower in
may be a reasonable choice for the management of risperidone-treated patients.172 Ziprasidone has also
delirium.160-162 Sasaki et al. reported the effect of been used for the treatment of delirium.173,174 This
quetiapine therapy in 12 patients with delirium of drug is associated with a low risk of sedation and
multiple causes.163 Patients were treated for a mean EPS. However, in a case report of the use of ziprasi-
(±SD) of 4.8±3.5 days with a flexible dose of queti- done for delirium, the drug was effective, but the
apine (mean maximum dose, 63.5 mg per day). patient exhibited QTc-interval prolongation requir-
Delirium rating scale scores improved significantly, ing drug discontinuation.173
and no patient experienced significant adverse Overall, haloperidol and atypical antipsy-
events. In a retrospective review of the medical chotics appear to be equally efficacious for the
records of 22 mixed medical–surgical patients, que- treatment of delirium in acutely ill hospitalized
tiapine (median dose, 211 mg daily) was as effec- patients.175,176 However, this statement must be
tive as haloperidol in increasing DRS score by more tempered by the fact that placebo-controlled, ran-
than 50% from baseline.164 One patient receiving domized trials supporting the efficacy of these
quetiapine experienced mild to moderate sedation, agents for the treatment of delirium are lacking. In
and two patients receiving haloperidol developed addition, all antipsychotic agents include a boxed
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 288
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151. Riker RR, Fraser GL, Richen P. Movement disorders 173. Leso L, Schwartz T. Ziprasidone treatment of delirium.
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treatment of delirium in the intensive care unit. antipsychotics for the treatment of delirious elders. J Am
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Accessed August 20, 2009.
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CHAPTER 16
Sleep Disorders
Lisa L. Forsyth
293
TisdaleC16_293-300 1/12/10 2:41 PM Page 294
hours. Third, effects of withdrawal of therapy with affect sleep, and these must be considered when eval-
a drug may produce a sleep disturbance. uating a patient for a possible drug-induced sleep dis-
order.63,66,67 Polysomnography (PSG) is an assessment
of electrophysiologic parameters during sleep that
CLINICAL PRESENTATION AND incorporates an electroencephalogram, electro-ocu-
DIFFERENTIAL DIAGNOSIS logram, and electromyelogram.63 Other measures of
sleep include sleep latency (time to fall asleep), REM
The prevalence of sleep disturbance, specifically latency (time to first REM sleep), number of awaken-
insomnia, is much greater in women and in elderly ings, and the number of stage shifts during sleep.68
patients.64,65 Patients suffering from sleep distur- The effects of drugs on sleep are often identified
bance often report an inability to fall asleep, to stay and characterized based on subjective data, PSG
asleep, or both, or of not feeling rested after having measures, objective evidence of sleepiness and alert-
time to sleep.62 Often these conditions are followed ness from a Multiple Sleep Latency Test, and/or by
by daytime sleepiness and an inability to concen- objective performance data. Evidence of disturbance
trate. The common signs and symptoms of sleep dis- during sleep on the PSG does not always correlate
orders are listed in Table 16–3. A number of medical with patients’ subjective symptoms.62,63 Venlafaxine
and psychiatric conditions (Table 16–4) are known to and bupropion have been reported to induce insom-
nia in as little as 4 days and 4 weeks, respectively.16,55
The time of onset of insomnia associated with the
TABLE 16–3 Signs and Symptoms Associated other agents listed in Table 16–1 is highly variable.
with Drug-Induced Sleep Disorders55,56,66 Patient assessment should start with a medica-
tion history and physical examination. Further
• Inability to fall asleep
psychiatric assessment should be undertaken if
• Inability to maintain sleep
indicated. When a drug-induced sleep disorder is
• Not feeling rested following adequate sleep duration
suspected, patients should be questioned specifi-
• Excessive daytime sleepiness
cally regarding the use of medications known to
• Poor cognitive performance
affect neurotransmitters, the frequency and timing
• Lack of concentration
of drug administration, and any recent discontinu-
TisdaleC16_293-300 1/12/10 2:41 PM Page 296
with difficulty falling asleep or with excessive day- drug therapy and to ensure the resolution of
time sleepiness may benefit from therapy with a symptoms.
short-acting benzodiazepine such as triazolam or
with a hypnotic drug such as zolpidem or zale-
plon.56,84-86 Patients who are unable to maintain INFORMATION FOR PATIENTS
sleep or have trouble awakening may benefit from
an intermediate-acting benzodiazepine such as Patients who are prescribed medications that are
estazolam or temazepam. The long-acting benzodi- known to cause sleep disorders should be instruct-
azepines (flurazepam and quazepam) may be help- ed to contact their health care provider if they
ful when there is daytime anxiety in addition to a experience difficulty falling asleep, do not feel rest-
sleep disturbance. There is no rationale, however, ed after having adequate time to sleep, or are exces-
for the combined use of two benzodiazepines for sively tired during the day. Patients should be
the treatment of insomnia and anxiety. In every advised to consult with their physician or pharma-
case, the lowest effective drug dose should be given cist before beginning treatment with any nonpre-
for the shortest possible period of time. Tolerance scription medication to avoid interactions that
can develop in as little as 2 weeks with continual could precipitate sleep disturbances. Finally,
use of some benzodiazepines.56 One strategy used patients should be warned not to change the dose
to help prevent tolerance involves the administra- or administration times of prescribed medications
tion of benzodiazepines for 3 to 4 days per week without consulting their physician or pharmacist.
rather than daily.
When long-term treatment of insomnia is
required, antidepressants are among potential References
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Cognitive Disorders
Michele Y. Splinter
301
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tex and thalamus. Memory loss in patients with nisone.46,47 It has been hypothesized that dexam-
Alzheimer’s disease or Parkinson’s disease with ethasone may be more neurotoxic than pred-
prominent dementia has been associated with a nisone because of a lesser degree of plasma
significant decline of cortical cholinergic innerva- protein binding and because of the presence of a
tion due to cell loss in the nucleus basalis.38 High- fluoride atom in its chemical structure.46 Altered
frequency oscillations that unite information brain membrane lipid content and synaptic
related to different aspects of a perceived object transmission in hippocampal neurons have been
from widely distributed cortical neurons appear associated with fluoride anions.46
to emanate from the thalamus.33 The action of Acute changes in mental status can occur
acetylcholine in the cortex and thalamus and the with the use of selective serotonin reuptake
interactions between the neurotransmitters inhibitors, because of hyponatremia secondary to
acetylcholine, gamma-aminobutyric acid (GABA), the syndrome of inappropriate antidiuretic hor-
and glutamate appear to be central to the mainte- mone (ADH) secretion.26,48,49 This syndrome may
nance of conscious awareness. Rebound insomnia also be caused by other medications, including
and anxiety have been reported in association carbamazepine, tricyclic antidepressants,
with benzodiazepine and barbiturate withdrawal, monoamine oxidase inhibitors, and neurolep-
and hallucinations and delirium have been asso- tics.49 These classes of medications may facilitate
ciated with barbiturate withdrawal.39 Down-regu- the secretion of ADH or increase renal respon-
lation of high-affinity GABA receptors occurs siveness to ADH.49
during benzodiazepine and barbiturate therapy, A decline in cognitive function has been found
and the withdrawal syndrome probably reflects a to be significant in studies of some cancers, partic-
state of GABA underactivity in conjunction with ularly breast cancer.1 It has been hypothesized that
a surge in output of excitatory neurotransmitters two distinct pathways are involved: psychological
normally inhibited by GABA. There also appears and social factors associated with the diagnosis of
to be a noradrenergic mechanism contributing to cancer and a physiologic effect of cancer treat-
consciousness, because 2-receptor antagonists ment, especially with medications that cross the
and variations in norepinephrine concentration blood–brain barrier. Other confounders include
alter anesthetic dose requirements.33 In addition, dose intensity, duration of treatment, concomitant
2-receptor agonists increase the depth of anes- medications, radiation therapy and other toxicities
thesia. of the treatment, including anemia, vascular injury
Antiepileptic medications diminish neuronal and neurotoxicity.
irritability, and therefore may inhibit neuronal Specific mechanisms of cognitive disorders
excitability and impair cognitive function.27,40 associated with several classes of medications are
High serum concentrations of valproate have been summarized in Table 17–2.25,27,37,39,40,42,43,45,48-54
shown to affect both function and morphology of
the brain.41 Hypothesized mechanisms include an
interference with pituitary adrenal function, CLINICAL PRESENTATION AND
hyperammonemia, or changes in blood–brain bar- DIFFERENTIAL DIAGNOSIS
rier permeability. Histologic examination of brains
of rats aged 3 to 30 days who had received pheny- The clinical presentation of patients with drug-
toin, phenobarbital, valproate, vigabatrin, induced cognitive disorders is diverse and may
diazepam, and clonazepam revealed apoptotic neu- involve acute or chronic changes in states of wake-
rodegeneration.42,43 fulness, attention, or memory.55 Anticholinergic
The hippocampus, which is critical for the drugs have been associated with memory impair-
formation of new memories, possesses the high- ment, confusion, hallucinations, sedation, and
est concentration of corticosteroid-binding sites dysphoria.15 The most common cognitive effects
in the brain.44 Glucocorticoids inhibit glucose associated with anticonvulsants are psychomotor
transport into cells by 25% to 30%, thereby accel- slowing, reduced vigilance, and impairment in
erating the usual decline in adenosine triphos- memory and mood.28 In contrast, many patients
phate concentrations after ischemia or receiving corticosteroids exhibit mood elevation,
hypoglycemia.45 This lessens the cell’s ability to and some may experience euphoria, insomnia,
inhibit neuronal insults, leading to neuronal restlessness, and increased motor activity.56 Others
death. In several studies involving children with become anxious, depressed, or psychotic.
acute lymphoblastic leukemia, those treated with Common central nervous system adverse signs and
dexamethasone performed less well on cognitive symptoms caused by medications are listed in
testing than did children treated with pred- Table 17–3.
TisdaleC17_301-314 1/12/10 2:42 PM Page 304
Central nervous system effects of benzodi- was near or above 100 mcg/mL, magnetic reso-
azepines include sedation, hypnosis, decreased nance imaging documented pseudoatrophy, and
anxiety, muscle relaxation, anterograde amnesia, there was a loss of 18 to 26 IQ points as tested on
and anticonvulsant activity.57 As the dose is the Wechsler Intelligence Scale for Children-III.
increased, sedation progresses to hypnosis and Some of these reports also mentioned the simul-
then to stupor. There have been reports of delirium taneous presence of other overdose symptoms,
in hospitalized patients receiving benzodiazepines, such as tremor, weight gain, alopecia, ataxia, and
more often associated with long-acting benzodi- nystagmus.
azepines and higher doses of all benzodiazepines.4 Differentiating between cognitive dysfunction
Long-term use of benzodiazepines in the elderly that is drug-induced with that due to a non-drug-
has been associated with a higher risk for cognitive induced disease process can be complex. This is
decline than with episodic, recurrent, or no use of especially true in patients with disorders such as
benzodiazepines.16 epilepsy, Parkinson’s disease and human immun-
Cases of a reversible pseudoatrophy of the odeficiency virus (HIV).15,59,60 The “five foes” of
brain and mental deterioration have been report- mental competence in patients with epilepsy have
ed in association with valproate in children.41 In been described as heredity, brain damage, seizures,
these reports, the serum valproate concentration antiepileptic medications, and psychosocial
TisdaleC17_301-314 1/12/10 2:42 PM Page 305
when the upper limit of the therapeutic range is tive study of hospitalized elderly patients, delirium
exceeded. Doses must be individualized for efficacy prolonged the duration of hospitalization from 7.2
and to prevent toxicity. Some patients may not be days to 12.1 days, and increased mortality from 1%
able to tolerate the medication at a lower serum con- to 8%.29
centration, while others may tolerate much higher
concentrations. Additive effects are often observed
when sedative or hypnotic medications are taken PREVENTION
concurrently.57 Tolerance may develop to some
effects of medications, but other effects may linger. A number of strategies have been used to reduce
With benzodiazepines, patients report subjectively the likelihood of the occurrence of drug-induced
that drowsiness subsides after a few days, but toler- cognitive disorders. These include adjusting drug
ance to the impairment of some measures of psy- doses in patients with liver or kidney disease,
chomotor performance, such as visual tracking, does limiting the total dose of medications with
not occur. known dose–toxicity relationships, monitoring
Adverse central nervous system reactions have plasma concentrations, slowly titrating the dose,
been attributed to histamine2-receptor block- using alternative agents, limiting the total num-
ers.17,72-73 Slugg and colleagues determined that ber of medications, and using consensus criteria.
ranitidine-induced adverse central nervous sys- Table 17–7 provides a summary of measures that
tem reactions are more likely to occur in patients can be taken to prevent drug-induced cognitive
with estimated creatinine clearances <50 mL/min disorders.
than in those with estimated creatinine clear- Adjusting the dose and/or the dosing interval
ances >50 mL/min.72 Patients with creatinine in patients with liver or kidney disease is not only
clearances <50 mL/min had higher peak plasma important when initiating therapy, but it is also
concentrations, higher average plasma concentra- critical in patients with severe illness in which
tions, and larger areas under the plasma concen- organ function may decline suddenly and precipi-
tration:time curve than patients who did not tously. Histamine2-receptor blockers are an exam-
have kidney disease. ple of a class of medications for which careful dose
Postoperative confusion occurs commonly, adjustment is necessary.72 Other medications
with a reported incidence between 5% and 45% in should be avoided altogether in patients with liver
the elderly.74 Common causes include opioids, or kidney disease. Meperidine, for example, has a
benzodiazepines, and anticholinergics.22,74 Short- neurotoxic active metabolite, normeperidine, that
term and long-term postoperative cognitive dys- accumulates after repeated doses in patients with
function has been evaluated in both elderly and kidney disease.77
middle-aged patients.73,74 Postoperative cognitive Another strategy is to limit the total dose of a
dysfunction was present in 25.8% and 9.9% of potentially offending agent for which a known
1218 patients ≥60 years of age at 1 week and 3 dose–toxicity relationship exists.62 In patients
months after surgery, respectively, as compared requiring pain management with opioids, for
with 3.4% and 2.8% in control subjects (P<0.0001 example, the addition of a nonopioid co-analgesic
and P = 0.0037).75 Risk factors were increasing age, or an adjuvant analgesic and around-the-clock
duration of anesthesia, minimal education, a sec- administration can decrease the total required opi-
ond operation, postoperative infections, and respi- oid dose.62,77 Proper management of pain is impor-
ratory complications. In a study investigating tant, as was demonstrated in a study of
patients 40 to 60 years of age who were undergoing postoperative patients 50 to 80 years of age, which
surgery, cognitive dysfunction was reported in found that pain, not analgesic intake, predicted a
19.2% at 1 week postoperatively, as compared with decline in mental status during the first 5 days after
4% of control subjects (P<0.001).76 The major risk surgery.78 Other pain management approaches to
factors for this group of patients at 7 days was sup- consider include the use of a therapy targeting the
plementary epidural analgesia and reported avoid- cause of pain (antitumor therapies such as radio-
ance of alcohol consumption. therapy, chemotherapy, and surgery) or use of a
regional anesthetic or neuroablative interven-
tion.62
MORBIDITY AND MORTALITY Medications such as anticonvulsants and lithi-
um require routine plasma concentration monitor-
There are few published data regarding the influ- ing to maintain concentrations within specified
ence of drug-induced cognitive impairment on ranges.65 For some medications, minor adverse
morbidity or mortality. However, in one prospec- effects often appear as the plasma concentrations
TisdaleC17_301-314 1/12/10 2:42 PM Page 309
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SECTION IV
DRUG-INDUCED
PSYCHIATRIC DISEASES
CHAPTER 18 Depression
CHAPTER 19 Anxiety
CHAPTER 20 Psychosis
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CHAPTER 18
Depression
ANTIVIRAL AGENTS
Efavirenz29 1.6–2.0% A
CARDIOVASCULAR AGENTS
Clonidine15 1.5% C
Guanethidine10-13 1.5% C
Methyldopa 3.6% B
Reserpine14 7% B
RETINOIC ACID DERIVATIVES
Isotretinoin2-9 1–5.5% B
ANTIDEPRESSANTS120,a 1 –4% A
ANTICONVULSANTS57,58
Levetiracetam65-67 4% A
Phenobarbital60 40% B
Primadone61 70% B
62,63
Phenytoin NK C
Tiagabine63 3% A
Topiramate64 5–10% A
Vigabatrin68 12.1% A
ANTIMIGRAINE AGENTS
Triptans76 23.2% B
ANTIPSYCHOTICS120,a
Aripiprazole NK C
Quetiapine NK C
HORMONAL AGENTS
Corticosteroids47-52 1.3–18% B
Oral contraceptives45,46 NK B
GnRH agonists33-38 26–54% B
Tamoxifen39-44 1–20% A
SMOKING CESSATION AGENTS
Varenicline117,118 NK B
IMMUNOLOGIC AGENTS
Interferon-␣79-86,98-100 13–33% A
Interferon-87- 97 0–33% A
GnRH = gonadotropin-releasing hormone; NK = not known.
a
Refers to risk of suicidal ideation when used as antidepressant.
impart above and beyond that normally present in with isotretinoin submitted to the Food and Drug
the population of patients with disease. Administration (FDA). These reports have document-
Several literature sources suggest a possible causal ed a temporal relationship between use of the drug
association between isotretinoin and depression. and onset or worsening of depression. In addition,
There has been a relatively large number of reports of cases of positive dechallenge with discontinuation of
serious depression (37 cases of suicide and 394 cases isotretinoin therapy and initiation of psychiatric
of depression between 1982 and 2000) associated treatment and positive rechallenge have been report-
TisdaleC18_315-332 1/20/10 11:07 PM Page 319
ed.3-5 A retrospective case-crossover study assessing ies.21-23 In a community sample, Palinkas reported
the risk of depression in patients treated with that elderly women taking digoxin had higher rates
isotretinoin in Quebec revealed a relative risk of 2.68 of significant depressive symptoms than women
(95% confidence interval [CI], 1.10–6.48).6 Another not taking digoxin (10.5% vs. 6.5%), although this
retrospective study from Saskatchewan and the difference was not statistically significant.22 In a
United Kingdom (U.K.) compared patients treated second study, digoxin exposure was associated with
with isotretinoin to those treated with antibiotics for an increased risk of depression in patients with a
acne.7 There was no increased risk of depression or history of myocardial infarction.20 Psychiatric
suicide in patients treated with isotretinoin. A adverse effects have been reported in association
prospective, case–control study compared 100 sub- with most antibiotics, but are still considered rela-
jects treated with isotretinoin to 100 subjects treated tively rare events.21 Depression has been observed
with topical cream or oral antibiotics.8 This study in patients taking fluoroquinolones and the antitu-
used two depression scales and collected information bercular agents cycloserine and ethionamide.25-27
on the severity of acne, social support, stress, and These data, however, are limited to case reports, and
family history as potential confounders. Depression the overall prevalence is unknown.
developed in two patients treated with isotretinoin, Both non-nucleoside reverse transcriptase
but the overall difference between the two groups inhibitors (NNRTIs) and protease inhibitors have
was not statistically significant.8 Another prospective been associated with depression. The NNRTI
study administered depression inventories to 33 sub- efavirenz appears to confer the greatest risk. In over
jects at various times during isotretinoin treatment. 1,000 patients treated with efavirenz in clinical tri-
In this study, patients’ depression scores improved as als for an average of 1.6 years, severe depression was
their acne improved, although improvements were reported with an incidence of 1.6%, and suicidal
not statistically significant.9 Despite the lack of con- ideation occurred in 0.6% of patients.28 The risk of
sensus in the literature, many health care providers depression and suicidal ideation increased to 2% in
prescribe isotretinoin with caution and consider patients with a history of psychiatric disorders. In
depression a substantial risk associated with this contrast, a 48-week randomized, controlled trial of
drug. patients receiving a protease inhibitor–containing
Antihypertensive agents, including angiotensin- regimen or efavirenz-containing once-daily regi-
converting enzyme (ACE) inhibitors, -blockers, men failed to find a difference in the risk of depres-
calcium-channel blockers, anti-adrenergic agents sion during maintenance treatment.29 In addition,
(e.g., reserpine, methyldopa, guanethidine, and nevirapine, abacivir, and indinavir have been noted
clonidine), and thiazide diuretics have been impli- in clinical case reports to cause depression.30-32
cated in causing depression in case reports. With The prevalence of drug-induced depression asso-
the exception of anti-adrenergic agents and - ciated with hormonal agents ranges from 1% to 54%.
blockers, little empirical evidence exists to support Agents that affect sex-hormone production appear to
this association. Reserpine, methyldopa, and be associated with significant risks for inducing
guanethidine increase patients’ risk of depression, depression. Gonadotropin-releasing hormone
but these agents are no longer commonly used.10-14 (GnRH) agonists induce a profoundly hypoestro-
The association between clonidine and depression genic state and are associated with significant depres-
is supported by case-report data. However, larger sive symptoms in approximately 50% of patients.33-37
evaluative studies suggest that the incidence of Tamoxifen, an antiestrogenic agent, does not appear
depression in patients taking clonidine is similar to to confer the same risk. Depression as an adverse
that in the general population.15 The risk of depres- effect of tamoxifen was not supported by early place-
sion associated with -blocker therapy remains bo-controlled trials in patients with breast cancer.39
somewhat controversial. In addition to case reports, However, several published reports suggest that
two epidemiologic studies support an association depression may occur in up to 15% to 20% of tamox-
with depression, but this association was not con- ifen-treated patients with breast cancer and that it is
firmed in two prospective studies.16-19 It has been often overlooked or erroneously attributed to the ill-
suggested that true depressive disorders rarely ness.40-42 These reports do not control for confound-
develop in patients treated with -blockers, but that ing factors, such as the effects of the illness,
these patients experience typical -blocker adverse diagnosis, or adverse effects of chemotherapy, and
effects, which leads to misdiagnosis of depression. may overestimate the incidence of tamoxifen-
Studies that have incorporated diagnostic criteria induced depression. The Breast Cancer Prevention
for depressive disorders have failed to identify an (P-1) Study of the National Surgical Adjuvant Breast
association between -blockers and depression.20,21 and Bowel Project provided additional controlled
Digoxin also has been associated with depres- data regarding the association between tamoxifen
sion in case reports and two small prospective stud- and depression.43 The P-1 study was a multicenter
TisdaleC18_315-332 1/20/10 11:07 PM Page 320
phenytoin use to depression are much less con- prescription was found between those receiving
vincing. There are case reports of two patients with sumatriptan (4.2%) and those receiving naratriptan
epilepsy who had supratherapeutic serum pheny- or zolmitriptan (3.9%) (P = 0.87).
toin concentrations (22.7 mcg/mL and 25.5 Several medications used in immunotherapy and
mcg/mL) who also had depressive symptoms. chemotherapy, including interferon-alfa, interferon-
When the phenytoin dose was decreased or the , and interleukin (IL)-2 have demonstrated associa-
medication was discontinued, the symptoms tions with depression. In addition, the immuno-
resolved.62 A prospective study of 277 subjects in suppressant agent mycophenolate was reported to
whom tiagabine or placebo was added to baseline cause depression in a patient using the drug for myas-
AED therapy found depression in 3% of those thenia gravis.77 Multiple types of alfa interferons
treated with tiagabine.63 Topiramate treatment has (INF␣) are available: recombinant INF␣2a; recombi-
been associated with new-onset depression in 5% nant INF␣2b; INF␣n3, a mixture of at least 15 differ-
to 10% of patients.64 Depression was reported in ent interferon subtypes produced from human
4% of levetiracetam-treated subjects as compared leukocytes; peginterferon ␣2a, a combination of
with 2% in those treated with placebo.65 A retro- recombinant INF␣2a and an inert 40kD polyethylene
spective case series and an additional case report glycol polymer; peginterferon ␣2b, a combination of
have also implicated levetiracetam as a cause of recombinant INF␣2b and an inert 12-kD polyethyl-
depression.66,67 Vigabatrin-associated depression ene glycol polymer; and INF alfacon-1 (consensus
occurred in 12.1% of patients treated in double- INF), a recombinant, synthetic product. Depression
blind, placebo-controlled clinical trials (P<0.001).68 has been reported in association with each type of
Depression often is cited as an adverse effect of INF␣.78-86 Several trials investigating the relationship
benzodiazepines, both during therapy and after dis- of depression and the various INF␣s have been con-
continuation.69 However, the literature supporting ducted, with treatment-emergent depression reported
incident depression in patients taking benzodi- in 16% to 96%78-80 of patients. Although none of
azepines is not robust, and depression is reported these trials were placebo-controlled, many used stan-
infrequently in controlled clinical trials. Case dardized instruments to assess depression. One study
reports and observational studies have identified an examined the effect of INF␣ over time and found
increased risk of depression in patients taking ben- decreased numbers of patients with depression after 6
zodiazepines.70-73 These reports, however, do not months of therapy (8–33%) as compared with 1
control for confounding variables, such as history month (79–96%; P = 0.03).80
of depression, presence of comorbid depression, or Two  interferons are available in the U.S. for
concomitant medications, and are therefore diffi- treatment of multiple sclerosis (MS). Interferon-beta
cult to interpret. Depression and anxiety are highly (INF) 1a is available for intramuscular or subcuta-
comorbid syndromes, and the emergence of depres- neous injection and INF1b is administered subcuta-
sion during benzodiazepine therapy may occur neously. The data regarding INF-precipitated
from a relapse or as a coincidental finding. depression are less clear than those for depression
Moreover, alprazolam administered in higher doses induced by INF␣. Two controlled trials suggest an
has been shown to have an antidepressant effect.74 increased risk of depression associated with INF1a,
Physostigmine was associated with immediate with incidences ranging from 20% to 33%.105,106 Two
depressive symptoms in nine normal volunteers other studies of INF1a have not revealed an
administered high intravenous doses.75 Whether increased prevalence of depression as compared with
the results of this study apply to patients with that associated with placebo.107,108 Only one trial
myasthenia gravis who take oral physostigmine, compared the two commercially available formula-
with relatively low bioavailability, is unknown. tions of INF1a. The Evidence for Interferon Dose-
Only a single epidemiologic study exists to Effect: European-North American Comparative
implicate triptans as causative agents for depression. Efficacy (EVIDENCE) study assigned 677 subjects to
A cohort analysis of the West Midlands General receive either INF1a 44 mcg subcutaneously three
Practice Research Database in the U.K. examined the times weekly or INF1a 30 mcg intramuscularly
incidence of depression in migraineurs receiving weekly for 24 weeks.91 No difference in depression
any oral triptan, sumatriptan, or the more lipophilic between the two treatment groups was reported
medications (naratriptan or zolmitriptan).76 A larger (17% vs. 18%).
proportion of the 1,062 patients (23.2%) receiving A long-term seminal trial of INF1b demonstrat-
any oral triptan were diagnosed with depression, as ed higher rates of depression with the clinically-used
compared with 16.8% of 18,033 patients not receiv- 8 MU dose compared with those associated with
ing an oral triptan (P<0.001). When specific medica- placebo at each yearly timepoint.92 Two trials have
tions were compared, no difference in the number been conducted to specifically examine rates of
of patients diagnosed with depression after their first depression associated with INF1b. One study report-
TisdaleC18_315-332 1/20/10 11:07 PM Page 322
The antihypertensive agents reserpine, guanethi- GnRH agonists induce a hypogonadal state,
dine, and methyldopa all likely induce depression by resulting in a significant reduction in both estrogen
depleting CNS bioamine activity.123 Guanethidine and androgen production. Significant fluctuation
and reserpine deplete norepinephrine at the synapse. in serum estrogen concentrations and low estro-
Methyldopa is transformed into ␣-methyl norepi- genic states have been associated with substantial
nephrine, which is less active than norepinephrine mood symptoms in patients with premenstrual dys-
and replaces it at the sympathetic nerve endings, phoric disorder and during menopause. The signif-
thus acting as a false neurotransmitter. Notably, the icant decline in estrogen production associated
norepinephrine depletion caused by reserpine gener- with GnRH agonist therapy is believed to be the
ated one of the early theories of the pathogenesis of cause of depressive symptoms in these patients.
depression (e.g., the monoamine hypothesis).124,125 Estrogen may affect mood in several ways, such as
Clonidine also reduces central norepinephrine out- by increasing the availability of neurotransmitters,
put via stimulation of ␣2-adrenergic receptors.126 including serotonin, by enhancing the degradation
-blockers exert a specific centrally-mediated of monoamine oxidase.130 Estrogen modulates sero-
effect on both -adrenergic and serotonin recep- tonin in other ways, including regulation of trypto-
tors. Chronic -receptor blockade results in phan, a serotonin precursor, and increasing the
increased -receptor binding, an effect opposite to number of serotonin transport sites.131 Tamoxifen,
that associated with antidepressants. This reduces an estradiol receptor antagonist, also may produce
-receptor binding and receptor density.127,128 depressive symptoms caused by a decline in estro-
The mechanism of digoxin-induced depression gen function. However, raloxifene, a selective estra-
is unknown, although alteration of CNS norepi- diol receptor antagonist, without CNS activity, does
nephrine synthesis is suspected. In animal models, not appear to induce depression.132
digitalis has been shown to inhibit CNS synthesis of A number of mechanisms have been proposed
norepinephrine and to decrease norepinephrine regarding the mood effects of OCs. Estrogen may
uptake by CNS tissue, with an apparent overall acti- induce a pyridoxine deficiency resulting in a decrease
vation of CNS noradrenergic function. Altered activ- in serotonin and ␥-aminobutyric acid (GABA) con-
ity of CNS dopaminergic and serotonergic systems centrations in the CNS. Vitamin B6 has been suggest-
also has been demonstrated, particularly with high ed as an effective treatment.133 Other possible
digitalis doses.24 Similarly, the mechanism of mechanisms include an estrogen- and progesterone-
isotretinoin-induced depression is not clear, but ani- mediated augmentation of GABA’s inhibition and
mal studies suggest alterations in the dopaminergic, suppression of glutamate and a progesterone-mediat-
serotonin, and possibly norepinephrine systems.129 ed increase in monoamine oxidase activity.130,134
TisdaleC18_315-332 1/20/10 11:07 PM Page 324
Corticosteroids are thought to induce mood decreased secretion of serotonin. This polymorphism
symptoms by elevating plasma cortisol concentra- is relatively common, with approximately 48% of
tions. Patients with Cushing’s disease have been people having at least one C1019G allele. This find-
reported to have high rates of depressive symp- ing may help explain the very common occurrence
toms.135 Moreover, abnormalities of the HPA axis of depression in patients treated with INF␣.142
with hypercortisolemia are found in patients with Vinca alkaloids have been shown to inhibit the
MDD.136 It is of interest that corticosteroids are as transport of dopamine hydroxylase, thereby pre-
likely to induce mania as depression, suggesting a venting the conversion of dopamine to norepi-
complex interaction.48 nephrine,101 the resultant effect of which could be
The mechanism of AED-induced depression depression. The mechanism of varenicline-induced
likely involves GABA, an inhibitory neurotransmit- depression is unknown, but the partial ␣42-nico-
ter, alterations in serotonin activity or a combina- tinic receptor agonist indirectly modulates
tion of these. Some evidence suggests that dopamine,143 which may in turn modulate mood.
antidepressant agents enhance activity at GABA-B
receptors and decrease activity at GABA-A recep-
tors.137 Therefore, agents that primarily act at the CLINICAL PRESENTATION AND
GABA-A receptors, such as phenobarbital, tiagabine, DIFFERENTIAL DIAGNOSIS
or topiramate, or indiscriminately increase the
amount of GABA available to both receptors, such as Drug- or substance-induced depression is defined
tiagabine, may be associated with greater potential by DSM-IV as a prominent and persistent distur-
for inducing depression. Both phenobarbital and bance of mood that occurs during use or within 1
phenytoin reduce unbound plasma tryptophan con- month of intoxication or withdrawal of therapy
centrations, which influences serotonin turnover.138 with a medication.1 The key feature of diagnosis is
In addition, the enzyme-inducing AEDs can cause a the temporal association between the development
folate deficiency. Decreases in plasma folate concen- of depressive symptoms and the use of a causative
trations may reduce methylation reactions involv- drug. The disturbance of mood or presence of
ing neurotransmitters and monoamines, which may depression should be severe enough to result in
be implicated in depression induction.139 impairment of daily function. In addition, the clini-
The mechanisms of depression caused by the cian must rule out the possibility of preexisting
immunologic agents have not been elucidated com- depression and the influence of the disease state
pletely. Most work in this area has been conducted being treated, particularly psychological stressors.
with INF␣, and several mechanisms have been pro- Symptoms associated with drug-induced depres-
posed that may be applicable to INF and IL-2. INF␣ sion (Table 18–3) are similar to those observed in
induces the production of proinflammatory patients with MDD, with few exceptions. More severe
cytokines, such as IL-6, which may lead to depres- symptoms including suicidal ideation and psychotic
sion.81 An increase in the Montgomery–Asberg symptoms have been reported in association with
Depression Rating Scale scores was significantly and INF␣, corticosteroids, and varenicline.48,52,82,117,118
positively correlated with increases in serum IL-6 With most agents, the onset of depression generally
concentrations.70 INF␣ affects the serotonergic sys- occurs during the first weeks of treatment. The medi-
tem to increase serotonin transporter messenger an onset of symptoms in FDA-reported cases of
ribonucleic acid and uptake activity, suppress sero- isotretinoin-associated depression during the first
tonin concentrations in brain or serum, and induce course of therapy was 30 days, and the median recov-
the catabolism of tryptophan.81 The net effect of ery time was 4.5 days.5 During the rechallenge course,
these alterations in the serotonin system is to
decrease the amount of serotonin at the active recep-
tor sites and potentiate depression. INF␣ administra- TABLE 18–3 Signs and Symptoms Associated
tion is also associated with activation of the HPA,81 with Drug-Induced Depression
which has been associated with depression and with
• Depressed mood
increases in serum IL-6 concentrations.140,141 A deple-
• Diminished interest or pleasure in most activities
tion of tryptophan, the amino acid precursor to sero-
• Sleep changes (insomnia or hypersomnia)
tonin, caused by INF␣ administration has also been
• Appetite increase or decrease
hypothesized.142 A polymorphism (C1019G) on the
• Hopelessness/helplessness
allele coding for the 5-HT1A receptor (HTR1A) has
• Suicidal ideation
also been implicated in the development of INF␣-
• Fatigue
induced depression. The HTR1A receptor is the
• Decreased concentration
major autoreceptor on the serotonergic raphe neu-
• Psychomotor agitation or retardation
rons. Alterations in this receptor can lead to
TisdaleC18_315-332 1/20/10 11:07 PM Page 325
the time to onset of symptoms was shorter.144 Patients and hypothyroidism and unrealistic expectations,
treated with GnRH agonists have depressive symp- leading to discouragement and frustration.152
toms that are consistent with the time to reach a
hypogonadal state.33,34 When the hypogonadal state
is of short duration, as with in vitro fertilization treat- RISK FACTORS
ment, depressive symptoms are transient and less
severe.38 However, during sustained treatment for Female sex, family history of mood disorder, child-
endometriosis, depressive symptoms appear to be hood abuse, anxiety disorders, sleep disorders, and
persistent and generally more severe, sometimes neurologic disorders are known risk factors for MDD.1
resulting in the need for discontinuation of treat- It is unclear, however, whether these factors also
ment.35,39,145 Drug-induced suicidality is temporally increase the risk of drug-induced depression. Much of
associated with initiation of treatment and represents the literature regarding drug-induced depression aris-
a marked change in thoughts and behavior from es from case reports, database evaluations, and obser-
baseline.120 Suicidality associated with anticonvul- vational studies, which are not designed to identify
sants and antidepressants occurs early in treatment, risk factors. Factors that appear to increase the risk of
and must be distinguished from the underlying mood drug-induced depression are listed in Table 18–5.
disorder for which they have been prescribed. A history of depression or another psychiatric
Conditions and diseases associated with depres- disorder is the most consistently identified risk fac-
sion must be ruled out in order to arrive at a diagno- tor for depression associated with most of the
sis of drug-induced depression (Table 18–4). The causative drugs. In addition, the presence of psy-
incidence of depression in patients with epilepsy chological stressors has been noted to increase the
ranges from 4% to 62%, depending on the method risk. While increased stress may be expected in
of diagnosis and the population studied.146,147 One patients with serious medical illnesses, it is unclear
study found that patients with hypertension were whether increased stress increases the risk of
three times more likely to have depression than nor- depression associated with drugs such as immuno-
motensive patients.148 Many chronic health condi- logic or cancer chemotherapeutic agents. Patients
tions for which immunologic agents are used have with a history of drug-induced depression are like-
been associated with high rates of depression. The ly to be at greater risk upon repeated exposures.15
prevalence of depression in patients with chronic Dose may be an important risk factor for
hepatitis C is 11% to 30%,149 while the prevalence of depression associated with some agents.
depression in patients with cancer is 28%.150 Depression is more likely to occur when higher
Multiple sclerosis is also associated with a 15% to doses of corticosteroids are used (>80 mg/day pred-
30% point prevalence of depression and a lifetime nisone equivalents).53 It is unclear whether multi-
depression incidence of 40% to 60%.151 Fatigue, a ple courses of corticosteroids increase the risk of
symptom common to all of the disease states in this depression. However, patients with a history of
category, often can be confused with depression. steroid-induced depression should be monitored
Alternatively, depression may be underdiagnosed closely. Likewise, oral contraceptives with higher
because of the expectation that patients will present estrogen content are more commonly associated
with fatigue. Other conditions that may cause mis- with depression. Some open-label data suggest that
diagnosis of depression include hyperthyroidism the risk of neuropsychiatric adverse effects associ-
ated with long-term treatment (>6 months) with
efavirenz were more than five times greater in
patients with plasma efavirenz concentrations
TABLE 18–4 Conditions to Consider in the >2.74 µg/L.153
Differential Diagnosis of Drug-Induced Depression Several factors have been specifically associated
with an increased risk of treatment of emergent
• Substance-use disorder
depression or negative affect in patients taking OCs
• Preexisting mood disorder
(Table 18–5). Whereas the overall risk for depression
• General medical conditions
caused by these drugs is considered low, patients pre-
• Endocrine
senting with any of these factors should be consid-
• Infectious
ered at greater risk. The risk may vary with the type
• Deficiency state
of OC used. Monophasic OCs exert greater mood-sta-
• Collagen disorders
bilizing effects than triphasic products. In addition,
• Metabolic disorders
patients with premenstrual mood symptoms may
• Neurologic disorders
have an increased risk of negative mood effects with
• Cardiovascular disease
OCs containing low amounts of progesterone or a
• Malignant disease
low progesterone-to-estrogen ratio. Women without
TisdaleC18_315-332 1/20/10 11:07 PM Page 326
of suicidality associated with antidepressant treat- from this group had depression (Hamilton Rating
ment must be balanced with the much greater risk of Scale for Depression, >17) during the course of 24 to
suicidality in patients with untreated depression. 48 weeks of INF treatment.162 Amantadine, a medica-
tion with both antiviral and dopaminergic effects,
was studied in 14 subjects who were treated with
PREVENTION peg-INF␣2a and ribavirin for hepatitis C. As com-
pared with the control group, amantadine-treated
There is very little information available regarding subjects were significantly less likely to have depres-
preventive strategies for drug-induced depression. sion by week 24 of treatment.163
However, some interventions may prove useful
(Table 18–6). Identifying patients with risk factors
(e.g., history of depressive episode) and implement- MANAGEMENT
ing a prospective monitoring plan seems prudent,
but will not prevent drug-induced depression. Appropriate management (Table 18–7) of drug-
Careful monitoring and early detection may, howev- induced depression begins with prompt recognition
er, minimize the negative sequelae associated with of the emergence of depressive symptoms. In some
depression. Treating psychosocial stressors with cases, depressive symptoms may be transient or
interventions such as counseling and education may mild, as in patients receiving GnRH agonist therapy
also prove beneficial, but this strategy has not been as part of in vitro fertilization treatment.38 For many
systematically evaluated. Pretreatment or prophylax- patients, education and support may be the only
is for depressive symptoms may be useful in some intervention needed. Psychological interventions or
cases. Sabet reported the successful pretreatment psychotherapy prove beneficial for patients with
(with lithium and protriptyline) of an individual mild-to-moderate symptoms of MDD, but the bene-
with a history of steroid-induced depression.160 In a fit of psychotherapy in patients with drug-induced
retrospective review of patients receiving leuprolide depression is unclear. For more severe or persistent
for treatment of endometriosis, concomitant treat- depressive symptoms, therapy with the offending
ment with sertraline minimized the emergence of agent will likely have to be discontinued or antide-
depressive symptoms.158 Convincing evidence exists pressant treatment may need to be initiated, and in
regarding the benefit of pretreatment for depression some cases, both strategies are required. Children,
in patients with melanoma receiving INF␣. adolescents, and young adults (18–24 years) receiv-
Musselman et al.161 randomly assigned 40 patients ing antidepressants for depression or other psychi-
with melanoma to receive pretreatment with parox- atric disorders should be monitored frequently
etine (n = 20) or placebo (n = 20) 2 weeks prior to and (weekly to biweekly) during the first few weeks for
throughout the 12-week INF␣ regimen. The risk of treatment-emergent suicidality or worsening of
developing depression was lower in the paroxetine depression. The emergence of suicidal ideation or
group (11% vs. 35%; relative risk, 0.24; 95% CI, psychotic symptoms should always be considered
0.08–0.93) and pretreated patients were less likely to serious, and these patients should receive immediate
discontinue INF␣ because of depressive symptoms intervention, including hospitalization.
(5% vs. 35%; relative risk, 0.14; 95% CI, 0.05–0.85). There are insufficient data to recommend spe-
A small group (n = 10) of patients with hepatitis C cific doses of antidepressant therapy for the treat-
who had a history of major depression were admin- ment of drug-induced depression, although in
istered escitalopram preventively during treatment most reports doses similar to those used in patients
with peg-INF␣2a and ribavirin. Only one patient with endogenous depression have been adminis-
tered. Duration of therapy should be based on
patient response and clinical judgment. In cases in
TABLE 18–6 Approaches to Help Prevent Drug- which it would be best for a patient to continue to
Induced Depression
• Assess patient for history of depressive episodes or
TABLE 18–7 Management of Drug-Induced
history of drug-induced depression at baseline
Depression
• If Yes:
• Consider individual risk–benefit of drug therapy • Discontinue the offending agent, if possible
• Select alternative drug within therapeutic category, • Substitute medication within therapeutic class
if possible • Counseling or supportive therapy for mild depressive
• Pretreatment with selective serotonin reuptake symptoms
inhibitor if undergoing therapy with interferon or • Initiate antidepressant therapy for persistent or mod-
gonadotropin-releasing hormone agonist erate-to-severe depressive symptoms
TisdaleC18_315-332 1/20/10 11:07 PM Page 328
receive therapy with the causative agent, clinicians inhibitors, and electroconvulsive therapy have been
should consider factors such as severity of presen- used to manage steroid-induced depression.48
tation, current mood, and level of psychological There is inherent difficulty in recommending
stress before deciding to discontinue drug therapy. antidepressant therapy for patients with epilepsy
While not always possible, in some cases substi- because of the epileptogenic potential of most anti-
tuting another medication in the same drug or ther- depressant drugs. Bupropion may exert proconvul-
apeutic class but with a lower risk of causing sant properties in persons without epilepsy,
depression may represent the best management particularly in doses >450 mg/day.169 Tricyclic anti-
strategy. For example, patients experiencing -block- depressants also may have epileptogenic potential,
er-induced depression may benefit from receiving a particularly amoxapine, clomipramine, maproti-
hydrophilic -blocker or an antihypertensive drug line, and mianserin.139 Although selective sero-
from a different class (e.g., ACE inhibitor or diuret- tonin-reuptake inhibitors are generally preferred in
ic).164 Similarly, patients experiencing OC-induced patients with epilepsy, they have been associated
depression may benefit from an OC with a lower with seizures in case reports. This may be caused,
estrogen content or different estrogen:progesterone in part, by an increased incidence of hyponatrem-
ratio. Patients with varenicline-induced neuropsy- ia, which may induce seizures.170
chiatric side effects should be considered for nicotine
replacement or bupropion for smoking cessation.
No specific treatments have been proposed for
depression associated with the immunologic agents.
INFORMATION FOR PATIENTS
Discontinuation of therapy is sometimes considered,
Patients should be informed regarding the possibil-
but remission of depression does not always occur
ity of the emergence of depressive symptoms when
simultaneously with the discontinuation of interfer-
prescribed a drug associated with depression. They
on.147 For patients with hepatitis C, selective sero-
should be instructed to report any symptoms of
tonin reuptake inhibitors may be the best choice, as
depressed mood or extreme irritability, anxiety,
they are well tolerated by patients with liver disease,
anhedonia, difficulty sleeping, fatigue, feelings of
whereas tricyclic antidepressants with significant
hopelessness or helplessness, change in appetite or
anticholinergic effects may increase the cognitive
weight, or thoughts of death. Patients with a histo-
dysfunction that occurs in these patients.147 Gleason
ry of depression may be at greater risk for experi-
et al.165 conducted a study using citalopram to treat
encing drug-induced depression. Patients should
depression in patients with hepatitis C. Of the 15
be encouraged to inform their provider of any his-
subjects participating in the trial, four had previous-
tory or treatment of any psychiatric disorder.
ly taken INF␣ and four were currently receiving INF␣
The FDA requires pharmacists to distribute
therapy. Citalopram 10 to 40 mg/day was adminis-
medication guides to patients receiving medica-
tered to all subjects, with a resultant improvement in
tions with specific warnings of suicidality or other
mood. In another study, 13 patients on therapy with
severe neuropsychiatric side effects. Medication
INF␣ had depression, 85% of whom were responsive
guides are intended to inform patients about a
to treatment with citalopram.166 Similar results were
known serious side effect of a drug. These guides
achieved with citalopram in another study.157 There
are available at http://www.fda.gov/cder/offices/
are case reports of patients with INF␣-induced
ods/medication_guides.htm.
depression who were responsive to treatment with
methylphenidate or venlafaxine.167,168
Selection of specific INF␣ therapy based on
patients’ depressive symptoms has been proposed.
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CHAPTER 19
Anxiety
Julie A. Dopheide
product that has been used as a sedative. Thyroid hormone supplementation does not
Symptoms of worsening anxiety and insomnia routinely lead to anxiety. However, excessive doses
have been reported after abrupt discontinuation of may result in emotional symptoms, such as feeling
valerian, suggesting that receptor dependence “on edge” or jittery, and physical symptoms,
occurs over time, an effect similar to that associat- including sweating or tachycardia.4,50 One study of
ed with benzodiazepines.44,45 40 women with subclinical hypothyroidism ran-
Varenicline is a selective ␣42-nicotinic acetyl- domly assigned to receive either placebo or thyrox-
choline partial receptor agonist that is indicated for ine 50 to 100 mcg/day found no clinical benefit
smoking cessation. During a controlled clinical from thyroxine supplementation over a period of 6
trial in 250 Asian patients taking varenicline, anxi- months. Significantly elevated anxiety scores, as
ety developed in 5.6%, as compared with 2.4% in compared with baseline, were reported in 8 of 20
the placebo group.46 Case reports of insomnia, anx- women treated with thyroxine, as compared with
iety, depression and psychosis associated with only 1 of 14 women treated with placebo.50 Herbal
varenicline therapy for smoking cessation prompt- supplements for which thyroid-stimulating effects
ed the Food and Drug Administration (FDA) to are claimed can cause anxiety symptoms as well.
issue a public health advisory in January 2008 (see Gonadotropin-releasing hormone agonists such as
section entitled “Information for the Patient”).47 leuprolide and goserelin are used in women to treat
CNS-active agents are more obvious potential endometriosis and in men for the treatment for
causes of anxiety. However, new-onset symptoms prostate cancer, and have been associated with
of anxiety have been associated with hormones mood swings, anxiety, and panic attacks.24,28
and other steroidal compounds, as well as with Symptoms typically resolve with cessation of treat-
antihypertensive drugs and even lipid-lowering ment.24 Danazol is an androgen that is sometimes
agents.7,15,16,36 Reports of drug-induced anxiety used for the treatment of endometriosis and fibro-
associated with antiinfective agents, antiinflamma- cystic breast disease. The risk of danazol-induced
tory agents, antineoplastic agents, and herbal sup- anxiety and irritability is similar to that associated
plements have been published.7,16,22,36,40 Drugs of with leuprolide and goserelin.7
abuse or toxins are also known to cause anxiety Mood swings including anxiety are a well-
during intoxication or withdrawal. known adverse effect associated with the abuse of
Supplementation of the sex hormones estro- anabolic steroids, including nandrolone,
gen, progesterone, and testosterone has been oxymetholone, stanozolol, and oxandrolone.7,9
linked with mood swings, including anxiety.23,24 Anxiety is less common than rage, aggression, and
The degree to which these hormones induce anxi- irritability, but panic attacks and worsening anxi-
ety is related to sex, individual susceptibility, and ety have been reported.7,9
dose or fluctuation in plasma concentration. For Antibiotics have been associated with neu-
example, estrogen withdrawal has been linked to ropsychiatric adverse effects, including anxiety,
worsening anxiety, insomnia, and panic attacks in although the occurrence is difficult to predict
women.7,23 A wide range in severity of anxiety because of multiple possible mechanisms and con-
symptoms has been reported in premenstrual founding variables.7,26,51 Fluoroquinolones are the
women, postpartum, and during perimenopause, class of antiinfective agents associated with the
as plasma estrogen concentrations decline before highest incidence of adverse central nervous sys-
stabilizing at menopausal concentrations. tem effects, including anxiety and insomnia.7,26
TisdaleC19_333-343 1/12/10 2:45 PM Page 336
stood. Estrogen exerts multiple complex effects on al, and cognitive symptoms that may cause them
neurotrophins, cortisol, and neurotransmitter sys- to lose the ability to interact with others, think
tems.24 One theory linking estrogen dysregulation to clearly, or participate in the activities of daily liv-
anxiety involves estrogen’s role in effective serotonin ing. Table 19–4 differentiates physical, emotional
use. When plasma estrogen concentrations decline and cognitive symptoms of anxiety that may be
significantly, the associated serotonin dysregulation rated as mild, moderate, or severe depending on
causes anxiety.23 Progesterone deficiency and supple- the impact on functioning. Emotional symptoms
mentation has been linked with anxiety and irritabil- include excessive fear, tension, nervousness, and
ity in women.23,24 One potential mechanism feeling jittery, irritable, or “on edge.” Cognitive
involves progesterone’s neuroactive steroid metabo- symptoms include difficulty concentrating,
lites (e.g., 5-tetrahydroprogesterone, allopreg- “blanking out,” and excessive worries. Physical
nanolone). These metabolites are allosteric symptoms include insomnia, restlessness, racing
modulators of GABA-A, causing anxiolytic effects in heart, difficulty breathing, sweating, flushing,
some and anxiogenic effects in others, depending on weakness, and exhaustion.
which metabolite is predominant. The development Patient assessment should begin with docu-
of anxiety may be related to an individual’s genetic menting the patient’s experience of anxiety subjec-
susceptibility to forming these metabolites.56 In addi- tively and objectively. Standardized anxiety rating
tion, progesterone possesses some antiestrogen activ- scales (e.g., Hamilton Anxiety Rating Scale, Covi
ity that can precipitate anxiety in some individuals.23 Anxiety Scale) are useful to establish objective
Similarly, testosterone excess or deficiency in women measures of anxiety and to monitor persistence or
and men can result in anxiety, irritability, and aggres- remittance of symptoms over time.4,58 The time
sion.41,56,57,59 Case studies in men with Parkinson’s course of the onset of anxiety in relation to initia-
disease and low plasma testosterone concentrations tion or discontinuation of drug therapy is crucial
reported significant improvement in associated to determine whether the anxiety is likely drug-
symptoms of anxiety after testosterone supplementa- induced.
tion.42 GnRH agonists are synthetic derivatives of the Dopaminergic blockade associated with con-
native decapeptide produced by the hypothalamus, ventional antipsychotics, such as haloperidol, or
and may cause anxiety via reversible suppression of with atypical agents including risperidone, ziprasi-
the synthesis and release of luteinizing hormone and done, and aripiprazole can result in akathisia, the
follicle-stimulating hormone.28 subjective feeling of motor restlessness. Akathisia is
frequently accompanied by an intolerable feeling
of anxiety.10 An individual’s sensitivity to experi-
CLINICAL PRESENTATION AND encing caffeine-induced anxiety can vary greatly,
DIFFERENTIAL DIAGNOSIS but symptoms generally manifest within 15 to 30
minutes after ingesting between 200 and 500 mg of
Signs and symptoms associated with drug-induced caffeine or 3 to 5 cups of brewed coffee. Caffeine
anxiety are listed in Table 19–4. An individual with and guarana produce emotional, cognitive, and
significant anxiety suffers from physical, emotion- physical symptoms of anxiety during acute intoxi-
TisdaleC19_333-343 1/12/10 2:45 PM Page 338
TABLE 19–4 Signs and Symptoms Associated TABLE 19–5 Conditions to Consider in the
with Drug-Induced Anxiety1-4,8-16 Differential Diagnosis of Drug-Induced Anxiety1,4,15-
17,33,55
Emotional
• Feeling jittery • Hyperthyroidism
• Irritability • Asthma
• Tearfulness • Hypoglycemia
• Feeling of impending doom • Delirium
• Feelings of inferiority • Addison’s disease
• Sadness • Mitral valve prolapse
• Fear of losing control • Cushing’s disease
• Fear of going crazy • Irritable bowel syndrome
• Feeling “on edge” • Premenstrual syndrome
Cognitive • Perimenopause
• Difficulty concentrating • Premenstrual dysphoric disorder
• Rapid or racing thoughts • Chronic pain
• Blanking out • Hypertension
• Intrusive thoughts • Pheochromocytoma
• Obsessive thoughts • Traumatic brain injury
• Extreme worries • Seizure disorder or epilepsy
• Systemic lupus erythematosus
Physical
• Dementia
• Restlessness
• Multiple sclerosis
• Flushing
• Fibromyalgia
• Diarrhea
• Attention deficit/hyperactivity disorder
• Choking sensation
• Nausea, vomiting
• Shaky voice
• Difficulty speaking ment. Associated symptoms that are more indica-
• Tremulousness tive of substance-induced anxiety versus a primary
• Exaggerated startle response anxiety disorder include new-onset panic attacks
• Hypervigilance after the age of 45, vertigo or loss of balance, loss
• Exhaustion of bladder or bowel control, and slurred speech or
• Chest pain amnesia. Also, drug-induced anxiety typically does
• Palpitations not meet the duration criteria for a primary anxi-
• Poor eye contact ety disorder. For example, in order to meet the cri-
• Fatigue teria for generalized anxiety disorder, anxiety
• Insomnia symptoms must cause functional impairment for 6
months.1,4 In individuals with cancer, distinguish-
ing drug-induced anxiety is particularly difficult
cation and during withdrawal. Anxiety associated because of high levels of situational anxiety related
with benzodiazepine withdrawal is related to the to the diagnosis and the need to endure treatment
half-life of the benzodiazepine. For short- to inter- over months to years.48
mediate-acting agents such as alprazolam or Figure 19–1 outlines a systematic approach to
lorazepam, withdrawal symptoms can occur with- patient assessment and lists key questions useful in
in 6 to 24 hours of abrupt cessation, whereas with- assessing drug-induced anxiety and differentiating it
drawal symptoms can occur within 2 to 3 days of from a primary anxiety disorder.4,59 Laboratory tests
discontinuing drugs with longer half-lives, such as are useful to determine whether there is an underly-
clonazepam or diazepam.13,14 ing medical cause or associated medical problem
It can be difficult to distinguish drug-induced such as hyperthyroidism or mitral-valve prolapse.
anxiety from other possible causes of anxiety in
many patients. Conditions to consider in the dif-
ferential diagnosis of drug-induced anxiety are list- RISK FACTORS
ed in Table 19–5.1,4,15-17,33,55 A thorough physical
examination and medication and substance abuse Risk factors for drug-induced anxiety are listed in
history are necessary for comprehensive assess- Table 19–6.1-4,13,14,24,39,55,60 Clinical studies show
TisdaleC19_333-343 1/12/10 2:45 PM Page 339
to 1 mg administered two or three times daily active agent is essential. Individualized discontinu-
offers the advantage of rapid onset (30–45 min- ation regimens should be developed based on
utes), intermediate duration of effect (~6–8 hours), patient tolerance. For example, decreasing the dose
and no active metabolites that can accumulate. of a benzodiazepine by 25% per week is well toler-
Clonazepam 0.25 to 0.5 mg administered once or ated by some patients, but others may require
twice daily can be considered if less frequent more gradual tapering over weeks or even
administration is desired, but the onset of effect months.4,13 Patients who have difficulty withdraw-
may be longer (1–2 hours) and the drug can accu- ing from benzodiazepine therapy because of exces-
mulate over time, because of a long half-life of 20 sive anxiety should be offered the option of
to 50 hours. Appropriate duration of therapy therapy with anticonvulsant drugs, as these agents
varies, based on the necessary duration of therapy have been used effectively to prevent anxiety and
with the causative agent.4 Anxiety related to abrupt other benzodiazepine withdrawal symptoms such
benzodiazepine discontinuation may be attenuat- as insomnia and tremulousness.13,14
ed through slower withdrawal of therapy (over When drug-induced anxiety occurs, the care-
months instead of weeks). Alternatively, therapy giver should reassure the patient that drug-induced
with an agent that increases ␥-aminobutyric acid anxiety is usually of short duration (days to weeks)
activity, such as valproic acid, can be initiated to and responds to a decreased dose or discontinua-
diminish withdrawal symptoms and associated tion of the causative agent along with supportive
anxiety.13 treatment. Patients at risk for anxiety should be
Caffeine-induced anxiety and withdrawal counseled regarding the type of anxiety symptoms
symptoms abate with time (typically 3–7 days) and that may occur in association with the drug (e.g.,
may be managed with mild analgesics to treat panic attacks, jitteriness, fearful thoughts), the typ-
headache symptoms.6,17,22 There is evidence that ical time of onset of symptoms, and available inter-
exercise attenuates caffeine-induced anxiety.18 ventions should anxiety occur.
Nicotine supplementation with gradual tapering
can lessen anxiety associated with nicotine with-
drawal.23
The management of thyroid-induced anxiety is
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CHAPTER 20
Psychosis
Jessica L. Gören
dence of drug-induced psychosis. It is likely that hypothesis is only one mechanism involved in the
drug-induced psychosis is underdiagnosed. generation of psychotic symptoms.2-3,5-7
Altered serotonin (5-HT) receptor functioning
is also associated with psychosis. Patients with
MECHANISMS schizophrenia are known to have abnormal 5-HT
receptor functioning, and many antipsychotic
Psychosis is not a single disorder, but rather a agents induce significant effects on serotonergic
symptom induced by multiple mechanisms. Table functioning.110-115 LSD, an agent known to induce
20–2 lists the presumed mechanism of psychosis hallucinations, is structurally related to serotonin.
induced by specific drugs. Overlap in clinical pres- LSD and psilocybin induce psychosis through stim-
entation of idiopathic psychosis and psychosis ulation of the 5-HT2A receptor.107,108
caused by both legal and illicit drugs suggests sim- Glutamate is the major excitatory neurotrans-
ilar mechanisms. Understanding of drug-induced mitter in the brain.5-7 Antagonism of the glutamate
psychosis, therefore, may be enhanced by a discus- N-methyl-D-aspartate receptor by PCP and keta-
sion of the mechanisms associated with idiopathic mine induces states that may be the best model of
psychosis and the psychosis associated with illicit idiopathic psychosis.116 Biologic changes that sup-
drug use. port hypoglutamatergic function in schizophrenia
Psychosis is often associated with alterations of include decreased glutamate in the cerebrospinal
dopamine concentrations in various regions of the fluid, altered N-methyl-D-aspartic acid (NMDA)
brain.2,6 Enhanced dopaminergic function in the receptor densities, and decreased glutamate
mesolimbic pathway is associated with hallucina- release.117-120
tions, delusions, and paranoia.2-3,5-7 Increased It has been hypothesized that altered intracel-
release of dopamine, decreased metabolism or lular signal transduction may be involved in psy-
uptake of dopamine, or both can cause psychotic chosis.121 Antipsychotic agents induce genes to
symptoms. This is supported by the observation increase expression of c-fos or its protein product.
that the administration of mesolimbic dopamine This may alter expression of other genes, the prod-
antagonists leads to clinical improvement of psy- ucts of which are involved directly in psychosis.
chotic symptoms.6 Another mechanism posited to play a role in psy-
Other neurotransmitters may indirectly alter chosis is episodic dysfunction of myelin sheaths
synaptic concentrations of dopamine and cause disrupting subcortical and cortical processes121,
psychosis. Glutamate, serotonin, norepinepherine, which may lead to positive psychotic symptoms
and acetylcholine are believed to produce second- and cognitive dysfunction.
ary effects on dopamine neurotransmission and to The biologic mechanism of psychosis is com-
play a role in psychosis.2-3,5-7 plex and probably involves multiple pathways. As
The hyperdopaminergic state is an important time progresses, it is likely that additional mecha-
mechanism of psychosis.5-7 However, on the basis nisms will be discovered. Therefore, the ability to
of studies of both idiopathic and iatrogenic psy- predict which drugs may induce psychosis based
chotic states, it is clear that the hyperdopaminergic on pharmacologic activity is limited, although the
TisdaleC20_344-356 1/12/10 2:46 PM Page 347
alteration of dopamine and serotonin pathways is and social isolation.2-7 Cognitive symptoms can be
consistently associated with psychosis. diverse but often present as difficulties with con-
centration and memory.7 Positive symptoms are
more typically associated with drug-induced psy-
CLINICAL PRESENTATION AND chosis than negative symptoms (Table 20–3).
DIFFERENTIAL DIAGNOSIS There is no individual test that is diagnostic for
drug-induced psychosis. Diagnosis depends on
Many symptoms in patients with drug-induced identification of a temporal relationship between
psychosis are similar to those of patients with idio- the ingestion of the suspect substance and the
pathic psychoses observed in conditions such as onset of psychotic symptoms, clinical presenta-
schizophrenia.4,8 Schizophrenia is defined by a tion, and a thorough medical and medication his-
triad of symptoms: positive, negative, and cogni- tory.4,8 Patients with acute psychosis may or may
tive. Positive symptoms include delusions, halluci- not be able to provide an accurate history.
nations, and disorganized speech and behavior.2-8 Consultation with family, friends and other health
Negative symptoms include flat affect, avolition, care providers is useful in understanding any pre-
TisdaleC20_344-356 1/12/10 2:46 PM Page 348
abnormalities (e.g., electrolyte abnormalities) all inhibitor may lead to decreased metabolism of spe-
increase the risk of drug-induced psychosis. cific drugs, increased plasma concentrations, and
Posttraumatic head injury can cause organic psy- potential for adverse effects.126,129 Alternatively, dis-
chosis as well as predispose a patient to drug- continuation of an agent that was inducing the
induced psychosis.123-125 As the number of risk metabolism of a drug could lead to decreased drug
factors increases, so does the likelihood of drug- metabolism, increased blood concentrations, and
induced psychosis. increased side effects, including psychosis.125,128-129
Patient populations in need of special atten- Some agents vulnerable to drug interactions and
tion are the elderly, infants and children, and drug-induced psychosis include stimulants, steroids,
patients with concomitant illnesses. Weight- and opiates, anticholinergics, some antibiotics and
age-based dosing are important to decrease the risk antiviral agents, angiotensin–converting–enzyme
of drug-induced psychosis in the elderly and in inhibitors, dopaminergic agents, and anticonvul-
children. Individual drug-prescribing information sant medications.2-3,5
cites the dose adjustments, if any, that are neces- Diligent assessment of medication profiles can
sary because of concomitant illnesses such as help clinicians identify and prevent or treat the
hepatic or renal failure. drug-induced psychosis attributable to drug inter-
In people of any age, concurrent administra- actions. Familiarity with those drugs commonly
tion of multiple medications may affect both the implicated in drug interactions could help reduce
pharmacokinetics and the pharmacodynamics of the risk of drug-induced psychosis.
drugs.5,7,126-130 Increased anticholinergic burden
from multiple medications or taking >9 medica-
tions daily substantially increases the risk of drug- MORBIDITY AND MORTALITY
induced psychosis.2,5,7
Drug interactions that enhance the pharmaco- Drug-induced psychosis often requires medical
logic effects, increase the serum concentration of attention to protect the safety of the patient or
drugs, or both increase the incidence of drug- those around them, although harm due directly to
induced psychosis. Pharmacodynamic interactions the psychotic state is relatively uncommon.
occur when two medications with similar pharma- Typically, keeping the patient in a safe environ-
cologic effects exert additive or synergistic effects. ment until the psychosis resolves is all that is nec-
The result is an exaggeration of expected adverse essary. More severe cases may require the
effects. For example, stimulants and bupropion both short-term use of antipsychotic medications.
increase dopamine and norepinephrine concentra- Death is rarely directly related to psychosis.2-3
tions in the brain and thus can be anxiogenic. The Death as a direct outcome of the drug is most often
addition of a stimulant to bupropion treatment a result of a severe intoxication (as may occur with
could lead to significant anxiety that had been mild stimulants) or drug withdrawal (as may occur with
or not present at all with bupropion monotherapy. benzodiazepines).2-5,93-94
Another potential pharmacodynamic effect There is limited information available on the
could result from the combination of two drugs emergency room visits and hospitalizations related
that antagonize each other’s effects.131-133 For to drug-induced psychosis. One study estimated
example, use of a dopamine agonist in combina- that 1% of all emergency room visits were related
tion with a dopamine antagonist, which is some- to psychosis.137 However, the authors did not dif-
times prescribed when dopamine agonists induce ferentiate between idiopathic and drug-induced
psychosis in patients with Parkinson’s disease, psychosis.
could decrease dopaminergic antagonism and lead Psychosis impairs judgment and insight, which
to an increase in the dopamine antagonist dose.132- can cause a person to make poor decisions and/or
136
Although one would not expect a particularly engage in risky behaviors resulting in poor out-
robust change in the dopaminergic antagonism, comes such as motor vehicle accidents, suicide, or
other pharmacologic effects, such as anticholiner- assault.2-4 During the psychotic state, patients may
gic transmission, could be increased, leading to a misinterpret surrounding events or participate in
higher incidence of adverse effects. illegal activities that could lead to incarceration.2-4
Medications commonly associated with phar-
macokinetic drug interactions include antibiotics
(e.g., ketoconazole, erythromycin), psychotropics PREVENTION
(e.g., fluvoxamine, fluoxetine, nefazodone), and
others (e.g., cimetidine, quinidine, protease Drug-induced psychosis may be prevented by min-
inhibitors).126,129-130 Addition of a cytochrome P-450 imizing risk factors (Table 20–8). A thorough histo-
TisdaleC20_344-356 1/12/10 2:46 PM Page 351
dramine, dextromethorphan, and caf- 11. Martin W, Unutzer J, Szuba MP. Exacerbation of
feine.24,56,94,144-145 The combination of pseu- psychosis with inhaled albuterol. J Clin Psychopharmacol.
1995;15:446-447.
doephedrine and dextromethorphan increases the 12. Gluckman L. Ventolin induced psychosis. N Z Med J.
risk of psychosis.57 In addition, patients should be 1974;80:411.
instructed to avoid excessive consumption of caf- 13. Snoey ER, Bessen HA. Acute psychosis after amantadine
feinated products.68-69 Education concerning which overdose. Ann Emerg Med. 1990;19:668-670.
foods and beverages are high in caffeine may be 14. Borison RL. Amantadine-induced psychosis in a geriatric
patient with renal disease. Am J Psychiatry. 1979;136:111-
necessary depending on the medical sophistication 112.
of the patient. 15. Food and Drug Administration Medwatch Safety Alert
In conclusion, drug-induced psychosis is often Adderall. July 2006. Available at:
a preventable disease. Careful inquiry regarding all http://www.fda.gov/medwatch/safety/2006/Jul_PIs/Adder
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SECTION V
DRUG-INDUCED
PULMONARY DISEASES
CHAPTER 21
CoraLynn B. Trewet
TABLE 21–1 Agents Implicated in Drug-Induced Interstitial Lung Disease/Pulmonary Fibrosis (Continued)
which may also contribute to pulmonary toxicity.6 Amiodarone is the most widely reported non-
Patients receiving therapy with potentially cytotoxic drug known to cause pulmonary fibro-
causative agents are often immunocompromised sis.4,6,9-23 The incidence of amiodarone-induced
and more susceptible to adverse effects.306 In addi- lung toxicity has ranged from 0.1% to 50% in var-
tion, drugs that may cause this disease are used pri- ious reports.6,9-23 Amiodarone is an example of a
marily by physicians who are not pulmonary drug that may cause interstitial pneumonitis or
specialists, and who may not recognize and diag- pulmonary fibrosis. In patients receiving intra-
nose pulmonary fibrosis.6 It is believed that, venous amiodarone, such as patients who have
because of the lack of reporting mechanisms in the undergone cardio thoracic surgery, interstitial
United States and much of Europe, the incidence pneumonitis may occur. In contrast, patients on
of drug-induced pulmonary toxicity is underesti- long-term oral amiodarone therapy are more like-
mated. A call for an international registry of ly to develop pulmonary fibrosis. 9-11,13,14 In
patients with idiopathic pulmonary fibrosis has patients receiving daily amiodarone doses of <200
been recommended, and many believe that a reg- mg, the incidence of pulmonary fibrosis is low
istry is needed for drug-induced pulmonary fibrosis (0.1–1.6%), whereas the incidence in patients
as well.307 receiving maintenance doses of >400 mg daily is
Information regarding the incidence of inter- 5% to 15%. The incidence may be even higher in
stitial lung disease associated with specific drugs is high-risk patients receiving larger doses. 9-11
somewhat scarce because of few cumulative data Approximately 1% of patients receiving gold salts
and a reliance on reported cases. However, the inci- experience pulmonary toxicity, which is similar
dence of interstitial lung disease associated with to expected incidences associated with other non-
some agents has been reported. The estimated inci- cytotoxic agents.49-51,308
dence of pulmonary fibrosis associated with
bleomycin is 4%.55-63 The incidence of carmustine-
induced pulmonary toxicity is estimated to be MECHANISMS
between 10% and 30%. One study found an inci-
dence of pulmonary toxicity of 10% in patients The exact mechanisms of pulmonary toxicity and
receiving carmustine 1,000 mg/m2, but an inci- lung injury induced by drugs are not known.
dence of 100% in those who received 1,400 mg/m2, Proposed mechanisms are based on theories of the
suggesting a dose-dependent relationship.3 The manner in which the lungs respond to injury
incidence of pulmonary fibrosis associated with (Table 21–2). Although different drugs may cause
mitomycin monotherapy is approximately 5% to pulmonary fibrosis via different mechanisms, the
10%. However, when used in combination with histopathologic changes that occur in the lungs of
vinca alkaloids, the incidence increases to patients with drug-induced pulmonary fibrosis are
35%.3,228,229 Methotrexate induces pulmonary generally similar to those in patients with idio-
fibrosis in 3% to 4% of patients when used for pathic pulmonary fibrosis, with the persistence of
rheumatoid arthritis and psoriasis, but the inci- an inflammatory lesion resulting in alveolar, capil-
dence increases to 7% when used at higher and lary, or parenchymal-cell injury.2 Abnormal repair
more frequent doses for the treatment of malig- disrupts the production of connective-tissue ele-
nancies.4,178 ments, and the normal lung is replaced by cystic
TisdaleC21_357-377 1/20/10 11:13 PM Page 362
spaces separated by thick fibrous tissue; this condi- produce an interstitial reaction that is histological-
tion is known as “honeycomb lung.”309 ly different from the marked atypical cytotoxic
Contributing mechanisms of injury include reactions. Unlike the effects of cytotoxic drugs, in
cytokine imbalance, extracellular matrix remodel- which the histology is uniform, noncytoxic drugs
ing and fibrosis, apoptosis of epithelial cells and an exert more variable toxicity reactions, ranging
imbalance of oxidants or antioxidants.2 It is from eosinophilia to noncardiac pulmonary edema
thought that lung injury promotes recruitment of to granulomatous interstitial lung disease.312 The
circulating immune cells, which work together to mechanism of amiodarone-induced pulmonary
release cytokines. Animal and human studies have toxicity is largely due to the drug’s unique pharma-
shown an influx of inflammatory cells during cokinetic properties. Amiodarone is an
bleomycin-induced pulmonary fibrosis.4 Excess amphiphilic molecule that contains a highly apo-
oxygen produces highly reactive, partially reduced lar aromatic ring system and a polar side chain
oxygen metabolites, including a superoxide anion with a positively charged nitrogen atom.4,314
(O2), hydrogen peroxide (H2O2), and the vitamin E Amphiphilic molecules are known to cause the
hydroxyl radical. The epithelial lining of the lungs inhibition of lysosomal phospholipases, which
contains many oxidants and antioxidants. Drugs results in a phospholipid storage disorder in the
such as bleomycin, cyclophosphamide, and nitro- lungs.314 During long-term therapy with amio-
furantoin can produce toxicity through increasing darone, both the drug and its metabolite accumu-
production of oxidants, while drugs such as car- late in the lung and interfere with the normal
mustine, cyclophosphamide, nitrofurantoin may processing of endogenous phospholipids, which
induce toxicity by inhibiting the antioxidant sys- also accumulate in the lung.6 The breakdown of
tem.3,308 The imbalance of oxidants and antioxi- phospholipid-laden macrophages subsequently
dants in the lower respiratory tract causes an results in pulmonary inflammation and fibro-
accumulation of inflammatory cells such as alveo- sis.4,314
lar macrophages and neutrophils.2 For example, Some mysteries still abound regarding the
bleomycin is known to be a powerful oxidizing mechanism of pulmonary toxicity associated with
agent in the presence of iron and oxygen. The oxi- other agents. For example, patients who experi-
dants generated in this reaction may lead to cellu- ence pulmonary toxicity induced by methotrexate
lar apoptosis.310 Bleomycin may also generate rarely experience recurrence upon rechallenge. It is
fibrin in the alveolar compartment.311 Bleomycin is thought that methotrexate may predispose the
best known for its characteristic bronchiolitis oblit- patient to opportunistic infections, particularly
erans with organization pneumonitis, known as Pneumocystis jiroveci pneumonia, which may be an
BOOP, or may also present as an eosinophilic underlying factor in the toxicity.308
hypersensitivity reaction.312 Both BOOP and the
hypersensitivity reaction are less prevalent in
patients with drug-induced pulmonary toxicity, CLINICAL PRESENTATION AND
but are more likely to present as interstitial pneu- DIFFERENTIAL DIAGNOSIS
monitis, which may progress to fibrosis.2
Nitrofurantoin has also been shown to exert The clinical presentation of pulmonary fibrosis is
toxic effects through production of reactive oxy- diminished lung compliance, which presents in a
gen species.313 Most noncytotoxic agents, however, manner similar to that of restrictive airway disease.
TisdaleC21_357-377 1/20/10 11:13 PM Page 363
Signs and symptoms of drug-induced pulmonary lung bases.315 In the late phases of the disease,
fibrosis are listed in Table 21–3. The majority of cyanosis, cor pulmonale, right ventricular heave,
patients describe a gradual or insidious onset of and peripheral edema may be evident.315
exertional dyspnea, and a nonproductive cough Pulmonary-function tests (PFTs) should be per-
rarely accompanied by a fever.2 The dry cough is formed as a diagnostic tool. PFTs may be normal
refractory to treatment with antitussive agents.315 initially, but may later reveal a restrictive impair-
The onset of illness may be abrupt or it may extend ment and a reduced carbon monoxide diffusing
over weeks to months.306 The duration of drug capacity (DLCO). PFTs indicating reduced total lung
therapy prior to the onset of pulmonary fibrosis is capacity and forced vital capacity suggest restric-
highly variable, and complicated by the fact that tive lung disease rather than obstructive disease. In
most patients report symptoms for more than 6 the setting of restrictive disease, the measurement
months prior to presentation. In most situations, of DLCO helps distinguish between intrinsic lung
an abrupt onset represents interstitial pneumonitis disease, in which DLCO is usually reduced, from
whereas a progressive pattern over time represents other causes of restriction, in which DLCO is usual-
pulmonary fibrosis. This often correlates with ly normal. Patients with reduced DLCO capacity by
duration of therapy, as short-term treatment is >15% from baseline should be examined for addi-
more likely to result in interstitial pneumonitis tional signs and symptoms of pulmonary toxici-
acutely whereas a longer treatment duration is ty.3,319 It is important to note, however, that
more likely to present as pulmonary fibrosis. patients in whom pulmonary fibrosis did not
Physical examination findings show digital club- develop have also been shown to have reduced
bing in 25% to 50% of cases as well as end-expira- DLCO.318 The patient may be too ill to undergo
tory crackles.2,3 The crackles are detected in more extensive PFTs beyond measurement of arterial
than 80% of patients and are described as “dry” blood gases, which often show hypoxemia, espe-
and “Velcro” in quality, with a prevalence in the cially with exercise.4,319 For this reason, PFTs may
be more helpful in monitoring of therapy rather
than diagnosis of toxicity.
Diagnosis is not definite without an examina-
TABLE 21–3 Signs and Symptoms of Drug- tion of lung tissue via lung biopsy. However, this is
Induced Interstitial Lung Disease/Pulmonary rarely a practical approach for patients in tradition-
Fibrosis al medical settings.316 Pulmonary fibrosis can also
be diagnosed using chest radiography, but it is
• Nonproductive cough important to note that this test is nonspecific.2 The
• Exertional dyspnea disease usually begins asymmetrically and appears
• Lung crackles at the bases of the lung to be very focal or unilateral upon imaging.312 In
• May experience: patients with fully developed fibrosis, the typical
• Fever chest radiograph shows diffuse opacity, which has
• Fatigue been described as “ground glass” in appearance.
• Digital clubbing One-third of all cases of idiopathic interstitial
• Later stages: pneumonitis have been reported to be overlooked
• Cyanosis by relying on chest radiography diagnosis alone.317
• Cor pulmonale The patient may be symptomatic before the chest
• Right ventricular heave radiograph appears abnormal, but high-resolution
• Peripheral edema computed tomography (HRCT) should reveal
• Abnormal chest radiograph with diffuse opacity abnormalities if this occurs.312,315 In patients with
(“ground-glass” appearance) idiopathic pulmonary fibrosis, HRCT diagnosis was
• Abnormal high-resolution computed tomography 90% accurate, and combined with clinical findings
with diffuse opacity (“ground-glass” appearance) can lead to specific diagnosis in 60% to 80% of
• Laboratory tests: cases of drug-induced pulmonary toxicity.2,315 This
• Leukocytosis has allowed for earlier diagnosis and helps to nar-
• Increased erythrocyte sedimentation rate row the wide differential diagnosis that may
include heart failure, aspiration, infection, or acute
• Pulmonary-function tests:
respiratory distress syndrome (Table 21–4).312,315,317
• Reduced total lung capacity and forced vital
Because pulmonary fibrosis is isolated to the
capacity
lungs, little systemic evidence of the disease has
• Reduced diffusing capacity for carbon monoxide
been found. Results of blood tests may be influ-
>15% from baseline
enced by concomitant illnesses, such as an ele-
TisdaleC21_357-377 1/20/10 11:13 PM Page 364
regarding gene expression in patients with pul- mg/kg daily for patients with amiodarone-induced
monary fibrosis, which may lead to preventive pulmonary fibrosis until clinical and radiographic
treatments.339 improvement occurs. If the patient does not
respond, the dose may be increased. Tapering of
prednisone therapy should occur gradually and
MANAGEMENT with caution. The total treatment duration should
be approximately 6 to 12 months. Providers should
The cornerstone of therapy for drug-induced pul- carefully monitor patients’ pulmonary function
monary toxicity is discontinuation of therapy with after corticosteroid therapy has been discontinued,
the causative agent. Corticosteroid therapy is because of the long half-life of amiodarone and the
regarded as the standard treatment, despite the fact risk of recurrence.6,319
that there has not been substantive evidence of In most documented cases of drug-induced
efficacy. More data exist regarding treatment pulmonary fibrosis, a positive clinical response
options for idiopathic pulmonary fibrosis than for has been reported within the first 7 to 10 days
drug-induced pulmonary fibrosis. Noncortico- after discontinuing the causative agent and initiat-
steroid agents that have been studied for the treat- ing therapy with corticosteroids. In some cases,
ment of pulmonary fibrosis, both drug-induced positive response has been reported even sooner.
and idiopathic, are included in Table According to guidelines, a favorable response is
21–7.311,315,316,338-349 Approximately 20% of patients depicted by a decrease in symptoms, specifically
with idiopathic pulmonary fibrosis demonstrated an improvement in dyspnea on exertion or a
clinical improvement without corticosteroid thera- decline in the frequency or severity of cough, and
py, but alternative treatment strategies have pro- a reduction in parenchymal abnormalities on
duced less favorable results.340 The American HRCT. Furthermore, physiologic improvement is
Thoracic Society (ATS) guidelines for idiopathic defined by the presence of two or more of the fol-
pulmonary fibrosis include the use of prednisone lowing: >10% increase in total lung capacity or
40 to 100 mg daily for 2 to 4 months, followed by vital capacity; >15% improvement in DLCO, or at
tapering of therapy. The ATS guidelines also recom- least 3 mL/min/mm Hg; and an improvement or
mend consideration of the addition of azathio- normalization of oxygen saturation (>4% increase)
prine or cyclophosphamide as well as colchicine or partial pressure of oxygen (>4 mm Hg from pre-
for treatment of idiopathic pulmonary fibro- vious measurement) achieved during a formal car-
sis.315,349 diopulmonary exercise test.315
For management of bleomycin-induced pul-
monary fibrosis, drug discontinuation and corti-
costeroid therapy are recommended. Agents that
have been investigated in animals include thalido- TABLE 21–7 Therapeutic Approaches for
mide, curcumin, aerosolized heparin, and Interstitial Lung Disease/Pulmonary
aerosolized urokinase.311,338,345,346 Patients may Fibrosis311,315,316,338-349
respond to treatment with corticosteroids, but pul-
Drug Dose (if known)
monary disability often remains after resolution of
symptoms.4 Patients who experience drug-induced Drug-induced
pulmonary fibrosis associated with cytotoxic Prednisone Variable start dose with extend-
agents may also experience repeated episodes of ed taper 0.75–1 mg/kg common
pneumothorax because of poor reexpansion of the Fluticasone 880 mcg inhaled twice daily
fibrotic lung.6
Idiopathic
Data are lacking with regard to the efficacy of
corticosteroids for the management of amio- Colchicine 0.6 mg 1–2 times daily
darone-induced pulmonary toxicity. However, Azathioprine 2–3 mg/kg lean body weight
some evidence suggests that corticosteroid therapy daily
delays mortality and promotes clinical improve- Cyclophosphamide 2 mg/kg lean body weight daily
ment. Recurrence of amiodarone-induced pul-
Pirfenidone
monary fibrosis was linked to early
discontinuation of corticosteroid therapy.319 For Interferon
this reason, corticosteroids are the mainstay of N-acetylcysteine
therapy, especially in situations in which discon- Leukotriene B4
tinuation of amiodarone therapy is undesirable.
Prostaglandin E2
Prednisone is recommended at a dose of 0.75 to 1
TisdaleC21_357-377 1/20/10 11:13 PM Page 369
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bleomycin induced lung fibrosis through regulation of
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CHAPTER 22
Asthma and
Bronchospasm
tively low doses of ibuprofen, naproxen, and erant asthma had bronchospasm related to aceta-
diclofenac of 98%, 100%, and 93%, respectively, in minophen ingestion.5 Furthermore, case–control
aspirin-intolerant patients.17 Drugs that are poor studies have found that increasing frequency of
inhibitors of COX-1 (acetaminophen and salsalate) acetaminophen use is associated with asthma in
or drugs that are partially selective inhibitors of adults.145,146 An ecologic study of aggregate aceta-
COX-2 (meloxicam) usually induce asthma only at minophen consumption and asthma rates in
high doses. The prevalence of acetaminophen- Europe demonstrated a 0.52% increase in the
induced bronchospasm in aspirin-sensitive prevalence of wheezing in 13- to 14-year-olds for
patients with asthma is 0% to 6% at doses of 650 each gram increase in per capita acetaminophen
mg or less,5 and most patients can tolerate aceta- sales.147 Meloxicam loses its selectivity as the dose
minophen doses up to 500 mg.102 A case–control increases, but may be tolerated in doses up to 22.5
study evaluating the cross reactivity of acetamino- mg in aspirin-intolerant patients. Bronchospasm
phen in aspirin-intolerant patients found that 24% related to selective COX-2 inhibitors has been
and 32% had bronchospasm after an oral challenge found in two case reports.148,149 However, eight
with 1,000 mg or 1,500 mg of acetaminophen, clinical trials enrolling a total of 378 patients
respectively. None of the patients with aspirin-tol- receiving therapeutic doses of celocoxib or rofecox-
TisdaleC22_379-398 1/12/10 2:49 PM Page 381
ib have found no cross reactivity between selective tion with propafenone, which has weak -blocking
COX-2 inhibitors and aspirin in aspirin-intolerant activity in the majority of patients, but which has
patients.150 The incidence of cross reactivity may more potent -blocking activity in the 7% to 10%
be small enough that the combined sample size of of patients who are poor metabolizers of
these trials may not be large enough to demon- cytochrome P-450 2D6.109
strate cross sensitivity. Angiotensin-converting–enzyme (ACE) inhi-
Bronchospasm has been reported in associa- bitor–induced cough appears to be a class effect.
tion with intravenous hydrocortisone succinate The prevalence of ACE inhibitor–induced cough in
when administered to patients with asthma,151 and the general population is approximately 10% to
in particular, aspirin-intolerant asthmatic 20%, with reports in different populations ranging
patients.152 One study found that the prevalence of from 0% to 44%.13-15 The frequency of cough
bronchospasm associated with hydrocortisone suc- caused by ACE inhibitors appears greater in
cinate in aspirin-sensitive patients was 2%.78 patients with heart failure (26%) than in patients
Bronchospasm has also been reported in associa- with hypertension (14%).156 The prevalence of ACE
tion with methylprednisolone sodium succinate. It inhibitor–induced cough and bronchospasm in
is not clear as to whether the bronchospasm is patients with reactive airway disease appears simi-
caused by the steroid moiety or the succinate.78 lar to that in the general population.13,157,158
Even at high doses, -blockers rarely cause Although the incidence of cough and bron-
bronchospasm in patients without asthma. chospasm associated with angiotensin II receptor
However, they are a common trigger of bron- antagonists is low, and they are often used in
chospasm in patients with asthma. The prevalence patients with ACE inhibitor–induced cough, cases
of bronchospasm associated with non-selective - of cough and bronchospasm have been reported in
blockers is unknown, but it has been estimated patients taking losartan.89,90
that 50% to 100% of patients with asthma exhibit Bronchospasm can occur as part of moderate
symptoms of bronchospasm after a single dose of a or severe anaphylaxis (anaphylactic or anaphylac-
nonselective -blocker.139,153 In addition to prob- toid reactions), with dyspnea and bronchospasm
lems caused by oral or intravenous administration occurring in 55% to 60% of cases.159,160 Any med-
of these drugs, fatal asthma has also been reported ication can cause anaphylaxis.161 A thorough dis-
in association with topical ophthalmic use of tim- cussion of drug-induced anaphylaxis is provided
olol.25 Because of the frequency and severity of the in Chapter 6.
reactions, nonselective -blockers are contraindi- Rarely, paradoxical bronchospasm associated
cated in patients with asthma.26 Cardioselective - with bronchodilators delivered by metered-dose
blockers decrease, but do not eliminate, inhaler or nebulization has been reported.162-166
-blocker–induced bronchospasm. At higher doses, Although the cause is unknown, it is postulated
these agents lose their selectivity, and the risk for that propellants, preservatives, or other additives
bronchospasm increases.26,154 Decreased forced may play a role. Bronchospasm occurs in up to
expiratory volume in 1 second (FEV1) and symp- 6.9% of asthmatic patients after they inhaled from
toms of bronchospasm have been demonstrated in a placebo metered-dose inhaler containing only
asthmatic patients receiving cardioselective - inert ingredients.167 The incidence of bron-
blockers.26,155 A 12-month comparative study of chospasm decreases to 1.55% to 4% when active
topical timolol and betaxolol demonstrated no sig- drug is added.67 Inactive ingredients in metered-
nificant differences between the groups in mean dose inhalers implicated include chlorofluorocar-
spirometric values or number of dropouts due to bons, sorbitan trioleate, oleic acid, and soya
respiratory symptoms.27 A meta-analysis evaluat- lecithin.67 Some reports have implicated newer
ing cardioselective -blockers in patients with reac- metered-dose inhalers containing hydrofluoroalka-
tive airway disease concluded that these agents do ne delivery systems in causing paradoxical bron-
not produce clinically significant adverse respirato- chospasm.162,164,168 However, many of these
ry effects in this population.28 However, the stud- inhalers contain similar inert ingredients.169 Other
ied populations did not include patients with preservatives and additives of concern include sul-
severe disease, and therefore, the results may not fites, benzalkonium chloride, and ethylenedi-
be extrapolated to this population. Four cases of aminetetraacetic acid (EDTA). Sulfites and
amiodarone-induced bronchospasm have been metabisulfite have been commonly used in wine,
reported.10-12 It is plausible that bronchospasm due food and some pharmaceutical products to prevent
to amiodarone use may be related to its noncom- microbial spoilage and oxidative discoloration.
petitive inhibition of -adrenergic receptors. Sulfites are no longer used in inhaled asthma
Bronchospasm has also been reported in associa- drugs. However, sulfites are still used in injectable
TisdaleC22_379-398 1/12/10 2:49 PM Page 382
forms of isoproterenol and epinephrine. Sulfite- new coccine, ponceau, quinolone yellow, and sun-
induced bronchospasm rarely occurs in patients set yellow.2,67,123
without airway hyperresponsiveness.67 The preva-
lence of sulfite sensitivity in patients with asthma
has been reported to be 5% to 11%.123,124 However, MECHANISMS
more recent reports have indicated that approxi-
mately 5% of steroid-dependent asthmatic patients Drug-induced asthma or bronchospasm can be
and 1% of asthmatic patients who do not require caused by several mechanisms. Most reports of
steroids are sensitive to sulfites.125 Benzalkonium bronchospasm are isolated cases, and the mecha-
chloride is a bacteriostatic agent that is still found nism is unknown. Mechanisms of bronchospasm
in some multidose vials of albuterol and metapro- associated with individual drugs, when known, are
terenol. EDTA is a stabilizing agent that is also listed in Table 22–2. Bronchospasm can be caused
found in some nebulizer preparations. Both com- by a direct irritation of the airway such as that
pounds have been implicated as a potential cause caused by N-acetylcysteine or bisulfites, IgE-medi-
of paradoxical bronchoconstriction induced by ated reactions in anaphylaxis, precipitation of IgG
nebulized medications.67,68,166 Inhalation of benza- antibodies such as that which may occur in associ-
lkonium chloride causes dose-related cumulative ation with methyldopa, mast-cell degranulation in
bronchoconstriction.67 In amounts similar to those anaphylactoid reactions, or as a result of an intend-
present in multiple-dose vials of albuterol (300 µg), ed or unintended pharmacologic effect in patients
benzalkonium chloride caused marked bron- taking aspirin or -blockers.2
choconstriction in 61% of patients and enhanced Aspirin-induced asthma is a variant of
lung response to inhaled histamine 1 hour later.68 non–drug-induced asthma, characterized by pro-
However, when patients inhaled a single dose of gressive airway inflammation and hyperreactivity,
albuterol with or without benzalkonium chloride, and is associated with exacerbations of asthma and
no difference was seen in pulmonary function.68,166 rhinitis after the ingestion of aspirin and most
EDTA is added to some pharmaceutical prepara- other NSAIDs.170 Airway hyperreactivity and
tions as a chelating agent to prevent solution dis- inflammation are progressive and independent of
coloration.68 Although EDTA has been shown to aspirin exposure, which serves as a trigger for an
cause bronchoconstriction when large doses are acute reaction. Aspirin-induced asthma is charac-
inhaled,20 clinically important bronchospasm did terized by an association between aspirin intoler-
not occur when concentrations similar to those ance, asthma, and nasal polyposis, referred to as
found in commercial products were used.69 the “aspirin triad” or “Samter’s syndrome.”171,172
A number of case reports of bronchospasm The mechanism of AIA is not completely under-
related to tartrazine, an azo dye used in food and stood.173 It is unlikely that the response to aspirin is
drugs (FD&C Yellow No. 5), have been reported, caused by an IgE-dependent mechanism, because of
primarily in aspirin-sensitive patients.2,123,130 The the cross reactivity between aspirin and NSAIDs with
prevalence of tartrazine-induced bronchospasm is dissimilar chemical structures, because NSAIDs that
unknown, but it appears to occur almost exclusive- do not inhibit COX do not precipitate bron-
ly in aspirin-sensitive patients.2,130 Cross sensitivity chospasm, and because cross desensitization occurs
of tartrazine with aspirin in aspirin-sensitive with other NSAIDs with dissimilar chemical struc-
patients with asthma was initially estimated to be tures after aspirin desensitization. Currently pro-
between 7% and 26%, although most of these stud- posed mechanisms of AIA are presented in Figure
ies were unblinded and poorly controlled.2,123,130 22–1. Aspirin-induced asthma is characterized by
The incidence of cross reactivity to tartrazine in increased production of cysteinyl leukotrienes (Cys-
aspirin-sensitive patients is more likely to be 0% to LTs; leukotrienes C4, D4, and E4) and eosinophilic
2.4%.67,130,131 However, because of the perceived infiltration.173 Cys-LTs are metabolic products of
potential for serious reactions, and the ubiquity of phospholipid metabolism. Once phospholipid is lib-
tartrazine in food and nonprescription and pre- erated from the nuclear membrane, it is converted by
scription medications, the Food and Drug phospholipase A2 to arachidonic acid, which is then
Administration requires all products containing biotransformed into thromboxanes and
tartrazine to list this compound as an ingredient prostaglandins by COX-1 or COX-2, or lipoxins and
on the package label.2,67,130 Rarely, patients with 5-hydroperoxyeicosatetraenoic acid (5-HETE) by 5-
AIA may demonstrate similar reactions to other lipoxygenase (5-LO) and 5-lipoxygenase activating
dyes, such as amaranth, brilliant blue (FD&C Blue protein (FLAP). 5-HETE is further metabolized by 5-
No. 1), erythrosine, indigo carmine (indigotin, LO/FLAP to leukotriene A4 (LTA4), which is then con-
FD&C Blue No. 2), FD&C Red No. 40, methyl blue, verted to leukotriene B4 by LTA4 hydrolase or
TisdaleC22_379-398 1/12/10 2:49 PM Page 383
leukotriene C4 (LTC4) by LTC4 synthase. LTC4 is con- AIA.175 Cys-LTs are potent inflammatory mediators
verted to leukotriene D4 (LTD4) by ␥-glutamyl causing eosinophil chemotaxis, microvascular per-
transpeptidase, which is then metabolized by dipep- meability, mucous-gland secretion, and bronchocon-
tidase to leukotriene E4 (LTE4).173,174 Cys-LTs are striction.176 Compared with eosinophils from aspirin
thought to be the primary mediators of AIA, as tolerant asthmatics, circulating blood eosinophils
biosynthesis of Cys-LTs appears to be up regulated in from patients with AIA carry larger amounts of LTC4
TisdaleC22_379-398 1/12/10 2:49 PM Page 384
Phospholipid
Phospholipase A2
LTC4 LTB4
PGD2
␥-Glutamyl transpetidase
LTD4
Pro-Inflammatory Anti-Inflammatory
Dipeptidase
LTC4 PGD2 PGE2
LTD4 PGF2 PGI2
LTE4 TXA2 LXA4 LTE4
LTB4
synthase, the rate-limiting enzyme for Cys-LT pro- inflammatory mediators.178 COX enzymes metabo-
duction. Patients with AIA have a larger quantity of lize arachidonic acid to the proinflammatory medi-
eosinophils in bronchial tissue compared to patients ators prostaglandins D2 (PGD2) and F2␣ (PGF2␣),
with aspirin tolerant asthma, and Cys-LT concentra- and the antiinflammatory mediator prostaglandin
tions in bronchial lavage fluids correlate with the E2 (PGE2).180 Exposure to aspirin and most NSAIDs
degree of eosinophilic infiltration of bronchial tissue results in decreased production of COX metabolic
in patients with AIA.177 In addition, LTC4 synthase is products such as prostaglandin E2, which normally
overexpressed in the bronchial mucosa of patients inhibits 5-lipooxygenase (LO).176 Inhaled PGE2 pro-
with AIA.177 A single nucleotide polymorphism, tects against aspirin-induced bronchospasm and
A(–444)C (rs730012) in the promoter gene for LTC4 decreases the amount of LTE4 secreted in the urine
synthase associated with severe AIA has been identi- in patients with AIA.180 Plasma concentrations of
fied in Polish and Japanese patients and appears to PGD2 and PGF2␣ are lower in aspirin-tolerant asth-
be a marker of severe AIA. This allele is not associat- matic patients as compared with patients with AIA,
ed with AIA as a whole, nor has it been associated and concentrations of PGE2 and thromboxane B2
with mild disease.178 are decreased in patients with AIA.179,181 In patients
It is postulated that aspirin and NSAID inhibi- with AIA, lipoxin biosynthesis may be
tion of COX forces arachidonic acid through the reduced.178,182 Lipoxin A4 attenuates LTC4-induced
leukotriene metabolic pathway.179 COX exists in bronchoconstriction, and aspirin-derived lipoxins
several isoforms, with COX-1 expressed constitu- may contribute to the antiinflammatory action of
tively in most tissues and COX-2 induced by the drug. When inhibited by aspirin, COX-2 has
TisdaleC22_379-398 1/12/10 2:49 PM Page 385
the ability to create 15-hydroxyeicosatetraenoic and PGE2, which can activate rapidly acting recep-
acid, which is further converted by 5-LO to lipoxin tors of the afferent neuronal pathway, stimulating
epimers.183 Altered COX-2 regulation and function the cough reflex.13,188 In addition, bradykinin,
may be responsible for decreased production of PGI2, and PGE2 can directly activate unmyelinated
lipoxins and PGE2.183 Thus, decreased production sensory C fibers, which are involved in the cough
of PGE2 and lipoxins in conjunction with height- reflex.187-189 The accumulation of substance P may
ened biosynthesis of leukotrienes may precipitate also play a role in ACE-inhibitor–induced cough, as
bronchoconstriction in patients with AIA.180 it serves as a neurotransmitter for the afferent neu-
Therefore, AIA appears to be a complicated interac- rons, in particular sensory C fibers, and can cause
tion involving the imbalance of proinflammatory bronchoconstriction.187,189 Also, a genetic predis-
and antiinflammatory eicosanoids. position for ACE-inhibitor–induced cough may
-Blockers competitively inhibit stimulation of exist.190 Polymorphism in the genes for ACE191 and
-adrenergic receptors, resulting in unopposed the bradykinin B2 receptor192,193 have been associ-
parasympathetic tone.26,139 Both 1- and 2-adrener- ated with ACE-inhibitor–induced cough.
gic receptors exist in the heart and the lungs, but 1- Paradoxical bronchospasm after medication
receptors are found primarily in the heart, whereas inhalation may be caused by several different mech-
the density of 2-receptors is fourfold greater than anisms, including turbulent airflow due to inappro-
1-receptors in the lungs.139 In general, -blockade priate inhaler use, the deep inspiratory maneuver
does not cause bronchospasm in healthy individuals. used for drug inhalation, IgE-mediated reactions to
However, in almost all asthmatic patients, nonselec- product excipients (e.g., soy lecithin), bronchial irri-
tive -receptor inhibition causes bronchospasm.184 tation caused by propellants (e.g., chlorofluorocar-
In addition, nonselective -blockade increases non- bons), excipients in metered-dose inhalers (e.g.,
specific bronchial hyperresponsiveness in asthmatic oleic acid), and hyperosmolar or acidic nebulizer
patients.139 Bronchospasm induced by -blockers solutions. Bronchospasm may also be caused by
may also occur when the drug is administered via the preservatives (e.g., sulfites, benzalkonium chloride,
ocular route. -Blockers administered topically into EDTA) in nebulized solutions.162,165,194 Three differ-
the eye drain into the nasolacrimal duct and are ent mechanisms have been proposed to explain sul-
absorbed via the nasal mucosa, bypassing first-pass fite-induced bronchospasm.2 First, initial reports
metabolism.185,186 Thus, the plasma concentrations indicated that sulfite-related bronchospasm was
resulting from two drops of timolol 0.5% given via caused by an IgE-mediated reaction, and there are
the ocular route can approximate those that are reports of anaphylactic reactions in patients with
achieved following a 10-mg oral dose.185 positive sulfite skin tests.125 Second, sulfite may be
Nonselective -blockade substantially shifts the converted to sulfur dioxide in an acidic or warm
dose–response curve of inhaled 2-adrenergic agonist environment.2,125 Sulfur dioxide may cause bron-
(2-agonists), limiting their effectiveness in reversing choconstriction by a direct effect on tracheal
bronchospasm caused by nonselective -blockers. bronchial receptors causing a cholinergic reflex or
Cardioselective -blockers preferentially bind to 1- augmenting mast-cell mediator release.194,195 Sulfur
adrenergic receptors, but this selectivity is attenuated dioxide concentrations of 0.1 to 6 ppm have been
at higher doses. Bronchospasm caused by cardiose- reported in commercially available nebulizer solu-
lective -blockers may be easier to reverse with tions. When exercising, sensitive patients with asth-
inhaled 2-agonists.26,155 ma may experience bronchospasm when inhaling as
The mechanism of ACE-inhibitor–induced little as 0.1 ppm, and 6 ppm may cause bron-
cough has not been clearly elucidated. In addition chospasm in patients without asthma.194 Finally, a
to converting angiotensin I to angiotensin II, ACE reduction in the concentration of sulfite oxidase,
is a kinase responsible for metabolism of the proin- the enzyme responsible for the final oxidation of
flammatory kinins bradykinin, substance P, and sulfite to inactive sulfate, has been demonstrated in
neurokinin A.139 It has been proposed that ACE- sulfite-sensitive asthmatic patients.124,195
inhibitor–induced cough may result from the accu- It is thought that benzalkonium chloride caus-
mulation of these substances in the lungs. es bronchospasm by causing nonspecific histamine
Bradykinin and substance P activate mast cells, release from mast cells due to direct surface activa-
releasing proinflammatory mediators.187 In addi- tion and the stimulation of central and neural
tion, bradykinin is a vasodilator and increases vas- pathways in the lung.21,22 The response is dose-
cular permeability. Inhaled bradykinin causes related over a dose range of 0.13 to 2.0 mg/mL and
bronchospasm. These actions may be mediated increases with subsequent doses.166,194 A decrease
through bradykinin-induced increases in the pro- in FEV1 of >20% has been demonstrated in associa-
duction of thromboxane A2, prostacyclin I2 (PGI2) tion with benzalkonium chloride doses ranging
TisdaleC22_379-398 1/12/10 2:49 PM Page 386
ACE-inhibitor–induced cough is typically char- life, and the disease was more progressive and
acterized as dry, irritating and nonproductive with severe.211 A study of 300 patients in the United
a persistent tickling sensation in the back of States found the prevalence to be only 1.3 times
the throat.14,15 The cough may present within greater in women than in men, and the severity of
hours of the first dose, or it may be delayed up to the disease was similar in both sexes.213 There
12 months after the initiation of therapy. ACE- appears to be no ethnic or familial distribution of
inhibitor–induced cough may cause hoarseness, AIA, with only 6% of patients in the European
vomiting, and stress incontinence, and the cough study and 1% in the U.S. study having a family his-
may worsen in the supine position or at tory of AIA.211,213
night.189,207 Although the cough may resolve with- Some patients with aspirin intolerance do not
in a week after the discontinuation of ACE- have concomitant asthma. These patients experi-
inhibitor therapy,189 it may linger for 1 to 3 ence urticaria and gastrointestinal effects but not
months in some individuals.14 The differential bronchospasm. In general, the more severe the
diagnosis of ACE-inhibitor–induced cough underlying, preexisting asthma, the greater the risk
includes asthma, chronic smoking, COPD, post- of drug-induced bronchospasm.
nasal drip, heart failure, upper-respiratory-tract ACE-inhibitor–induced cough occurs more
infection, and gastroesophageal reflux.189,207,208 often in female patients,209,214,215 in patients of East
Diagnosis of ACE-inhibitor–induced cough Asian descent,216-218 and in the elderly.217 One
requires discontinuation of the drug and monitor- study219 indicated a higher incidence of ACE-
ing of the cough. Diagnosis is confirmed by resolu- inhibitor discontinuation because of cough in
tion of the cough within 1 to 4 weeks after African-Americans, but a meta-analysis218 did not
discontinuation. The cough usually recurs upon confirm these findings. Patients with chronic lung
rechallenge with the same or another ACE disease such as COPD or asthma do not appear to
inhibitor.209 be at a greater risk for cough associated with ACE
Patients with paradoxical responses to inhaled inhibitors.13 Patients with heart failure have a
drugs demonstrate a lower-than-expected response higher incidence of cough, but it is unclear
to the drug or worsening of their pulmonary symp- whether the cough is related to ACE inhibitors or
toms. The response is usually rapid, and may occur diminished left ventricular function.156
within minutes of inhaling the agent.210 Patients
with known severe asthma have reported severe
wheezing, chest tightness, and dyspnea after MORBIDITY AND MORTALITY
ingesting sulfite-containing foods. The diagnosis of
sulfite sensitivity is made by taking a detailed his- Any drug reaction that causes acute bronchospasm
tory and may be confirmed by rechallenge.67 or worsens asthma has the potential to negatively
impact patient morbidity and mortality. Patients
with AIA tend to have more severe asthma. In
RISK FACTORS these patients, aspirin therapy may be associated
with aggressive airway remodeling and, in some,
Risk factors for drug-induced asthma and bron- decreased diffusion capacity. A study evaluating
chospasm are listed in Table 22–5. The principal factors associated with the development of severe
risk factor for drug-induced bronchospasm is pre- asthma found that >30% of patients with severe
existing asthma. However, smoking, preexisting asthma experienced aspirin intolerance, and
airway disease, older age, and respiratory infection aspirin was a significant risk factor for the develop-
may also increase the risk for drug-induced bron- ment of severe asthma (odds ratio 5.44; 95% confi-
chospasm.3 dence interval [CI], 2.47–8.41)].220 Another study
Aspirin-induced asthma occurs primarily in evaluating 3307 adult patients with severe or diffi-
adults and generally does not manifest until the cult-to-treat asthma demonstrated that the mean
20s or 30s.170 The frequency of AIA increases with percent predicted postbronchodilator FEV1 was
age, and the incidence is fourfold higher in decreased in those who were aspirin-intolerant as
patients 40 years of age or older as compared with compared with those who were aspirin-tolerant,
those younger than 20.2 Women are affected 2 to and patients with aspirin-intolerant asthma were
2.5 times more often than men.141,211,212 In a study more likely to be assessed by physicians as having
of 500 aspirin-intolerant asthmatic patients from severe asthma.221 A greater percentage of aspirin-
10 European countries, the prevalence of AIA was intolerant subjects had a history of intubation
2.3 times greater in women than in men. In (20% vs. 11%), and over a 3-month period, had
women, the onset of symptoms occurred earlier in more unscheduled office visits (54% vs. 44%) and
TisdaleC22_379-398 1/12/10 2:49 PM Page 389
emergency department visits (18% vs. 13%).221 A apy, decreased quality of life, or greater use of
survey of 500 patients with AIA in 10 European health care resources.189 Patients may seek nonpre-
countries found that inhaled and oral corticos- scription or prescription medication to relieve the
teroids were required in 80% and 50% of the cough.
patients, respectively. The average corticosteroid The morbidity and mortality associated with
dose was equivalent to prednisone 8 mg daily.211 In paradoxical bronchospasm is unknown. However,
a 6-year follow-up of 145 patients with asthma, an ineffective or worsening response from a bron-
25% of those who underwent mechanical ventila- chodilator during an active asthma attack could
tion had aspirin intolerance.222 NSAID exposure lead to significant morbidity.
has also been shown to be a risk factor for rapid-
onset fatal or near-fatal asthma.223 However,
aspirin-induced asthma is not a risk factor for mor- PREVENTION
tality if aspirin and NSAID avoidance is ensured.224
The risk of increased morbidity and mortality The primary strategy for preventing drug-induced
due to -blocker–induced bronchospasm is asthma or bronchospasm is avoidance of causative
unknown, but fatalities due to bronchospasm agents (Table 22–6). Alternative analgesic treat-
caused by these agents have occurred.25 ments for patients with AIA include acetamino-
Furthermore, -blockers shift the dose–response phen, salsalate, meloxicam, and celecoxib.139,150,226
curve for 2-agonists to the right, making bron- Cases of successful use of COX-2 inhibitors have
chospasm caused by -blockers more difficult to been reported.227 However, there have also been
treat.139 One retrospective analysis of emergency reports of bronchospasm induced by COX-2
room visits and hospitalizations found that, as inhibitors.228 Eight combined studies (n=206)
compared with controls, patients with asthma tak- demonstrated that COX-2–selective NSAIDs may
ing cardioselective -blockers were at increased risk be used safely in patients with AIA.150 All NSAIDs,
of emergency room visits (relative risk [RR], 1.40; including those that are COX-2 selective, should be
95% CI, 1.20–1.60] and combined hospital and used with caution because of the black-box warn-
emergency room visits (RR, 1.34; 95% CI, 1.16- ings associated with their use. These warnings
1.55). Patients with COPD taking cardioselective - include increased risk of serious cardiovascular
blockers also had an increased risk for emergency thrombotic events, including myocardial infarc-
room visits (RR, 1.19; 95% CI, 1.02–1.39).225 tion and stroke, as well as increased risk of serious
Despite these risks, the morbidity and mortality gastrointestinal adverse events such as bleeding,
benefits of -blockers in some populations—such ulceration, and perforation of the stomach or
as patients who have had a myocardial infarction— intestines. These adverse effects may be fatal.229
are significant, and the risks and benefits of the use According to a systematic review, fewer than 2% of
of a cardioselective -blocker should be evaluat- patients are sensitive to both aspirin and acetamin-
ed.154 ophen, and reactions associated with acetamino-
Although rare, ACE inhibitors can contribute phen have a tendency to be less severe.17
to deteriorating lung function in patients with Acetaminophen and salsalate are poor COX-1
asthma.187 The persistent cough associated with inhibitors and reactions typically emerge after
ACE inhibitors may cause discontinuation of ther- ingestion of high doses (acetaminophen
1,000–1,500 mg or salsalate 2,000 mg). Even at LT1 receptor antagonists (zafirlukast and mon-
these high doses, adverse effects are milder than telukast) should play a role in the management of
those experienced with older NSAIDs and AIA.150 In one small study (n = 7), patients after an
aspirin.230 Aspirin desensitization is a possible aspirin challenge demonstrated a mean maximal
alternative if avoidance of aspirin, aspirin-contain- decrease in FEV1 of 4.9% with placebo compared to
ing products, or NSAIDs in patients with AIA is not a 2.9% decrease with zileuton. Only two patients in
possible. Aspirin desensitization, a process involv- the study experienced complete inhibition of
ing repeated exposure to aspirin in increasing aspirin-induced respiratory adverse effects.232
doses in order to eliminate adverse effects related Another small study (n = 6) evaluated the effect of
to its use, allows patients to take aspirin or cross- zileuton and placebo before and during an aspirin
reacting NSAIDs.139,170,230 Numerous aspirin desen- challenge. The mean aspirin dose provoking a res-
sitization protocols exist. One protocol involves piratory reaction ranged from 57 mg (30–100 mg)
administering small doses of aspirin every 2 to 24 during initial challenge and increased to 122 mg
hours until 400 to 650 mg is tolerated by the (45–325 mg) in patients taking zileuton 600 mg
patient.150 Another protocol desensitizes patients four times daily. No participants were able to toler-
over several days, after which a maintenance dose ate typical aspirin doses, and the authors conclud-
of 650 mg twice daily is prescribed.231 The effects of ed that the dose of zileuton was inadequate in
aspirin desensitization last indefinitely after the preventing aspirin-induced respiratory reac-
desensitized state is achieved, but long-term thera- tions.233 A study of similar design (n = 8) demon-
py is necessary to maintain desensitization.150,231 In strated much different results with zileuton,
addition to benefiting from aspirin or NSAID use, showing decreased LTE4 excretion and a FEV1
one long-term study demonstrated improvements decrease of 18.6% with placebo as compared with
in clinical courses, decreased steroid doses, and 4.4% after zileuton.234 Differences between the
improved global assessment scores after 6 months studies may be due to differences in zileuton doses.
of aspirin 1,300 mg daily in patients with AIA. One study used escalating doses of zileuton, where-
These improvements did not diminish during the as the other used a previously determined thresh-
remaining 1 to 5 years of the study.231 old dose. Differences between the studies may also
Because of the benefits demonstrated with - be related to differences in disease severity of the
blockers, their use may be necessary in patients patients studied.235 Montelukast, a leukotriene-
with comorbid or preexisting conditions, such as receptor antagonist, has also been studied in
myocardial infarction, angina pectoris, hyperten- patients with AIA. In a small study of the effects of
sion, arrhythmias, or heart failure.155 Nonselective montelukast in which patients with AIA took esca-
-blockers are contraindicated in patients with lating doses of aspirin, 9 of 10 patients experienced
asthma. However, one meta-analysis concluded respiratory effects and only 1 patient was protected
that -blockers that are selective for 1-receptors while taking therapeutic doses of aspirin.231
should not be avoided in patients who may bene- Although leukotriene modifiers may play a role in
fit from their use.28 Reports of bronchospasm with AIA, insufficient evidence exists to determine the
low doses and 2-receptor blockade associated with exact role. Patients taking a 5-lipoxygenase
high doses of cardioselective -blockers have been inhibitor or a Cys-LT1 receptor antagonist should
documented. Therefore, the chosen cardioselective continue to exercise caution with aspirin, NSAIDs,
-blocker should have a short half-life and be initi- and other cross-reacting agents, because bron-
ated at the lowest possible dose, upward titration chospasm may occur.150
of which should occur slowly.155 Although cardios- Older studies have demonstrated the effective-
elective -blockers are associated with a lower inci- ness of the inhaled anticholinergic bronchodila-
dence of respiratory adverse effects than tors ipratropium and oxatropium in patients with
nonselective -blockers, both types should be -blocker–induced bronchoconstriction. Ipratro-
avoided in patients with severe asthma. Patients pium is the preferred treatment for -blocker–
requiring therapy with a topical ophthalmic - induced bronchospasm (Table 22–7).1 Other med-
blocker to decrease intraocular pressure should also ications that have been documented to reverse -
use a cardioselective agent such as betaxolol.155 blocker–induced bronchospasm include 2-
agonists, atropine, aminophylline, isoproterenol,
steroids, halothane, and glucagon.155
MANAGEMENT Once ACE inhibitor-induced cough is suspect-
ed, the agent should be discontinued to determine
Based on one of the proposed mechanisms of AIA, whether the cough is drug-induced.189 The cough
both 5-lipoxygenase inhibitors (zileuton) and cys- usually resolves within 7 days, but may take as
TisdaleC22_379-398 1/12/10 2:49 PM Page 391
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SECTION VI
DRUG-INDUCED
CARDIOVASCULAR DISEASES
CHAPTER 27 Hypertension
CHAPTER 28 Hypotension
CHAPTER 23
Kevin M. Sowinski
TABLE 23–1 Agents Implicated in Drug-Induced Myocardial Ischemia and/or Acute Coronary Syndromes
Drug Incidence Level of Evidence
(see page xii for explanation)
Drug Discontinuation3-16
Argatroban NK C
Aspirin NK C
-blockers NK C
Clonidine NK C
Clopidogrel NK C
Heparin NK C
Nitroglycerin NK C
Analgesics7, 17-27
NSAIDs A,B,C
Selective COX-2 inhibitors RR: 1.86
Non-selective NSAIDS RR: 1.51, 1.63
Narcotics NK C
Other Analgesics
Ketamine NK C
Gold sodium thiomalate NK C
Nefopam NK C
Penicillamine NK C
Anti-HIV 111-118
Abacavir, didanosine RR: 1.49-1.89 B
Protease inhibitors RR: 1.15 B
Cardiovascular Drugs
Calcium channel blockers17, 155-180 NK C
ACE inhibitors17, 181, 182 NK C
-adrenergic blockers17, 171, 174, 183-186
[ophthalmic and systemic] NK C
Stress testing agents /-adrenergic receptor agonists187-209 NK C
Other Cardiovascular Drugs17, 210-215
Alfuzosin NK C
Diazoxide NK C
Disopyramide NK C
Diuretics NK C
Encainide NK C
Fenoldopam NK C
Hydralazine NK C
Isosorbide dinitrate (sublingual) NK C
Minoxidil NK C
Nitroprusside NK C
Prazosin NK C
Propafenone NK C
(Continued)
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TABLE 23–1 Agents Implicated in Drug-Induced Myocardial Ischemia and/or Acute Coronary Syndromes (Continued)
Drug Incidence Level of Evidence
Hormones/Hormone Modifying Agents17, 216-256
Female sex hormones 0-5 fold increase in risk A
Corticosteroids (oral) NK C
Desmopressin NK C
Leuprolide NK C
Oxytocin NK C
Prostaglandin F2 (dinoprost) NK C
Prostaglandin E2 (sulprostone) NK C
Tamoxifen NK C
Thyroid hormone NK C
Vasopressin NK C
Illicit Drugs 17,26,122,257-318
Amphetamines NK C
Anabolic steroids NK C
Butane inhalation NK A
Cocaine MI: 0.7-6.0%
Chest pain: 39.4% A
Glue sniffing NK C
LSD NK C
Marijuana NK C
Heroin NK C
Toluene inhalation NK C
Others:35, 111-113, 122, 317, 350-377 378-410
Acetylcholine NK C
Allopurinol NK C
Anesthetics28-31 NK C
Anti-cancer agents32-81,82-100 NK C
Antidepressants17, 101-110 NK C
Anti-infectives17, 119 NK C
Antimigraine17, 122-149 NK C
Antipsychotics17, 108, 120, 121 NK C
Azaribine NK C
Beclomethasone NK C
Blood modifiers17, 150-154 NK C
Bromocriptine NK C
Caffeine NK C
Cetirizine NK C
Cimetidine NK C
Cisapride NK C
Dolasetron NK C
Ethanol NK C
(Continued)
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TABLE 23–1 Agents Implicated in Drug-Induced Myocardial Ischemia and/or Acute Coronary Syndromes (Continued)
Drug Incidence Level of Evidence
Iloprost NK C
Immune modulators319-323 NK C
Ioversol NK C
Nicotine NK C
Ondansetron NK C
Rosiglitazone Odds ratio 1.43 B
Sildenafil NK C
Sympathomimetics17, 104, 283, 295, 324-349 NK C
Terfenadine NK C
Theophylline NK C
Tegaserod NK C
ACE = Angiotensin-converting enzyme; COX = Cyclooxygenase; HIV = Human immune deficiency virus; LSD = Lysergic acid diethylamide;
MI = Myocardial infarction; NSAID = Nonsteroidal antiinflammatory drug; NK = not known; RR = relative risk
Data regarding drugs that may cause myocar- ously, they nevertheless suggest that drug-induced
dial ischemia or infarction were provided in a paper ischemia and acute coronary syndromes are a com-
summarizing 20 years of reports (1975–1994) to a mon and important problem. Because of the
Netherlands national center for adverse drug nature of these reports, the underlying conditions
reporting.17 During this period, 19,141 adverse drug of the patients cannot be determined.
reactions were reported, of which 220 described With the exception of certain groups (e.g.,
likely cases of drug-induced chest pain or myocar- cocaine users, patients with chronic coronary artery
dial infarction. The article describes 183 cases for disease, or those at high risk for coronary events)
which sufficient data were provided to evaluate the the incidence of these drug-induced diseases is like-
cases and adjudicate the findings. Data obtained ly to be low. However, several drugs/drug classes,
from spontaneous reporting systems such as that in including cocaine, oral contraceptives/hormone-
this article or from reports to the Food and Drug replacement therapy, cytotoxic agents, ergot alka-
Administration (FDA) must be interpreted cautious- loids, and triptans may cause myocardial ischemia
ly, as they typically suffer from both underreporting or acute coronary syndromes in individuals who do
and selective reporting. Of particular note in this not have clinically evident cardiovascular dis-
article is the absence of several classes of drugs or ease.290 To put into perspective the difficulty of
drug classes that are well known to cause myocar- determining the incidence of drug-induced
dial ischemia or infarction, specifically cocaine and ischemia and acute coronary syndromes, it is help-
cytotoxic drugs. In addition, the underlying dis- ful to review the epidemiology of myocardial
eases of those patients for which adverse drug reac- ischemia and acute coronary syndromes associated
tions were reported are not described. with cocaine and oral contraceptives, the drugs for
which the most data are available. The risk of
cocaine-induced myocardial infarction is estimated
EPIDEMIOLOGY to be 24 to 31 times the baseline risk during the first
hour after cocaine exposure.286,287,291 The reported
The incidence of drug-induced ischemia and acute lifetime risk of acute myocardial infarction in
coronary syndromes in the general population is chronic cocaine users is 6 to 7 times greater than
unknown and, with the exception of a small num- that in nonusers. In view of the fact that 25 million
ber of drugs, nearly impossible to determine. Americans have used cocaine at least once in their
Nonetheless, drug-induced acute coronary syn- lifetime, cocaine-induced myocardial ischemia/
drome and ischemia are not trivial. Both chest pain infarction has the potential to be a major public
and myocardial infarction were among the most health problem. In the year 2000, 175,000 emer-
common adverse events with serious outcomes gency room visits were cocaine-related, 40% of
reported to the FDA’s voluntary reporting system which included patients with chest discomfort.
between 1969 and 2002.412 While these reporting Cocaine or cocaine metabolites are detectable in the
systems are flawed for the reasons discussed previ- urine of 14% to 25% and 7% of patients presenting
TisdaleC23_399-427 1/20/10 11:24 PM Page 405
to the emergency room with nontraumatic chest myocardial infarction.7,18,411 Prospective well-
pain in urban and suburban hospitals, respectively. designed studies comparing the effects of COX-2
Although these data do not provide the actual inci- inhibitors to those of other NSAIDs are not avail-
dence of chest pain or acute coronary syndrome able, although until recently it was thought that
associated with cocaine, they do provide some nonselective NSAIDs did not increase cardiovascular
alarming information regarding the epidemiology risk. While these trials have limitations, it seems
and potential impact of this drug-induced dis- clear that there is an increase in risk associated with
ease.286,287,290,291 The actual incidence of cocaine- both selective and nonselective NSAIDs and that the
induced myocardial infarction among patients who risk is variable within each group of agents. The data
present to the emergency department with cocaine- suggest that the cardiovascular risk is highest with
induced chest pain is highly variable, but it is rofecoxib, followed by celecoxib and diclofenac, fol-
thought to range between 0.7% and 6.0 %.413-416 lowed by naproxen and ibuprofen. Whether this is
Soon after oral contraceptives became available due to decreasing COX-2 selectivity from rofecoxib
in the early 1960s, the first case report of myocardial to ibuprofen is a topic of considerable debate.22
infarction associated with these drugs was pub- Two of the selective COX-2 inhibitors, rofecoxib
lished.417 Since then, controversy regarding the and valdecoxib, were withdrawn voluntarily from
potential for myocardial ischemia/infarction the worldwide market in September 2004 and April
induced by oral contraceptives and other female hor- 2005, respectively. “Black box” warnings for the
mones has lingered. Because exogenous female hor- remaining selective COX-2 inhibitor, celecoxib, and
mones (i.e., oral contraceptives and all other NSAIDs except aspirin were added to pack-
hormone-replacement therapy) are used by millions age inserts in 2006, stating: “NSAIDs may cause an
of women worldwide, the importance of the poten- increased risk of serious cardiovascular thrombotic
tial for myocardial ischemia or acute coronary syn- events, myocardial infarction, and stroke, which can
dromes associated with these agents is clear. Usually, be fatal. This risk may increase with duration of use.
oral contraceptives are taken by otherwise healthy Patients with cardiovascular disease or risk factors
young women with a low background risk of coro- for cardiovascular disease may be at greater risk.” At
nary artery disease and resulting myocardial the very least, these new warnings should cause
ischemia or acute coronary syndromes. Numerous health care professionals to question the routine use
studies have been conducted to determine the risk of of these agents in patients with cardiovascular dis-
an acute coronary syndrome or other coronary event ease. The concerns have led to a scientific statement
associated with oral contraceptive drugs, but the risk from the American Heart Association with recom-
remains poorly defined. Depending on the study mendations for the clinical use of these agents.421
conducted, type and dose of oral contraceptive used,
and population studied, the degree of increased risk
of myocardial ischemia/infarction associated with
oral contraceptives varies widely, from no increased
MECHANISMS
risk to a fivefold higher risk.417 The hazard increases
Mechanisms of drug-induced myocardial ischemia
in women who smoke, have hypertension, or are
and/or acute coronary syndromes are listed in
over the age of 35 years.417 The effect of hormone-
Table 23–2.
replacement therapy on the risk of coronary events is
better established. Numerous studies have been pub-
lished that have called into question the safety of use
Drug-Induced Myocardial Ischemia
of hormone-replacement therapy for reducing the Myocardial ischemia results from an imbalance in
risk of primary or secondary coronary events.418,419 In coronary blood flow, myocardial oxygen supply, and
January 2003, the FDA approved new labeling for all the metabolic needs of the myocardium (myocardial
estrogen and estrogen/progesterone products, high- oxygen demand). Myocardial ischemia occurs when
lighting “the increased risk for heart disease, heart myocardial oxygen demand exceeds myocardial oxy-
attacks” and that “these products are not approved gen supply. Figure 23–1 illustrates the determinants
for heart disease prevention.”420 of myocardial oxygen supply and demand and pro-
Selective COX-2 inhibitors were introduced into vides potential mechanisms by which drugs may
the U.S. market in the late 1990s, with the potential cause myocardial ischemia. The three major determi-
to revolutionize the manner in which pain and nants of myocardial oxygen demand are heart rate,
inflammatory disorders were managed. However, contractility, and left ventricular systolic wall ten-
several randomized active and placebo-controlled sion.422 Heart rate is the easiest of these factors to
trials, observational studies, and meta-analyses have assess clinically; an increase in heart rate leads to
raised concerns that the selective COX-2 inhibitors increased myocardial oxygen demand. Myocardial
and nonselective NSAIDs may increase the risk of contractility is reflected by the rate of rise in the
TisdaleC23_399-427 1/20/10 11:24 PM Page 406
TABLE 23–2 Mechanisms of Drug-Induced Myocardial Ischemia and Acute Coronary Syndrome
Drug-Induced Disease and Mechanism Examplesa
Drug-Induced Myocardial Ischemia
• Increased Myocardial Oxygen Demand
• Increased heart rate Directly: Cocaine, adrenergic adrenergic -agonists,
sympathomimetics, withdrawal of -antagonists
Indirectly: potent vasodilators (Nifedipine,
minoxidil, hydralazine)
• Increased myocardial contractility Directly: Cocaine, adrenergic -agonists, sympathomimetics,
withdrawal of -antagonists
Indirectly: potent vasodilators (Nifedipine, minoxidil,
hydralazine)
• Increased left ventricular systolic wall tension
• Increased preload
• Increased afterload Cocaine, phenylephrine
• Deceased Myocardial Oxygen Supply (temporary,
nontotal occlusion)
• Increased coronary vascular resistance (vasospasm, Cocaine, anti-migraine agents (ergot alkaloids, triptans)
thrombosis)
• Decreased coronary diastolic perfusion pressure Enalapril, nifedipine, minoxidil, hydralazine, nitroprusside,
adenosine, dipyridamole
• Decreased oxygen-carrying capacity
Drug-Induced Acute Coronary Syndromes
• Acute coronary syndrome associated with acute
drug therapy
• Coronary artery thrombosis, superimposed on a Cocaine, oral contraceptives, estrogens, COX-2 inhibitors,
damaged atherosclerotic plaque NSAIDs
• Coronary artery vasospasm (with or without a Cocaine, anti-migraine agents (ergot alkaloids, triptans)
superimposed coronary artery thrombosis)
• Acute coronary syndrome associated with chronic
drug therapy
• Increased cardiovascular risk Cocaine, estrogens, COX-2 inhibitors, NSAIDs, HIV
agents/protease inhibitors, oral contraceptives,
rosiglitazone
COX = cyclooxygenase; HIV = human immunodeficiency virus; NSAIDs = nonsteroidal antiinflammatory drugs.
a
This is only a partial list of drugs; for most drugs, the mechanisms are not known.
intraventricular pressure during isovolumetric con- ers) or indirectly by reflex mechanisms (e.g., potent
traction and is influenced by a number of variables, vasodilators such as nifedipine, minoxidil, and
including the autonomic nervous system, heart rate, hydralazine) may induce myocardial ischemia.
blood calcium concentration, and body temperature. Similarly, drugs that increase systolic blood pressure
The third determinant, systolic wall tension, is (e.g., cocaine, phenylephrine) may also induce
directly related to ventricular systolic pressure and myocardial ischemia. Clinicians should be alert to
ventricular wall radius and is inversely related to wall drugs that modify any of these factors, as they may
thickness. Preload and afterload are important deter- cause ischemia.
minants of these components. Reducing systolic Myocardial oxygen supply is determined by coro-
blood pressure reduces afterload, which ultimately nary blood flow and the oxygen-carrying capacity of
decreases myocardial oxygen demand. A drug may blood.422 The most important of these determinants
cause myocardial ischemia simply by modifying any clinically is coronary blood flow. Normally, the arteri-
one of these factors. For example, drugs that increase olar resistance vessels are the most important regula-
heart rate, either directly (e.g., cocaine, -adrenergic tors of coronary blood flow, whereas large epicardial
receptor agonists, abrupt discontinuation of -block- vessels are low-resistance vessels. Complex factors
TisdaleC23_399-427 1/20/10 11:24 PM Page 407
Humoral Factors
Vascular Resistance
Diastolic Phase Systolic Left Ventricular
Duration Pressure Volume
Myocardial Myocardial
Contractility
Oxygen Supply Oxygen Demand
FIGURE 23–1 Factors affecting myocardial oxygen supply and demand. Adapted from Ardehali and Ports.422
that determine coronary blood flow include duration treatment migraines, triptans, are contraindicated in
of diastole and coronary vascular resistance. patients with coronary artery disease. Like ergot alka-
Coronary vascular resistance is determined by meta- loids, the purported mechanism of increased
bolic control, autoregulation, extravascular compres- ischemia is coronary artery vasoconstriction or
sive forces, and humoral and neural factors. Drug vasospasm or both, in the case of triptans, mediated
therapy may reduce myocardial oxygen supply by by agonism of 5-hydroxytriptophan (5-HT) receptors.
influencing any of these determinants. Most com- One often-unrecognized mechanism by which a
monly, when considering drug-induced reductions in drug may reduce myocardial oxygen supply is reduc-
myocardial oxygen supply, agents that cause throm- tion of blood pressure too aggressively, leading to
bosis or vasospasm of large coronary epicardial vessels reductions in diastolic perfusion pressure and coro-
are thought of as typical culprits. However, drugs that nary blood flow. Patients with existing coronary ath-
cause microvascular changes should also be consid- erosclerosis are particularly at risk for drug-induced
ered. Unfortunately, these changes are more difficult ischemia via this mechanism. Any drug that reduces
to assess clinically. Finally, oxygen-carrying capacity blood pressure, especially potent vasodilators, may
can be affected by conditions such as anemia. cause ischemia or an acute coronary syndrome via
There are several examples of drugs that may pre- this mechanism. An observational study suggested
cipitate ischemia by decreasing myocardial oxygen that the short-acting dihydropyridine calcium-chan-
supply. Cocaine causes ischemia not only via increas- nel blocker nifedipine may increase the risk of
es in heart rate and blood pressure, but also via coro- ischemic events and myocardial infarction in
nary vasoconstriction, which is mediated by patients with coronary artery disease, likely through
cocaine-induced blockade of norepinephrine reup- this mechanism.159,177 This study was highly contro-
take, leading to increased plasma norepinephrine versial and led to debate for many years. While the
concentrations and enhanced ␣1-adrenoceptor-medi- debate was contentious in many ways, there was
ated vasoconstriction.286,290,294,296 Some data also sug- general agreement that short-acting dihydropyridine
gest that cocaine increases plasma concentrations of calcium-channel blocking agents such as the imme-
endothelin-1, a powerful vasoconstrictor that con- diate-release formulations of nifedipine or nicardip-
tributes to coronary vasospasm.290 Each of these ine should be avoided in patients with coronary
mechanisms contributes to cocaine-induced coro- artery disease.160 Whether or not these restrictions
nary artery vasospasm. The ergot alkaloids and asso- should be applied to all calcium-channel blockers is
ciated derivatives are widely known to cause coronary still being debated. Another drug thought to increase
vasoconstriction. The mechanism of ergot-induced the risk of acute myocardial infarction by reducing
coronary artery vasoconstriction is simply an exten- coronary perfusion pressure is enalapril. In a land-
sion of the drug’s therapeutic effects, which is cerebral mark clinical trial, the Cooperative North
vasoconstriction. Another group of drugs used in the Scandinavian Enalapril Survival Study-II (CONSEN-
TisdaleC23_399-427 1/20/10 11:24 PM Page 408
result in necrosis of myocardial tissue. Thus, a drug- It should be emphasized that these cases of drug-
induced acute coronary syndrome could result from induced ischemia or acute coronary syndrome occur
drug-induced coronary vasospasm (e.g., cocaine) or primarily in patients with a history of coronary
drug-induced coronary artery thrombosis (e.g., estro- artery disease. Following the short-term treatment of
gens, cocaine, COX-2 inhibitors). For example, in the- an acute coronary syndrome, discontinuation of
ory, selective COX-2 inhibitors, which do not inhibit heparin and aspirin leads to an increase in adverse
COX-1 and therefore do not decrease plasma concen- cardiovascular events.14 These events seem to “clus-
trations of platelet-derived thromboxane, may exert ter” early (~10 hours) after discontinuation and have
different influences on the occurrence of cardiovascu- been attributed to rethrombosis in coronary arteries.
lar events than other nonselective NSAIDs such as Maintenance of aspirin therapy has been proposed as
aspirin or naproxen. Inhibition of COX-2 is believed a means of reducing the risk of this phenomenon.
to suppress the endothelial production of prostacy- Additional data have suggested that discontinuation
clin, while leaving the production of thromboxane of clopidogrel may result in an increased risk of
A2, mediated by COX-1, relatively unaffected. This death or recurrent acute coronary syndrome.6 In that
may potentially lead to vasoconstriction, platelet study, the incidence of death and recurrent myocar-
aggregation, thrombosis, and ultimately an acute dial infarction was higher in the first 90 days follow-
coronary syndrome.20,22 ing clopidogrel discontinuation, in patients with
acute coronary syndromes who were treated both
Acute Coronary Syndrome Associated medically and with intervention. The mean duration
with Long-Term Drug Therapy/Increased of clopidogrel therapy prior to discontinuation was
Cardiovascular Risk approximately 300 days, and more than 80 percent
Drugs may also increase the risk for the development of patients had received clopidogrel for more than 3
of coronary artery disease by accelerating the natural months. The theoretical mechanism of this
course of pathogenesis of atherosclerosis. The follow- increased risk is platelet activation and increased
ing have been identified as modifiable risk factors by thrombotic risk immediately upon discontinuation
the American Heart Association: cigarette smoking, of therapy. This has led to some questions about the
elevated plasma low-density lipoprotein cholesterol appropriate duration of clopidogrel therapy.6 Finally,
concentrations, reduced plasma high-density there is some evidence, though conflicting, that
lipoprotein cholesterol concentrations, hyperten- abrupt discontinuation of statins may increase the
sion, obesity, and diabetes.426 Thus, any drug that risk of cardiovascular events.16 Further research in
alters these risk factors in a negative way has the this area is required.
potential to increase the risk of a coronary event. In summary, there are numerous ways in
Examples of drugs that have been shown to acceler- which drugs may cause myocardial ischemia or
ate the development of coronary atherosclerosis acute coronary syndromes. Cocaine is an example
include protease inhibitors (via induction of dyslipi- of a drug that may cause this drug-induced disease
demia) and cocaine. Postmortem studies of cocaine by many of these mechanisms, including increased
abusers have shown that cocaine accelerates the myocardial oxygen demand (increased heart rate,
development of atherosclerosis by causing structural contractility, blood pressure, and development of
changes in the endothelial membrane, resulting in left ventricular hypertrophy), decreased myocar-
increased permeability to low-density lipoproteins. dial oxygen supply (platelet aggregation and
In addition, cocaine has been shown to enhance thrombus formation, coronary artery vasoconstric-
white-cell migration and increase the expression of tion), and enhanced development of coronary
adhesion molecules in the endothelium.290 Other artery disease (premature atherosclerosis).
examples, among many others, may include oral
contraceptives, COX-2 inhibitors, and rosiglitazone.6
CLINICAL PRESENTATION AND
Drug Discontinuation DIFFERENTIAL DIAGNOSIS
Several drugs are known to cause myocardial
ischemia or acute coronary syndromes when abrupt-
Drug-Induced Myocardial Ischemia
ly discontinued, in most cases in patients who have The clinical presentation of a patient with drug-
underlying coronary artery disease (see Table 23–1). induced ischemia is similar to that of any patient
There are several mechanisms by which this may with angina or ischemia associated with atheroscle-
occur. For example, abrupt discontinuation of - rotic coronary artery disease. The most apparent dif-
blockers may lead to increased myocardial oxygen ference is that drug-induced ischemia may occur in
demand secondary to -adrenoceptor upregulation individuals who do not have, or who are not at risk
and hypersensitivity to catecholamine stimulation. for, coronary artery disease. For example, it is unusu-
TisdaleC23_399-427 1/20/10 11:24 PM Page 410
al for a young individual to present with symptoms patients. The typical woman who presents with an
consistent with myocardial ischemia. Pharmacists acute coronary syndrome secondary to oral-contra-
and other health care professionals must be aware of ceptive therapy is usually over the age of 35 years,
drugs, both licit and illicit, that may precipitate smokes cigarettes, and may not have any other obvi-
angina or an acute coronary syndrome and evaluate ous cardiovascular risk factors. This presentation
the causality in appropriate patients. contrasts with that of the typical women presenting
Typical signs and symptoms that are associated with a non–drug-induced acute coronary syndrome.
with angina pectoris are summarized in Table 23–3. Acute coronary syndromes classically present as
Briefly, angina typically presents as substernal, ret- prolonged chest discomfort described as oppressive
rosternal, or transsternal discomfort that radiates, pain, choking, squeezing, or burning that may radiate
usually, to the neck and left arm. The discomfort is to the neck, throat, jaw, shoulders, or both arms. The
usually characterized by a dull sensation, rather discomfort associated with an acute coronary syn-
than a sharp or stabbing pain, and patients may drome is generally similar in quality and location as
describe it as a strangling or constricting sensation. anginal pain, except that the duration is longer (>30
Patients often use the following descriptors to minutes), it occurs at rest, and is not relieved by sub-
describe the discomfort: pressure, heaviness, full- lingual nitroglycerin or rest. Patients may present
ness, squeezing, burning, aching, gas, “vise-like,” or with other symptoms, such as nausea, vomiting,
anxiety. Anginal discomfort usually has a gradual diaphoresis, shortness of breath, weakness, light-
onset and lasts only a few minutes if the precipitat- headedness, or a sense of impending doom. Not all
ing factor is removed. In addition, relief is usually patients present with classic symptoms; some present
afforded by rest, sublingual nitroglycerin, or both. with atypical signs or symptoms, are asymptomatic,
Longer durations of angina may imply severe or are unable to provide a history. The physical exam-
ischemia, coronary vasospasm, unstable angina, or ination is not necessarily helpful in establishing the
impending or ongoing myocardial infarction. diagnosis of an acute coronary syndrome. However,
the findings are important as a guide to immediate
management and as a baseline for future comparison.
Drug-Induced Acute Coronary Syndrome Signs or symptoms of left or right ventricular dysfunc-
In most situations, the clinical presentation of a tion may be detected. Patients may present with
patient with drug-induced acute coronary syndrome is bradycardia or tachycardia, low-grade fever, elevated
similar to that of any patient with non–drug-induced respiratory rate, and leukocytosis. Most of these find-
acute coronary syndrome. However, there are several ings are nonspecific and do not confirm the diagno-
exceptions to this generalization. Like myocardial sis of an acute coronary syndrome.425 We assume that
ischemia, acute coronary syndromes are relatively the presentation of a drug-induced acute coronary
unusual in young populations (<45 years of age). syndrome is similar to that of other causes of acute
Approximately 25% of all acute myocardial infarc- coronary syndromes. For many drugs this may be
tions in individuals 18 to 45 years of age have been true, although data are not available, except for
associated with frequent cocaine use.296 The typical cocaine. Like other acute coronary syndromes,
patient who presents with cocaine-induced acute patients with cocaine-induced acute coronary syn-
coronary syndromes is a relatively young man who dromes experience pressure-like chest discomfort,
smokes cigarettes and does not have any other obvi- anxiety, palpitations, dizziness, and nausea. Dyspnea
ous cardiovascular risk factors. Thus, in younger and diaphoresis occur in 60% and 40% of patients,
patients without any obvious risk for acute coronary respectively. However, it has been suggested that
syndromes, the use of cocaine or other drugs that are fewer than 50% of patients actually experience chest
known to be associated with drug-induced acute coro- pain with cocaine-associated acute coronary syn-
nary syndromes should be considered. However, clini- dromes, making the identification of cocaine-induced
cians must consider the possibility of cocaine use in acute coronary syndromes more difficult.291
any patient who presents with an acute coronary syn- The classification and diagnosis of an acute
drome. Since cocaine accelerates cardiovascular risk, it coronary syndrome is based on three important
is certainly possible that its use is associated with acute features: chest pain, electrocardiographic changes,
coronary syndromes in older patients. Current recom- and serum biomarker (troponin) concentra-
mendations suggest that urine screening for cocaine tions.1,427 The diagnostic features of an acute
metabolites should be used only in patients who are myocardial infarction are provided in Table 23–4.
unable to communicate or when other sources of a The classification and diagnosis of drug-induced
reliable patient history are unavailable.291 acute coronary syndromes is generally performed
Like cocaine-associated acute coronary syn- in the same manner as with non–drug-induced
dromes, acute coronary syndromes associated with acute coronary syndromes. Interested readers are
oral contraceptives usually occur in younger directed to these guidelines for more in-depth dis-
TisdaleC23_399-427 1/20/10 11:24 PM Page 411
atherosclerosis. In fact, nearly 50% of patients with pain is very high. In patients who suffer a cocaine-
cocaine-related chest pain or myocardial infarction induced myocardial infarction, the risk of compli-
do not have evidence of coronary atherosclerosis.290 cations is substantially higher. In a study of
Tobacco smoking also increases the risk of a coro- patients with cocaine-induced myocardial infarc-
nary event while taking oral contraceptives or hor- tion, the risk of cardiac complications, most com-
mone-replacement therapy.417 This increase in the monly heart failure and arrhythmias, was 38%.288
risk of a coronary event associated with smoking is The majority of complications occurred within the
consistent with the increased risk associated with first 12 hours of hospitalization. Interestingly, no
smoking in patients with coronary artery disease or patients died during the hospitalization period. In
in those at high risk for a coronary event. another series, the risk of death associated with
continued cocaine use was approximately 5%.431
of angina symptoms and/or use of sublingual nitro- ischemia; (2) patients with no history of coronary
glycerin is warranted. More aggressive monitoring of artery disease who experience drug-induced ischemia;
chronic antianginal medications may be necessary. and (3) patients with drug-induced acute coronary
There are no strong recommendations for con- syndromes. In all three cases, it should be obvious
sidering drugs to be absolutely contraindicated in that illicit drugs that are the cause of any of these
patients with known coronary artery disease for drug-induced or drug-exacerbated diseases should be
the avoidance of drug-induced myocardial immediately and permanently discontinued.
ischemia and myocardial infarction, with a few
exceptions. The use of sildenafil in patients receiv- Drug-Induced Ischemia in Patients
ing long-term nitrate therapy for exertional angina with Coronary Artery Disease
(i.e., patients with chronic coronary artery disease
Standard therapy for non–drug-induced ischemia
and angina) has been strongly discouraged by the
secondary to coronary artery disease typically
American Heart Association.355 This strong state-
includes short-term management, long-term (pro-
ment is necessary because of the increased risk of
phylactic) therapy, and risk-factor modification.432,433
coronary events and death when sildenafil is used
Acute therapy typically involves the administration
in combination with short- or long-term nitrate
of sublingual nitrates when an anginal attack occurs
therapy. Ergot alkaloids should also be avoided in
or just before exertion in an effort to prevent or treat
patients with underlying coronary artery disease.
ischemia. In addition, most patients also require
In patients without a history of coronary artery
long-term prophylactic therapy with a -blocker, cal-
disease, strategies for avoidance of drug-induced
cium-channel blocker, a long-acting nitrate, or all
ischemia or infarction may be less clear. The approach
three. The treatment of drug-induced ischemia is no
in these patients should be increased awareness of
different from that of classic non–drug-induced
drugs that have been associated with drug-induced
ischemia. Unless patients have been warned that a
ischemia or infarction. Unfortunately, no routine
particular drug they are receiving has the propensity
monitoring or prevention strategies can prevent the
to increase the risk of ischemia and subsequent angi-
occurrence of drug-induced myocardial ischemia or
na, most patients will not associate an increase in the
infarction in all individuals. However, individuals
incidence of chest pain with specific drug therapy.
who smoke should be strongly advised against using
Patients should be made aware that specific drugs
oral contraceptives or hormone-replacement therapy.
they are receiving may cause angina and potentially
In response to the clinical data suggesting an
exacerbate their disease. When possible, the most
increase in cardiovascular events, NSAIDs have
effective treatment is to discontinue therapy with
come under intense scrutiny. A discussion of the use
the offending agent. In some cases, this is not possi-
of NSAIDs in patients with cardiovascular disease is
ble, and maximization of the patient’s medical ther-
provided in the next section.
apy of the underlying ischemia is necessary.
tion above, it is prudent to treat these individuals elevation [STSE] acute coronary syndromes [ACS]
with risk-factor–reduction therapies. and non–ST-segment elevation [NSTSE] ACS) and
management of cocaine-induced acute coronary syn-
drome from two distinct guidelines. Management of
Drug-Induced Acute Coronary Syndromes cocaine-induced acute coronary syndromes is the
The therapies for acute coronary syndromes are out- only drug-induced treatment illustrated since this is
lined in consensus guidelines and reviews and are the only specific drug for which guidance exists and
summarized in Table 23–8.1,424,428 The consensus a specific section is devoted to its treatment.
guidelines outlined in the table illustrate standard The management of conventional (non–drug-
treatment of acute coronary syndromes (ST-segment induced) acute coronary syndromes typically
includes antiplatelet agents (i.e., aspirin), unfrac- pain is not responsive, nitroglycerin, nitroprusside
tionated heparin or low-molecular-weight heparin, (for persistent hypertension not controlled with
nitrates, -blockers, anxiolytic drugs, and anal- nitroglycerin) or phentolamine (alternative) are rec-
gesics. In patients with STSE ACS, the addition of ommended. Patients should then be managed
revascularization therapy with percutaneous coro- based on whether they are classified as high or low-
nary intervention (PCI) or thrombolytic therapy is risk as outlined in Figure 23–2.291
generally indicated, and glycoprotein IIb/IIIa recep- Considerable controversy exists regarding
tor antagonists are used in select patients. In whether -blockers, thrombolytic therapy, and calci-
patients with NSTSE ACS, thrombolytic agents are um-channel blockers should be used for the manage-
not indicated, but PCI and glycoprotein IIb/IIIa ment of cocaine-induced acute coronary syndromes.
receptor antagonists may be used. In general, ther- In theory, -receptor-blocking drugs have the poten-
apy for a drug-induced acute coronary syndrome is tial to exacerbate coronary artery and systemic vaso-
the same as that for a non–drug-induced acute coro- constriction. As described above, cocaine inhibits
nary syndrome. The therapies are similar mainly peripheral norepinephrine reuptake, leading to
because there are few data to suggest that they increased plasma norepinephrine concentrations and
should be different. Following in-hospital care, enhanced ␣1-adrenoceptor-mediated vasoconstric-
patients with evidence of drug-induced myocardial tion. When administered to patients who have
infarction or atherosclerosis should be treated in a ingested cocaine, -blockers, especially nonselective
manner similar to that of patients with a non–drug- agents, may further enhance coronary vasoconstric-
induced acute coronary syndrome. Aggressive car- tion through enhancement of unopposed ␣1-adreno-
diovascular risk-factor reduction with smoking ceptor agonism, potentially further increasing blood
cessation therapy and control of hypertension, dia- pressure and heart rate and possibly increasing the
betes, and plasma lipids is necessary. Treatment risk of seizures and mortality.286 Available data suggest
with traditional secondary prevention therapies, that labetalol (a -adrenergic and ␣1-receptor
including aspirin, clopidogrel, -blockers, statins, inhibitor) may convey benefit in patients with
and angiotensin-converting enzyme inhibitors cocaine-induced acute coronary syndromes, but
should also be used in these patients. labetalol administration has also been associated with
increased seizure activity and mortality in animal
models and little effect on coronary vasoconstriction
Treatment of Cocaine-Induced in humans.1,284 Carvedilol, which is also a -adrener-
Acute Coronary Syndromes gic and ␣1-receptor inhibitor, may theoretically ben-
As illustrated in Table 23–8, treatment guidelines efit patients with cocaine-induced acute coronary
for cocaine-induced ACS have been published. In syndromes as well, although data supporting
addition, new sections regarding cocaine have been carvedilol use in this situation are not available.
added to consensus guidelines for the management Several treatment guidelines and expert reviews sug-
of acute coronary syndromes.1,2,291 The mechanism gest that -blockers of any kind should not be admin-
of cocaine-induced acute coronary syndrome is istered during the acute phase of an acute coronary
multifactorial (increased myocardial oxygen syndrome.1,286,290,428 However, these recommenda-
demand, decreased myocardial oxygen supply due tions have been questioned. Results of a retrospective
to vasoconstriction, and thrombus formation), but, study indicated that -blockers are associated with a
unlike non–drug-induced acute coronary syn- substantially lower risk of cocaine-induced myocar-
dromes, a major component of cocaine’s effect is dial infarction.434 The authors of this study suggested
secondary to coronary vasoconstriction (in contrast that warnings against -blocker use may apply only
to that of a classic acute coronary syndrome). to patients with acute cocaine intoxication. In view of
Therefore, treatment approaches target the vaso- the retrospective nature of the study, prospective ani-
constrictive component as well as the classic thera- mal and human studies are needed to further define
peutic targets. In addition, cocaine toxicity affects this issue. The current recommendations against -
other organ systems, particularly the central nerv- blocker administration provide the most prudent
ous system, increasing the risk of seizures, hyper- approach to treating patients with cocaine-induced
thermia, and subarachnoid hemorrhage. These acute coronary syndrome.
factors must be considered when treating cocaine- Thrombolytic administration to individuals
induced acute coronary syndromes. American with cocaine-induced acute coronary syndrome is
Heart Association recommendations for treatment also very controversial. There have been several
of cocaine-induced chest pain are provided in reports of intracranial hemorrhage or death sec-
Figure 23–2, and are based on risk profile. All ondary to thrombolytic use in this popula-
patients should be evaluated in a chest-pain unit tion.284,435,436 Therefore, an alternative approach to
and receive aspirin and benzodiazepines initially. If thrombolytics as a first-line therapy is to adminis-
TisdaleC23_399-427 1/20/10 11:24 PM Page 416
Oxygen
FIGURE 23–2 Therapeutic recommendations for cocaine-associated chest pain and acute coronary syndromes. ACE =
angiotensin-converting enzyme; ASA = acetylsalicylic acid (aspirin); IV = intravenous; LVSD = left-ventricular systolic dys-
function; NTG = nitroglycerin; NSTE ACS = non–ST-segment elevation acute coronary syndrome; PCI = percutaneous coro-
nary intervention; STEMI = ST-segment myocardial infarction.
(ST-segment elevation [STSE] acute coronary syndromes [ACS] and non–ST-segment elevation [NSTSE] ACS) Adapted from McCord et al.291
ter benzodiazepines, aspirin, and nitrates followed used in patients with cocaine-induced acute coro-
by calcium-channel blockers or phentolamine.286 If nary syndromes. This recommendation is consis-
this initial medical therapy fails, reperfusion thera- tent with that of standard treatment of chronic
py with thrombolytics or revascularization with and acute coronary syndromes. Verapamil or dilti-
PCI should be the next option. These issues related azem should not be used in the presence of left-
to cocaine-induced acute coronary syndromes sug- ventricular systolic dysfunction. Therapy with
gests that the standard treatment of drug-induced calcium-channel blockers should be reserved for
acute coronary syndromes is less than clear, and is patients with cocaine-induced acute coronary syn-
sometimes dependent on the specific drug causing dromes who do not respond to therapy with nitro-
the acute coronary syndrome. glycerin and benzodiazepines.291
The use of calcium-channel blockers for the Finally, after hospitalization, outpatient treat-
treatment of cocaine-induced chest pain and acute ment of patients with evidence of cocaine-induced
coronary syndromes is also controversial. In theo- myocardial infarction or atherosclerosis should be
ry, calcium-channel blockers should reverse the similar to that used for patients with a non–drug-
vasoconstriction frequently associated with induced acute coronary syndrome. Aggressive car-
cocaine ingestion. In cardiac catheterization stud- diovascular risk-factor reduction with smoking
ies, verapamil has been shown to reverse cocaine- cessation therapy and control of blood pressure,
associated vasospasm. However, results of animal diabetes, and plasma lipids is necessary. Traditional
studies regarding the effects of calcium-channel secondary prevention methods including aspirin,
blockers on survival, seizure frequency, and clopidogrel, statins, and angiotensin-converting
arrhythmias associated with cocaine-induced enzyme inhibitors should be used in these patients.
ischemia have been variable. Current recommen- Therapy with -blockers should be used if required
dations suggest that the short-acting dihydropyri- based on risk and in consideration of the potential
dine calcium-channel blockers should never be for continued cocaine use.
TisdaleC23_399-427 1/20/10 11:24 PM Page 417
Alternatives to the Use of NSAIDs ated with illicit-drug use (e.g., cocaine, ampheta-
mines). The best method to avoid these toxicities is
Current guidelines recommend against the routine through public health initiatives that warn about
use of nonselective NSAIDs and selective COX-2 the dangers of illicit-drug use.
NSAIDs.1,2 Although these recommendations are
focused on the treatment of acute coronary syn-
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CHAPTER 24
Heart Failure
␣1-Antagonists
Doxazosin7 RR, 2.04 (95% CI, 1.79–2.32) A
Amantadine8 NK C
Aminocaproic acid9 NK C
Amphotericin B10,11 NK C
Anagrelide12 2.4% B
Anthracyclines13,14
Doxorubicin15-17, 19 0–16% A
Epirubicin19 20% A
Antidigoxin antibody fragments20 NK C
Antiarrhythmic agents21, 22 5–10%24 A
Disopyramide24 16% A
Dronedarone25 3.2% A
Encainide23 2.6% A
Ethmozine23 2.4% A
Lorcainide23 0.7% A
Lidocaine21 9% A
Mexiletine23 0.9% A
Propafenone23 4.7% A
Tocainide23 1.6% A
-Blockers26 2% B
Propranolol27 1–5.4% B
Blue cohosh28 NK C
Bromocriptine29 NK C
Cabergoline30-32 NK C
Calcium-channel blockers A
Diltiazem33 20.5% A
Nifedipine34 24–26% A
Verapamil35 NK C
Carbamazepine105 NK C
Clozapine36-39 NK C
Corticosteroids40 Adjusted OR, 2.7 (95% CI, 2.5–2.9)2 B
Prednisolone41 Dose <7.5 mg/day; RR, 1.5 (95% CI, 1.3–1.8) B
Dose ≥7.5 mg/day; RR, 3.7 (95% CI, 2.7–5.1)
Cyclophosphamide42,43 NK C
Cytarabine44 NK C
Dapsone45 NK C
Etanercept46 NK C
Fluorouracil47 NK C
Foscarnet48 NK C
Glitazones49-53 RR, 1.72 (95% CI, 1.21–2.42)57
Rosiglitazone54-56 OR, 2.1 (95% CI, 1.08–4.08) vs. placebo58 A
(Continued)
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ure. The agents implicated were mostly related to highlighting the significant hazard of the use of
excessive intravascular volume expansion (mostly diltiazem in patients with left ventricular dysfunc-
due to overhydration), as well as -blockers and tion after myocardial infarction.33 In a random-
verapamil, each in one patient.109 In a review of ized, double-blind crossover study of 8 weeks of
100 hospitalizations due to heart failure in treatment with isosorbide dinitrate alone, isosor-
patients over 65 years of age, Garcia Robles et al. bide dinitrate in combination with nifedipine, or
identified 2 cases (2%) caused by -blockers.26 nifedipine alone in 28 patients with mild to mod-
Other studies revealed coronary ischemia, respira- erate heart failure, Elkayam et al.34 observed inci-
tory infection, uncontrolled hypertension, dences of hospitalization for heart failure of 26%
arrhythmias, and poor adherence to medication and 24% in the isosorbide dinitrate plus nifedipine
as common precipitants of exacerbations of heart and nifedipine alone groups, respectively (as com-
failure.108-112 pared with none in the isosorbide dinitrate alone
group).
EPIDEMIOLOGY Glitazones
The incidence of drug-induced heart failure is out- The glitazones are now well known to cause fluid
lined in Table 24–1. The exact incidence of drug- retention.49,50,52,53 Tang et al.50 reviewed the records
induced heart failure is difficult to determine, of 111 consecutive patients with heart failure and
because it is often difficult to differentiate drug- diabetes who were prescribed a glitazone and
induced heart failure from the many other precipi- reported that the incidence of fluid retention was
tants of this syndrome.108 17%. In the randomized A Diabetes Outcome
Progression Trial (ADOPT), an incidence of edema
of 14.1% was reported in the rosiglitazone group as
Calcium-Channel Blockers compared with 7.2% in patients receiving met-
In a post hoc analysis of the Multicentre Diltiazem formin and 8.5% in those receiving glyburide dur-
Postinfarction Trial (MDPIT), Goldstein et al.33 ing the 4-year period of follow-up.113
reported new or worsened heart failure in 12.0% More recently, several clinical trials and meta-
and 20.5% of 623 patients receiving placebo or dil- analyses have investigated the impact of glitazone
tiazem, respectively, with left ventricular ejection therapy on cardiovascular outcomes, including the
fraction (LVEF) <0.40 at baseline. There was no dif- incidence of heart failure. In the Diabetes
ference in the incidence of new or worsened heart Reduction Assessment with Ramipril and
failure in patients with LVEF >0.40 at baseline, Rosiglitazone Medication (DREAM) study, 5,269
TisdaleC24_428-444 1/12/10 2:51 PM Page 432
adults with impaired fasting glucose or impaired associated with the highest (4.7%). In a random-
glucose tolerance or both and no previous cardio- ized, controlled trial investigating the impact of
vascular disease were randomly assigned to receive antiarrhythmic therapy postmyocardial infarction,
rosiglitazone or placebo.55 Heart failure developed Greene et al. documented an incidence of heart
in 14 (0.5%) participants in the rosiglitazone group failure requiring hospitalization in 26% of patients
and in 2 (0.1%) in the placebo group (P = 0.01). An receiving encainide, flecainide, moricizine, or
increased incidence of heart failure was also docu- imipramine as compared with 18% of those receiv-
mented in an interim analysis of the Rosiglitazone ing placebo.22 Pfisterer estimated that the inci-
Evaluated for Cardiac Outcomes and Regulation of dence of drug-induced heart failure associated with
Glycemia (RECORD) study, in which 4,447 patients older antiarrhythmic agents (excluding ibutilide
with inadequate glycemic control were randomly and dofetilide) is about 5% overall and approxi-
assigned to receive add-on rosiglitazone therapy or mately 10% in those with a history of heart fail-
metformin plus sulfonylurea (control group). The ure.24
hazard ratio for the development of heart failure Amiodarone, ibutilide, and dofetilide appear
associated with rosiglitazone was 2.15 (95% confi- to exert minimal negative inotropic effects, and
dence interval [CI],: 1.3–3.57].56 Pioglitazone has amiodarone and dofetilide have been shown to
also been associated with an increased risk of heart not adversely affect survival in patients with
failure. In the Prospective Pioglitazone Clinical heart failure.1 Therefore, although not part of the
Trial In Macrovascular Events (PROactive) study, in routine treatment of patients with heart failure,
which 5,238 patients with type 2 diabetes and evi- amiodarone is the agent most likely to be safe
dence of macrovascular disease were randomly and effective if antiarrhythmic therapy is neces-
assigned to receive pioglitazone or placebo, piogli- sary to prevent recurrent atrial fibrillation or
tazone was associated with an increase in the inci- symptomatic ventricular arrhythmias. 1,2
dence of heart failure (11% vs. 8%; P<0.0001).60 However, the Antiarrhythmic Trial with
Several meta-analyses have also documented an Dronedarone in Moderate to Severe CHF
increased incidence of heart failure in patients Evaluating Morbidity Decrease (ANDROMEDA)
receiving glitazones (Table 24–1).54,57,58,61 trial found that dronedarone, a novel antiar-
Notably, although both rosiglitazone and rhythmic drug with properties similar to amio-
pioglitazone have been associated with an darone, was associated with increased early
increased incidence of heart failure, to date only mortality related to the worsening of heart fail-
rosiglitazone has been shown to be associated with ure in patients who were hospitalized with symp-
an increased risk of myocardial infarction (odds tomatic heart failure and severe left ventricular
ratio [OR] 1.43; 95% CI, 1.03–1.98).114 Neither systolic dysfunction.25 During a median follow-
rosiglitazone nor pioglitazone has been found to up of 2 months, 8.1% of patients receiving
increase the risk of cardiovascular mortality.54,57,61 dronedarone died, as compared with 3.8% receiv-
A joint consensus statement by the American Heart ing placebo (hazard ratio [HR], 2.13; 95% CI,
Association and the American Diabetes Association 1.07–4.25), and this excess mortality was
recommended cautious use of lower doses of glita- predominantly related to worsening of heart
zones in patients with New York Heart Association failure (3.2% vs. 0.6%). This increase in mortal-
(NYHA) functional class I–II symptoms and avoid- ity was not observed in another trial in
ance of these agents in those with NYHA class which patients with decompensated heart fail-
III–IV symptoms.51 ure or NYHA class IV heart failure were excluded
(no difference in all-cause mortality, and a reduc-
Antiarrhythmic Agents tion in death from cardiovascular causes—
dronedarone, 2.7%, vs. placebo, 3.9%; HR, 0.71;
Ravid et al.23 reviewed the incidence of drug- 95% CI, 0.51–0.98).115
induced heart failure in 407 patients during 1,133
serial electrophysiologic drug tests with encainide,
moricizine, lorcainide, mexiletine, propafenone, or
Anthracyclines
tocainide. Using a strict definition of heart failure, The incidence of drug-induced heart failure is
they reported an overall incidence of drug-induced best characterized for doxorubicin. Von Hoff et
heart failure of 1.8%. The incidence was 3.8% in al.15 reviewed eight National Cancer Institute tri-
patients with a history of heart failure. In this als involving over 3,900 patients and reported an
study, lorcainide was associated with the lowest overall incidence of doxorubicin-induced heart
rate of heart failure (0.7%), while propafenone was failure of 2.2%. However, a more recent retro-
TisdaleC24_428-444 1/12/10 2:51 PM Page 433
um-channel blockers appear to have the strongest ation of oxygen free radicals, interference with -
negative inotropic effects,22,23,133 whereas amio- adrenergic stimulation of the heart, disturbances in
darone, ibutilide, and dofetilide appear to have no intracellular calcium transport, reduced adenosine
adverse negative inotropic effects. Although the diphosphate–stimulated respiration, or release of
mechanism by which dronedarone causes worsen- excessive vasoactive compounds such as histamine
ing heart failure is unclear, the ANDROMEDA and catecholamines have all been suggested as pos-
investigators postulated that it may be related to sible mechanisms.134,135 Although anthracycline-
partial inhibition of a specific tubular organic induced heart failure is generally considered
cation transporter in the kidney.25 irreversible, case reports of complete recovery after
doxorubicin-induced cardiac dysfunction have
been published.106,134,136
Anthracyclines
Although the mechanisms of anthracycline-
induced heart failure have not been entirely eluci-
Trastuzumab
dated, they are thought to involve oxidative The mechanism of trastuzumab-induced cardiac
damage.134 Formation of a toxic metabolite, gener- dysfunction is unknown, but it is different from
TisdaleC24_428-444 1/12/10 2:51 PM Page 436
that induced by the anthracyclines.96 In contrast to frequency of ventricular premature beats and inci-
the effect of anthracyclines, trastuzumab car- dence of sudden cardiac death.143
diotoxicity is associated with a loss of contractility,
rather than myocyte death.137 This is supported by
myocardial biopsies from patients with trastuzum- CLINICAL PRESENTATION AND
ab cardiac dysfunction, which do not show typical DIFFERENTIAL DIAGNOSIS
ultrastructural changes on electron microscopy.138
Data from in vivo and in vitro studies suggest that The clinical presentation of patients with drug-
the mechanism of toxicity may be at least partly induced heart failure is not different from that
directly related to HER-2 blockade and may be from other causes. Symptoms may occur gradually
associated with disruption of the epidermal growth following initiation of a culprit drug. Signs and
factor signaling system that is present within the symptoms associated with drug-induced heart fail-
heart.96,139 Trastuzumab-induced cardiac dysfunc- ure are presented in Table 24–4.
tion does not appear to be related to cumulative The differential diagnosis of drug-induced ver-
trastuzumab dose, it is largely reversible (although sus other causes of exacerbation of symptoms of
this has been questioned140), and rechallenge is heart failure may be difficult to distinguish from
generally well tolerated.96 other common precipitants, such as sodium and
fluid excesses, ischemia, poor adherence to medical
NSAIDs and COX-2 Inhibitors therapy, uncontrolled hypertension, arrhythmias
(especially atrial fibrillation), systemic infections,
The NSAIDs are a chemically diverse group of com- impairment in kidney function, anemia, thyrotox-
pounds associated with a common mechanism of icosis, ethanol ingestion, pulmonary embolism,
action which is inhibition of the cyclooxygenase and respiratory insufficiency (Table 24–5).26,108-112
enzyme. In patients with heart failure, renal home- In general, a temporal sequence of administration
ostasis is maintained mostly by renal prostaglandin of a new potentially offending agent (or dose
E2 (PGE2). Inhibition of cyclooxygenase by increase) with gradually increasing symptoms of
NSAIDs disrupts renal homeostasis and leads to
sodium and water retention and exacerbation of
symptoms of heart failure.75,141 These agents have
also been reported to antagonize the actions of
angiotensin-converting–enzyme (ACE) inhibitors TABLE 24–4 Signs and Symptoms Associated
and diuretics.141 There appears to be little clinical- with Drug-Induced Heart Failure
ly important difference between these agents in
• Ascites
terms of their potential to exacerbate symptoms of
• Jugular venous distention
heart failure.141,142 The mechanism for sodium and
• Hepatojugular reflux
fluid retention associated with COX-2 inhibitors is
• Hepatomegaly
similar to that of NSAIDs.84,142
• Peripheral edema
• Rales
-Blockers • Pleural effusion
• Pulmonary edema
-Blockers likely cause their acute effect in patients
• Third heart sound (S3)
with heart failure by reducing contractility
• Gallop rhythm
through competitive antagonism of 1-receptors.
• Abdominal pain
Longer-term treatment has been shown to improve
• Nausea
contractility and LVEF and to exert major benefi-
• Bloating
cial effects on the incidence of hospitalization and
• Cough
mortality.122,124 Several mechanisms have been pos-
• Dyspnea
tulated to explain the beneficial effect of -blockers
• Hemoptysis
in heart failure, including reduction in long-term
• Orthopnea
exposure to catecholamines; restoration of myocar-
• Paroxysmal nocturnal dyspnea
dial inotropic and chronotropic responsiveness;
• Nocturia
reduction in circulating plasma concentrations of
• Weakness
vasoconstrictors such as norepinephrine, renin,
• Fatigue
and endothelin; reduction in myocardial gene pro-
• Decreasing cognitive function (especially in older
duction of inflammatory cytokines; attenuation of
patients)
left ventricular remodeling; and reduction in the
TisdaleC24_428-444 1/12/10 2:51 PM Page 437
dexrazoxane, N-acetylcysteine, vitamin E, amifos- risk for drug-induced heart failure, identify drug-
tine, carvedilol, ACE inhibitors, vitamin A, vitamin induced causes of exacerbations of symptoms of
C, selenium and glutathione.150 Dexrazoxane heart failure, guide treatment choices to avoid
(60–900 mg/m2 with 60 mg/m2 of doxorubicin or agents that could exacerbate heart failure, institute
500 mg/m2 with 50 mg/m2 of doxorubicin) is indi- appropriate preventive measures when necessary,
cated for reduction of the incidence and severity of counsel patients with heart failure on the use of
cardiomyopathy associated with doxorubicin in nonprescription medications, and ensure that
women with breast cancer who received a cumula- patients are receiving all proven efficacious thera-
tive dose of 300 mg/m2 and who would benefit pies for heart failure (ACE inhibitors, -blockers,
from further doxorubicin administration.134 spironolactone, digoxin) at target doses.
Dexrazoxane is not indicated for use during the
initiation of therapy with doxorubicin. Other
potential strategies to limit anthracycline toxicity
include limiting the cumulative dose of anthracy-
INFORMATION FOR PATIENTS
cline, replacing bolus administration with slow When the use of a potentially offending agent is
infusion, and using liposomal anthracyclines in unavoidable in patients with left ventricular dys-
place of traditional formulations. function, patients should be alerted to the signs and
Depending on the indication, several alterna- symptoms of heart failure. Early detection and treat-
tives to NSAIDs or COX-2 inhibitors exist. For ment of drug-induced heart failure may prevent
example, for the treatment of osteoarthritis in the hospitalization or death. This is particularly impor-
presence of heart failure, nonpharmacologic (e.g., tant in light of studies that have shown that, even in
physical therapy) and traditional pharmacologic patients with long-standing heart failure, knowledge
(e.g., acetaminophen, intraarticular injections) and of the signs and symptoms of heart failure is very
nontraditional pharmacologic (e.g., glucosamine) poor.153,154 All patients with heart failure should be
therapies may be preferable. In patients initiated alerted to the dangers of nonprescription therapies
on -blockers for heart failure, starting at low doses such as nonprescription NSAIDs, licorice-containing
with slow and careful of titration of doses over 6 to herbal remedies, and sympathomimetics such as
8 weeks or more will help to minimize adverse those in cough and cold preparations. Patients with
effects on ventricular function.1,2,124 heart failure should consult their physician or phar-
macist prior to initiating therapy with any new
medications, including nonprescription and herbal
MANAGEMENT remedies. Education of patients and their families
and friends is very important to improve patients’
The management of acute exacerbations of heart fail- recognition of early warning symptoms and signs,
ure symptoms includes aggressive diuresis and gener- ensure early intervention before acute heart failure
al supportive care.1,151 Following the discontinuation deterioration, and avoidance of exacerbations of
of therapy with the offending agent, management of drug-induced heart failure. In addition, patients
drug-induced heart failure exacerbations is the same should weigh themselves daily to track changes in
as the usual management of heart failure. Generally, body weight that might be indicative of fluid reten-
recovery of the myocardium is related to the elimina- tion (>1 kg/day). In certain situations, patients may
tion half-life of the offending agent (the exception is be taught how to adjust their diuretic dose based on
doxorubicin, with an average onset of recovery of 30 these changes in body weight and symptoms.
days after the last dose15). After the acute event, cli-
nicians should be vigilant in ensuring that all
patients with heart failure are receiving all efficacious
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CHAPTER 25
Supraventricular
Arrhythmias
James E. Tisdale
22 minutes
23 minutes
of drugs administered orally or intravenously, sinus dence of sinus bradycardia and sinus pauses associ-
bradycardia and sinus pauses may be induced by ated with specific agents, where known, is present-
drugs administered as eye drops. Numerous cases ed in Table 25–1, and the incidence of
of sinus bradycardia associated with topical adren- drug-induced AV nodal blockade associated with
ergic b-receptor antagonists (b-blockers) have been specific drugs, where known, is presented in Table
reported.331,332 The incidence of sinus bradycardia 25–2.
associated with topical timolol is significantly Amiodarone has been reported to cause sinus-
higher (18.4%) than that associated with topical node and AV nodal bradyarrhythmias requiring
carteolol (4.5%).331 The lower incidence of sinus pacemaker insertion.11 In a study of 15,824
bradycardia associated with carteolol may be a patients with atrial fibrillation and a history of
result of the intrinsic sympathomimetic activity of myocardial infarction who were receiving amio-
the drug. darone, the incidence of pacemaker implantation
Drugs that have been reported to cause AV was 2.2% per person-year (mean duration [±SD] of
nodal blockade are listed in Table 25–2.4,5,17,83,86, follow-up, 1.8±1.5 years), and was 5.2% per per-
90,105,107,111,115,190-192,333-447
son-year during the first 90 days of therapy.11 The
odds ratio for pacemaker insertion to treat brad-
yarrhythmias associated with amiodarone use was
EPIDEMIOLOGY 2.14 (95% confidence interval [CI] 1.30 to 3.54).448
Although the incidence of sinus bradycardia asso-
The overall incidence of drug-induced sinus brady- ciated with conventional doses of intravenous
cardia or AV nodal blockade is unknown. The inci- amiodarone (1 to 2 g/24 hr) is similar to that asso-
ciated with oral amiodarone,449 the incidence may with digoxin is unknown. In an analysis of patients
be as high as 10% when doses of 3 g per 24 hours with a discharge diagnosis of digoxin intoxication,
are administered.450 “definite” sinus bradycardia and sinus pauses <2 sec-
Sinus bradycardia or arrest or AV nodal blockade onds were documented in 26% and 19%, respective-
may be caused by digoxin, primarily in overdose or ly, of those with digoxin intoxication.83 In addition,
other situations in which serum digoxin concentra- “definite” second or third degree AV nodal blockade
tions become elevated.83 The overall incidence of was documented in 33% of patients with digoxin
sinus bradycardia or AV nodal blockade associated intoxication.83 Sotalol has been reported to cause
clinically important sinus bradycardia and sinus system (e.g., b-blockers) and drugs that stimulate
pauses in up to 17.2% of patients being treated for the parasympathetic nervous system (e.g., neostig-
atrial fibrillation, with 2.5% requiring permanent mine, physostigmine, pyridostigmine) may cause
pacemaker implantation.269 sinus bradycardia or AV nodal blockade. The action
Zelster et al.359 reviewed a series of 169 consec- potentials of both the sinus node and the AV node
utive patients admitted or discharged with the depend primarily on calcium and sodium flux, and
diagnosis of second or third degree AV nodal block- calcium or sodium channel inhibitors may cause
ade that was not caused by acute myocardial sinus bradycardia, AV nodal blockade, or both.
infarction, vasovagal syncope, radiofrequency Nitrates may cause a syndrome associated with
ablation, or digitalis toxicity. Of these, 54% were sinus bradycardia and hypotension.177-185 Sinus
receiving therapy with b-blockers with or without bradycardia induced by nitrates is an idiosyncratic
diltiazem, diltiazem alone, or verapamil. The inves- reaction. This syndrome resembles neurocardio-
tigators reported that drug discontinuation was fol- genic syncope, but may occur when patients are in
lowed by resolution of AV nodal blockade in 41% the supine position. The mechanism of nitrate-
of patients, but that 56% of these patients subse- induced sinus bradycardia remains unclear, but
quently had recurrence of AV nodal blockade in evidence suggests that nitrates may stimulate
the absence of causative drugs. Based on their cri- peripheral sensory receptors with vagal afferents to
teria for causation, the investigators concluded the medulla, resulting in sympathetic nervous sys-
that drugs were the specific cause of AV nodal tem inhibition via stimulation of central a2-recep-
blockade in only 15% of the patients who were tors (Table 25–3).451
receiving therapy with b-blockers with or without
diltiazem, diltiazem alone, or verapamil.359
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
MECHANISMS
Normal heart rate is usually defined somewhat
Drug-induced sinus bradycardia may be caused by arbitrarily as ranging between 60 and 100 bpm.
inhibition of automaticity of the node, slowing of However, many individuals routinely have heart
sinus node conduction, or prolongation of sinus rates <60 bpm and even <50 bpm without evidence
node repolarization (Table 25–3). AV nodal block- of symptoms. Patients with symptomatic sinus
ade may be caused by agents that inhibit AV node bradycardia resulting in the need for medical atten-
conduction or prolong AV node repolarization tion typically have heart rates between 30 and 50
(Table 25–4). Both the sinus node and the AV node bpm, resulting in hemodynamic compromise.
are heavily influenced by sympathetic and Signs and symptoms associated with clinically
parasympathetic nervous system activity. Drugs important sinus bradycardia and sinus pauses are
that inhibit activity of the sympathetic nervous listed in Table 25–5.1
First degree AV nodal block is a common elec- QRS complexes are present on ECG but bear no
trocardiographic phenomenon that is almost relationship to one another (Figure 25–4). Third
always asymptomatic3, and is therefore not a drug- degree AV nodal blockade can occur either in the
induced disease as defined in this text. However, AV node itself or further down in the bundle of
second and third degree AV blockade can result in His.3
bradycardia, leading to symptoms that result in the Second or third degree AV nodal blockade may
need for medical attention or even requiring hospi- result in bradycardia, with heart rates in the range
talization. of 40-60 bpm. Symptoms of second or third degree
Second degree AV block occurs most common- AV nodal blockade are the same as those associated
ly in two distinct patterns. Mobitz type I second- with sinus bradycardia (Table 25–5).
degree AV block (also known as Wenckebach) is Drug-induced sinus bradycardia or AV nodal
characterized by progressive prolongation of the blockade must be distinguished from other causes
PR interval on ECG until a P wave is not followed of sinus or AV node impairment. Dysfunction of
by a QRS complex (Figure 25–2).3 Mobitz type I is the sinus node unrelated to drug therapy is com-
usually caused by impulse conduction delay in the mon, with a prevalence as high as 1 in 600 patients
AV node (as opposed to further down in the bun- over the age of 65 years.452 Intrinsic AV nodal
dle of His).1 Mobitz type II second degree AV block abnormalities also may occur during the aging
is typified by constant PR intervals with abrupt, process. Transient sinus node dysfunction may
intermittent absence of QRS complexes (Figure occur in the setting of acute myocardial ischemia
25–3). Mobitz type II second degree AV block often or infarction when the infarct/ischemia-related
occurs in specific patterns with P wave to QRS com- vessel is the right coronary artery or the left cir-
plex ratios such as 2:1, 3:1, or 4:1. This type of sec- cumflex artery, but permanent sinus-node damage
ond degree AV block is likely caused by in this setting is uncommon. Myocardial infarction
impulse-conduction delay in the bundle of His. may result in some degree of permanent AV nodal
During third degree AV nodal blockade, the AV dysfunction in some patients. Conditions to con-
node is completely unable to conduct impulses, sider in the differential diagnosis of drug-induced
and atrial depolarization occurs independently of sinus bradycardia or AV nodal blockade are listed
ventricular depolarization. Therefore, P waves and in Table 25–6.1
RISK FACTORS
FIGURE 25–3. Mobitz type II second degree AV nodal Risk factors for drug-induced sinus bradycardia are
blockade associated with amiodarone. listed in Table 25–7.41,136,453 Conditions that may
Reproduced with permission from Mangiardi et al.363 result in elevated plasma concentrations of drugs
known to cause sinus bradycardia increase the risk.
Drug-induced sinus or AV node dysfunction Patients with kidney disease who are receiving renal-
can often be distinguished from non–drug-related ly eliminated drugs that may cause sinus bradycar-
sinus bradycardia or AV nodal blockade. When a dia (atenolol, clonidine, digoxin) are also at
patient with symptoms that appear to be related to increased risk. Kidney disease has been identified as
sinus bradycardia/sinus pauses/sinus arrest or AV a risk factor for sinus bradycardia associated with
nodal inhibition seeks medical attention, therapy clonidine.41 Drugs that have been reported to cause
with drugs known to induce sinus or AV node dys- sinus bradycardia that require dose adjustment in
function should typically be discontinued. If the patients with kidney disease are listed in Table 25–8.
sinus or AV node dysfunction persists after five In addition, concomitant use of drugs that inhibit
half-lives of the respective drug(s) have passed, a the hepatic metabolism of drugs known to induce
drug-induced cause may be ruled out. While await- sinus bradycardia should be avoided (Table 25–9).454
ing drug washout, evaluation and diagnostic test- Other interactions may result in sinus brady-
ing for nonpharmacologic causes can be cardia. Dipyridamole inhibits the cellular uptake of
performed, including determination of serum adenosine455; therefore, patients receiving adeno-
potassium and magnesium concentrations, thyroid sine concomitantly with dipyridamole are at
function tests, and assessment for myocardial increased risk of adenosine-associated sinus brady-
TABLE 25–6 Conditions to Consider in the TABLE 25–7 Risk Factors for Drug-Induced Sinus
Differential Diagnosis of Drug-Induced Sinus Bradycardia or Atrioventricular (AV) Nodal
Bradycardia or Atrioventricular Nodal Blockade1 Blockade
Intrinsic causes Sinus bradycardia41,136,453
• Idiopathic degeneration due to aging • Pretreatment heart rate <60 bpm
• Myocardial ischemia/infarction (transient) • Underlying sinus-node dysfunction (may occur with
• Infiltrative diseases (sarcoidosis, amyloidosis, advancing age)
hemochromatosis) • Impaired baroreflex control (risk factor for nitro-
• Collagen vascular diseases (systemic lupus erythe- glycerin-induced sinus bradycardia)
matosus, scleroderma, rheumatoid arthritis) • Concomitant use of >1 sinus-node inhibiting drug
• Myotonic muscular dystrophy • Elevated plasma drug concentrations due to organ
• Surgical trauma (valve replacement, heart transplanta- dysfunction or drug interactions
tion, correction of congenital heart disease) Atrioventricular nodal blockade
• Infectious diseases (Chagas’ disease, endocarditis) • Concomitant use of >1 AV nodal blocking drug
Extrinsic causes • Pretreatment PR interval >0.2 sec
• Autonomically mediated syndromes • Underlying AV nodal disease (may occur with
• Neurocardiac syncope advancing age)
• Carotid sinus hypersensitivity • Elevated plasma drug concentrations due to organ
• Situational disturbances (coughing, micturition, dysfunction or drug interactions
defecation, vomiting) • Hypothyroidism (may be a risk factor for amio-
• Hypothyroidism darone-induced AV block)363
• Hypothermia
• Electrolyte abnormalities
• Hyperkalemia with or without diltiazem or verapamil and those
• Hypokalemia not receiving therapy with drugs that could induce
• Hypermagnesemia AV nodal blockade. Possible risk factors for drug-
induced AV nodal blockade are listed in Table 25–7.
Risk factors have been identified for AV nodal block-
cardia/sinus pauses.6 A number of drugs inhibit the ade induced by digoxin, and include the drug inter-
elimination of digoxin, particularly amiodarone,456 actions listed above, inadequate dose reduction in
verapamil,457 and quinidine,458 and concomitant patients with kidney disease, hypokalemia, hypo-
use of these drugs with digoxin increases the risk of magnesemia, hypoxia, and hypothyroidism.461
digoxin-induced sinus bradycardia, unless appro-
priate digoxin dose reduction is implemented. In
addition, patients receiving therapy with more MORBIDITY AND MORTALITY
than one drug known to reduce heart rate are at
increased risk.41,459 The incidence of morbidity, hospitalization, or
Women are at greater risk for amiodarone- death associated with drug-induced sinus bradycar-
induced bradycardia requiring implantation of a dia or AV nodal blockade is unknown. Drug-
permanent pacemaker.460 In a study of 1,005 induced sinus bradycardia or AV nodal blockade
patients with new-onset atrial fibrillation, the haz- may result in the need for temporary or permanent
ard ratio for amiodarone use requiring a perma- pacemaker implantation.11,30,448 In a population of
nent pacemaker was 4.69 (95% CI, 1.99 to 11.05) patients with new-onset atrial fibrillation, the
in women, as compared with 1.05 (95% CI, 0.42 to adjusted hazard ratio for amiodarone use leading
2.58) in men.460 Mechanisms for the increased risk to a requirement for a permanent pacemaker was
of bradycardia requiring pacemaker implantation 2.01 (95% CI, 1.08 to 3.76).460 Death due to drug-
in women are unknown. induced sinus bradycardia or AV block is likely very
Specific risk factors for the majority of drug- uncommon.
induced AV nodal blockade have not been identi-
fied. In the study by Zelster et al.359 of 169
consecutive cases of AV nodal blockade, there were PREVENTION
no significant differences in age, male sex, or pres-
ence of hypertension or ischemic heart disease Drug-induced sinus or AV node dysfunction (or
between patients receiving therapy with b-blockers both) is often preventable (Table 25–10). When
TABLE 25–9 Drugs Known to Cause Sinus Bradycardia or Atrioventricular Nodal Blockade That Are
Substrates for Enzymes of the Cytochrome P-450 System454
1A2 2B6 2C8 2C19 2C9 2D6 3A4
Amitriptyline Methadone Paclitaxel Amitriptyline Amitriptyline Amitriptyline Amiodarone
Clozapine Citalopram Fluoxetine Flecainide Cocaine
Olanzapine Diazepam Carvedilol Carbamazepine
Propranolol Propranolol Fluoxetine Diazepam
Verapamil Imipramine Diltiazem
Lidocaine Dronedarone
Metoprolol Lidocaine
Nebivolol Methadone
Propafenone Nicardipine
Propranolol Paclitaxel
Thioridazine Tacrolimus
Timolol Verapamil
TABLE 25–10 Approaches to Help Prevent Drug- TABLE 25–11 Management of Drug-Induced
Induced Sinus Bradycardia and Atrioventricular Sinus Bradycardia or Atrioventricular (AV) Nodal
(AV) Nodal Blockade Blockade
For all drugs that may cause sinus bradycardia, AV • Discontinue the causative agent
block, or both • Temporary pacemaker
• Patient should take pulse daily, report if <50 bpm. • If underlying sinus or AV node dysfunction—perma-
• Do not exceed maximum daily doses. nent pacemaker may be necessary (if AV node dys-
• Use combinations of drugs that may cause sinus function, must be a ventricular pacemaker)
bradycardia or AV block only when necessary and • In severe cases: atropine 0.5–1.0 mg every 3–5 min-
when the benefits likely outweigh the risks. utes until heart rate increases or total dose of 0.04
• Avoid sinus or AV node–inhibiting drugs in patients mg/kg is administered
with underlying sinus node dysfunction, unless a • If due to calcium-channel blocker or b-blocker over-
functioning pacemaker is present (in the case of AV dose:
node inhibiting drugs, there must be a functioning • Gastric lavage
ventricular pacemaker). • Activated charcoal 25–50 g in an aqueous slurry of
120–240 mL water
For digoxin
• Glucagon 2.0–5.0 mg intravenously
• Measure serum digoxin concentrations:
• Temporary pacemaker, if necessary
• If kidney function is changing.
• If a drug that interacts with digoxin is added to
therapy. may be administered in doses of 0.5 to 1.0 mg every
• Every 6 mo if there is no organ dysfunction or con- 3 to 5 minutes to a total dose of 0.04 mg/kg, the dose
comitant use of interacting drugs. at which full blockade of the parasympathetic nerv-
ous system occurs in humans.462
If the drug-induced bradycardia or AV block is
to ensure that AV nodal blockade is not progressing. a result of an overdose of verapamil, diltiazem or a
In addition, combinations of AV nodal blocking b-blocker, gastric lavage may be performed if the
drugs are best avoided in patients with pretreat- patient presents within 1 hour of ingestion.
ment PR intervals >0.2 seconds. If the PR interval Activated charcoal may be administered and may
progresses to >0.2 seconds while on AV nodal block- be particularly useful if the drug was ingested in
ing therapy, it is not necessary to discontinue ther- the form of a sustained-release preparation.
apy, but more frequent ECG monitoring is Although administration of calcium salts has been
recommended and administration of additional AV shown to be effective for reversing the hemody-
nodal blocking agents should be avoided. namic effects of calcium-channel blockers, calcium
salts have not been particularly effective for revers-
ing the electrophysiologic effects of these drugs.463
MANAGEMENT Glucagon 2 to 5 mg intravenously may be effective
for reversing the bradycardic effects of calcium-
Management options for patients with drug- channel blockers or a b-blocker.463,464 Insertion of a
induced sinus bradycardia or AV nodal blockade are temporary pacemaker may be necessary.
presented in Table 25–11. In some cases, a reduction For patients with a history of myocardial infarc-
in dose of the offending medication may be suffi- tion or heart failure in whom sinus bradycardia or
cient, but in most cases in which drug-induced sinus AV nodal blockade induced by b-blockers develops,
or AV node dysfunction has resulted in a hospital- implantation of a permanent pacemaker may be
ization, discontinuation of therapy is necessary. In necessary to allow the patient to continue therapy
the case of sinus bradycardia or AV block induced by with these agents,465 which have been shown to
adenosine, treatment is not usually required because prolong survival in these specific conditions.466,467
the drug is metabolized very quickly (half–life 5 10
seconds) and the heart rate usually returns to pre-
treatment values within 20 to 30 seconds. INFORMATION FOR PATIENTS
Percutaneous insertion of a temporary pacemak-
er may be necessary. If the patient is subsequently Patients should be instructed that specific drug(s)
diagnosed with underlying intrinsic sinus or AV node may cause the heart rate (pulse) to become slower.
dysfunction, therapy with the offending medication Patients should be taught to take their pulse and
may be reinitiated after the implantation of a perma- to monitor their heart rate daily. Patients should
nent pacemaker. In severe cases, intravenous atropine be instructed to consult their pharmacist or physi-
cian if their heart rate falls below 50 beats per patients with acute idiopathic atrial fibrillation, 62%
minute, or if they feel lightheaded, dizzy, tired, of cases were associated with heavy alcohol use.489
weak, short of breath, or experience chest pain. In a prospective cohort study of the association
between self-reported alcohol use and incident atri-
al fibrillation, moderate alcohol intake was not asso-
ATRIAL FIBRILLATION/ ciated with new-onset atrial fibrillation. However,
ATRIAL FLUTTER consumption of 35 or more drinks per week was
associated with a hazard ratio for atrial fibrillation of
Atrial fibrillation is a supraventricular arrhyth- 1.45 (95% CI, 1.02 to 2.04) in men.546 About 5% of
mia that is characterized on ECG by an irregular- cases of atrial fibrillation in men were estimated to
ly irregular pattern of narrow QRS complexes, an be attributable to heavy alcohol intake.
absence of discernible P waves, and an undulat- In a randomized study of the prevention of frac-
ing baseline (Figure 25–5). Atrial flutter is a tures in postmenopausal women, the bisphospho-
supraventricular arrhythmia that is characterized nate drug alendronate was found to increase the risk
on ECG by a regular pattern of narrow QRS com- of “serious” atrial fibrillation (1.5% vs. 1.0% in the
plexes, with discernible P waves that exhibit a placebo group; relative hazard, 1.51; 95% CI, 0.97 to
“sawtooth” appearance (Figure 25–6). Atrial flut- 2.40; P = 0.07).496 However, alendronate did not
ter is often associated with a ratio of P waves to increase the risk of “all atrial fibrillation adverse
QRS complexes of 4:1, 3:1 or, in some cases, 2:1. events.” In addition, in a case–control study in
women, a higher proportion of patients with atrial
fibrillation had ever used alendronate as compared
CAUSATIVE AGENTS with those who had never used any bisphosphonate
(odds ratio of atrial fibrillation, 1.86; 95% CI, 1.09 to
Drugs that have been associated with atrial fibrilla- 3.15).497 Furthermore, another bisphosphonate drug,
tion or atrial flutter are listed in Table zoledronic acid, was reported to increase the risk of
25–12.123,162,196,218,349,468-545 The majority of drugs “serious” atrial fibrillation as compared with placebo
that have been associated with induction of atrial (1.3% vs. 0.5%, P<0.001).545 However, zoledronic acid
fibrillation or flutter are cardiovascular agents, but did not increase the risk of all atrial fibrillation events.
drugs from other classes have been implicated as In a cohort study of 15,795 patients with fractures
well, including the bisphosphonate drugs alen- treated with oral bisphosphonates, the adjusted risk
dronate496,497 and zoledronic acid.545 of atrial fibrillation was higher than that in an age-
and sex-matched group of patients with fractures
who did not receive the drugs (1.18; 95% CI, 1.08 to
EPIDEMIOLOGY 1.29).547 A database analysis of over 40,000 women
conducted in the United Kingdom showed no evi-
The overall incidence of drug-induced atrial fibrilla- dence of an overall risk of bisphosphonate-associated
tion or flutter is not known, but it is likely very low. atrial fibrillation, but a potential increased risk of atri-
Adenosine has been reported to cause a substantial al fibrillation associated with alendronate during the
incidence of atrial fibrillation in patients undergo- first few months of therapy.548 However, other studies
ing treatment for AV nodal reentrant tachycardia.475 have not reported an increased risk of atrial fibrilla-
Although the incidence of alcohol-induced atrial tion associated with bisphosphonates.549,550
fibrillation (often referred to as the “holiday heart” Determining whether bisphosphonate drugs are asso-
syndrome) is unknown, in a case–control study of ciated with atrial fibrillation requires further study.
FIGURE 25–6. Atrial flutter with 2:1 atrioventricular conduction induced by propafenone.
Reproduced with permission from Tai et al.498
New-onset atrial flutter associated with drugs is cytokines,496,555 which have been associated with
also uncommon, but has been reported to occur in the development of atrial fibrillation.556 Further
patients with atrial fibrillation who are receiving study is necessary to determine the mechanism of
Vaughan Williams class IC antiarrhythmic agents (fle- bisphosphonate-induced atrial fibrillation and to
cainide or propafenone) or amiodarone (Table 25–12). confirm that this is truly a disease that is induced
by drugs from this class.557
Many of the drugs that have been reported to
MECHANISMS cause atrial fibrillation or atrial flutter have common-
ly been used for the management of these arrhyth-
Mechanisms by which some drugs induce atrial fib- mias. Despite the fact that flecainide has been shown
rillation or flutter are presented in Table 25–13. Atrial to be effective for the prevention and management of
fibrillation is believed to be induced by ectopic atrial fibrillation, data from studies in animals indi-
impulses originating from pulmonary veins, atria, or cate that flecainide may shorten atrial conduction
both, and it has been proposed that adenosine may velocity558 and wavelength,559 effects which may pro-
induce increased atrial ectopic activity, which may mote the development of atrial fibrillation.
then trigger the development of atrial fibrillation.475 Amiodarone-induced atrial fibrillation may, at least in
In addition, atrial fibrillation is maintained by multi- some cases, be due to amiodarone-induced thyrotox-
ple reentrant wavelets, and evidence indicates that icosis.560.561 Dobutamine has been shown to shorten
the shorter the wavelength, the more likely that atri- atrial effective refractory periods,562 while theo-
al fibrillation develops and is sustained.551,552 phylline has been shown to increase atrial automatic-
Wavelength is the product of the atrial conduction ity.563 Mechanisms by which other drugs may induce
velocity and the atrial effective refractory peri- atrial fibrillation or flutter require further study.
od.551,552 Adenosine has been shown to shorten the
atrial effective refractory period, and therefore may
promote reduction in atrial wavelength and the CLINICAL PRESENTATION AND
development of multiple reentrant atrial DIFFERENTIAL DIAGNOSIS
wavelets.553,554 The mechanism of alcohol-induced
atrial fibrillation is believed to be related to increased The symptoms of drug-induced atrial fibrillation
sympathetic nervous system stimulation.494 and atrial flutter are related to the degree of tachy-
Mechanisms by which the bisphosphonate cardia and the resultant effect on blood pressure
drugs alendronate and zoledronic acid may cause and cardiac output (Table 25–14). The symptoms of
atrial fibrillation are unclear. It has been suggested atrial fibrillation may be indistinguishable from
that bisphosphonate drugs may cause atrial fibrilla- those of atrial flutter, and therefore atrial fibrilla-
tion through the release of inflammatory tion and atrial flutter must be distinguished from
one another (and from other tachyarrhythmias) by drug-induced atrial fibrillation or flutter is also some-
ECG (Figures 25–5 and 25–6). what variable; a case of albuterol-induced atrial fibril-
The onset of drug-induced atrial fibrillation or lation lasted several hours,484 whereas atrial flutter
flutter is variable, depending on the inducing drug. associated with amiodarone or propafenone may
Adenosine-induced atrial fibrillation or flutter occurs require intervention to terminate the arrhythmia.498
within 1 minute of administration of this extremely Sinus rhythm was the preceding rhythm in 88%
short-acting agent.349 In a study of amiodarone- or of patients in whom atrial fibrillation associated with
propafenone-induced atrial flutter, the mean (±SD) adenosine developed, whereas the remaining 12% of
time of onset was 5.0+5.5 months after the initiation patients had atrial ectopic activity prior to the devel-
of treatment,498 whereas atrial flutter has been opment of atrial fibrillation.475 The mean ventricular
reported in association with flecainide therapy of 2 rate associated with adenosine-induced atrial fibrilla-
months’ duration.517 The duration of episodes of tion was 107+43 bpm.475 Adenosine-induced
TABLE 25–14 Signs and Symptoms Associated TABLE 25–15 Conditions to Consider in the
with Drug-Induced Atrial Fibrillation/Flutter Differential Diagnosis of Drug-Induced Atrial
Fibrillation/Flutter
• Palpitations
• Dizziness • Atrial fibrillation or flutter not induced by drugs
• Light-headedness • Sinus tachycardia
• Shortness of breath • Atrial tachycardia
• Chest pain (if underlying coronary artery disease is • Atrioventricular nodal reentrant tachycardia
present) • Ventricular tachycardia
• Near-syncope
• Syncope
(58%), and therefore may be somewhat predictive
of impending drug-induced atrial fibrillation.475
episodes of atrial fibrillation tend to be of short dura- Alcohol dose is a risk factor for alcohol-induced
tion. The mean duration of episodes of atrial fibrilla- atrial fibrillation. In one study, the mean dose of
tion associated with adenosine was 5.6+6.7 minutes alcohol consumed during the week prior to the
(range, 8 seconds to 20.7 minutes).475 atrial fibrillation episode was 186g, as compared
Conditions to consider in the differential diag- with 86g in a control population in whom alcohol-
nosis of drug-induced atrial fibrillation/flutter are induced atrial fibrillation did not develop.493
presented in Table 25–15. Non–drug-induced atrial Another study found that the risk of alcohol-
fibrillation/flutter must be considered; drug-induced induced atrial fibrillation was increased in patients
atrial fibrillation/flutter is more likely in patients who consumed more than an average of 30g alco-
who are receiving drugs that have been reported to hol daily.492 Alcohol withdrawal may increase the
cause atrial fibrillation or flutter, particularly in risk of alcohol-induced atrial fibrillation.490
patients with no known risk factors or causes for In patients receiving amiodarone for treatment
non–drug-induced atrial fibrillation/flutter, such as of atrial fibrillation, amiodarone-induced atrial flut-
hypertension, ischemic heart disease, heart failure, ter does not appear to be related to age, sex, presence
valvular heart disease, rheumatic fever, or hyperthy- of structural heart disease, left ventricular function,
roidism, or in those who have undergone thoracic or duration of atrial fibrillation; however, left atrial
surgery within the previous 2 to 5 days. enlargement (>40 mm) may be a risk factor.498
Further study is needed to identify risk factors for
drug-induced atrial fibrillation or atrial flutter.
RISK FACTORS
Although all risk factors for drug-induced atrial fib- MORBIDITY & MORTALITY
rillation or flutter have not yet been fully charac-
terized, known risk factors are presented in Table Symptoms associated with drug-induced atrial fib-
25–16. Atrial fibrillation associated with adenosine rillation or flutter could potentially result in hospi-
does not appear to be related to sex or age and may talization or prolonged duration of stay in a
occur in patients with no history of atrial fibrilla- hospital or critical care unit, although prolonged
tion.475 Atrial fibrillation induced by adenosine is duration of hospital stay as a result of drug-
not related to the type of arrhythmia being treat- induced atrial fibrillation or flutter has not been
ed.475 Premature atrial contractions occur signifi- reported. Hypothetically, drug-induced atrial fibril-
cantly more frequently in patients who have lation could result in stroke, but this has not yet
experienced adenosine-induced atrial fibrillation been described. Death due to drug-induced atrial
(100%) as compared with those who did not fibrillation or flutter has not been reported.
TABLE 25–16 Risk Factors for Drug-Induced TABLE 25–17 Approaches to Help Prevent Drug-
Atrial Fibrillation/Flutter Induced Atrial Fibrillation/Flutter
Adenosine Alcohol492,493
• Premature atrial contractions • Avoid binge drinking/excessive doses
Alcohol • Consume <30g daily
• Dose > 30g daily Methylprednisolone524
• Withdrawal • Propafenone 300 mg three times daily
Amiodarone Other drugs
• Left atrial hypertrophy • Administer lowest effective dose
Other drugs
• Unknown
avoided because of the risk of exacerbation of heart
failure; intravenous digoxin or amiodarone should
be administered instead.564 In patients with rapid
heart rates that do not respond promptly to drug
PREVENTION therapy for ventricular rate control, or in patients
with atrial fibrillation/flutter in whom symptoms
For the most part, specific methods of prevention are unacceptable, direct-current cardioversion
have not been determined. However, the risk of should be administered. However, if atrial fibrilla-
alcohol-induced atrial fibrillation can be mini- tion has been present for >48 hours, or if the dura-
mized by avoiding binge drinking and excessive tion of the episode of atrial fibrillation is unknown,
doses of alcohol, and by consuming <30g alcohol patients should undergo transesophageal echocar-
daily (Table 25–17).492,493 Moretti et al.524 reported diography to rule out an atrial thrombus before
the case of a patient treated with intermittent electrical or pharmacologic cardioversion is per-
courses of high doses of intravenous methylpred- formed.
nisolone for multiple sclerosis in whom recurrent After the administration of agents to control
atrial fibrillation attributed to the corticosteroid the ventricular rate, drug-induced atrial fibrillation
developed. Pretreatment prophylaxis with sotalol or flutter should be converted to sinus rhythm,
was ineffective, but pretreatment prophylaxis with using either elective direct-current cardioversion or
oral propafenone 300 mg three times daily was pharmacologic cardioversion. Acceptable agents
effective at preventing methylprednisolone- for pharmacologic cardioversion include amio-
induced atrial fibrillation. darone, dofetilide, flecainide, ibutilide, or
propafenone (Table 25–18). If the atrial fibrillation
was induced by a sodium channel blocking agent,
MANAGEMENT conversion to sinus rhythm should be achieved
using direct-current cardioversion or ibutilide. It
The causative agent should be discontinued. In a should be noted, however, that the effectiveness of
series of cases of adenosine-induced atrial fibrilla- antiarrhythmic drug therapy for drug-induced atri-
tion, 67% of patients converted to sinus rhythm al fibrillation or atrial flutter has not been studied.
spontaneously, whereas 33% required cardiover- In patients with atrial fibrillation in whom new
sion.475 Therefore, hemodynamically stable drug- atrial flutter induced by amiodarone or
induced atrial fibrillation or atrial flutter is propafenone develops, radiofrequency catheter
associated with a high incidence of spontaneous ablation of the isthmus between the tricuspid
conversion, and treatment may not be necessary. In annulus and the inferior vena cava has been used
patients who do not convert spontaneously to sinus to terminate the atrial flutter while allowing
rhythm, intravenous drugs for ventricular rate con- patients to remain on antiarrhythmic drug therapy
trol should be administered (Table 25–18).564 For for the management of the atrial fibrillation.498,499
patients with normal left ventricular function, an Radiofrequency catheter ablation of drug-induced
intravenous b-blocker or calcium-channel blocker atrial flutter is successful in 90% to 100% of
should be administered. Diltiazem may be preferred patients, and drug-induced atrial flutter did not
over verapamil as a result of a lower risk of sympto- recur in 14 of 15 patients during a 1-year follow-up
matic hypotension.565 For patients with heart fail- period.498
ure due to left ventricular dysfunction, intravenous If the drug-induced atrial fibrillation is a result
calcium-channel blockers and b-blockers should be of a theophylline overdose, activated charcoal may
tachycardia may occur intermittently, which is despite the commonly held belief that paroxysmal
commonly referred to as “paroxysmal atrial tachy- atrial tachycardia is commonly associated with
cardia.” digoxin toxicity, it appears to occur relatively
rarely.
The incidence of multifocal atrial tachycardia
CAUSATIVE AGENTS associated with theophylline is dependent on
serum theophylline concentrations.586 In an analy-
Drugs that have been reported to cause atrial sis of 100 patients receiving theophylline, atrial
tachycardia are listed in Table 25–19.83,388,483,537,568- tachycardia did not occur in the patients with
586 serum theophylline concentrations <10 mcg/mL.
However, in patients with serum theophylline con-
centrations between 10 and 20 mcg/mL, the inci-
EPIDEMIOLOGY dence of atrial tachycardia was 8%, and the
incidence rose to 16% in patients with serum theo-
Paroxysmal atrial tachycardia is often described as phylline concentrations >20 mcg/mL.586
a characteristic arrhythmia associated with digoxin
toxicity.578 However, at one large urban medical
center, “definite” paroxysmal atrial tachycardia MECHANISMS
was documented in only 2% of 219 patients with a
discharge diagnosis of digoxin intoxication.83 In Mechanisms of drug-induced atrial tachycardia are
this analysis, paroxysmal atrial tachycardia not entirely clear, but are likely related to increas-
occurred less frequently than any other arrhythmia ing the automaticity of atrial tissue (Table
associated with digoxin intoxication. Therefore, 25–20).567 This may occur because of b-receptor
CLINICAL PRESENTATION AND with AV block are the same as those for digoxin
DIFFERENTIAL DIAGNOSIS toxicity. Since digoxin is cleared primarily by the
kidneys, renal dysfunction is a primary risk factor
The symptoms of drug-induced atrial tachycardia for digoxin toxicity and digoxin-induced atrial
are related to heart rate and the resultant effect on tachycardia with AV nodal blockade. In addition,
blood pressure and cardiac output (Table 25–21). drug interactions that result in increased serum
The diagnosis of drug-induced atrial tachycardia digoxin concentrations enhance the risk of digox-
must be made primarily on the basis of the appear- in-related arrhythmias. Amiodarone,456 vera-
ance on ECG (Figure 25–7). Conditions to consider pamil,457 and quinidine458 are known to
in the differential diagnosis of drug-induced atrial significantly increase serum digoxin concentra-
tachycardia are presented in Table 25–22. tions.
Paroxysmal atrial tachycardia with AV block asso-
ciated with digitalis toxicity may occur in patients
RISK FACTORS across a wide range of ages. In one series, in which 31
cases of paroxysmal atrial tachycardia with AV block
Risk factors for drug-induced atrial tachycardia are were reported in association with digitoxin, the age
presented in Table 25–23. Paroxysmal atrial tachy- range of patients varied from 20 to 73 years (average,
cardia with AV nodal blockade is extremely rare at 52).571 There were 15 women and 16 men, with a vari-
therapeutic serum digoxin concentrations, but ety of underlying cardiovascular disorders, including
occurs primarily when serum digoxin concentra- valvular heart disease (n = 14), congenital heart dis-
tions increase to >2.0 ng/mL. Therefore, risk factors eases (n = 6), and ischemic heart disease (n = 1).571 As
for digoxin-induced paroxysmal atrial tachycardia mentioned previously, elevated serum theophylline
concentration is a risk factor for theophylline-
TABLE 25–23 Risk Factors for Drug-Induced TABLE 25–24 Approaches to Help Prevent Drug-
Atrial Tachycardia Induced Atrial Tachycardia
Digoxin Digoxin
• Serum digoxin concentrations >2.0 ng /mL • Maintain serum digoxin concentrations <2.0 ng /mL
• Kidney disease • Appropriate dose adjustment for kidney disease
• Drug interactions leading to elevated serum digoxin • Appropriate dose adjustment in the presence of inter-
concentrations acting drugs, particularly amiodarone, verapamil, or
Theophylline quinidine
• Serum theophylline concentrations >20 mcg /mL Theophylline
• Maintain serum theophylline concentrations <20
mcg /mL
induced atrial tachycardia. New supraventricular
arrhythmias including multifocal atrial tachycardia
were reported in 7 patients with serum theophylline the elimination of digoxin, the initial digoxin dose
concentrations between 21 and 40 mcg/mL.585 should be 0.125 mg every other day.
Atrial tachycardia associated with theophylline
may be prevented by maintaining serum theo-
MORBIDITY AND MORTALITY phylline concentrations <20 mcg/mL.
tachycardia is a result of a theophylline overdose, ECG by regular, narrow QRS complexes, often with
activated charcoal may administered.566 an absence of discernible p waves (Figure 25–8).
TABLE 25–27 Signs and Symptoms Associated TABLE 25–29 Risk Factors for Drug-Induced
with Drug-Induced Atrioventricular Nodal Atrioventricular Nodal Reciprocating Tachycardia
Reciprocating Tachycardia
Albuterol
• Palpitations • Continuous intravenous infusion
• Dizziness • Intravenous infusion rate >60 mcg/min
• Light-headedness • Concomitant therapy with theophylline
• Shortness of breath Dobutamine
• Chest pain (if underlying coronary artery disease is • Male sex
present) • Elderly
• Near-syncope • Myocardial infarction score on dobutamine stress test
• Syncope
Furosemide
• Reported only in infants or children following cardiac
surgery
TABLE 25–28 Conditions to Consider in the • Continuous infusion resulting in profound diuresis
Differential Diagnosis of Drug-Induced (8–10 mL/kg /hr)
Atrioventricular (AV) Nodal Reciprocating Theophylline
Tachycardia • Serum theophylline concentrations >20 mcg /mL
• Concomitant therapy with albuterol
• Atrial fibrillation
• Atrial flutter
• Atrial tachycardia
• Sinus tachycardia
mg/kg/hr. A common factor in these three
• AV nodal reentrant tachycardia not induced by drugs
patients was substantial diuresis resulting from
• Ventricular tachycardia
the furosemide, in the range of 8 to 10 mL/kg/hr,
as compared with an average fluid elimination of
2.5 mL/kg/hr in 22 other patients who had
received a similar furosemide infusion.626 Serum
RISK FACTORS potassium concentration was below normal lim-
its in one of the three patients in whom the
Known or potential risk factors for drug-induced arrhythmia developed, but remained normal in
AVNRT are presented in Table 25–29. Albuterol- the other two cases. Therefore, it is possible that
induced AVNRT appears to be more likely in a large amount of fluid loss may be a risk factor
patients receiving the drug intravenously, particu- or predictor of drug-induced AVNRT in infants or
larly at infusion rates >60 mcg/min.597,603 AVNRT children receiving a continuous infusion of
associated with dobutamine occurs more common- furosemide after cardiac surgery. Serum theo-
ly in men than in women,615 and in elderly phylline concentration is a risk factor for theo-
patients.509,616 In addition, severity of myocardial phylline-induced supraventricular arrhythmias;
ischemia has been shown to be an independent new supraventricular arrhythmias were reported
predictor of dobutamine-induced AVNRT; in a in 7 patients with serum theophylline concentra-
study of 1,076 patients undergoing dobutamine tions between 21 and 40 mcg/mL.585 Risk factors
stress myocardial perfusion imaging, the mean for AVNRT associated with other drugs have not
myocardial infarction score (calculated based on been identified.
assessment of fixed perfusion defects during
myocardial perfusion scintigraphy) was 4.4±4.1 in
patients with AVNRT, as compared with 2.8±3.5 in MORBIDITY AND MORTALITY
those without it, and the infarction score was an
independent predictor of AVNRT.616 Drug-induced AVNRT may result in symptoms suf-
All of the reported cases of AVNRT associated ficient to result in presentation to the emergency
with continuous furosemide infusions (n = 3 department and hospitalization.605,606,624,628 In
patients) have occurred in infants or children addition, drug-induced AVNRT may result in pro-
after cardiac surgery. In these patients, the longation of stays in the intensive care unit and
arrhythmia occurred within 3 to 7 hours after the the hospital.625,626 Mortality associated with drug-
initiation of a furosemide infusion of 1.0 induced AVNRT is likely quite rare.
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Am J Respir Crit Care Med. 2002;166:333-339.
CHAPTER 26
Ventricular
Arrhythmias
James E. Tisdale
usually a manifestation of serum concentrations indicated by the term “monomorphic”, QRS com-
that are markedly elevated above the therapeutic plexes possess similar beat-to-beat morphologic
range, occurs as a result of profound inhibition of characteristics. Potent sodium channel blocking
the sodium–potassium–adenosine triphosphatase drugs may also cause a specific, often incessant
pump, leading to marked increases in intramy- ventricular tachycardia characterized by wide QRS
ocyte concentrations of calcium, provoking after- complexes with a sinusoidal appearance (Figure
depolarizations and ventricular ectopic activity.99 26–2). This incessant, sinusoidal ventricular tachy-
cardia is often slower than typical spontaneous
ventricular tachycardia, but occasionally can be
CLINICAL PRESENTATION AND quite rapid.28
DIFFERENTIAL DIAGNOSIS Drug-induced monomorphic ventricular
tachycardia may be nonsustained or sustained.
Whether drug-induced or due to other causes, Nonsustained ventricular tachycardia is defined as
monomorphic ventricular tachycardia is a series of at least three consecutive beats of ventricular
consecutive ventricular premature depolarizations tachycardia, lasting ≤30 seconds and terminating
and is characterized by wide, misshapen QRS com- spontaneously. Sustained ventricular tachycardia
plexes on an electrocardiogram (ECG), with a lasts >30 seconds and requires intervention for ter-
heart rate >100 bpm, and sometimes as high as mination. Sinusoidal-appearing ventricular tachy-
150 to 250 bpm (Figure 26–1). Heart rates are often cardia is often sustained and is more likely to be
faster and may be as high as 150 to 250 bpm. As incessant and refractory to overdrive pacing or
TisdaleC26_485-515 1/12/10 2:54 PM Page 487
direct current cardioversion than other monomor- drugs may increase the rate of a patient’s preexist-
phic ventricular tachycardias. Occasionally, sinu- ing ventricular tachycardia, make it more sympto-
soidal-appearing ventricular tachycardia is matic, more difficult to terminate, or both.97 The
characterized by frequent nonsustained episodes symptoms of drug-induced ventricular tachycardia
that terminate spontaneously but quickly recur.28 are related to heart rate and the resultant effect on
Drugs may cause new ventricular tachycardia blood pressure and cardiac output (Table 26–3).
in patients who did not previously have this However, in some patients, the initial symptom of
arrhythmia or may aggravate or worsen an under- drug-induced ventricular tachycardia may be sud-
lying ventricular tachycardia. For example, specific den cardiac death as a result of rapid degeneration
Amiodaroned
Synchronized direct Amiodaroneb
current cardioversion
intravenous lidocaine, administered as a loading feel palpitations, light-headed, dizzy, tired, weak,
dose of 75 mg, followed in 10 minutes by another or short of breath or experience chest pain.
loading dose of 50 mg, followed by a continuous
infusion of 2 mg/min.42 Flecainide-induced sinu-
soidal ventricular tachycardia has also been suc-
cessfully treated using high-dose intravenous TORSADES DE POINTES
amiodarone, administered as a loading dose of 600 Torsades de pointes is a potentially life-threatening
mg over 20 minutes, followed by 2 g over 24 hours, ventricular tachyarrhythmia associated with pro-
with a concomitant oral regimen of 2 g/24 hours.43 longation of the QT interval.109,110 QT interval pro-
longation and torsades de pointes may be
congenital or acquired. Acquired torsades de
INFORMATION FOR PATIENTS pointes is most often caused by drugs.110
the corrected QT (QTc) interval on ECG but have was made to determine the overall incidence of
not been reported to induce torsades de pointes are drug-induced ventricular proarrhythmia in a study
not included, as drug-induced QTc interval prolon- conducted by the Swedish Medical Products
gation in the absence of torsades de pointes is not Agency.462 This study was conducted over a period
a drug-induced disease. Up-to-date lists of drugs of 28 days in 32 hospitals, with a reference popula-
with the potential to cause torsades de pointes may tion of approximately 4.2 million people. All
be found at http://www.azcert.org/medical- episodes of ventricular arrhythmias that were
pros/drug-lists/drug-lists.cfm, a Web site main- encountered during admission to the hospital or
tained by the University of Arizona Center for that were tracked by ambulatory ECG recordings in
Education and Research on Therapeutics.111 the hospitals and that were considered to be asso-
ciated with drugs were recorded. Fourteen cases of
“medium or high confidence torsades de pointes”
EPIDEMIOLOGY were recorded. This corresponded to an incidence
of 3.3 cases per million during the 28-day period of
The incidence of drug-induced torsades de pointes the study, which was annualized to an incidence of
in the general population is unknown. An attempt 4 cases per 100,000 people annually.462 This study
TisdaleC26_485-515 1/12/10 2:54 PM Page 494
was very small and of very short duration. torsades de pointes may be caused by increased
Nonetheless, if this incidence could be extrapolat- inward calcium current through calcium channels
ed to the population of the U.S., it would corre- that become reactivated as a result of prolongation
spond to approximately 12,000 cases of in action potential duration.110,465,466
drug-induced torsades de pointes annually. Although inhibition of IKr current and prolon-
In another study conducted in Sweden, gation of ventricular repolarization and the corre-
adverse drug reactions reported to the Swedish sponding QTc interval are requisite for the
adverse drug reaction reporting system between development of torsades de pointes, those factors
1991 and 2006 were analyzed.463 Of 61,788 report- alone are not sufficient for the arrhythmia to
ed adverse drug reactions, 101 were drug-induced occur. Many patients taking drugs that inhibit IKr
torsades de pointes. Drug-induced torsades de current have QTc interval prolongation but do not
pointes was estimated to comprise 5% to 7% of all experience torsades de pointes. A major factor that
cases of ventricular tachycardia, ventricular fibril- is believed to increase the likelihood of torsades de
lation, or sudden cardiac death in a population- pointes, and which may in part explain the lack of
based study conducted in southwest France.464 a direct correlation between QTc interval and the
These studies did not attempt to determine the occurrence of torsades de pointes, is heterogeneity
overall incidence of drug-induced torsades de of repolarization (also referred to as dispersion of
pointes in the population. Further research is nec- repolarization or refractoriness).110 Action poten-
essary to determine the overall incidence of drug- tial duration varies throughout the three primary
induced torsades de pointes. ventricular cell types (epicardial, mid-myocardial
The incidence of torsades de pointes associated [M cells], endocardial), as a result of variations in
with specific agents is presented in Table 26–8. ion currents in the different cell types.110 The risk
of drug-induced torsades de pointes is believed to
be enhanced in patients with increased transmural
MECHANISMS dispersion of ventricular refractoriness. In addi-
tion, evidence exists to suggest that the risk of tor-
Torsades de pointes occurs in the setting of prolon- sades de pointes may be dependent on instability
gation of ventricular repolarization resulting in of the action potential and by the degree of trian-
lengthening of ventricular action potential dura- gulation of the action potential. Instability of the
tion, which is manifested as prolongation of the action potential indicates rapid fluctuations in
QTc interval on the ECG.109,110,465 As a result of acti- action potential duration. Triangulation of the
vation of inward depolarizing currents, action action potential refers to the ratio of the action
potential prolongation leads to increased suscepti- potential duration at 30% repolarization to that of
bility to early afterdepolarizations, which are man- action potential duration at 90% repolarization; as
ifested as depolarizing oscillations in membrane this ratio increases, the action potential takes on a
voltage during phase 2 or 3 of the action poten- more triangular shape. In vitro and ex vivo studies
tial.109 These early afterdepolarizations may result have suggested that the risk of torsades de pointes
in triggered upstrokes, which, when occurring dur- is enhanced when action potential instability and
ing the latter portion of phase 3 of the action triangulation are present.467 Further study is
potential, may initiate torsades de pointes via reen- required to better understand the conditions
try.109,465 required for torsades de pointes to develop in
Prolongation of ventricular repolarization and patients with QTc interval prolongation.
resulting action-potential duration lengthening
may occur as a result of decreases in outward cur-
rent or increases of inward current during the
plateau or repolarization phase of the action CLINICAL PRESENTATION AND
potential (or both). Drugs induce torsades de DIFFERENTIAL DIAGNOSIS
pointes through inhibition of outward current
through specific potassium channels, primarily the Symptoms associated with torsades de pointes are
rapid component of the delayed rectifier potassium similar to those of other tachyarrhythmias and are
channel (IKr), resulting in action potential prolon- related to heart rate and resulting effects on blood
gation.109,110,465 Some drugs, such as ibutilide, also pressure and cardiac output (Table 26–9). Although
appear to prolong ventricular action potential, in torsades de pointes is sometimes transient, self-lim-
part through activation of slow sodium current iting, and spontaneously terminating, it can
during phase 2 of the action potential. It is degenerate into ventricular fibrillation and cause
believed that early afterdepolarizations that trigger sudden cardiac death.
TisdaleC26_485-515 1/12/10 2:54 PM Page 495
TABLE 26–10 Conditions to Consider in the TABLE 26–11 Risk Factors for Drug-Induced
Differential Diagnosis of Drug-Induced Torsades de Torsades de Pointes
Pointes
• QTc interval >500 msec
• Sinus tachycardia • Increase in QTc interval by >60 msec compared with
• Atrial fibrillation the pretreatment value
• Atrial flutter • Female sex
• Atrial tachycardia • Advanced age
• Atrioventricular nodal reentrant tachycardia • Left ventricular systolic dysfunction
• Monomorphic ventricular tachycardia • Hypokalemia
• Non–torsades de pointes polymorphic ventricular • Hypomagnesemia
tachycardia • Bradycardia
• Elevated plasma concentrations of QT interval–pro-
longing drugs due to drug interactions or absence of
dose adjustment for organ dysfunction
• Concomitant administration of >1 agent known to
RISK FACTORS cause QTc interval prolongation or torsades de
pointes
Specific risk factors for drug-induced torsades de • Possible genetic predisposition
pointes have been identified (Table 26–11). • History of drug-induced torsades de pointes
Prolongation of the QTc interval on electrocardio-
graphy has repeatedly been determined to be a risk
factor. Other risk factors include female sex,
advanced age, bradycardia, hypokalemia, hypo- arrhythmogenic effects of estrogen in women or
magnesemia, left ventricular systolic dysfunction, protective effects of testosterone in men.470
and conditions leading to elevated plasma concen- Baseline QTc interval is longer in women than in
trations of causative drugs, such as kidney disease, men.471 In one series of 332 cases of torsades de
liver disease, drug interactions, or some combina- pointes associated with antiarrhythmic agents,
tion of these.109,110,170 70% of the cases occurred in women.472 Other stud-
Drug-induced torsades de pointes appears to ies have documented a female predisposition to
occur exceedingly rarely in patients without con- torsades de pointes associated with azimilide,170
comitant risk factors. An analysis of 144 published dofetilide,473 erythromycin,474 ibutilide,475 quini-
articles describing 249 patients who experienced tor- dine,476 sotalol,416 and terfenadine.477 The influ-
sades de pointes associated with noncardiac drugs ence of sex hormones on ventricular repolarization
revealed that nearly 100% of the patients had at least and risk for torsades de pointes has been investigat-
one risk factor, and 71% of the patients had at least ed and is a subject of ongoing study. One group of
two risk factors.469 More than two thirds of the investigators administered a small dose of intra-
patients were female; 41% had heart disease (defined venous ibutilide to healthy women during three
as myocardial infarction, heart failure, valvulopathy, phases of the menstrual cycle and attempted to
or cardiomyopathy); 28% had hypokalemia; 19% correlate plasma concentrations of estradiol and
had “drug toxicity” (defined as administration of progesterone with ibutilide-induced prolongations
higher-than-recommended doses or lack of dose in the QTc interval. QTc interval prolongation was
adjustment for organ dysfunction); 18% had a famil- not correlated with plasma estradiol concentra-
ial history of long-QT syndrome, a history of previ- tion, but was inversely correlated with the plasma
ous drug-induced torsades de pointes, or a history of progesterone concentration and the plasma prog-
drug-induced QT interval prolongation.469 Drug esterone-to-estradiol ratio, suggesting that estrogen
interactions leading to increased plasma concentra- may not be proarrhythmic, but that progesterone,
tions of the causative agent were present in 35% of an androgenic compound, may be protective.478 In
the patients. These data indicate that the vast major- vitro studies have shown that dihydrotestosterone
ity of patients in whom torsades de pointes induced shortens basal action potential duration and
by noncardiac drugs develops have risk factors that diminishes the effects of potassium channel block-
are easily identifiable. ing drugs on action potential duration.479
Explanations for an increased risk of drug- Therefore, androgens may protect against the elec-
induced torsades de pointes in specific patient pop- trophysiologic effects of drugs with the potential to
ulations are under investigation. Reasons that induced torsades de pointes.
women are at increased risk for drug-induced tor- Bradycardia has also been shown to be a risk
sades de pointes are unclear, but may involve factor for drug-induced torsades de pointes.
TisdaleC26_485-515 1/12/10 2:54 PM Page 497
TABLE 26–13 Drugs Known to Cause Torsades de Pointes That Are Substrates for Enzymes of the
Cytochrome P-450 System490
1A2 2B6 2C19 2C9 2D6 3A4
Amitriptyline Methadone Amitriptyline Amitriptyline Amitriptyline Amiodarone
Clozapine Citalopram Fluoxetine Chlorpromazine Chloroquine
Haloperidol Doxepin Doxepin Cisapride
Flecainide Clarithromycin
Fluoxetine Cocaine
Haloperidol Disopyramide
Imipramine Domperidone
Loratadine Erythromycin
Metoclopramide Haloperidol
Propafenone Loratadine
Sertraline Methadone
Thioridazine Pimozide
Quetiapine
Quinidine
Risperidone
Sertraline
Tacrolimus
Trazodone
Ziprasidone
actions are a particularly important risk factor for val–prolonging agent.491 In a similar study, auto-
drug-induced torsades de pointes. Of 25 cases of mated drug-dispensing data from 2 million health
torsades de pointes associated with terfenadine plan members from a total of 10 health mainte-
that were reported to the Food and Drug nance organizations were reviewed to determine
Administration (FDA), 9 patients were receiving the proportion of these patients who had been pre-
concomitant therapy with ketoconazole or itra- scribed QT interval–prolonging drugs, and the pro-
conazole, which inhibit the metabolism of terfena- portion of those patients for whom a second QT
dine.477 Numerous reported cases of drug-induced interval–prolonging drug or a drug known to alter
torsades de pointes occurred as a result of drug the clearance of the QT interval–prolonging med-
interactions leading to elevate plasma concentra- ication was prescribed.492 Of the patients from
tions of the offending agent.129,191,195,198, whom data were obtained, 11.4% had received pre-
206,209,250,262,267,273,275
QT interval–prolonging drugs scriptions for a potentially QT interval–prolonging
that are substrates for the cytochrome P-450 sys- drug. Of the patients who received prescrip-
tem, and therefore subject to drug interactions tions for a QT interval–prolonging drug, 4.6% also
when used in combination with inhibitors of received a prescription for a potentially interacting
enzymes of the cytochrome P-450 system, are list- drug that could increase the risk of torsades de
ed in Table 26–13.490 pointes.492
Use of combinations of QT interval–prolong- A history of drug-induced torsades de pointes
ing drugs increases the risk for drug-induced tor- increases the risk for torsades de pointes associated
sades de pointes. A retrospective cohort study of an with other QT interval–prolonging drugs.115, 132,377
outpatient prescription claims database revealed
that 9.4% of approximately 1.1 million patients
who filled a prescription for a QT interval–prolong- MORBIDITY AND MORTALITY
ing drug also filled an overlapping prescription for
a second QT interval–prolonging drug or for a drug Torsades de pointes may result in clinical symptoms
known to inhibit the clearance of the QT inter- requiring medical attention. More importantly, tor-
TisdaleC26_485-515 1/12/10 2:54 PM Page 499
sades de pointes may result in sudden cardiac October 2002, the FDA received 43 reports of tor-
death; the incidence of sudden death due to tor- sades de pointes and 15 reports of QTc interval pro-
sades de pointes is unknown. In recent years, a longation. Hospitalization was required in 47% of
number of drugs, including terfenadine, astemizole, these cases, and death occurred in 8%.
grepafloxacin, cisapride, and levomethadyl have In summary, drug-induced torsades de pointes
been removed from the U.S. market as a result of may result in morbidity requiring hospitalization
causing deaths due to torsades de pointes. and mortality due to sudden cardiac death.
In a retrospective analysis of 205 patients with Patients with a history of drug-induced torsades de
advanced heart failure, patients with a history of pointes and those currently receiving typical or
drug-induced torsades de pointes had a significant- atypical antipsychotic agents or erythromycin in
ly higher risk of sudden cardiac death during ther- combination with an inhibitor of the cytochrome
apy with amiodarone as compared with P-450 enzyme system are known to be at higher
amiodarone-treated patients with no history of risk of mortality.
drug-induced torsades de pointes (55% vs. 15%).493
These data suggest that drugs known to prolong
the QT interval should not be administered to PREVENTION
patients with advanced heart failure and a history
of drug-induced torsades de pointes. Some methods of prevention of drug-induced tor-
The risk of sudden cardiac death associated sades de pointes are listed in Table 26–14. Drug-
with antipsychotic drugs was investigated in a pop-
ulation-based case–control study of a longitudinal
database consisting of medical records from 150 TABLE 26–14 Prevention of Drug-Induced
general practitioners in Europe.494 Current use of Torsades de Pointes
antipsychotic agents was associated with a signifi-
• Avoid use of QTc interval–prolonging drugs in
cant increase in the risk of sudden cardiac death
patients with pretreatment QTc intervals >450 msec
(odds ratio, 3.3; 95% confidence interval, 1.8 to
• Reduce dose or discontinue QTc interval–prolonging
6.2). Previous use of antipsychotic drugs was not
agent if QTc increases >60 msec from pretreatment
associated with an increased risk of sudden cardiac
value
death. The risk of sudden cardiac death was high-
• Discontinue QTc interval–prolonging agent if QTc
est among patients receiving butyrophenones
increases to >500 msec
agents (such as haloperidol).494 The precise cause of
• Maintain serum potassium concentrations within
sudden cardiac death was not documented in this
normal range
study, but these drugs are known to be a cause of
• Maintain serum magnesium concentrations within
torsades de pointes, which may have contributed
normal range
to sudden cardiac death in these patients. A retro-
• When possible, avoid use of QTc interval–prolonging
spective cohort study of Medicaid enrollees in
drugs in patients with left ventricular systolic dys-
Tennessee also reported an increased risk of sudden
function, especially in patients with LVEF <20%
cardiac death associated with both typical and
• Adjust doses of renally eliminated QTc interval–pro-
atypical antipsychotic drugs.495
longing drugs in patients with kidney disease
In another study of a cohort of patients identi-
• Avoid use of hepatically metabolized QTc
fied from the Tennessee Medicaid database, the
interval–prolonging drugs in patients with advanced
multivariate-adjusted rate of sudden death from
liver disease
cardiac causes was twice as high in patients cur-
• Avoid drug interactions involving QTc interval–pro-
rently using erythromycin as compared with that
longing drugs that are substrates of the cytochrome
in patients who had not used the drug.496 Further,
P-450 enzyme system and cytochrome P-450 enzyme
the adjusted rate of sudden death from cardiac
inhibitors
causes was 5 times higher among patients who had
• Avoid concomitant administration of QTc
concurrently used drugs that inhibited activity of
interval–prolonging drugs
the cytochrome P-450 enzyme system while taking
• Avoid use of QTc interval–prolonging drugs in
erythromycin.496 These data indicate that erythro-
patients with a history of drug-induced torsades de
mycin use in combination with potentially inter-
pointes
acting drugs may markedly increase the risk of
• Avoid use of QTc interval–prolonging drugs in
cardiac mortality.
patients who have been diagnosed with one of the
An analysis was performed of reports to the FDA
congenital long-QT interval syndromes
of QTc interval prolongation and torsades de pointes
associated with methadone.334 From 1969 through
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TisdaleC27_516-528 1/12/10 2:56 PM Page 516
CHAPTER 27
Hypertension
Joseph J. Saseen
induced exacerbations of hypertension are likely cific agents are also presented in Table 27–1. The
more common. exact incidence of drug-induced hypertension
The seventh report of the Joint National associated with several agents is unknown; howev-
Committee on Prevention, Detection, Evaluation, er, these agents have been shown to increase blood
and Treatment of High Blood Pressure (JNC-7) has pressure.
identified several drugs that can cause hyperten-
sion.2 These agents may either cause hypertension
or be a reason for resistant hypertension.108 This MECHANISMS
chapter expands on the list provided by the JNC-7
to include additional agents. Estimated incidences Arterial blood pressure is regulated by several fac-
of drug-induced hypertension associated with spe- tors: the adrenergic nervous system, the
TisdaleC27_516-528 1/12/10 2:56 PM Page 518
renin–angiotensin–aldosterone system, kidney func- Certain drugs that alter hormonal regulation
tion and blood flow, hormonal regulatory systems (e.g., oral contraceptives, corticosteroids) can cause
(adrenal cortical hormones, vasopressin, thyroid, hypertension. The estrogen component of oral
insulin), and the vascular endothelium (nitric oxide, contraceptives is primarily responsible for blood-
bradykinin, prostacyclin, endothelin).5,110 Drug- pressure elevation, but the mechanism is unclear.
induced alterations of these systems may explain In premenopausal women, oral contraceptive use
persistent increases in blood pressure associated achieves serum estrogen and progestin concentra-
with certain agents. The various mechanisms by tions that are higher than those that result from
which drugs may induce hypertension (Table 27–2) endogenous hormone production. This is in sharp
are broadly categorized as: fluid-volume expansion, contrast to the use of estrogen-replacement thera-
stimulation of sympathetic nervous system activity, py (ERT) or hormone-replacement therapy (HRT)
interference with the action of antihypertensive in postmenopausal women, during which serum
drugs, paradoxical responses to antihypertensive estrogen and progestin concentrations are lower
agents, and unknown mechanisms.5 than those associated with premenopausal endoge-
Certain drugs (e.g., cocaine, amphetamines, nous hormone production. Clinical trials have
ephedra, some antidepressants) can activate the shown that the use of either ERT or HRT in both
sympathetic nervous system through norepineph- premenopausal and postmenopausal women
rine or norepinephrine-like stimulation. Stimu- increases the risk of cardiovascular events.116-119
lation of peripheral adrenergic ␣-receptors causes However, ERT or HRT does not cause drug-induced
vasoconstriction, while stimulation of myocardial hypertension in postmenopausal women.120
adrenergic -receptors increases heart rate and con- Hormonal dysregulation can cause hyperten-
tractility, both of which can increase blood pres- sion by inducing insulin resistance (the metabolic
sure. Under normal circumstances, compensatory syndrome), sodium and water retention, or myriad
mechanisms are triggered that decrease total other effects. Other miscellaneous agents cause
peripheral resistance, which usually maintains nor- hypertension via unique mechanisms outside of
mal blood pressure. However, drugs that cause these neurohumoral effects. Both erythropoietin-
hypertension may blunt or impair this compensa- alfa and darbepoetin-alfa can cause dose-depend-
tory response. ent increases in blood pressure.121 Possible
The renin–angiotensin–aldosterone system mechanisms include increased hematocrit and ery-
functions with the kidneys to regulate arterial throcyte mass, changes in the production or sensi-
blood pressure. Decreases in blood pressure or kid- tivity of endogenous vasopressor and vasodilatory
ney blood flow, volume depletion, or sodium factors, alterations in vascular smooth muscle,
depletion all increase secretion of renin from the direct vasoconstriction, and arterial remodeling by
kidney. Renin mediates the transformation of stimulation of vascular cell growth.122 However,
angiotensinogen to angiotensin I, which is con- the exact mechanism is unknown.
verted by angiotensin-converting enzyme to The adrenergic antihypertensive agents -
angiotensin II. Angiotensin II is a potent direct blockers and centrally acting ␣-receptor agonists
vasoconstrictor that stimulates production of can cause rebound hypertension when therapy is
aldosterone, which causes sodium and water reten- abruptly discontinued.8-27 Long-term exposure to -
tion. Several drugs (e.g., nonsteroidal antiinflam- blocking agents causes upregulation and increased
matory drugs [NSAIDs], including the cyclo- expression of -receptors. When -blocker therapy
oxygenase-2 [COX-2] selective inhibitor celecoxib, is abruptly discontinued, excessive stimulation of
certain immunosuppressants) can indirectly trigger these additional -receptors occurs, potentially
renin release, primarily by decreasing kidney perfu- resulting in increases in blood pressure and heart
sion.111,112 In premenopausal women, estrogens rate, leading to rebound hypertension. Cardio-
have been shown to stimulate the renin- selective -blockers or those with intrinsic sympa-
angiotensin-aldosterone system by increasing thomimetic activity have been touted as not being
hepatic production of angiotensinogen.113,114 associated with rebound hypertension, but this has
These effects are normally overcome by negative- not been proved. The mechanism by which
feedback mechanisms that prevent excessive renin rebound hypertension occurs with central ␣-ago-
release. However, this may not occur in patients nists has not been fully established, but is believed
taking drugs known to induce hypertension or in to be similar to that of -blockers. When exposed to
patients with chronic kidney disease or cardiovas- long-term central ␣-agonist therapy, ␣-receptor
cular risk factors. Generalized vasoconstriction, density, sensitivity, or both can increase.5 Abrupt
especially in the kidney, is the hypothesized cause discontinuation of therapy with the central ␣-ago-
of cyclosporine-induced hypertension.50,115 nist leads to elevated plasma norepinephrine con-
TisdaleC27_516-528 1/12/10 2:56 PM Page 519
TABLE 27–3 Blood Pressure Classification According to the JNC-72 to Detect Drug-Induced Hypertensiona
Systolic Blood Diastolic Blood
Classification Pressure (mm Hg) Pressure (mm Hg)
Normala <120 and <80
Prehypertensionb 120–139 or 80–89
Stage 1 hypertension 140–159 or 90–99
Stage 2 hypertension ⱖ160 or ⱖ100
JNC-7 = Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.2
a
Blood pressure values ⱖ120/ 80 mm Hg are considered above goal for patients with left ventricular dysfunction.
b
Blood pressure values ⱖ130/ 80 mm Hg are considered above goal for patients with diabetes, chronic kidney disease, coronary artery
disease, noncoronary atherosclerotic vascular disease (e.g., ischemic stroke, peripheral arterial disease), or primary-prevention patients
with Framingham scores ⱖ10%.3
TisdaleC27_516-528 1/12/10 2:56 PM Page 521
PREVENTION
Prevention strategies for drug-induced hyperten-
sion are listed in Table 27–7. Drug-induced hyper- TABLE 27–7 Approaches to Help Prevent Drug-
tension is ideally detected by closely monitoring Induced Hypertension.
blood pressure. Clinic-based blood pressure meas- • Avoid use of agents reported to cause drug-induced
urements should be obtained 2 to 4 weeks after hypertension in high-risk patients.
starting a drug known to increase blood pressure. • For patients taking agents known to cause drug-
Home or ambulatory blood pressure monitoring induced hypertension:
may be helpful, but are not essential.136-138 • Avoid tyramine-containing foods in patients taking
Moreover, both home and ambulatory blood pres- monoamine oxidase inhibitors.
sure values are lower than those measured in the • Use minimum effective dose of NSAIDs, including
clinic. Average home blood pressure measure- celecoxib.
ments are typically 5 mm Hg lower than clinic val- • Measure blood pressure at least every 2–4 wk.
ues, and 24-hour ambulatory blood pressure • Evaluate for symptoms of hypertension-related tar-
measurements in individuals with hypertension get organ damage periodically.
are typically 10 mm Hg lower.138 Patients with self- • Engage in lifestyle modifications:
measured blood pressure values of 135/85 mm Hg • Weight reduction: Maintain normal body weight
are generally considered to have hypertension.2 body-mass index, 18.5–24.9 kg/ma
However, clinic-based blood pressure measure- • Adopt the DASH eating plan: consume a diet
ments are sufficient for detecting drug-induced rich in fruits, vegetables and low-fat dairy prod-
hypertension. ucts with a reduced content of saturated and
The most effective prevention strategy is avoid- total fat.
ing the use of agents known to cause drug-induced • Reduce dietary sodium intake to 1.5 g sodium
hypertension. This is especially important in • Engage in regular aerobic physical activity (at
patients with either established cardiovascular dis- least 30 min/day, most days of the week).
ease or multiple risk factors for drug-induced • Moderate alcohol consumption: limit consump-
hypertension or cardiovascular disease (see Table tion to ⱕ2 drinks/day in most men and ⱕ1
27–6). For women requiring oral contraceptive drink/day in women and lighter-weight persons.
therapy, preparations with low estrogen (ⱕ30 mcg
DASH = Dietary Approaches to Stop Hypertension; NSAID =
ethinyl estradiol) and progestin (ⱕ1 mg norethin- nonsteroidal antiinflammatory drug.
drone) content appear to be associated with the a
Body-mass index is calculated as the weight in kilograms
lowest risk of hypertension.
divided by the square of the height in meters.
TisdaleC27_516-528 1/12/10 2:56 PM Page 523
strongly suspected, the offending agent should be hypertension is the primary goal in these
discontinued when possible (Table 27–8). Blood patients.
pressure should then return to baseline values A consensus guideline based on reports from
within 2 to 4 weeks under most circumstances. If clinical trials and from clinical experience using
the blood pressure remains consistently elevated cyclosporine in patients with rheumatoid arthritis
after discontinuing therapy with the offending was published in 1999.141 When patients taking
agent, further investigation to evaluate primary cyclosporine have stage 1 hypertension on at least
hypertension or other secondary causes is needed. two consecutive visits, the cyclosporine dose
The offending agent should not be reintroduced. should be reduced by 25%. The dose should be
However, if no reasonable treatment alternative reduced by 50% in those in whom stage 2 hyper-
can be identified, a reintroduction of therapy with tension develops, and initiation of antihyperten-
a reduced dose and blood pressure monitoring may sive pharmacotherapy may be necessary. If blood
be attempted. Lifestyle modifications to lower pressure remains elevated despite initial dose
blood pressure, as previously discussed, should be reductions, additional reductions and initiation of
implemented in these patients. antihypertensive pharmacotherapy should be con-
When certain offending agents must be con- sidered. Persistent blood pressure elevation may
tinued, specific management approaches may be require cyclosporine discontinuation if an accept-
considered (see Table 27–8). Cyclosporine and able alternative drug can be used.
tacrolimus, which are calcineurin inhibitors, are Dihydropyridine calcium-channel blockers
immunosuppressant agents that are used in (e.g., amlodipine, felodipine) are preferred agents
patients after solid organ transplantation and to for the treatment of cyclosporine-induced hyper-
treat a variety of other conditions.51-53,101 Patients tension.115,141 These agents do not interact with
with calcineurin inhibitor–induced hypertension cyclosporine and promote vasodilation of the
usually cannot discontinue therapy with the afferent and efferent renal arterioles. Pharma-
drug. Therefore, managing the drug-induced cologically, this mechanism of action is ideal for
pharmacy). If persistent increases in systolic or dias- 9. Shiroff RA, Mathis J, Zelis R, et al. Propranolol
tolic blood pressure values are detected (even if rebound—a retrospective study. Am J Cardiol.
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of antihypertensive treatment. JAMA. 1978;239:833.
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CHAPTER 28
Hypotension
may decline by 15%, and roughly 1 L of blood may also leads to arteriolar vasoconstriction and water
pool in capacitance vessels below the conservation by the kidney. All of these reflex
diaphragm.10,11 The resultant reduction in venous mechanisms limit the potentially adverse hemody-
return and decreases in cardiac output and blood namic effects of an upright posture; however,
pressure stimulate arterial baroreceptors, which should any one or a combination of these mecha-
trigger intricate compensatory mechanisms. nisms fail, orthostatic hypotension may result.5
Centrally mediated activation of the sympathetic Diseases such as diabetes mellitus and
efferent neurons increases vascular tone, myocar- Parkinson’s disease, which may impair mobility or
dial contractility, and heart rate. Cardiopulmonary lead to extended inactivity, have been associated
volume receptors cause vasopressin release, which with orthostatic hypotension. Conditions that
TisdaleC28_529-553 1/12/10 2:57 PM Page 535
impair diastolic filling such as blood loss, dehydra- episode of systemic hypotension characterized by
tion, and excessive diuresis may also lead to this both bradycardia and peripheral vasodilation.16
condition. A decrease in blood pressure may occur Overall, patients experiencing orthostatic
after eating, as a result of splanchnic blood pool- hypotension may report blurred vision, neck pain,
ing.12 weakness, buckling of the legs, cognitive slowing,
In healthy patients of any age, orthostatic headache, seizures (usually clonic jerks), or post-
hypotension occurs infrequently. However, as prandial angina pectoris. Focal neurologic find-
patients age, changes in cardiovascular physiology ings, if present, may suggest concomitant
as well as concomitant diseases or exposure to cerebrovascular disease.17 If syncope occurs,
medications that may reduce blood pressure patients typically respond immediately after being
increase the risk of orthostatic hypotension. placed in a horizontal position. Once the patient is
Physiologic changes that may contribute to ortho- horizontal, hypoperfusion-related symptoms typi-
static hypotension include alterations in barore- cally resolve.16 The syncope associated with ortho-
ceptor activity, parasympathetic activity, arterial static hypotension is generally differentiated from
and cardiac compliance, renal sodium conserva- other causes by a lack of postictal confusion or
tion, vasopressin response, plasma renin activity, drowsiness. Common findings associated with
plasma angiotensin and aldosterone concentra- orthostatic hypotension include mild anemia,
tions, and plasma volume.13 hypohidrosis, a parkinsonian-like syndrome, recur-
Genomic factors can also play a role in the rent urinary tract infections or bladder dysfunction
development of orthostatic hypotension. A single- or both, sleep apnea, hoarseness, nasal stuffiness,
nucleotide polymorphism with a glycine to argi- impotence, and constipation or diarrhea or both.5
nine switch at position 389 of the 1-adrenergic Symptoms of syncope are most commonly docu-
receptor has been found to significantly lower con- mented in the morning, after medication adminis-
tractile responsiveness to catecholamines, thus tration or following meals.
increasing susceptibility to orthostatic hypoten- A diagnosis of drug-induced orthostatic
sion.14 hypotension requires documentation of hypoten-
Even in healthy elderly patients, orthostatic sion accompanied by one or more of the previous-
hypotension can be unmasked or exacerbated by ly discussed symptoms.18 A detailed medication
the administration of drugs that interfere with the history, which includes a review of prescription
cardiovascular reflex response. For example, anti- and nonprescription medications and herbal sup-
hypertensive agents may produce hypotension by plements, a medical history, a thorough physical
decreasing sympathetic outflow, through central exam, and in some cases, specific diagnostic tests
and peripheral vasodilatory actions, or by deplet- should be used to rule out other possible causes of
ing intravascular volume. Drugs can induce hypotension. Conditions to consider in the differ-
hypotension through many different mechanisms ential diagnosis of drug-induced hypotension are
(Table 28–2).5,11,51,75-80,83,98,111,126-132,133,137,150,200,201, presented in Table 28–4.12-16 To evaluate a patient
216,217,206,236-253
for possible orthostatic hypotension, blood pres-
sure and heart rate should be measured at three dif-
ferent times: after the patient has rested in the
CLINICAL PRESENTATION AND supine position for 5 minutes, immediately after
DIFFERENTIAL DIAGNOSIS the patient stands, and 1 to 2 minutes after stand-
ing. If the heart rate does not increase in the pres-
Orthostatic hypotension may manifest with symp- ence of orthostatic hypotension, then baroreceptor
toms as mild as light-headedness or as severe as reflex dysfunction may be implicated. Early-morn-
presyncope or syncope (Table 28–3).5,15,16 Syncope ing measurements, especially after a high-carbohy-
is defined as a sudden, transient loss of conscious- drate meal, are helpful to identify postprandial
ness with a loss of postural tone usually lasting no hypotension. Heart-rate responses to deep breath-
more than 15 seconds.15 Presyncope can be charac- ing and to the Valsalva maneuver may also aid in
terized as near fainting, light-headedness, or differentiating between autonomic impairment
extreme dizziness; it may be a part of a continuum and other causes of orthostatic hypotension.
that leads to syncope or may occur as an isolated Detection may require multiple blood pressure
event. The “common faint,” or neurocardiogenic measurements on different days, which may neces-
syncope (also called “vasovagal syncope”), is the sitate use of an ambulatory blood pressure moni-
most common type of syncope.5 Neurocardiogenic tor. Patients should be instructed to measure their
syncope is a syndrome in which the triggering of a blood pressure before breakfast, after taking their
neural reflex results in a usually self-limited medications, after meals, and before bedtime.13
TisdaleC28_529-553 1/12/10 2:57 PM Page 536
Drug Mechanism
Alfuzosin24,352 Blockade of central and/or peripheral ␣-adrenoreceptors
Aripiprazole24,352
Chlorpromazine24,352
Clozapine24,352
Doxazosin353
Haloperidol24,352
Loxapine24,352
Olanzapine24,352
Pimozide24,352
Prazosin353
Quetiapine24,352
Risperidone24,352
Tamulosin353
Terazosin353
Thioridazine24,352
Thiothixene24,352
Trifluoperazine24,352
Ziprasidone24,352
Dobutamine, high-dose297-299 The following patient characteristics may be responsible:
• Inadequate increase in cardiac output due to impaired sys-
tolic reserve
• Marked prolongation of isovolumic relaxation time due to
induced myocardial ischemia
• Marked isolated reduction in systemic vascular resistance
• Decrease in cardiac output associated with cavity obliter-
ation and reflex bradycardia
Clonidine97 Direct stimulation of ␣-receptors in the vasomotor center
Guanfacine97 of the medulla leading to:
Guanabenz97 • Reduction in peripheral vascular resistance
Methyldopa97 • Decreased heart rate (secondary to increased vagal tone).
Reserpine132,133 Depletion of catecholamine and 5-hydroxytryptophan in
the central nervous system resulting in:
• Decreased peripheral resistance
• Reduced cardiac output
Chlorpromazine24 • Calmodulin-mediated inhibition of phosphodiesterase
Prochlorperazine24 • Relaxation of vascular smooth muscle
Promethazine24
Amitriptyline229 Reduced systemic vascular resistance due to
Clomipramine229 ␣-adrenoreceptor blockade
Desipramine229
Doxepin229
Imipramine229
Trazodone354
Amlodipine125 Blockade of L-type calcium channel
Diltiazem125
Felodipine125
Gabapentin250
Isradipine125
Nicardipine125
Nifedipine125
(Continued)
TisdaleC28_529-553 1/12/10 2:57 PM Page 538
Drug Mechanism
Nimodipine125
Nisoldipine125
Pregabalin250
Verapamil125
Pentamidine, intravenous251 Vasomotor reaction
Muromonab-CD340 Cytokine release syndrome
Interleukin-2355 Increase capillary permeability
Decreased peripheral vascular resistance
Amifostine356 Direct arteriolar vasodilatation
Diazoxide136-138
Epoprostenol341
Hydralazine136-138
Iloprost343-345
Minoxidil140-142
Nitroprusside143 Director arteriolar and venous vasodilation
316
Bosentan Inhibition of endothelin-1
Treprostinil317
Milrinone357,358 Inhibition of phosphodiesterase type III
Nesiritide23 Stimulates guanylate cyclase-linked natriuretic peptide
A/B receptors
Diphenhydramine14 Inhibition of fast sodium channels
Inhibition of potassium channels in overdose
Dacarbazine359 Calcium chelation by citric acid in the preparation
Carmustine360,361 Vasodilation due to alcohol content of the diluent
Vincristine314,315 Neurotoxicity
Inhibition of norepinephrine secretion
Vinblastine313 Neurotoxicity
Magnesium362 Opposition of calcium-dependent arterial constriction
Amiodarone201 Vasoactive solvents in the intravenous formulation
Etoposide363
Amyl nitrate184,185 Increase intracellular cyclic guanosine monophosphate
Isosorbide dinitrate193-198 concentrations
Isosorbide mononitrate193-198
Nitroglycerin193-198
Procainamide, intravenous216 Ganglionic blockade
Central nervous system sympathetic inhibition
Vardenafil364 Inhibition of vascular phosphodiesterase type V
Sildenafil364
Phenytoin244-247 Vasodilation from the propylene glycol content (phenytoin
Fosphenytoin248 only); unknown for fosphenytoin
261
Bromocriptine
Although invasive tests are usually not necessary, Increased
ciated dopamine, which in
with a drop exerts hypotension
blood pressurethrough the
or cardiac
365
Carbidopa–levodopa
plasma norepinephrine concentrations determined following:
arrhythmia when moved from the horizontal to
366
inEntacapone
the horizontal
267
and upright positions may assist Systemic, mesenteric,
the vertical and renal vasodilatation mediated
position.
inPergolide
identifying 267
autonomic dysfunction. The head- by dopamine receptors
upPramipexole
tilt-table test is considered the standard in the Displacement of norepinephrine from nerve terminals
Rasagiline365
diagnosis of syncope. 12-16
The test is considered Decreased renin and aldosterone secretion.
267
Ropinirole
positive if the patient experiences symptoms asso- Reduction in sympathetic outflow
(Continued)
TisdaleC28_529-553 1/12/10 2:57 PM Page 539
Drug Mechanism
Selegiline365
Tolcapone366
Fenoldopam162 Systemic, mesenteric, and renal vasodilatation mediated by
dopamine receptor activation
Donepezil367 Overactivation of muscarinic and nicotinic sites of
Galantamine367 autonomic and somatic nerves
Propofol180 Direct vasodilatation of venous smooth muscle
Fludarabine Unknown
Levofloxacin
TABLE 28-4 Conditions to Consider in the TABLE 28–5 Risk Factors for Drug-Induced
Differential Diagnosis of Drug-Induced Hypotension13
Hypotension12-16
• Large meals
• Autonomic Neuropathies • Prolonged recumbency
• Primary • Isometric exercise
• Bradbury–Eggleston syndrome • Standing motionless
• Shy–Drager syndrome • Alcohol
• Riley–Day syndrome • Straining at stool or with voiding
• Dopamine–-hydroxylase efficiency • Hot weather
• Secondary • Rapid ascent to high altitude
• Diabetes mellitus • Hot baths/showers
• Uremia • Fever
• Guillain–Barré syndrome • Hyperventilation
• Amyloidosis • Underlying cardiovascular disease
• Porphyria • Intravascular volume depletion
• Idiopathic • Overdiuresis
• 1-Receptor polymorphisms • Hyponatremia, hypokalemia
• Transient Neurogenic Syncope • Decreased hepatic drug metabolism
• Micturition syncope • Poor hepatic blood flow
• Carotid sinus syncope
• Vasovagal syncope
• Bezold–Jarisch reflex activation
• Glossopharyngeal neuralgia at risk for antihypertensive-induced orthostatic
hypotension, a low dose of the antihypertensive
• Endocrinologic Disorders agent should be administered first in a supervised
• Pheochromocytoma environment and the patient should be monitored
• Hypoaldosteronism for an appropriate time interval before providing
• Renal vascular hypertension maintenance therapy. Syncopal episodes can be
• Vascular Insufficiency/Vasodilatation minimized by initiating therapy at the lowest pos-
• Varicose veins sible dose, administering the first dose at bedtime,
• Arteriovenous malformations and increasing the dose slowly. If a diuretic is to be
• Absent venous valves given concomitantly with another antihyperten-
• Carcinoid syndrome sive drug, doses of the medications should be
• Cardiogenic shock spaced as far apart as possible.39 In patients who
• Mastocytosis experience histamine-related hypotension associ-
• Hyperbradykininism ated with vancomycin or the opioid derivatives,
• Hypovolemic Disorders prophylactic doses of oral or intravenous hista-
• Anemia mine blockers may help prevent future episodes.
• Decreased plasma volume Methylprednisolone may be administered 1 to 3
• Hemorrhage hours before the first, second, and third doses of
• Anorexia nervosa muromonab-CD3 to prevent cytokine-mediated
• Diarrhea hypotension.40 Doses of atracurium and mivacuri-
• Overdialysis um should be divided or administered over 1 to 2
• Overdiuresis minutes, or both, to decrease the risk of histamine-
• Miscellaneous related hypotension.41 To reduce the risk of ACE
• Anaphylaxis inhibitor-induced hypotension, the initial dose of
• Nutritional deficiencies (vitamin B12, folate) these drugs should be reduced by 50% if the sys-
• Pregnancy tolic blood pressure is ≤100 mm Hg; however, if the
• Space flight systolic blood pressure is <90 mm Hg, an ACE
inhibitor should be initiated only with caution and
with careful monitoring.28,29
Other strategies to reduce hypotension include
PREVENTION elevating the head of the patient’s bed to a 5- to 20-
degree angle. This helps activate the
Table 28–6 summarizes strategies for prevention of renin–angiotensin–aldosterone system and reduces
drug-induced orthostatic hypotension.12-16 In those nocturnal diuresis while preserving interstitial
TisdaleC28_529-553 1/12/10 2:57 PM Page 541
bedtime. Side effects include supine hypertension, hypotension remains controversial. Although the
piloerection, pruritus, and tingling of the scalp. true mechanism is unknown, NSAIDs are postulat-
The use of nonsteroidal antiinflammatory ed to inhibit vasodilatory prostanoids and enhance
drugs (NSAIDs) for management of drug-induced vascular sensitivity to angiotensin II, thereby
TisdaleC28_529-553 1/12/10 2:57 PM Page 543
increasing peripheral vascular resistance. In addi- inhibitor paroxetine has robust data suggesting
tion, these agents cause sodium retention, thus that it improves symptoms of patients with vasova-
increasing intravascular volume. Indomethacin 50 gal syncope who are unresponsive to or intolerant
mg orally three times daily and flurbiprofen of traditional medications. In these studies, parox-
50–200 mg orally two to three times daily, either etine was well tolerated.69
alone or in combination with fludrocortisone, Subcutaneous octreotide, a somatostatin ana-
have each been shown to relieve symptoms of logue, can be used to treat postprandial hypoten-
orthostatic hypotension and increase blood pres- sion owing to its ability to decrease splanchnic
sure.55-58 However, indomethacin should be avoid- blood flow and the release of insulin and
ed, when possible, because of the increased risk of glucagon. Effects are observed within 4 hours of
confusion, and all NSAIDS should be used with injection, with only mild gastrointestinal side
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CHAPTER 29
TABLE 29–1 Agents Implicated in Drug-Induced Valvular and Pericardial Heart Disease
Drug Incidence Level of Evidence
(see page xii for explanation)
AORTIC REGURGITATION
Bromocriptine3,97 NK B
Cabergoline877,79,80,86-91,97 16.7–68.8% B
Dexfenfluramine4–15 6.6–38% B
Dexfenfluramine in combination with phentermine4-15 6.6–38% B
Ergotamine16,17 NK C
Fenfluramine4-15,18-21 6.6–38% B
Fenfluramine in combination with phentermine5-15,18-21 6.6–38% B
MDMA98 14% B
Methysergide59,62,63 0.02% B
Pergolide22,76-78,80,81,82-88,90-97 0.005–67% B
MITRAL REGURGITATION
Bromocriptine3 NK C
Cabergoline77,80,86-91,97 28.6–68.8% B
Dexfenfluramine4-15 1.3–3.5% B
Dexfenfluramine in combination with phentermine4-15 1.3–3.5% B
Ergotamine16,17,23 NK C
Fenfluramine4-15,18-21 1.3–3.5% B
Fenfluramine in combination with phentermine4-15,18-21 1.3–3.5% B
MDMA98 14% B
Methysergide59,62,63 0.02% B
Pergolide22,76-78,80-88,90-97 0.005–75% B
TRICUSPID REGURGITATION
Bromocriptine3 NK C
Ergotamine16,23 NK C
MDMA98 45% B
Methysergide59,62,63 0.02% B
Pergolide22,76-78,80-88,90-97 0.005–78% B
MITRAL STENOSIS
Ergotamine16,17,23 NK C
Methysergide59,62,63 NK B
ACUTE EFFUSIVE PERICARDITIS
Busulfan24,25 NK C
Clozapine99-109 NK B
Cromolyn sodium26 NK C
Cyclophosphamide24,27,28 NK C
Cytarabine24,29-32 NK C
Dantrolene sodium32,22 NK C
Daunorubicin24,34 NK C
Doxorubicin24,34 NK C
Hydralazine (secondary to SLE-like syndrome)35-37 2% C
(Continued)
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TABLE 29–1 Agents Implicated in Drug-Induced Valvular and Pericardial Heart Disease (Continued)
Drug Incidence Level of Evidence
Isoniazid 30% (secondary to SLE-like syndrome)38,39 30% C
Methyldopa (secondary to SLE-like syndrome)40 NK C
Mesalamine112-121 NK C
Methotrexate110,111 NK C
Minoxidil41-44 3.8–20% C
Phenylbutazone45 NK C
Phenytoin (secondary to SLE-like syndrome)35 NK C
Procainamide (secondary to SLE-like syndrome)48-53 18–57% C
Sulfasalazine112,123 NK C
Tretinoin24,54 NK C
CONSTRICTIVE PERICARDITIS
Cyclophosphamide55 NK C
Cytarabine56 NK C
Ergotamine57 NK C
Methysergide58-63 0.02% C
Procainamide (secondary to SLE-like syndrome)48 NK C
HEMOPERICARDIUM
Busulfan64 NK C
Fibrinolytics65-71 8.75–42% C
Vitamin K antagonists (oral)72-74 NK C
MDMA = methylenedioxymethamphetamine; NK = not known; SLE = systemic lupus erythematosus.
py with vitamin K antagonist anticoagulants such as isoniazid and procainamide are approximately
warfarin.72-74 30% and 18–57%, respectively.48 Pericarditis in
patients with SLE secondary to hydralazine37 and
methyldopa40 is relatively uncommon. Cardiac
EPIDEMIOLOGY tamponade occurring in patients with idiopathic
or drug-induced SLE is rare.36,37
There are no available estimates of the overall inci- Although the vascular complications associat-
dence or frequency of drug-induced valvular and ed with ergot alkaloid treatment have been known
pericardial diseases. However, incidences of pericar- for well over a century, the frequency of valvular
dial effusion due to minoxidil, pericarditis in disease is less well characterized. Early reports
patients with drug-induced SLE, valvular disease relied on auscultatory findings, which are less sen-
with long-term ergot alkaloid therapy, hemoperi- sitive than echocardiography in the detection of
cardium after fibrinolysis for myocardial infarction, valvular disease. Graham and colleagues62,63 esti-
and regurgitant valvular disease induced by anorec- mated that the incidence of methysergide-associat-
tic agents have all been relatively well described. ed valvular disease is 1 in 5,000 patients treated.
The incidence of pericardial effusion occurring The incidence of echocardiographically detected
during minoxidil therapy ranges from 3.8% (73 of pericardial effusion and hemopericardium after fib-
1,919 patients)41 to 20% (1 of 5)43 depending on rinolysis is highly variable, ranging from 8.75% in
the population studied, with a higher frequency 80 consecutive patients treated with streptokinase69
noted in patients with kidney disease. The preve- to 24% in 112 patients treated with alteplase.71 In a
lence of acute pericarditis in those with idiopathic study of 192 patients who underwent serial echocar-
SLE ranges from 30% to 45%.48 Reported rates of diography on days 1, 5, 10, and 21 of the study and
acute pericarditis complicating drug-induced SLE then annually for 3 years, pericardial effusion was
are similar to those associated with idiopathic SLE; detected at least once in 43% of patients, and the
the incidences of acute pericarditis associated with incidence was similar in those who received fibri-
TisdaleC29_554-568 1/12/10 2:59 PM Page 557
noblytics (42%) and those who did not (50%).70 The to either nonergot drugs (such as ropinirole or
frequency of pericardial effusion varies depending pramipexole) or controls report a frequency of 18%
on the duration of echocardiographic follow-up, to 37% in ergot-treated patients, 0% to 25% in
with an increasing frequency occurring during the non-ergot-treated patients and 4% to 18% in con-
first 5 days after myocardial infarction, regardless of trols, with ergot-treated patients at increased risk of
whether fibrinolytic drugs were administered.70 valvular heart disease.79,80,81,83,84,87,93,94
The best-studied example of drug-induced
valvular heart disease is that of mitral and aortic
regurgitation caused by the anorexiant agents fen- MECHANISMS
fluramine and dexfenfluramine. In 1997, the FDA
defined anorexiant drug–related cardiac valvulopa- Although there are a number of proposed mecha-
thy as moderate or greater mitral regurgitation, nisms for drug-induced valvular and pericardial heart
mild or greater aortic regurgitation, or both detect- disease (Table 29–2), a common link between valve
ed on a standard echocardiogram, in the absence of regurgitation after ergotamine, methysergide, fenflu-
other known causes of valvular disease. Patients ramine, and dexfenfluramine is that these agents are
with these drug-related findings are defined as structurally similar to serotonin and are potent ago-
“FDA-positive.”8 Using that definition, the report- nists of the 5-hydroxytryptamine (HT)2B subtype of
ed prevalence of fenfluramine-associated and serotonin receptor, which promotes serotonin
dexfenfluramine-associated valvular disease ranged release.5,7,130-132 The type of valvular lesions observed
from <0.1% to 38%, depending on the population in association with these agents is similar to that
studied and method used.8,9 If the reports of FDA- observed in patients with carcinoid heart syndrome,
positive valvular heart disease due to anorexiant which is also associated with high concentrations of
drugs are limited to controlled studies, the inci- circulating serotonin.5 Human cardiac valves express
dence varies from 1% to 15%, which is still signifi- large numbers of 5-HT2B receptors and no apprecia-
cantly higher than the incidence reported in ble 5-HT2C receptors.80 Examination of the affected
controls (3–6%).5,6,128,129 Aortic regurgitation native valves excised after valve-replacement surgery
occurs more frequently than mitral regurgita- reveals glistening white leaflets and chordae covered
tion.6,77,78 A prospective study did not find an asso- with a thick coating; however, underlying structures
ciation between phentermine (when taken without in the valves are preserved. On histologic examina-
fenfluramine or dexfenfluramine) and valvulopa- tion, there is a proliferation of myofibroblasts with
thy, and as a result, phentermine remains current- deposition of abundant extracellular matrix.
ly used as monotherapy.5,10 Moderate to severe Echocardiography has defined diastolic doming and
cardiac valvular regurgitation disease associated anterior leaflet thickening with affected mitral
with ergot alkaloids in patients with Parkinson’s valves. Leaflet mobility is preserved in the anterior
disease has also been well studied. Case–control leaflets, but is impaired in the posterior leaflets.6,16
studies comparing the frequency of cardiac valvu- Animal models suggest that activation of the 5-HT2B
lar disease with ergot drugs (pergolide, cabergoline) receptor and decreased 5-HT transporter gene activi-
presenting with suspected drug-induced valvular and rheumatoid arthritis.135 The diagnoses of
disease should undergo evaluation to exclude the malignancy, trauma, and uremia should be consid-
diagnosis of carcinoid tumor using a 24-hour urine ered in patients presenting with cardiac tampon-
collection for determination of 5-hydroxy- ade.135 Viral, bacterial, and fungal infection, as well
indolacetic acid excretion, serum analysis of chro- as tuberculosis, uremia, myocardial infarction, neo-
mogranin A, as well as radiologic imaging to plasm, trauma, and collagen vascular disease
exclude the presence of a primary tumor or liver should be considered in patients presenting with
metastases.3,138 Alternative causes of mitral regurgi- acute or constrictive pericarditis.135
tation should be excluded, including myxomatous
degeneration of the mitral valve, infective endo-
carditis, rheumatic heart disease, SLE, amyloidosis, RISK FACTORS
congenital heart disease, papillary muscle rupture,
Marfan’s syndrome, and hypertrophic cardiomy- Risk factors for certain types of drug-induced
opathy.135,136 Other causes of aortic regurgitation valvular and pericardial heart disease have been
should be excluded, including congenital abnor- identified (Table 29–5). Risk factors for the develop-
mality of the aortic valve, calcific degeneration, ment of mitral or aortic regurgitation associated
rheumatic disease, myxomatous proliferation, with fenfluramine and dexfenfluramine include
infective endocarditis, aortic dissection, Marfan’s duration of therapy, dose, older age, and female
syndrome, and traumatic injury.135,136 Other dis- sex.6 Exposure to fenfluramine or dexfenfluramine
eases causing tricuspid regurgitation that should be for <3 months is associated with a lower incidence
considered include left ventricular dysfunction and of valvulopathy than that associated with treat-
heart failure, cardiac tumors, pulmonary hyperten- ment durations >6 months.13,21,129 Doses >60
sion, mitral stenosis, congenital heart disease such mg/day have also been associated with the devel-
as Ebstein’s anomaly, rheumatic heart disease, col- opment of valvular regurgitation.21 Continuous
lagen vascular diseases, and intrinsic pulmonary use of methysergide or ergotamine for >9 months,
diseases such as chronic obstructive pulmonary rather than episodic use, has been associated with
disease.135,136 Patients with mitral stenosis should the development of valvulopathy.23,58 Larger doses
be evaluated for rheumatic heart disease and other of ergotamine (>6 mg/day) and methysergide (>8
degenerative valvular diseases in addition to carci- mg/day) have also been associated with the devel-
noid syndrome, including Fabry’s disease, opment of valvular heart disease.23,57,58 In a
mucopolysaccharidosis, Whipple’s disease, gout, transthoracic echocardiographic study of 78
TisdaleC29_554-568 1/12/10 3:00 PM Page 561
TABLE 29–4 Conditions to Consider in the TABLE 29–5 Risk Factors for Drug-Induced
Differential Diagnosis of Drug-Induced Valvular Valvular and Pericardial Heart Disease
and Pericardial Heart Disease
Valvular heart disease associated with fenfluramine
All valvular heart disease and dexfenfluramine
• Carcinoid syndrome • Duration of use >3 mo
Mitral regurgitation • Older age
• Myxomatous degeneration • Female sex
• Infective endocarditis • Dose >60 mg
• Rheumatic heart disease Valvular heart disease associated with ergotamine and
• Systemic lupus erythematosus methysergide
• Amyloidosis • Dose of ergotamine >6 mg/day
• Congenital heart disease • Dose of methysergide >8 mg/day
• Papillary muscle rupture • Continuous use rather than episodic use
• Marfan’s syndrome • Duration of use >9 mo
• Hypertrophic cardiomyopathy Valvular heart disease associated with pergolide and
Aortic regurgitation cabergoline
• Congenital heart disease • Cumulative dose >1,000 mg
• Calcific degeneration • Longer duration of use
• Rheumatic heart disease • Hypertension
• Myxomatous proliferation • Male sex
• Infective endocarditis Pericarditis associated with chemotherapy
• Aortic dissection • High doses (see text)
• Marfan’s syndrome
Pericardial effusion associated with minoxidil
• Traumatic injury
• Kidney disease
Tricuspid regurgitation
Hemopericardium associated with fibrinolytic therapy
• Left ventricular dysfunction and heart failure
and vitamin K antagonists
• Cardiac tumor
• Presence of pericarditis or pericardial effusion
• Pulmonary hypertension
• Excessive anticoagulation (dose)
• Mitral stenosis
• Recent cardiothoracic surgery
• Congenital heart disease
• Rheumatic heart disease
• Collagen vascular disease
• Intrinsic pulmonary disease patients with Parkinson’s disease, the incidence of
• Fabry’s disease valvulopathy was higher in those who received
• Mucopolysaccharidosis cumulative doses of pergolide of 4,400 g as com-
• Whipple’s disease pared with patients who received cumulative doses
• Gout of 2,200 g.76 Another case–control analysis suggest-
• Rheumatoid arthritis ed that even lower cumulative doses of either per-
PERICARDIAL TAMPONADE golide or cabergoline were associated with
• Malignancy left-sided valvulopathy.77 In that study, age, male
• Trauma sex, history of hypertension, and duration of use of
• Uremia either pergolide or cabergoline were also risk fac-
• Acute or constrictive pericarditis tors.77 Several other case–control studies79,80,84,87,91-
93
• Viral infection have found a positive relationship between
• Bacterial infection either cumulative dose or duration of therapy with
• Fungal infection pergolide or cabergoline and risk of valvulopathy,
• Tuberculosis although conflicting data exist.85,90,94 When caber-
• Uremia goline is used for treating prolactinomas, doses are
• Myocardial infarction approximately one-tenth those used to treat
• Neoplasm Parkinson’s disease, and valvulopathy has not been
• Trauma observed.124-127 Single doses or initial courses of
• Collagen vascular disease cancer chemotherapy with any of the agents listed
in Table 29–1 may cause pericarditis occurring
early (within hours to 1 month) after initial treat-
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Practice Guidelines (Writing Committee to revise the 204.
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SECTION VII
DRUG-INDUCED
ENDOCRINE DISEASES
CHAPTER 30 Glucose and Insulin Dysregulation
CHAPTER 30
Devra K. Dang, Frank Pucino, Jr., Charles D. Ponte, and Karim Anton Calis
well as a patient’s underlying disease state(s). For tributing factor, as occurs in cases when a drug
example, in the Diabetes Control and unmasks a patient’s preexisting diabetes.25
Complications Trial, the incidence of severe hypo-
glycemia associated with insulin administration
was threefold higher in the intensively treated
group (insulin pump or 3 daily insulin injec- CLINICAL PRESENTATION AND
tions) as compared with the conventionally treated DIFFERENTIAL DIAGNOSIS
group (1 to 2 daily insulin injections).158 Within a
specific drug class, the incidence of drug-induced The signs and symptoms of drug-induced hyper-
hyperglycemia or hypoglycemia also may vary. For glycemia and diabetes mellitus are listed in Table
example, hyperglycemia and diabetes mellitus 30–5. The diagnosis of diabetes mellitus can be
occur more commonly with olanzapine and cloza- made if, on two separate occasions, a patient’s gly-
pine as compared to the other atypical antipsy- cosylated hemoglobin (A1C) is 6.5%, fasting
chotic drugs.1,192 However, an increased plasma glucose is 126 mg/dl, or the patient is
background risk for diabetes mellitus with schizo- found to have a plasma glucose of 200 mg/dl two
phrenia, in addition to the rising incidence of dia- hours after a 75 gram oral glucose load; or if the
betes in the general population, complicate patient has classic symptoms of diabetes and a ran-
determination of precise risk estimates. The inci- dom plasma glucose of 200 mg/dl.194 Depending
dence of treatment-related hyperglycemia also may on the causative agent, drug-induced hyper-
be higher if the patient has predisposing risk fac- glycemia can appear within hours or weeks to
tors for diabetes mellitus, such as obesity or a fam- months after administration of the offending
ily history. Hypoglycemia is more common with agent. Hyperglycemia may be severe in some cases,
long-acting (e.g., chlorpropamide and glyburide) manifesting as diabetic ketoacidosis and hyper-
than shorter-acting (e.g., tolbutamide) sulfony- glycemic coma.
lureas.190,193 The reported incidence of drug- Although there is considerable interindividual
induced hypoglycemia may also vary depending variation, the typical signs and symptoms associat-
on the definition of hypoglycemia used. In addi- ed with drug-induced hypoglycemia are presented
tion, factors such as the presence of active drug in Table 30–6. The glycemic threshold at which
metabolites, the route of elimination, and the pres- patients experience hypoglycemic symptoms
ence of other risk factors for hypoglycemia also varies. Symptoms commonly manifest when plas-
account for the difference in reported incidences of ma glucose falls below 60 mg/dl. However, factors
hypoglycemia among the drugs. Finally, the route such as prolonged hyperglycemia, caffeine use, or
of administration and systemic availability of a frequent episodes of hypoglycemia may shift this
drug may also influence the incidence of drug- threshold in either direction. Patients who experi-
induced hyperglycemia or hypoglycemia. For ence repeated episodes of hypoglycemia over a
example, inhalation of corticosteroids or pentami- short period of time may become unaware of these
dine infrequently causes alterations in glucose events. They do not experience typical hypo-
homeostasis as compared with administration via glycemic symptoms and may fail to take corrective
the oral or parenteral route.38, 168 action because of central nervous system impair-
ment.195 Severe hypoglycemia can lead to cognitive
dysfunction, mental status changes, seizures,
MECHANISMS coma, or even death.
Before implicating a drug as the cause of glu-
Drugs induce hyperglycemia or hypoglycemia cose or insulin dysregulation, other possible caus-
through multiple mechanisms, including alter- es must be ruled out (Table 30–7). Hyperglycemia
ation of insulin secretion or clearance, changes in may occur during periods of physiologic stress,
insulin sensitivity (either directly at the receptor such as surgery, infection, or trauma. Elevations
level or by indirect effects on weight or adiposity), in serum glucose associated with Cushing syn-
changes in gluconeogenesis or glucose metabolism, drome may result either from exogenous adminis-
and direct cytotoxic effects on pancreatic -cells. tration or endogenous overproduction of
(Drug-induced pancreatitis is addressed in Chapter glucocorticoids. When assessing possible causes
41.) The mechanisms by which specific agents are of hypoglycemia, intentional self-administration
thought to alter glucose or insulin regulation are of hypoglycemic drugs, usually insulin or a sul-
listed in Tables 30–3 and 30–4. With some drugs, it fonylurea (i.e., factitious hypoglycemia), and
is not clear whether hyperglycemia is a direct effect iatrogenic causes (including medication-dispens-
of the drug itself or if the drug is simply a con- ing errors) should be considered.196 Hypoglycemia
TisdaleC30_569-585 1/20/10 11:30 PM Page 575
also occurs in patients with acute illness. adequately assess drug-induced causality, it is
Uncommon causes of hypoglycemia include important to consider variables such as temporal
insulin-producing tumors (e.g., insulinoma) and sequence, biologic plausibility, and whether
several other rare disorders (Table 30–7).197 To hyperglycemia or hypoglycemia is a known class
TisdaleC30_569-585 1/20/10 11:30 PM Page 577
TABLE 30–5 Signs and Symptoms Associated TABLE 30–7 Conditions to Consider in the
with Drug-Induced Hyperglycemia Differential Diagnoses of Drug-Induced Glucose
and Insulin Dysregulation
Mild-to-moderate disease
• Blurred vision Hyperglycemia
• Excessive thirst • Acromegaly
• Fatigue/weakness • Cushing syndrome
• Polydipsia • Diabetes mellitus
• Polyphagia • Liver cirrhosis
• Polyuria • Metabolic acidosis
• Unexplained weight loss • Metabolic syndrome
Severe disease • Pancreatitis
• Abdominal pain • Parenteral nutrition therapy (dextrose administration)
• Coma • Renal failure
• Dehydration • Stress hyperglycemia
• Hypokalemia Hypoglycemiaa
• Hypotension • Acquired severe liver disease
• Kussmaul respiration and breath with fruity odor • Adrenal insufficiency (e.g. Addison disease, adrenal
• Lethargy crisis)
• Metabolic acidosis • Alcoholism
• Muscle cramping • Beckwith–Wiedemann syndrome
• Nausea and vomiting • Carnitine deficiency
• Obtundation • Congenital hyperinsulinemic hypoglycemia of
infancy
• Congestive heart failure
• Defective type 1 glucose transporter in the brain
TABLE 30–6 Signs and Symptoms Associated
• Erythroblastosis fetalis
with Drug-Induced Hypoglycemia
• Factitious or iatrogenic hypoglycemia
Mild-to-moderate disease • Galactosemia
• Dizziness • Glycogen storage disease
• Headache • Hepatic failure
• Hunger • Hereditary fructose intolerance
• Shakiness /tremors • Hypopituitarism
• Sweating/diaphoresis • Insulinoma
• Tachycardia • Islet cell hyperplasia/nesidioblastosis
• Weakness/fatigue • Isolated growth hormone deficiency
Severe disease • Isolated adrenocorticotropic hormone deficiency
• Behavioral changes such as anxiety and irritability • Lactic acidosis
• Blurred vision • Large non--cell tumor
• Coma • Noninsulinoma pancreatogenic hypoglycemia syn-
• Confusion and difficulty concentrating drome
• Loss of consciousness • Persistent hyperinsulinemic hypoglycemia of
• Seizure infancy
• Postoperative removal of pheochromocytoma
• Pseudohypoglycemia (i.e., in vitro glycolysis resulting
in artifactually low glucose concentrations as
or drug effect in the absence of other potential
observed with leukemias, polycythemia, and
confounders (e.g., concomitant diseases or med-
hemolytic anemia)
ications).
• Renal failure
• Reye’s syndrome
• Sepsis
RISK FACTORS • Small size for gestational age infants
a
Adapted, in part, from Service.197
Tables 30–8 and 30–9 list the risk factors for
drug-induced hyperglycemia and hypoglycemia,
respectively. Patients with type 2 diabetes melli-
TisdaleC30_569-585 1/20/10 11:30 PM Page 578
TABLE 30–8 Risk Factors for Drug-Induced TABLE 30–9 Risk Factors for Drug-Induced
Hyperglycemia Hypoglycemia
Patients with underlying risk factors for type 2 dia- • Advanced age
betes mellitus198 • Decreased carbohydrate intake (e.g., overnight fast,
• Age 45 yr missed meals)
• Family history of diabetes • Hepatic dysfunction (decreased gluconeogenesis)
• High-density lipoprotein cholesterol 35 mg/dl • Higher doses or misuse of offending drug
(0.9 mmol/L), a triglyceride level 250 mg/dl • History of hypoglycemia
(2.82 mmol/L), or both • Hospitalization within past 30 days
• History of gestational diabetes mellitus or delivery • Increased carbohydrate utilization (e.g., exercise) or
of a baby weighing 9 lb reduced stores (e.g., malnutrition)
• History of vascular disease • Pharmacodynamic or pharmacokinetic interactions
• Hypertension ( 140/ 90 mm Hg in adults) (e.g., increased response or concentration [or both]
• Overweight or obese (body-mass indexa 25) of suspected drug)
• Polycystic ovary syndrome • Recent or excessive alcohol intake
• Poor dietary habits • Renal dysfunction (decreased insulin clearance)
• Previously identified impaired fasting glucose or • Tight glycemic control in patients with diabetes
impaired glucose tolerance • Use of more than one drug that can induce hypo-
• Race /ethnicity (e.g., African-Americans, Hispanic- glycemia
Americans, Native Americans, Asian-Americans,
and Pacific Islanders)
• Sedentary lifestyle
• Higher doses (e.g., thiazide diuretics or corticos-
teroids) or misuse of suspected drug
MORBIDITY AND MORTALITY
• Use of more than one drug that can induce hyper-
Drug-induced hyperglycemia may be transient or
glycemia
may result in permanent changes in glucose regu-
• Drug interactions—use of drugs that may increase
lation. Similar to other causes of diabetes mellitus,
the concentration or hyperglycemic effect (or both)
drug-induced hyperglycemia is believed to increase
of offending drug
the risk of microvascular (retinopathy, neuropathy,
a
Body-mass index is the weight in kilograms divided by the nephropathy) and macrovascular (atherosclerotic
square of the height in meters. cardiovascular disease, cerebrovascular disease, and
peripheral vascular disease) complications, delayed
wound healing and resolution of infections, hyper-
osmolar coma, and death. Cases of diabetic
tus or those predisposed to this condition (e.g., ketoacidosis and death have been reported in asso-
individuals with metabolic syndrome) may be at ciation with many of the agents listed in Table
particular risk for drug-induced hyperglycemia 30–1. Diabetic nephropathy, sensorimotor periph-
because of worsening of preexisting insulin eral neuropathy, ketoacidosis, hyperosmolar coma
resistance and -cell dysfunction. Those with or precoma, myocardial infarction, and stroke were
other underlying disease states also may be at reported in a cohort of renal transplant recipients
increased risk. For example, hypertension and (followed on average for 9.3 years) in whom post-
schizophrenia are associated with a higher inci- transplantation diabetes mellitus developed. The
dence of diabetes mellitus and therefore may immunosuppressive regimen prescribed for these
confound the diagnosis of drug-induced hyper- patients consisted of cyclosporine and corticos-
glycemia.2,198 Polypharmacy is another impor- teroids.201 Drug-induced hyperglycemia may not
tant risk factor, since the use of multiple always lead to the development of macrovascular
medications associated with glucose or insulin complications. This was evident in the
dysregulation may lead to additive pharmacoki- Antihypertensive and Lipid-Lowering Treatment to
netic and/or pharmacodynamic effects. For Prevent Heart Attack Trial (ALLHAT), a large, ran-
example, the combined use of sulfonylureas and domized, controlled study of older patients with
nonsteroidal antiinflammatory drugs, including hypertension, some with and others without meta-
ibuprofen and aspirin, may lead to an increased bolic syndrome.26 Although the incidence of newly
risk of hypoglycemia due in part to decreased diagnosed diabetes was greater in chlorthalidone-
sulfonylurea metabolism or increased insulin treated patients as compared with those treated
release.183,199,200
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177. Limburg PJ, Katz H, Grant CS, et al. Quinine-induced 198. American Diabetes Association. Screening for type 2
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incidence of hypoglycaemia in African patients treated inflammatory drugs increase insulin release from beta
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1996;335:800-806. hypoglycemia in a patient receiving sulfonylurea. Ann
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CHAPTER 31
Thyroid
Disorders
Judy T. Chen, Betty J. Dong, Frank Pucino, Jr., and Karim Anton Calis
HYPOTHYROIDISM
Aldesleukin4-9 9% Ba
Aloe10 NK C
Amiodarone11-13 4.3–5% Ab
Bexarotene14-16 6–40% A
Ethionamide17-19 NK C
Interferon-␣20-26 11.8% Ac
Interferon-27-34 0.8–33% Bc
Iodinated compounds35-39 NK Ad
Kelp40, 41 NK B
Leuprolide acetate42-44 NK C
Lithium45-54 1.5–5.7% B
Octreotide55-57 4% B
Oxcarbazepine58 NK C
59
Paroxetine NK C
Pegylated interferon-␣60-64 6–12.8% Bc
Rifampin65-67 NK C
Setraline68 NK C
Sunitinib69-71 36–53% B
Thalidomide72 14% B
Quetiapine73-76 NK Be
HYPERTHYROIDISM
Amiodarone11-13 1.4–5.3% A
Cyclosporin77 NK C
Interferon-␣20-26 11.8% Ac
Interferon-27-34 0.8–33% Bb
Iodinated compounds35-39 NK Ac
Lenalidomide78 NK C
Leuprolide acetate42-44 NK C
Lithium45-54 0.1% B
Pegylated interferon-␣60-64 6–12.8% Bc
NK = Not known.
a
Thyroid dysfunction has been reported in a randomized controlled trial evaluating aldesleukin in combination with antitumor vaccines.
Weill et al. reported thyroid abnormalities with aldesleukin in combination with lymphokine-activated killer cells.8,79
b
Connolly et al. reported thyroid abnormalities in an amiodarone plus -blocker group; no thyroid abnormalities were reported with -
blocker monotherapy.12
c
Thyroid abnormalities with interferon have been reported in as monotherapy21-34, 60-64 or in combination with ribavirin.20
d
This category comprises over 50 drug entities, including iodinated glycerol, potassium iodide, and povidone–iodine (see Table 31–3). Despite
great variability in the quality of published reports for specific agents, the overall body of evidence suggests a consistent “class effect.” As
such, iodinated compounds are classified here according to the highest level of evidence available for iodine rather than for individual agents.
e
Although quetiapine does not meet the strict criteria for level B, a higher risk of hypothyroidism as compared with placebo (odds
ratio, 1.75; 95% confidence interval, 0.89–3.44) that required thyroid-hormone replacement was observed in ~23% of patients and sug-
gests a higher level of causality.76
TisdaleC31_586-604 1/12/10 3:32 PM Page 588
Drug Mechanism
Growth hormone Decreases TSH release and/or response to TRH
Haloperidol Increases TSH release and/or response to TRH
Heparins (fractionated and unfractionated) Displacement from protein-binding sites
Heroin Increases TBG; decreases TSH release and/or response to
TRH
Imatinib135 Increases hepatic metabolism
Iodine-containing compounds (e.g., contrast agents) Inhibits iodide binding/transport; inhibits iodination; inhibits
endocytosis; inhibits proteolysis; inhibits intrathyroidal deio-
dination of T4; inhibits TH secretion; inhibits peripheral deiod-
ination; increases TSH release and/or response to TRH;
decreases thyrotropin-receptor response
Ketoconazole Inhibits coupling
L-asparaginase Decreases TBG
Levodopa–carbidopa Decreases TSH release and/or response to TRH
Lithium Inhibits iodide binding/transport; inhibits iodination; inhibits
endocytosis; inhibits TH secretion; increases TSH release
and/or response to TRH, or both; increases autoimmunity,
goitrogens
Metformin95 Decreases TSH release and/or response to TRH
Methadone Increases TBG
Metoclopramide Increases TSH release and/or response to TRH
Mifepristone90, 91 Inhibits iodide binding/transport
Minerals (bromine, calcium, fluorine, nitrate, rubidium) Goitrogens
Mitotane Increases TBG
Nicotinic acid Decreases TBG
NSAIDs Displacement from protein-binding sites; inhibits TH-receptor
binding/uptake /action
Octreotide Decreases TSH release and/or response to TRH
Omeprazole94 Decreases TH bioavailability
Opiates Decreases TSH release and/or response to TRH
Orphenadrine Displacement from protein-binding sites
Perchlorate Inhibits iodide binding/transport
Perphenazine Increases TBG
Phenobarbital Increases hepatic metabolism
Phentolamine Decreases TSH release and/or response to TRH
Phenytoin Displacement from protein-binding sites; increases hepatic
metabolism; inhibits TH-receptor binding/uptake /action;
decreases TSH release and/or response to TRH
Pimozide Decreases TSH release and/or response to TRH
Propranolol Inhibits intrathyroidal deiodination of T4; inhibits peripheral
deiodination
Propylthiouracil Inhibits intrathyroidal deiodination of T4; inhibits peripheral
deiodination
Raloxifene86 Decreases TH bioavailability
(Continued)
TisdaleC31_586-604 1/12/10 3:32 PM Page 590
Drug Mechanism
Rifampin Increases hepatic metabolism
Salicylamides Inhibits iodide binding/transport; inhibits iodination; inhibits
coupling; displacement from protein-binding sites; goitrogens
Serotonin antagonists Decreases TSH release and/or response to TRH
Sertraline Increases hepatic metabolism of TH
Sevelamer Decreases TH bioavailability
Sodium polystyrene sulfonate Decreases TH bioavailability
Spironolactone Increases TSH release and/or response to TRH
Sucralfate Decreases TH bioavailability
Sulfonamides Inhibits iodide binding/transport; inhibits iodination; inhibits
coupling
Sulfonylureas Inhibits iodide binding/transport; inhibits iodination; inhibits
coupling; displacement from protein-binding sites
Tamoxifen Increases TBG
Thioamides Inhibits coupling
Thioridazine Decreases TSH release and/or response to TRH
Thyroid hormones Decreases TSH release and/or response to TRH
NSAIDs = nonsteroidal antiinflammatory drugs; TBG = thyroid-binding globulin; TH = thyroid hormone; TPN = total parenteral nutrition;
TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone.
thyroid screening and treatment remain contro- thyroidism in the general population is 2% to
versial because of the absence of supporting evi- 16%. 102 In women with underlying multinodu-
dence.96 lar goiter, the prevalence of subclinical hyper-
thyroidism is 20%. 103
The overall incidence of drug-induced thy-
EPIDEMIOLOGY roid disorders has not been clearly elucidated.
The incidence associated with specific agents,
In the general population, the prevalence of where known, is listed in Table 31–1.4-79 Thyroid
hypothyroidism is estimated to be 1.5% to 2% disorders associated with amiodarone and lithi-
in women and 0.2% in men. 99 This condition is um are the most extensively documented.
more common than hyperthyroidism, and its Amiodarone contains 37.3% iodine by weight,
incidence increases with advancing age. A 20- and global variations in iodine intake influence
year follow-up study of 2,779 adults in the epidemiology of amiodarone-induced thy-
Whickham, England, reported an annual inci- roid dysfunction.104 In countries such as the U.S.
dence of overt hypothyroidism of 3.5 and 0.6 and the United Kingdom, where iodine intake is
cases per 1,000 women and men, respective- adequate, the incidence of amiodarone-induced
ly. 100 In women 75 to 80 years of age, the annu- hyperthyroidism and hypothyroidism is 1.7% to
al incidence increased to 14 cases per 1,000. 3% and 13% to 22%, respectively.102,105 However,
With increased use of sensitive TSH assays, the in areas with inadequate iodine intake, hyper-
diagnosis of subclinical thyroid disease has thyroidism occurs in 10% to 12% of amio-
become more prevalent. In the United States darone-treated patients, whereas only 6.4% have
(U.S.), subclinical hypothyroidism affects up to hypothyroidism.102,105,106 The epidemiology of
20% of patients over 60 years of age. 101 In the lithium-induced thyroid dysfunction has also
Whickham study, the annual incidence of been well described, with hypothyroidism and
hyperthyroidism was 0.8 case per 1,000 goiter observed in 4% to 34% of patients
women. 100 The prevalence of subclinical hyper- exposed to this drug.45,46,49,107,108 Exposure to
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FIGURE 31–1 Thyroid-hormone biosynthesis and secretion and target sites for drug-induced alterations.
Steps of thyroid-hormone biosynthesis and secretion and the sites for drug-induced changes. (1) Iodide is first trapped and
actively transported into the follicular cell by a sodium/iodide symporter in the basement membrane. (2) Thyroid peroxi-
dase (TPO) then catalyzes the formation of an active iodinated species (enzyme-bound hypoiodite [EOI]) important for
iodination of thyroglobulin (Tg) in the follicular lumen, resulting in the formation of mono-iodotyrosine (MIT) and di-
iodotyrosine (DIT). (3) The oxidized form of TPO (compound I) then initiates the coupling reaction, generating liothyronine
(T3 ) and levothyroxine (T4 ) through combining DIT with MIT or DIT, respectively. (4) Tg is then internalized from the lumen
by endocytosis. (5) Hormone release occurs after proteolysis in the endosome and lysosome system. (6) Deiodination gen-
erates iodide from free MIT and DIT, which is then recirculated, and (7) also results in the formation of T3 from T4. (8)
Thyroid hormone is subsequently released into the circulation, (9) extensively bound to serum proteins, primarily thyrox-
ine-binding globulin (TBG) for transport. It may then undergo (10) hepatic metabolism (glucuronidation, sulfation, deiodina-
tion), (11) peripheral deiodination (activation through T4 conversion to T3 or inactivation of T3 and T4), or (12) bind to thyroid
hormone (TH) receptors to elicit a pharmacodynamic response. (13) Release of thyrotropin (thyroid-stimulating hormone
[TSH]) from the anterior pituitary (adenohypophysis) in response to thyrotropin- releasing hormone (TRH) from the hypo-
thalamus has a stimulatory effect on most steps of iodine metabolism and hormone synthesis and release. Drug and
chemical compounds are known to alter the function of each of these steps, result in goiter, or (14) to initiate an immune
reaction resulting in thyroiditis. See Table 31–281-95 for a listing of specific drug actions. Modified with permission from
Taurog.112
TABLE 31–3 Iodine Content of Selected Medications and Dietary Supplements38, 117-119
Medication Route Iodine Content (mcg)
Amiodarone Oral 75,000/tablet
Calcium iodide Oral 26,000/mL
Diatrizoate meglumine Parentera l /urogenital 85,000–358,000/mL
Diatrizoate meglumine/sodium Ora l /parenteral 292,000–370,000/mL
Diatrizoate and iodipamide meglumine Parenteral 380,000/mL
Diatrizoate sodium Ora l /parentera l /rectal/ 600,000/g,
urogenital 120,000–300,000/mL
Ethiodized oil Parenteral 370,000/mL
Hydriodic acid syrup Oral 13,000–15,000/mL
Iocetamic acid Oral 465,000/mL
Iodamide meglumine Parenteral 300,000/mL
Iodinated glycerol Oral 15,000/tablet
6,000–25,000/mL
Iodine-containing vitamins (various) Oral 54–200/tablet
Iodine
Gel Topical 9,000/g
Gel pad 9,000/g
Ointment 47,000/g
Solution 20,000/mL
Tincture 20,000–70,000/mL
Iodine and potassium iodide Topical 108,225–126,450/mL
(Lugol’s solution, strong iodine tincture)
Iodine and sodium iodide Topical 40,321/mL
Iodine tincture (various)
Iodipamide meglumine Parenteral 257,000/mL
Iodixanol Parenteral 270,000–320,000/mL
Iodized organic oils Nasal 5,000–7,000/mL
Iodized salt Oral 67/1.5 g (1 serving)
Iodoform gauze Topical 4,800/100 mg
Iodoquinol Oral 134,274–415,610/tablet
Topical 6,000/g
Iohexol Parenteral 140,000–350,000/mL
Iopamidol Parenteral 250,000–370,000/mL
Iopromide Parenteral 150,000–370,000/mL
Iothalamate meglumine Parentera l /urogenital 81,000–282,000/mL
Iothalamate meglumine/sodium Parenteral 400,000/mL
Iothalamate sodium Parenteral 325,000–400,000/mL
Ioversol Parenteral 160,000–350,000/mL
Ioxaglate meglumine/sodium Parenteral 320,000/mL
Isopropamide iodide Oral 1,321–1,800/tablet
Kelp Oral 100–4,200/g
Levothyroxine Oral/Parenteral 63/100 mcg
Liothyronine Oral/Parenteral 15/ 25 mcg
Liotrix Oral 39/60–65 mg
(Continued)
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TABLE 31–3 Iodine Content of Selected Medications and Dietary Supplements38, 117-119
Medication Route Iodine Content (mcg)
Metrizamide Parenteral (subarachnoid) 170,000-300,000/mL
Potassium iodide Oral
(losat, Thyro-Block) Oral 99,385/tablet
Pima 99,385/tablet
SSKI 764,500/mL
Potassium iodide and nicotinamide Oral 115,000/tablet
Povidone–iodine 0.5–10% (various) Topical 500–10,000/mL
Sodium iodide Parenteral 85,000/mL
Thyroid, desiccated Oral 29/65 mg
Tyropanoate sodium Oral 430,000/capsule
Modified from Roti and Uberti.38
cal trial of euthyroid patients supplemented with of severe hypothyroidism also has been
kelp for 4 weeks found no signs or symptoms of described.70 Clinically significant thyroid dysfunc-
thyroid abnormality despite evidence of chemical tion has also been reported with sorafenib,
hypothyroidism.129 With amiodarone, the although not as frequently as with sunitinib.134
Wolff–Chaikoff effect persists, resulting in a con- Imatinib has been associated with increased dosage
tinuous decline in T4 production. In addition, requirements in patients who have undergone thy-
amiodarone may inhibit thyroid hormone cellular roidectomy and receiving thyroid hormone
uptake, pituitary and peripheral deiodination, and replacement therapy.135
binding to thyroid receptor sites.3
Lithium impairs thyroid hormone synthesis
Antibody Formation
by inhibiting iodide release from the thyroid tis-
sue.51,108,130-132 The resulting decrease in hormone Thyroid autoantibodies, antithyroid peroxidase
production induces sustained TSH release, which antibodies, and antithyroglobulin autoantibodies
can lead to development of a simple nontoxic have been detected in patients with both autoim-
goiter. The reported annual incidence of lithium- mune hypothyroidism and hyperthyroidism.101
induced goiter is 2.1%.133 However, regression of TSH-receptor antibodies and thyroid-stimulating
goiter was observed during a 15-year follow-up immunoglobulins that stimulate the TSH receptor
study in patients who continued to receive lithi- are present only in patients with hyperthyroidism.
um treatment. In this population, the incidence Antithyroid peroxidase antibodies are often pres-
of palpable goiter decreased from 53% to 29%.45 ent in patients experiencing hypothyroidism sec-
Lithium also may reduce iodine-concentrating ondary to lithium or interferon-␣.25,108 However, a
capacity and inhibit synthesis of iodotyrosine 15-year follow-up study of 150 patients reported a
and iodothyronines. 2 Interferon-␣–induced 1.7% annual rate of new-onset autoimmunity asso-
hypothyroidism is more common than hyperthy- ciated with lithium therapy, a rate similar to that
roidism and typically follows episodes of hyper- found in the general population.45,100 Antithyroid
thyroidism. peroxidase antibodies develop in 15% of patients
The mechanism of sunitinib-induced hypothy- receiving interferon-␣ and have been reported in
roidism is postulated to be secondary to impaired up to 53.3% of patients.20,136-142 The link between
iodine uptake or partial inhibition of thyroid per- interferon-1b and antithyroid antibodies is less
oxidase.70,71 The risk of hypothyroidism is positive- well defined. In a cohort of 156 patients using
ly correlated with the duration of sunitinib interferon-1b, de novo antithyroid antibodies
treatment. On average, the onset of symptoms developed in 6 patients but persisted in only 2.31
begins after 50 weeks of therapy.69 Progressive Interpretation is confounded by the patients’
worsening of preexisting hypothyroidism is underlying conditions (e.g., chronic hepatitis C,
observed in most cases, but sudden development multiple sclerosis) which also have been associated
TisdaleC31_586-604 1/12/10 3:32 PM Page 595
TABLE 31–4 Signs and Symptoms Associated TABLE 31–5 Conditions to Consider in the
with Drug-Induced Thyroid Disorders101 Differential Diagnosis of Drug-Induced Thyroid
Disorders
Hypothyroidism
• Ataxia Hypothyroidism
• Bradycardia • Autoimmune thyroiditis (e.g., Hashimoto’s disease)
• Coarseness or loss of hair • Congenital cretinism (maternal induced)
• Constipation • Dyshormonogenesis (e.g., defect in hormone synthe-
• Cool peripheral extremities sis/transport/action)
• Delayed tendon-reflex relaxation • Deficiency of TSH (e.g., pituitary or hypothalamic dys-
• Depression function)
• Dry skin and cold intolerance • Goitrogens (e.g., cabbage/rutabagas/turnips)
• Dyspnea • Iatrogenic thyroid gland destruction (e.g., surgery/radi-
• Fatigue and weakness ation)
• Goiter • Idiopathic atrophy
• Hoarse voice • Iodine deficiency
• Hyperlipidemia Hyperthyroidism
• Hypothermia • Graves’ disease
• Impaired hearing • Pituitary resistance to thyroid hormone
• Irregular or heavy menses and infertility • Thyroiditis
• Memory and mental impairment • Thyrotoxicosis factitia (self-administered thyroid hor-
• Myalgias mone)
• Paresthesias • Toxic uninodular goiter (Plummer’s disease)
• Puffy face, hands and feet (myxedema) • Toxic multinodular goiter
• Weight gain from fluid retention • Tumors (e.g., thyroid/pituitary/trophoblastic
• Yellow skin tumors/struma ovarii)
Hyperthyroidism
• Alteration in appetite
• Atrial fibrillation
• Changes in vision, photophobia, eye irritation, diplopia absence of symptoms may suggest subclinical
• Decreased menstrual flow hyperthyroidism. Conversely, an elevated serum
• Exertional intolerance and dyspnea TSH and a low serum FT4 concentration often indi-
• Exophthalmos cates hypothyroidism, while an elevated serum
• Fatigue and muscle weakness TSH and a normal or even low serum FT4 concen-
• Frequent bowel movement or diarrhea tration without symptoms may signify a subclini-
• Heat intolerance and sweating cal hypothyroidism. Before a diagnosis of
• Impaired fertility drug-induced thyroid disease can be confirmed,
• Lid retraction or lag nonthyroidal systemic illnesses and other causes
• Mental disturbances associated with alterations in thyroid function
• Nervousness and irritability tests must be excluded. A number of conditions
• Palpitations can result in altered thyroid hormone metabolism
• Peripheral edema and may even be present in patients who appear
• Pretibial myxedema clinically euthyroid. The “euthyroid sick” syn-
• Sleep disturbances (including insomnia) drome is characterized by alterations in thyroid
• Sudden paralysis laboratory parameters without clinical disease.
• Tachycardia Such conditions may include malnutrition, fasting,
• Thyroid enlargement infectious diseases, malignancy, surgery, chronic
• Tremor diseases (cardiac, pulmonary, renal, hepatic), acute
• Weight loss or gain psychiatric illness, and metabolic disorders (e.g.,
diabetes). Interpretation of laboratory findings in
such settings may be difficult, and treatment
should be directed at correction of the underlying
tration along with an elevated FT4 is generally illness.
indicative of hyperthyroidism, whereas a sup- In circumstances in which serum TSH and FT4
pressed or undetectable serum TSH concentration results are equivocal for the definitive diagnosis of
with a normal or even elevated serum FT4 in the hyperthyroidism, evaluation of serum total T3 and
TisdaleC31_586-604 1/12/10 3:32 PM Page 597
transferred through cow’s milk) exposure to these thyroid disease (e.g., type 2 amiodarone-induced
compounds. hyperthyroidism), this test is not readily available
or consistently helpful. A conservative approach to
minimize the risk of potential complications is to
MORBIDITY AND MORTALITY use the lowest effective dose of drugs that may
cause thyroid disorders for the shortest time possi-
Drug-induced thyroid disease may result in clinical ble. Because the onset of drug-induced thyroid dis-
manifestations of hypothyroidism, hyperthy- ease is highly variable, routine laboratory
roidism, or goiter. Left untreated, overt hyperthy- monitoring, patient education, and vigilance for
roidism may result in serious medical symptom onset are important components of dis-
complications, including structural thyroid gland ease surveillance. Specific strategies for prevention
changes, osteoporosis, exaggerated hyperthy- are summarized in Table 31–7.
roidism symptoms, and cardiac complications such
as dysrhythmias and heart failure, which may be
associated with substantial morbidity and mortali- MANAGEMENT
ty. Severe, uncontrolled hypothyroidism can result
in a decompensated thyroid state leading to In a patient with new-onset thyroid dysfunction,
hypothermia, biochemical abnormalities, respira- drugs with the potential to cause thyroid irregular-
tory failure, cardiovascular collapse, and myxede- ities should be discontinued, if feasible. Resolution
ma coma, which can be fatal. A goiter, when of the thyroid abnormality may require several
substantially enlarged, may be cosmetically unac- months and, in some cases, the condition may be
ceptable and lead to respiratory distress and swal- irreversible. Rechallenge with the offending agent
lowing difficulties that, in some cases, can be should not be attempted unless medically neces-
relieved only by surgical intervention. sary. If the drug cannot be discontinued or if the
condition does not resolve after discontinuation,
appropriate antithyroid therapy or thyroid hor-
PREVENTION mone replacement may be required (Table 31–8).
Drug-induced hypothyroidism is best treated
Baseline laboratory tests and physical examination, with levothyroxine. The initial dose should be
including evaluation of the thyroid gland, should 1.6 –1.7 mcg/kg/day, and the dose should be titrated
be performed in all patients receiving a drug with upward, as necessary, every 4 to 6 weeks until the
the potential to cause thyroid dysfunction (Table patient is clinically and chemically euthyroid. Lower
31–1).4-79 Except in patients who have an abnormal initial doses (e.g., 25 mcg) and a more gradual dosage
hypothalamic–pituitary–adrenal axis (e.g., those escalation (12.5–25 mcg every 6–8 weeks) may be
with Cushing’s syndrome or Addison’s disease), a necessary in the elderly and in those with clinically
baseline serum TSH concentration (and possibly a significant cardiovascular disease (e.g., angina, palpi-
serum FT4 determination) should suffice. In
patients with preexisting thyroid dysfunction, a
risk–benefit assessment should be performed to
determine the appropriateness of initiating therapy TABLE 31–7 Approaches to Help Prevent Drug-
with any drug known to cause thyroid disease. Induced Thyroid Disorders
During therapy, laboratory evaluation should be
• Avoid drugs known to cause thyroid disorders.
performed periodically, with the frequency based
• Avoid goitrogens.
on the patient’s risk factors for thyroid disease and
• Consume a sufficient amount of iodine to prevent a
the likely seriousness of drug-induced thyroid dis-
iodine deficiency.
ease should it occur. Patients receiving bexarotene
• Consume an adequate amount of selenium.
may benefit from monitoring of FT4 for manage-
• Correct underlying thyroid abnormalities.
ment of central hypothyroidism, since serum TSH
• Educate patients and families about the possible
alone cannot reliably be used as an indicator of
symptoms associated with drug-induced thyroid dis-
thyroid status.15 In patients receiving amiodarone,
ease and the need to promptly inform their health
interferon-alfa, sunitinib, or lithium, laboratory
care providers about symptoms.
tests (e.g., TSH, FT4, thyroid antibodies) should be
• Screen for thyroid abnormalities before initiating
monitored at baseline and at 3- to 6-month inter-
therapy and periodically thereafter.
vals, and if symptoms occur or dosages are modi-
• Use alternative agents that are not associated with
fied.92,159,160 Although serum interleukin-6
thyroid disease in high-risk patients, when possible.
concentrations may be elevated with destructive
TisdaleC31_586-604 1/12/10 3:32 PM Page 599
38. Roti E, Uberti ED. Iodine excess and hyperthyroidism. 59. Takahashi M, Sawayama E, Sawayama T, et al. Reversible
Thyroid. 2001;11:493-500. paroxetine-induced symptomatic hypothyroidism.
39. Braga M, Cooper DS. Clinical review 129: oral Pharmacopsychiatry. 2007;40:201-202.
cholecystographic agents and the thyroid. J Clin 60. Castera L, Constant A, Henry C, et al. Impact on
Endocrinol Metab. 2001;86:1853-1860. adherence and sustained virological response of
40. Suzuki H, Higuchi T, Sawa K, et al. “Endemic coast psychiatric side effects during peginterferon and ribavirin
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C H A P T E R 32
Hypothalamic, Pituitary,
Pituitary
and Adrenal Diseases
ORAL GLUCOCORTICOIDS
Prednisolone1 5% A
INHALED GLUCOCORTICOIDS
Fluticasone propionate2-7,10 NK B
Beclomethasome dipropionate3,4 NK B
Budesonide3,9 NK B
Triamcinolone acetonide3 NK B
Mometasone furoate7 NK B
NASAL GLUCOCORTICOIDS
Fluticasone propionate5,8,11 NK C
TOPICAL GLUCOCORTICOIDS
Triamcinolone acetonide12 NK C
Clobetasol propionate13,14,16 NK C
Dexamethasone15 NK C
Hydrocortisone butyrate17 NK C
Betamethasone18 NK C
Prednisolone acetate23,24 NK C
INJECTABLE GLUCOCORTICOIDS
Triamcinolone acetonide19-22 NK C
PROGESTINS
Medroxyprogesterone acetate26-28 NK C
Megestrol acetate29-31
OTHERS
Corticotropin or adrenocorticotropic hormone32-37 NK Ab
␥ -Hydroxybutyric acid25 NK C
NK = not known.
a
Incidence depends on dose, and duration of exposure.
b
Used as a confirmatory test to stimulate cortisol release.
32–4).32,36 A careful history in combination with nasal, and topical glucocorticoids are intended to
dynamic testing of the integrity of the HPA axis are circumvent systemic absorption, absorption may
essential to making a correct diagnosis. Other signif- occur when they are administered in high doses
icant laboratory findings in these patients include and may be sufficient to cause Cushing’s syn-
high concentrations of offending medication in the drome.1-18,40 High doses of drugs that possess gluco-
urine, elevation of total cholesterol, high concentra- corticoid-like activity may enhance GR binding, as
tions of very-low-density lipoprotein and triglyc- seen with oral progestins (e.g., 200–400 mg of MPA
erides, hypokalemia, and low bone density as or 160 mg of megestrol acetate).26–31 An additional
measured by dual-X-ray absorptiometry.33 risk factor for absorption of topical glucocorticoids
is their use on diseased or atrophic skin.17,40
Administration of high-potency glucocorti-
RISK FACTORS coids or drugs with a high affinity for GRs is anoth-
er known risk factor for drug-induced Cushing’s
Risk factors associated with Cushing’s syndrome syndrome. Of the available inhaled glucocorticoids
are presented in Table 32–5.40 Prolonged use of (IGCs), fluticasone is considered the most
high doses of drugs that can cause Cushing’s syn- potent.2,5 This agent’s unique pharmacologic and
drome is a known risk factor. Although inhaled, pharmacokinetic properties result in more pro-
longed drug retention at receptors in both blood
and systemic tissues. Clobetasol is one of the most
potent topical glucocorticoids and, when used in
TABLE 32–3 Signs and Symptoms Associated high doses and for prolonged periods, has been
with Drug-Induced Cushing’s Syndrome reported to induce Cushing’s syndrome.43
• Moon-shaped face
• Buffalo hump
• Central obesity
TABLE 32–4 Conditions to Consider in the
• Hirsutism
Differential Diagnosis of Drug-Induced Cushing’s
• Kyphosis
Syndrome
• Easy bruising
• Hypertension • Cushing’s disease
• Proximal muscle weakness • Renal insufficiency
• Psychiatric mood changes • Alcohol abuse
• Glucose intolerance • Obesity
• Diabetes • Pregnancy
• Oligomenorrhea or amenorrhea • Sleep disorders
• Osteopenia or osteoporosis • Psychiatric illness
• Thin skin • Stress
• Acne • Diabetes mellitus (Type 2)
• Striae • Metabolic syndrome
TisdaleC32_605-628 1/12/10 3:33 PM Page 609
TABLE 32–5 Risk Factors for Drug-Induced TABLE 32–6 Approaches to Help Prevent Drug-
Cushing’s Syndrome Induced Cushing’s Syndrome
• Administration of high doses of offending agent • Use lowest effective dose of offending agent.
• Prolonged duration of therapy • Avoid prolonged use.
• Use of high-potency glucocorticoids • Avoid drug combinations that will interact to increase
• Administration of drugs that inhibit the metabolism plasma concentrations of the offending agent.
of endogenous glucocorticoids • Use alternative route of administration to minimize
• Use of topical glucocorticoids in patients with broken systemic absorption.
or atrophic skin and in infants
ORAL GLUCOCORTICOIDS
Dexamethasone44 82% A
Prednisone44
INHALED GLUCOCORTICOIDS
Fluticasone propionate3,5,6,46 NK B
Beclomethasome dipropionate3,47 NK B
Budesonide3,45 NK B
Triamcinolone acetonide3 NK B
Mometasone furoate7 NK B
NASAL GLUCOCORTICOIDS
Fluticasone propionate5,50 NK C
Beclomethasome dipropionate51 NK C
TOPICAL GLUCOCORTICOIDS
Triamcinolone acetonide12 NK C
Clobetasol propionate13,14,16 NK C
Dexamethasone15 NK C
Hydrocortisone butyrate17 NK C
Betamethasone18 NK C
Prednisolone acetate24 NK C
INJECTABLE GLUCOCORTICOIDS
Triamcinolone acetonide21,22 NK C
PROGESTINS
Medroxyprogesterone acetate27,53,54 NK C
Megestrol acetate30,55,56 NK C
OTHERS
Ketoconazole57-59 NK Bb
Etomidate60,61 NK Bb
Mitotane62 NK Cb
Aminoglutethimide63 NK Ab
Rifampin64,65 NK C
Mirtazapine66 NK B
Hydromorphone67 NK C
Fentanyl68 NK C
Flunitrazepam69 NK Cc
NK = not known.
a
Incidence depends on dose and duration of exposure.
b
Used as medical treatment for hypercortisolism.
c
Not approved for use in the United States, but is sometimes acquired illegally for recreational use.
TisdaleC32_605-628 1/12/10 3:33 PM Page 612
itary and results in a lack of adrenal secretion of to suppress the HPA axis. These agents, MPA and
cortisol.38,72,76 megestrol acetate, possess glucocorticoid-like
Numerous studies have documented the abil- activity thought to be due to existing cross-reac-
ity of inhaled and nasal glucocorticoids to sup- tivity within this family of steroid receptors.27-
30,53-56
press the HPA axis, especially when administered Ketoconazole. etomidate, and other agents
in high doses or when combined with inhibitors used to treat Cushing’s disease have also been
of CYP450 3A4.5,44-51 At recommended doses, shown to cause SAI by interfering with cortisol
however, inhaled and nasal glucocorticoids rarely synthesis.38,57-63 Rifampin, phenytoin, and phe-
suppress adrenal function. Topical, intra-articu- nobarbital may suppress the axis by inducing
lar, intradermal, intramuscular, intralesional, and CYP450 isozymes that are responsible for corti-
paraspinal administration of glucocorticoids sol metabolism.38,64,65 Mirtazapine appears to
have also been implicated in SAI. 15-17,21,22,52 cause adrenal suppression by antagonizing cen-
Patients with compromised skin integrity who tral 5-hydroxytryptamine2 receptors responsible
use high-potency topical glucocorticoids (e.g., for the stimulation of cortisol secretion. 66
clobetasol propionate) may be at higher risk for Opioids inhibit CRH release by binding to hypo-
SAI .15-17,43,52 thalamic ␦- and -opiate receptors.67,68 Certain
When administered at high doses, progestins benzodiazepines may inhibit pituitary response
or progestin analogs appear to have the capacity to CRH.69
TisdaleC32_605-628 1/12/10 3:33 PM Page 613
per 100 years.72 However, the risk of crisis is much with topical glucocorticoids, use low-potency
higher in patients with primary adrenal insuffi- agents at lower concentrations, limit treatment
ciency (3.8 per 100 years) and in women (4.4 per duration, apply to smaller surface areas, and do not
100 years).72 use on damaged, broken, or thin skin.43
coid can be given in the form of rectal supposito- these develop. Patients should carry an information
ries.72,81 card with details about their current treatment and
Minor abnormalities discovered upon dynamic instructions for emergency treatment, including
testing should be treated only in the presence of instructions on doubling or tripling the glucocorti-
symptomatic adrenal insufficiency. Testing should coid dose during febrile illness or injury and using
be performed on any patient who reports suggestive alternative routes of administration during vomit-
symptoms or on any child whose growth velocity is ing.71,72,81 Patients should be instructed to rinse
slowed. The lowest effective dose of glucocorticoid their mouth after administration of an inhaled glu-
should be used, and dosing should be guided by cocorticoid to minimize side effects (e.g., thrush,
symptomatic management of fatigue and other hoarseness) as well as to decrease systemic absorp-
symptoms as described in Table 32–10.71,72,81 tion from oropharyngeal deposition. Lastly,
Because suppression of the HPA axis is a major patients should be educated to not use topical glu-
concern only when exogenous glucocorticoids are cocorticoids on thin skin areas (e.g., eyelid, scro-
withdrawn, practitioners should never abruptly tum), on broken skin, or over large surface areas.
stop oral glucocorticoids taken for longer than 14
days. A variety of recommendations for steroid
tapering are available; however, no consensus
DRUG-INDUCED
exists regarding the best approach.38,40 In general, HYPERPROLACTINEMIA
in patients who have been on long-term steroid
The regulation of prolactin is unique among other
therapy, the steroid should be gradually withdrawn
anterior pituitary hormones. Prolactin is regulated
toward physiologic doses over months. As the
through hypothalamic inhibition, and dopamine
steroid dose approaches physiologic levels, the
is the main inhibitory factor. As a result, drug-
taper should be slowed and the patient checked for
induced hyperprolactinemia may occur with any
HPA axis function. The primary modes to test HPA
drug that inhibits the action of dopamine in the
axis integrity are the ACTH test, either high- or
central nervous system.
low-dose, or measurement of a morning serum cor-
tisol level.38,40 A normal morning serum cortisol
concentration (>20 mcg/dL) or a normal ACTH test
indicates that daily steroid maintenance therapy is CAUSATIVE AGENTS
not needed. If the morning serum cortisol concen-
tration is between 3 and 20 mcg/dL, an ACTH test Specific drugs that have been reported to induce
or an CRH stimulation test may be useful in the hyperprolactinemia are listed in Table 32–16.82-132
assessment of pituitary–adrenal function.40 A
morning cortisol concentration <3 mcg/dL indi-
cates axis suppression and the need for continued EPIDEMIOLOGY
replacement therapy. Caution should be used to
prevent disease exacerbation during the steroid Hyperprolactinemia is the most common
taper and the resultant need to treat the patient endocrine disorder of the HPA axis, with an esti-
with another course of high-dose steroids.38 mated prevalence of 0.4% in the normal adult pop-
Adrenal crisis has been reported after the dis- ulation and as high as 9% among women with
continuation of MPA and megestrol acetate; there- amenorrhea.133 The prevalence is approximately
fore, tapering is also recommended for patients 5% among men presenting with impotence. The
receiving these agents. Although there is clear evi- highest prevalence is among women with amenor-
dence that adrenal suppression can occur in rhea and galactorrhea, at 70%.133 The incidence of
patients receiving inhaled, intranasal, and topical drug-induced hyperprolactinemia (DIH) is
glucocorticoids, supplementation during periods unknown. Antipsychotics are the drug class most
of stress and/or tapering of doses prior to complete often implicated in drug-induced hyperprolactine-
discontinuation is usually not needed.52 mia, and women are known to have a pronounced
prolactin-releasing response to these agents.82
ANTIDEPRESSANTS
Fluoxetine86 4.5% in men; 22% in women B
Paroxetine87 NK C
Fluvoxamine88 NK B
Citalopram89 NK B
Sertraline90 NK C
Venlafaxine91 NK C
Duloxetine91 NK C
Clomipramine92 NK C
Amitriptyline92 NK C
Amoxapine93 NK B
Meclobemide94.a NK B
ANTIEMETICS
Metoclopramide95,96 NK A
Domperidone,96,97,a NK A
ANTIHYPERTENSIVES
Methyldopa98,99 NK B
Reserpine100 NK B
Verapamil101 8.5% B
Labetalol (intravenous) 102 NK C
Atenolol103 NK C
ANTIPSYCHOTICS
Conventional104 48% in womenb; 29% in menb B
Phenothiazines (i.e., chlorpromazine, thioridazine, perphenazine)105 40–90%b A
Butyrophenones (i.e., haloperidol)106 40–90%b A
Thioxanthenes (i.e., thiothixene) 108 NK C
Miscellaneous (i.e., loxapine109, pimozide110) NK A
Risperidone104 88% in womenb; 70% in menb B
Olanzapine107 36%b A
Ziprasidone111 NK C
Quetiapine112 NK C
Molindone113 NK C
HORMONES
Estrogen114 12% B
Gonadotropin-releasing hormone analogs115,116 3.8% B
HISTAMINE2-RECEPTOR ANTAGONISTS
Cimetidine117,118 NK C
Famotidine119 NK C
OPIATES
Morphine and morphine analogs120 NK B
Methadone121 NK B
(Continued)
TisdaleC32_605-628 1/12/10 3:33 PM Page 618
TABLE 32–20 Risk Factors Drug-Induced TABLE 32–21 Approaches to Help Prevent Drug-
Hyperprolactinemia and Growth Hormone Induced Hyperprolactinemia
Deficiency
• Use lowest effective dose of offending agent.
• Hyperprolactinemia • Avoid drug interactions that increase plasma concen-
• Administration of high doses of offending agent trations of the offending agent.
• Use of potent D2-receptor antagonists • Avoid drugs that exert potent D2-receptor antagonism.
• Female sex
• Growth hormone deficiency
• Development of Cushing’s syndrome (see Table
32–5) make an effort to use the lowest effective dose of less
• Family history potent D2 antagonists. This can be achieved by
using a stepwise approach in the management and
administration of these agents, starting with a low
dose and titrating up to the desired effect or decreas-
oping hyperprolactinemia is associated with the ing the dose if and when adverse effects occur. In
use of potent D2 receptor antagonists such as con- addition, agents that interact pharmacokinetically
ventional antipsychotics, risperidone, and the (e.g., inhibit metabolism) with drugs known to
antiemetics, metoclopramide, and domperi- cause hyperprolactinemia should be avoided.
done.85,134 Although the dose of antipsychotic
drugs has been correlated with prolactin levels in
some studies, others have shown a tolerance to
drug effects with normalizing prolactin levels.134
MANAGEMENT
Higher doses of drugs with alternative mechanisms Management of DIH requires recognition that a
to potentiate prolactin (e.g. estrogen, antidepres- drug is the causative agent. Once a drug has been
sants) are probably needed to induce hyperpro- identified as the cause, the logical first step is to
lactinemia.85,135 It should be noted that mental attempt to discontinue the offending medication
illness itself is not a risk factor for DIH; however, and replace it with an appropriate alternative. This
women generally have a more pronounced pro- can be problematic when a patient is well con-
lactin elevation than men when taking conven- trolled with the offending agent and/or alterna-
tional antipsychotics.85 tives are not available. This is often the situation
practitioners face with conventional or first-gener-
ation antipsychotics. In these cases, changing to an
MORBIDITY AND MORTALITY antipsychotic with less potential to cause DIH
(e.g.,. quetiapine, aripiprazole, clozapine) is per-
The incidence of death due to DIH is unknown. haps the most appropriate option, as administra-
Spontaneous galactorrhea, amenorrhea, gyneco- tion of a dopamine agonist may worsen psychiatric
mastia in men, and sexual dysfunction may lead to symptoms.85,134 If maintaining the offending agent
embarrassment and reduced quality of life.85 is the only option, initiating a dopamine agonist
Osteoporosis is a long-term consequence that may and, in those who require it (e.g., patient with
lead to fracture, and certain fractures (e.g. hip) may estrogen deficiency), sex-steroid replacement are
increase the risk of death. Other potential long- pharmacologic options.82,85,133-136 Sex steroid
term consequences of DIH include pituitary monotherapy may be the safest option for patients
tumors, breast cancer, venous thromboembolism, treated with antipsychotics.
and depression.85,134 Most, if not all, symptoms The greatest evidence for the effectiveness of
resolve when prolactin levels return to normal.85 dopamine agonist use in patients with hyperpro-
lactinemia exists for the ergot derivatives, such as
bromocriptine and cabergoline.136 However, some
PREVENTION studies of the treatment of Parkinson’s disease
show that ergot derivatives (cabergoline and per-
Methods to prevent DIH are presented in Table golide) increase the risk of cardiac valvulopathy.137
32–21. DIH may be prevented by minimizing the It is unknown whether this adverse effect occurs
risk factors associated with hyperfunction of the when ergot derivatives are used for the treatment
hypothalamus, adrenal, or pituitary glands. When it of hyperprolactinemia, since much lower doses are
is necessary to use agents that have the potential to required. Pramipexole and ropinirole are non-ergot
induce hyperprolactinemia, practitioners should derivatives that may possess a safer cardiac profile;
TisdaleC32_605-628 1/12/10 3:33 PM Page 621
Phentolamine138 NK B
Isoproterenol138 NK B
Glucocorticoids139 Variable B
Somatostatin analogs140 NKb B
GnRH agonists141,c NK B
Amphetamine derivativesd
Methylphenidate145 NK C
Dextroamphetamine146 NK C
NK = not known. GnRH = gonadotropin-releasing hormone
a
Incidence depends on dose, and duration of exposure..
b
Unknown incidence due to use in patients with growth hormone excess.
c
After repeated dosing.
d
Studies report inhibition, no change, and even stimulation of GH secretion.
TABLE 32–25 Signs and Symptoms Associated TABLE 32–26 Conditions to Consider in the
with Drug-Induced Growth Hormone Deficiency Differential Diagnosis of Drug-Induced Growth
Hormone Deficiency
• Children
• Short stature • Prepubertal
• Reduced growth velocity • Idiopathic growth hormone deficiency
• Adults • Genetic growth hormone deficiency
• Central obesity • Brain tumor (craniopharyngioma)
• Decreased lean muscle mass • Central nervous system surgery or radiation
• Reduced muscle strength • Noonan Syndrome, Turner Syndrome
• Low bone mineral density • Hypothyroidism
• Dyslipidemia • Cushing’s disease /syndrome
• Increased homeostasis model assessment • Metabolic disturbances (e.g., uncontrolled diabetes)
• Difficulty forming relationships • Short stature associated with abuse or neglect
• Decreased well-being
• Reduced energy
• Emotional lability deficiency from other causes have reduced life
• Social isolation expectancy.154 Increased mortality is mostly attrib-
• Impaired socioeconomic performance uted to premature cardiovascular disease and may
be more pronounced in childhood-onset GH defi-
ciency and in females.158
in response to insulin-induced hypoglycemia is <5.1
mcg/L or <4.1 mcg/L using the GHRH–arginine stim-
ulation test as measured by radioimmunoassay in
adults.155 In children and adolescents, the diagnosis is PREVENTION
made if the serum GH concentration after provocative
testing is <10 mcg/L.152 The standard for the diagnosis Prevention of drug-induced GH deficiency
of GH deficiency is the insulin-induced hypoglycemia includes avoidance of known risk factors, primari-
stimulation test, but the GHRH–arginine stimulation ly Cushing’s syndrome. If glucocorticoid excess is
test provides a safer alternative in children and in the culprit, changing the route of administration
patients with a history of seizure disorder and cardio- to limit systemic absorption or using a lower-
vascular disease.155 Alternative causes, such as pitu- potency steroid may prove to be effective (Table
itary adenoma, genetic GH deficiency, abuse/neglect, 32–27).
and diabetes, must still be ruled out (Table 32–26).
MANAGEMENT
RISK FACTORS
Management of drug-induced GH deficiency is
The main risk factor associated with GH deficiency is dependent on recognition of the offending drug as
the presence of Cushing’s syndrome. This is usually the cause. It is imperative to discontinue the
manifested as weight gain and is frequently associat- offending medication and start an appropriate
ed with growth failure and GH deficiency. The sever- therapeutic alternative. In children whose growth
ity of growth impairment is directly related to the age has been impaired by persistent hypercortisolism,
at onset and the duration of hypercortisolemia.156 It GH therapy should be initiated as soon as cortisol
has been shown that 50% of patients with Cushing’s
disease have abnormally short heights.157 Therefore,
any drug that may induce Cushing’s syndrome or
cause sustained hypercortisolism (e.g., long-term TABLE 32–27 Approaches to Help Prevent Drug-
administration of glucocorticoids) should be consid- Induced Growth Hormone Deficiency
ered a risk factor (Table 32–20).
• Use lowest effective dose of offending agent.
• Avoid prolonged use.
• Avoid drug interactions that will increase plasma con-
MORBIDITY AND MORTALITY centrations of the offending agent.
• Use alternative route of administration to minimize
The risk of death from drug-induced GH deficiency
systemic absorption.
is unknown, but data suggest that adults with GH
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CHAPTER 33
Weight
Gain
ANTICONVULSANTS
Carbamazepine5-7 4.7–5.2%b; (16 wk)7 A
Gabapentin8-10 2.6% (26 wk)8 A
Pregabalin11-15 9% (14 wk)12; 11.4% (12 wk)16 A
Valproic acid16-21 NK A
ANTIDEPRESSANTS
Amitriptyline22-26 5.9%22,c A
Clomipramine27,28 28%27,c; 34.8% (2.5 yr)28 A
Citalopram28,29 14.3% (2.5 yr)28 A
Desipramine25,26,30 NK A
Doxepin31,32 NK A
Duloxetine33,34 8.4–10.8% (34 wk)34 A
Escitalopram33,35 10.5% (32 wk)33 A
Fluoxetine28,29,36 6.8% (26–32 wk)36; 8.7% (2.5 yr)28 A
28,29
Fluvoxamine 10.7% (2.5 yr)28 A
Imipramine23,37-39 8.3% (16 wk)39; 19.7% (long-term)39 A
Maprotiline40-42 NK A
Mirtazapine22,43-45 7.5% ; 49% (8 wk)22,d
22,c
A
Nortripyline23,25,46 NK A
Paroxetine28,29,36 25.5% (26 to 32 wk)36; 13.8% (34 wk)34; 14.3% (2.5 yr)28 A
Phenelzine47,48 NK B
Sertraline28,36 4.2% (26–32 wk)36; 4.5% (2.5 yr)28 A
ATYPICAL ANTIPSYCHOTICS
Aripiprazole49-52 8–30% (1 yr)52,e; 5% (6 wk)52,d A
Clozapine53-70 NK A
Olanzapine71-86 22.2% (8 wk) ; 56% (long-term)86; 40.6%
86
reported weight gain of >7.5% of baseline weight weight gain was reported in 9% to 20% of
in 4.7% of patients after 16 weeks.7 Gabapentin has patients.11,12 In a retrospective analysis of 101
been reported to cause dose-dependent increases in patients with epilepsy who were treated with pre-
weight.8-10 In a randomized, dose-controlled trial of gabalin add-on therapy for at least 1 year, 26
275 patients (doses ranging from 600 to 2,400 (25.7%) experienced weight gain of >10% of base-
mg/day), 16 patients (6%) experienced weight gain line weight.12 In a 6-month, randomized, con-
as an adverse event; 7 (2.6% of the total sample) of trolled trial specifically designed to assess weight
these patients experienced a weight gain >7% of gain associated with pregabalin therapy for epilep-
baseline weight after 26 weeks of therapy.8 In a sy, 41% (25 of 61) of patients experienced a weight
review of 44 patients treated with high-dose gain >5 kg.13 Valproic acid and valproate are well
gabapentin (mean dose 3,520 mg/day) for recognized as causes of weight gain, with numer-
intractable seizures, 34% gained 5% to 10% of ous reports in the literature describing significant
baseline weight and 23% gained >10% of baseline weight gain in adults and children.16-21 In their
weight over a period of at least 12 months.10 One review of 16 clinical trials, Jallon and Piccard noted
patient who was receiving 6,000 mg of gabapentin that the incidence of weight gain with valproic
per day discontinued treatment after gaining 27 kg acid varied from 4% to 71%.16 The magnitude of
during 1 year of treatment. Pregabalin has also weight gain reported in the literature has ranged
been reported to cause dose-dependent weight from 2 to 49 kg during long-term valproate thera-
gain.11-15 During clinical trials assessing the efficacy py.17-21 In a prospective, randomized clinical trial
of pregabalin for treatment of partial seizures, specifically designed to assess weight changes asso-
TisdaleC33_629-643 1/12/10 3:34 PM Page 633
TABLE 33–3 Extent of Weight Gain Reported with Selected Drugs and Drug Classes
Drug Extent of Weight Gain Reported in the Literaturea
ANTICONVULSANTS
Carbamazepine 7–15 kg over 2 mo6
>7.5% over 4 mo8
Gabapentin 6–15% over 6 mo10
5 to > 10% over 12 mo11
Pregabalin 4 kg over 6 mo15
5.2 kg over 24 mo12
Valproic acid 5.8 kg over 32 wk20
8–49 kg over 7.1 yr19
ANTIDEPRESSANTS
Amitriptyline 0.9–13.6 kg over 8 wk26
Citalopram 6.9 kg over 12 mo29
Clomipramine 4.9 kg over 2.5 yr28
Doxepin 2.7 kg over 9 to 13 wk31,32
Desipramine 0.9–9.5 kg over 8 wk26
Fluoxetine 5.2–7.7 kg over 8 to 12 mo29,36
Fluvoxamine 6.3 kg over 12 mo
Imipramine 2.3 kg/mo of therapy37
Maprotiline 4.2 kg over 4 wk42
Mirtazapine 2.4–16 kg over 1 to 5 mo43-45
Paroxetine 8.2–14.1 kg over 8 to 12 mo29,36
Phenelzine > 6.8 kg over 4 to 16 wk48
Sertraline 8.6 kg over 8 mo36
ATYPICAL ANTIPSYCHOTICS
Clozapine 4.45 kg over 10 wk155
7.5–10.9 kg over 6 mo to 1 yr55,60,63,64,68,69
Olanzapine 4.15 kg over 10 wk155
4.1–12 kg over 6 mo to 1 year71,73,74,78,80,81,83-85
Quetiapine 3.4 kg over 1 year90
Risperidone 2.1 kg over 10 wk155
2.3–8.9 kg over 1 yr85,94-97
Ziprasidone 0.04 kg over 10 wk155
CONVENTIONAL ANTIPSYCHOTICS
Chlorpromazine 2.58 kg over 10 wk155
6.5 kg over 1 yr68
Haloperidol 0.48 kg over 10 wk155
4.2-9.7 kg over 1 to 2 yr83,85,97
Lithium 1.4–11.5 kg over 1 to 6 yr82,110-112
Thioridazine 3.19 kg over 10 wk155
ADJUVANT CHEMOTHERAPY
Adjuvant chemotherapy for early-stage breast cancer 2.3–12.3 kg 1 to 2 yr after treatment127,128
(Continued)
TisdaleC33_629-643 1/12/10 3:34 PM Page 634
TABLE 33–3 Extent of Weight Gaina Reported with Selected Drugs and Drug Classes (Continued)
this time point for most patients. However, avail- resulting in overconsumption of high-calorie bev-
able data suggest that weight gain induced by erages.110,111,160
clozapine and olanzapine continues with treat-
ment duration.
Average weight gains ranging from 7.5 to 10.9
Adjuvant Chemotherapy in
kg over 6 months to 1 year of therapy have been
Early Stage Breast Cancer
reported in patients receiving clozap- Observational studies conducted in women with
ine.55,60,63,64,68,69 In one study, 21% of outpatients early-stage breast cancer have reported significant
with schizophrenia experienced a weight gain of weight increases in the majority of patients receiv-
≥20% of baseline weight, and 58% of outpatients ing adjuvant chemotherapy.122-128 Weight gain
experienced weight gains of ≥10% of baseline associated with adjuvant chemotherapy in this
weight during 1 year of clozapine therapy.60 patient population has been reported to range
Additional case reports have documented marked from 2.5 to 6.2 kg during the treatment phase, and
weight gains ranging from 30 to 50 kg associated from 2.3 to 12.3 kg for 1 to 2 years after treat-
with clozapine therapy.54,67,70 In patients receiving ment.127,128 Specific drugs reported to be associated
olanzapine, average weight gains of 4.1 to 12 kg with weight gain in this patient population include
have been reported following 6 months to 1 year of tamoxifen, prednisone, cyclophosphamide,
treatment.71,73,74,78,80,81,83-85 Of patients receiving methotrexate, and fluorouracil.125,126 In contrast,
long-term therapy with olanzapine during clinical some studies have reported no significant increas-
trials (median treatment period, 238 days), 56% es in weight in women who have received adjuvant
experienced a weight gain of ≥7% of baseline chemotherapy regimens consisting of cyclophos-
weight.86 phamide alone or in combination with paclitax-
Although conflicting data exist, antipsychotic- el.161,162 The exact cause of weight gain in patients
induced weight gain does not appear to be dose- with early-stage breast cancer is poorly understood,
related.157 Weight gain induced by clozapine and but may be related to the underlying disease state,
olanzapine is associated with increased appetite, increased calorie consumption, and decreased
carbohydrate craving, and binge eating in some physical activity.163
patients.56,67,158 Based on available information
regarding atypical antipsychotic agents, it appears
that clozapine and olanzapine are associated with
Hormones
the greatest degree of weight gain.159 Weight gain Weight gain is well documented as a consequence
with olanzapine and clozapine can progress over 6 of therapy with exogenously administered hor-
months to 1 year of therapy before reaching a mones, including glucocorticoids, insulin, and sex-
plateau, with most weight gain occurring during steroid analogs. In fact, some steroid hormones are
the first 12 weeks.57,58,74 However, some reports specifically used to promote weight gain in certain
have suggested that clozapine-induced weight gain patient populations.164-167 Daily oral prednisone
may persist for up to 3 to 4 years.57,66 As compared therapy has been associated with dose-dependent
with other atypical antipsychotics, ziprasidone and increases in weight ranging from 2.6 to 13 kg over
aripiprazole appear to be associated with the small- 1 year of treatment.129,131 Glucocorticoid-induced
est degree of weight gain.158,159 weight gain is characterized by central adiposi-
ty,153,154 which is associated with increased health
risks as compared with peripheral obesity.4
Lithium Insulin therapy is associated with an increase
Weight gain is a common adverse effect of lithium in body weight in patients diagnosed with both
therapy, occurring in up to 65% of patients during type 1 and type 2 diabetes.132-138 Weight gain is
long-term treatment.110-113,151 The average weight more common in patients receiving intensive
gain induced by lithium has been reported to range insulin therapy than in those receiving conven-
from 4.5 to 11.5 kg over 1 to 6 years.110-112 tional therapy.132-134,137 Weight gain has been
However, weight increases of up to 28 kg have been reported to range from 2.6 to 8 kg over 2 months
described.110 Women and patients with elevated to 1 year of insulin therapy.132,134,135,138 Although
baseline BMI may be more likely to gain weight sulfonylurea and thiazolidinedione drugs have
with lithium therapy than other patients. Weight been reported to cause increases in weight, partic-
gain induced by lithium occurs primarily within ularly when used in combination with insulin, the
the first 2 years of therapy before stabilizing, and is weight gain associated with these agents alone
characterized by an increase in appetite and thirst, does not typically exceed 5 kg.152,168,169
TisdaleC33_629-643 1/12/10 3:34 PM Page 636
with psychiatric illness as well as in patients who 8. Beydoun A, Fisher J, Labar DR, et al. Gabapentin
had no previous history of psychiatric illness.213-215 monotherapy: a 26-week, double-blind, dose-controlled,
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before and during therapy is recommended. generalized seizures. Neurology. 1997;49:746-752.
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fit from pharmacotherapy when the combination on therapy with adaptable dosages in 610 patients with
of behavioral modification, low-calorie diet, and partial epilepsy: an open, observation study. Seizure.
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a multicentric, double-blind, placebo-controlled trial. with sibutramine: a case report and pathophysiologic
Schizophr Res. 2007;93:99-108. correlation. J Psychosom Res. 2008;64:107-109.
201. Wu RR, Zhao JP, Jin H, et al. Lifestyle intervention and 215. Dogangun B, Bolat N, Rustamove I, et al. Sibutramine-
metformin for treatment of antipsychotic-induced induced psychotic episode in an adolescent. J Psychosom
weight gain. JAMA. 2008;299:185-193. Res. 2008;65:505-506.
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CHAPTER 34
Temperature
Dysregulation
Susan M. Wilson
tion. The reaction is mediated through immuno- body’s core temperature. Antipyretics are not effec-
logic mechanisms caused by drugs, most common- tive for the treatment of hyperthermia secondary
ly antibiotics.1 to NMS, serotonin syndrome, or malignant hyper-
Conditions to consider in the differential diag- thermia because the hyperthermia represents an
nosis of the drug-induced hyperthermia include alteration in thermoregulatory balance and hyper-
primary central nervous system disorders (infec- metabolism and not a fever.
tion, tumors, ischemic or hemorrhagic stroke, trau- Drug-induced hypothermia is much less com-
ma, seizures), systemic diseases (infections, cancer, mon than hyperthermia. Drug-induced hypother-
metabolic conditions, endocrinopathies, autoim- mia is not normally observed in association with
mune disorders), and toxins (carbon monoxide, prescription or nonprescription drugs, but rather
phenols, strychnine, tetanus). Drug rash with typically occurs in association with illicit drugs.
eosinophilia and systemic symptoms, discussed in Agents with agonist activity at the gamma-
Chapter 6, “Allergy, Pseudoallergy, and Cutaneous aminobutyric acid (GABA) receptor are often asso-
Diseases,” is another condition in which hyper- ciated with hypothermic effects. GABA is a primary
thermia is often observed. A comparison of the inhibitory central neurotransmitter. GABA,
signs and symptoms of the drug-induced hyper- dopamine, serotonin, and opioid peptides are
thermic conditions to aid in diagnosis is presented mediators in temperature regulation; the primary
in Table 34–1. effect of GABA is to decrease temperature.
In general, antipyretics have no role in the
treatment of drug-induced hyperthermia.
Although they are effective in the treatment of HYPERTHERMIA DUE
hyperthermia due to drug fever and serum sick-
ness–like reaction, careful temperature monitoring TO DRUG FEVER
is very important. The mechanism of fever in these Drug fever is generally recognized as a febrile
cases is a hypothalamus-mediated increase in the response to a medication for which no other cause
TABLE 34–1 Comparison of Signs and Symptoms Associated with Drug–Induced Hyperthermia
Characteristic Drug Fever SSLR NMS SS MH
Dose-related N N Y Y N
Usual onset from drug 7–10 days 7–21 days Days to weeks 24 hr Minutes
initiation
Symptom resolution 72 hr 4–14 days 24–72 hr 24–72 hr Minutes to
with drug withdrawal hours
Fever Y Y Y Y Y
Increased white cell count Y Y N Y N
Increased creatine kinase N N Y Y Y
Muscle rigidity N N Y N Y
Myoglobinuria N N Y Y Y
Rhabdomyolysis N N Y Y Y
Tachycardia N N Y Y Y
Hemodynamic alterations N N Y Y Y
Tachypnea/hypercarbia N N Y Y Y
Behavior changes N N Y Y N
Altered consciousness N N Y Y Y
Myoclonus N N N Y N
Tremor N N N Y N
Hyperreflexia N N N Y N
MH = malignant hyperthermia; N = not usually associated with this disease; NMS = neuroleptic malignant syndrome; SS = serotonin syn-
drome; SSLR = serum sickness–like reaction; Y = may be observed with this disease.
TisdaleC34_644-685 1/12/10 3:35 PM Page 646
may be elucidated.1 Drug fever tends to be a diag- the clinical presentation, which may include
nosis of exclusion following a review of a patient’s eosinophilia, and its usual recurrence with rechal-
drug therapy, clinical presentation characteristics, lenge.1,10,115,117,118 Drugs or their metabolites may
and laboratory values. An early presumptive diag- be directly antigenic or act as haptens and combine
nosis of drug fever and initiation of treatment may with endogenous proteins, which become anti-
reduce unnecessary further evaluation and patient gens. The immune response may include release of
discomfort. immune mediators and cause the release of pyro-
gens, thereby inducing fever.
CAUSATIVE AGENTS
CLINICAL PRESENTATION AND
Although any drug has the potential to cause drug DIFFERENTIAL DIAGNOSIS
fever, certain medications should be considered
with a higher level of suspicion. Drugs that have Signs, symptoms, and characteristics of drug fever
been reported to cause drug fever are listed in Table are presented in Table 34–3. The onset of fever is
34–2.4-113 Anticonvulsants, certain antihyperten- generally 7 to 10 days from the time of initiation of
sive drugs, antiarrhythmic agents, and antibiotics therapy with the culprit drug. The time of onset
are the drugs that have been most commonly asso- may vary by drug class, with the shortest time
ciated with drug fever. Of the antibiotics, peni- interval observed with antineoplastic agents
cillins and cephalosporins are most often (mean, 6 days) and antimicrobials (mean, 7.8
implicated. Antibiotics that are rarely or have days), and a much longer time interval observed
never been reported to cause drug fever include with central nervous system agents (mean, 18.5
chloramphenicol, erythromycin, clindamycin, and days) and cardiac drugs (mean, 44.7 days).7 Because
aminoglycosides.1,10 It is important for clinicians to of this variability, assessment of the temporal rela-
be aware of the clinical presentation of patients tionship between drug initiation and fever onset
with drug fever and to suspect this condition in does not generally aid in the diagnosis. Patients
patients with hyperthermia in whom other causes who have been previously sensitized have symp-
are unlikely or have been ruled out. toms much more quickly, usually within hours of
reintroduction of the offending drug.
The pattern of fever varies as well and may
EPIDEMIOLOGY present as continuous, remittent, intermittent, or
hectic.1,7,8,10,114 Hectic fever is variable or fluctuat-
The true incidence of drug fever is unknown ing; the use of antipyretics or other cooling meas-
because of underreporting and misdiagnosis. It ures may contribute to this pattern. Chills and
has been estimated that a drug is the cause of fever rigors may occasionally accompany fever, mimick-
in approximately 5% to 15% of hospitalized ing the symptoms of sepsis, thereby complicating
patients.114-116 The incidence is even higher in the diagnosis. Patients may experience a low max-
patients receiving antimicrobials other than imum temperature (Tmax), or it may be as high as
antibiotics, such as antiviral agents, and in 43°C.7 No strong association has been made
patients receiving other classes of medications, between Tmax and any patient characteristics,
particularly cardiovascular drugs.7 It has been pos- except an inverse relationship between Tmax and
tulated that the incidence of drug fever is higher age.7 Higher temperatures have been observed in
in older patients and in female patients; however, patients taking antineoplastic agents; however, this
this has not been substantiated.7,114 It has been may have been due to the underlying disease.
demonstrated that drug fever due to antibiotics is Cutaneous manifestations are observed in 18%
more likely to occur in younger patients.10 to 29% of patients.1,7,10 After discontinuation of
Determination of the true incidence is difficult the offending agent, a maculopapular rash may
because the total number of patients treated is not occur that may have an urticarial component with
known. or without petechiae.7,10,27,44,85,116,119
Heart rate may not increase to the extent
expected relative to the elevation in temperature in
MECHANISMS some patients. This relative bradycardia in patients
without another explanation (e.g., those taking -
Drug fever has been hypothesized to be a type III blockers, second- or third-degree heart block) has
hypersensitivity immune response reaction, based been used as evidence favoring the diagnosis of
upon the time course of the onset of symptoms, drug fever, particularly in patients in whom infec-
TisdaleC34_644-685 1/12/10 3:35 PM Page 647
6-Mercaptopurine4,5 NK C
Acyclovir6 NK C
Allopurinol7 NK C
Amitriptyline8 NK C
Amphetamines9 NK C
Ampicillin7,10 NK C
Amoxicillin/clavulanate11 NK C
Asparaginase12 NK C
Aspirin1,7 NK C
Azathioprine13-21 NK C
Benztropine22 NK C
Bleomycin23,24 NK C
Carbamazepine25,26 NK C
Carbenicillin27,28 NK C
10
Cefoperazone NK C
Cefotaxime10 NK C
Ceftazidime28 NK C
Ceftizoxime10 NK C
Ceftriaxone29 NK C
Cefuroxime10 NK C
Chlorpromazine30 NK C
Chlorambucil31 NK C
Cimetidine32 NK C
Clofibrate33 NK C
Cloxacillin34 NK C
Cytosine35,36 NK C
Diltiazem37 NK C
Doxepin8 NK C
Fluoroquinolones38 NK C
Fluoxetine8 NK C
Folic acid39 NK C
Furosemide40 NK C
Ganciclovir41 NK C
Haloperidol42 NK C
Heparin43 NK C
Hydralazine7 NK C
Hydroxyurea44-55 NK C
Ibuprofen56 NK C
Imipenem/cilastatin28,57 NK C
Imipramine8 NK C
(Continued)
TisdaleC34_644-685 1/12/10 3:35 PM Page 648
TABLE 34–3 Signs and Symptoms of Drug TABLE 34–4 Conditions to Consider in the
Fever Differential Diagnosis of Drug Fever
• Relative sense of well-being • Infection
• Headache • Sepsis
• Myalgias • Heat stroke
• More common • Endocrine disorders
• Fever • Hematologic or solid organ malignancy
• Leukocytosis • Drug withdrawal (alcohol, benzodiazepines, levodopa)
• Less common
• Maculopapular rash
• Relative bradycardia
patients may be at higher risk with other
• Thrombocytopenia
drugs.10,114
• Eosinophilia
• Elevated erythrocyte sedimentation rate
• Elevated serum aspartate concentration
MORBIDITY AND MORTALITY
The outcome for patients with drug fever may
tion or sepsis is suspected.114,115 Another common range from full recovery from very mild illness to
observation in patients with drug fever is the significant morbidity and mortality, although
appearance of well-being relative to the degree of death due to drug fever is relatively rare. In one
hyperthermia; often patients are not aware of the evaluation of 290 cases of drug fever, 10 patients
fever. died.7 Those who died were more likely to have
Laboratory abnormalities that may occur higher temperatures and an underlying diagnosis
include leukocytosis, thrombocytopenia, eosin- of cancer.7 Most other reviews and cases in the lit-
ophilia, and markedly elevated erythrocyte sedi- erature have not reported death as a common
mentation rate and serum aspartate amin- event associated with drug fever. Continuing the
otransferase, alanine aminotransferase, and alka- offending agent may put a patient at risk for more
line phosphatase concentrations.7,10,27,44,74,85,110,120 serious sequelae, including organ dysfunction, as
Patients may also experience headache and myal- the syndrome may be expected to worsen.
gias.7 Progression of disease and organ dysfunction is the
Differential diagnosis of drug fever is difficult most probable cause of death due to drug fever.
because of the inconsistent and nonspecific signs Admission to the hospital is common for the eval-
and symptoms described above. Patients often uation of fever, and the extensive laboratory and
undergo an extensive evaluation and treatment for radiologic testing required for hospitalized patients
infection, including blood cultures, radiologic may increase the length of stay and cost of treat-
studies, antibiotics, and antipyretic therapy. A rea- ment in these patients.1,7
sonable effort should be made to rule out other
causes (Table 34–4). However, depending upon the
severity of illness, a trial of discontinuing potential PREVENTION
fever-inducing medications may be considered.
The recurrence of drug fever may be prevented by
avoiding the offending agent and using an alterna-
RISK FACTORS tive drug if possible. Cross-sensitivity is a potential
concern but has not been reported after the reac-
Risk factors for the development of drug fever have tion has completely resolved. After discontinua-
not been fully elucidated. Patients with a prior tion of the offending agent, a secondary immune
drug allergy and those with a history of atopic dis- reaction may be observed if the patient is taking
ease have not been shown to be more susceptible another sensitizing drug.1 The mechanism by
to drug fever.7 Patients with glucose-6-phosphate which this occurs is not well understood but is not
dehydrogenase deficiency may be at higher risk for thought to be mediated via cross-allergenicity, as
drug fever associated with methyldopa, because of these drugs are often pharmacologically unrelat-
drug accumulation and higher serum concentra- ed.116 Desensitization protocols should be imple-
tions.73 Younger patients may be at higher risk for mented in patients for whom no other treatment
drug fever due to antibiotics; female and older options are possible. Desensitization is usually
TisdaleC34_644-685 1/12/10 3:35 PM Page 650
responding time interval expected for each drug sulfamethoxazole; and 1 case in 2,325 courses of
class. Patients receiving antibiotics, central nervous penicillin.134 The relative risk of SSLR associated
system agents, or cardiac drugs should report a with antibiotic therapy was 65.1. The risk of SSLR
fever that presents within 7 to 10 days, 3 weeks, or associated with cefaclor was 14.8 relative to amox-
4 to 6 weeks, respectively, after initiation of thera- icillin. Multiple courses of antibiotics have been
py. Finally, patients with a history of safe antibiot- found to increase the risk of the syndrome.134,169
ic use or a prior experience with drug fever should
be instructed to keep this information in their
health records and to provide this information to
prescribers and other health care professionals.
MECHANISMS
Like drug fever, SSLR is probably a type III hyper-
sensitivity reaction. The parent drug, reactive
metabolites, or a combination of the drug and
HYPERTHERMIA DUE TO SERUM endogenous proteins may form soluble immune
complexes or antigens. These circulating soluble
SICKNESS–LIKE REACTION immune complexes deposit in tissues and activate
Serum sickness occurs after the administration of an inflammatory response, causing the release of
heterologous antitoxin serum. When the syn- mediators such as histamine, serotonin, comple-
drome is associated with any other antigenic ment, and platelet-activating factor. This leads to
source, it is known as a serum sickness–like reac- tissue injury and the clinical manifestations of
tion (SSLR).123,124 SSLR occurs most commonly serum sickness.
because of drug administration. Although antibi-
otics are commonly implicated, SSLR has been
reported in association with a wide variety of med- CLINICAL PRESENTATION AND
ications. SSLR may be a form of drug fever, may
accompany drug fever, or may be an extension of
DIFFERENTIAL DIAGNOSIS
drug fever. The onset of SSLR after primary exposure to a
causative drug is usually 6 to 21 days but may be
as long as 4 to 6 weeks.161,172,193 The onset follow-
CAUSATIVE AGENTS ing secondary exposure is much shorter, usually 1
to 4 days.163,164 The reaction may occur even after
As first described, the primary drugs reported to discontinuation of a causative agent, and diagno-
cause SSLR were those that contain antigenic (for- sis can be considerably more difficult in this situa-
eign) material, such as antitoxins, vaccines and tion.136,161 Fever, malaise, and lymphadenopathy
antivenom.125-128 Since the advent of recombinant are the cardinal symptoms of SSLR (Table 34–8).
human-derived biologic agents, most reports of Patients may also experience arthralgias, particu-
SSRL have been described in association with larly in the major joints, and myalgias, commonly
antibiotics, classically cefaclor. Drugs that have in the hands and feet. Urticaria and various types
been reported to induce SSRL are listed in Table of skin eruptions are common, including a morbil-
34–7.129-192 liform or purpuric rash.142,175,191,194 Edema may
occur, usually in the hands and feet or the face
and neck. Laboratory abnormalities may include
EPIDEMIOLOGY leukocytosis with or without a left shift, increased
aspartate aminotransferase, alanine aminotrans-
It is difficult to determine the incidence of SSLR. ferase, lactate dehydrogenase, and alkaline phos-
Most available information is related to antibiotic- phatase concentrations, although these are
associated SSLR. It has been estimated that SSLR inconsistent findings. Proper diagnosis requires
occurs in approximately 0.2% of drug courses and careful questioning in patients with the suggestive
in 0.5% of pediatric patients receiving multiple signs and symptoms. Other conditions to consider
courses of antibiotics.133 Serum sickness accounts in the differential diagnosis include febrile illness
for up to 68% of drug-induced reactions reported and other drug-induced hyperthermic conditions
in association with cefaclor.152 One review of (Table 34–9). In general, the presence of fever,
antibiotic use found 5 cases of SSLR in 3,553 cours- arthralgias, and lymphadenopathy, although not
es of cefaclor; 5 cases in 5,597 courses of amoxi- always present, are useful clues to the diagnosis of
cillin; 1 case in 13,487 courses of trimethoprim– drug-induced SSLR.
TisdaleC34_644-685 1/12/10 3:35 PM Page 652
TABLE 34–8 Signs and Symptoms Associated TABLE 34–9 Conditions to Consider in the
with Drug-Induced Serum Sickness–Like Reaction Differential Diagnosis of Drug-Induced Serum
Sickness–Like Reaction
• Malaise
• Arthralgias • Infection
• Myalgias • Heat stroke
• Urticaria • Endocrine disorders
• Fever • Hematologic or solid organ malignancy
• Lymphadenopathy • Drug withdrawal (alcohol, benzodiazepines, levodopa)
• Morbilliform or purpuric rash
• Edema
• Leukocytosis
• Increased liver transaminases (aspartate aminotrans- potential for drug-induced SSLR, the approximate
ferase, alanine aminotransferase), lactate dehydroge- onset, signs and symptoms, and when to seek addi-
nase, and alkaline phosphatase tional medical intervention. Worsening fever, lym-
phadenopathy, and any joint pain or rash should
prompt patients to contact a health care profes-
sional for further instructions.
Another drug from the same pharmacologic class
may be initiated, with close monitoring and
thorough patient education. There are no data HYPERTHERMIA DUE TO
demonstrating a risk of cross reactivity, and there
are cases reported in which another drug from
NEUROLEPTIC MALIGNANT
the same class was used without sequelae.142,195 SYNDROME
Fluoxetine desensitization has been implement-
ed successfully in patients with a previous SSLR First described in 1960, neuroleptic malignant syn-
reaction.164 drome (NMS) is a serious, idiosyncratic reaction to
certain medications, primarily neuroleptics, that
results in a relative dopamine depletion causing
muscle rigidity, hyperthermia, autonomic instabil-
MANAGEMENT ity, and altered mental status.196 Although NMS is
an uncommon disorder, the sequelae may be seri-
Discontinuation of the causative drug is the pri- ous, particularly if the condition is unrecognized
mary treatment (see Table 34–5), and typically and left untreated.
signs and symptoms of SSLR will begin to abate
within 72 hours.161 In general, drug-induced SSLR
resolves 4 to 14 days after the discontinuation of
therapy, although it may take up to 1 month to CAUSATIVE AGENTS
completely resolve.175 Medical management may
include antihistamines for urticaria and pruritus, Hundreds of cases of NMS have been reported in
and in more severe or worsening cases, corticos- the literature, most secondary to neuroleptic
teroids.137 Steroids have proven very successful in agents, particularly haloperidol. 197-200 Other
rapidly reversing symptoms, including rash, joint agents that inhibit dopamine have been impli-
pain, and facial swelling or edema. Corticoste-roids cated, including prochlorperazine, metoclo-
may be administered intravenously or orally in a pramide, lithium, and anticonvulsants. 200-219
fixed or tapering regimen over 5 to 14 Drugs that have been associated with NMS are
days.137,139,142,150,151,157-159,161,167,168,172,180,181,188 listed in Table 34–10.197-280 The older, higher-
Monitoring parameters in patients with SSLR potency antipsychotic agents such as haloperidol
include those listed in Table 34–6, in addition to and fluphenazine are more likely to induce NMS
resolution of rash, pruritus, and arthralgias. than the newer, atypical agents such as risperi-
done and olanzapine, although this may be
because there is more experience with and expo-
sure to the older drugs. A NMS-like syndrome has
INFORMATION FOR PATIENTS been described in patients who abruptly discon-
tinue therapy with baclofen.281-285 In the majori-
Patient education is similar for drug fever and ty of these cases, patients were receiving baclofen
drug-induced SSLR. Patients should be aware of the intrathecally.281-283
TisdaleC34_644-685 1/12/10 3:35 PM Page 654
Amoxapine215,220 NK C
Aripiprazole221-227 NK C
Carbamazepine216-218 NK C
Chlorpromazine201,208,209 NK C
Clozapine218,228,231-237 NK C
Donepezil238 NK C
Droperidol201,202,239-242 NK C
Fluphenazine243,244 NK C
Haloperidol197-200 NK C
Lithium200,207-215,225,245 NK C
Lorazepam246 NK C
Loxapine228,247 NK C
Metoclopramide202-206 NK C
Molindone200,248,249 NK C
211,250-262
Olanzapine NK C
Paliperidone263 NK C
Perphenazine264-266 NK C
Phenelzine198,207 NK C
Phenytoin219 NK C
Prochlorperazine201 NK C
Promethazine220,243,267 NK C
Quetiapine261,268-271 NK C
Risperidone213,215,237,261,272,273 NK C
Thioridazine214,248,274 NK C
Thiothixene275,276 NK C
Trifluoperazine248,272,276-279 NK C
Ziprasidone245,280 NK C
NK = Not Known
hyperthermia. This occurs as a result of drug- tions, leukocytosis with or without a left shift, and
induced antagonism of dopamine receptors but electrolyte abnormalities (hypocalcemia, hypo-
has also been reported after discontinuation of kalemia, hypomagnesemia). Increased CK concen-
antiparkinsonian agents and amantadine, which trations have been found in over 95% of reported
are dopamine agonists. In these cases, NMS cases and may be demonstrated in patients with-
resolves after reinitiation of therapy with these out the classic muscle rigidity.276,286,301
drugs.209,297-300 Rhabdomyolysis and resultant myoglobinuria may
develop and, without intervention, may progress
to renal failure and metabolic acidosis.
CLINICAL PRESENTATION AND Temperature elevation may follow other signs and
DIFFERENTIAL DIAGNOSIS symptoms, and the absence of hyperthermia
should not preclude the consideration of NMS.
NMS usually occurs within hours to months after Temperatures in excess of 41.1°C may occur. NMS
the initiation of neuroleptic therapy or following is often confused with heat stroke, since both may
a dose increase, but may take up to a year or longer cause mental status changes and because neu-
to manifest. In most cases, NMS develops within roleptics are a risk factor for both conditions. In
the first 4 weeks of therapy with the offending contrast to those with NMS, patients with heat
agent. Classic signs and symptoms of NMS (Table stroke present with hot, dry skin, hypotension,
34–11) develop progressively over 1 to 3 days and and limb flaccidity.
include hyperthermia, severe muscle rigidity Temperature elevation may not be as pro-
(described as “lead-pipe rigidity”), autonomic dys- nounced in association with the atypical antipsy-
function (tachycardia, tachypnea, hypertension or chotics, particularly risperidone and
fluctuating blood pressure, diaphoresis), and men- paliperidone.263,273,302,303 In addition, NMS induced
tal status changes (delirium, stupor, obtundation, by atypical antipsychotics may be associated with
coma). Other signs that may be observed include a longer time to onset and the absence of muscle
increased serum creatine kinase (CK) concentra- rigidity.261,304,305 The presence of CK elevations in
these patients may be particularly useful in the
diagnosis.304 There tends to be a particular pattern
to the onset of the signs of NMS, which may help
TABLE 34–11 Signs and Symptoms Associated in early diagnosis and recognition. In more than
with Drug-Induced Neuroleptic Malignant 80% of cases, mental status changes and rigidity
Syndrome (or CK elevations) can be expected to precede auto-
nomic dysfunction and hyperthermia.298
• Diaphoresis
Because NMS has various manifestations, dif-
• Mental status changes
ferential diagnosis must include many neurologic,
• Altered consciousness
psychiatric, systemic, and drug-induced disorders.
• Muscle rigiditya (“lead-pipe rigidity”)
Catatonia may be an early sign of NMS and may be
• Increased serum creatine kinase
confused with the underlying illness, leading the
• Autonomic dysfunction
clinician to increase the dose of the neuroleptic,
• Hyperthermia
which may worsen the condition. Patients with
• Tachycardia
preexisting catatonia may be at increased risk for
• Tachypnea
NMS, but there is some speculation that NMS and
• Hypertension or fluctuating blood pressure
catatonia are part of the same neurochemical syn-
• Mental status changes
drome or that NMS is an exacerbation of catato-
• Delirium
nia.306-310 Catatonia is usually treated with
• Stupor
neuroleptics, and therefore NMS may be more like-
• Obtundation
ly to develop because of continued treatment or
• Coma
dose escalation. The initial presentation may be
• Leukocytosis with or without a left shift
helpful for differentiating catatonia from NMS:
• Electrolyte abnormalities
lethal catatonia often begins with extreme psy-
• Hypocalcemia
chotic excitement, while NMS usually begins with
• Hypokalemia
muscle rigidity, although there are exceptions. It
• Hypomagnesemia
should be recognized that there is a relationship
• Rhabdomyolysis and myoglobinuria
a
between the two syndromes, and in patients with
This classic sign may not always be observed in patients with neu-
catatonia or NMS with catatonic signs or symp-
roleptic malignant syndrome caused by atypical antipsychotics,
toms, consideration should be given to alternative
TisdaleC34_644-685 1/12/10 3:35 PM Page 656
mortality rate of 9.7% in patients who received dine) plus dantrolene has no proven advantage, it
drug therapy (dantrolene, bromocriptine, lev- may be considered in refractory or extremely
odopa, amantadine) as compared with 21% in severe cases, as this approach offers treatment with
patients who did not receive any specific drug ther- drugs with different mechanisms of action.344-
apy intervention.331 346,349,350
All medications that cause dopamine-depleting Although they successfully control some of the
or antagonistic effects should be discontinued, par- signs and symptoms of NMS, anticholinergic
ticularly any antipsychotic agents that have been agents are not recommended because they inhibit
initiated recently, or for which the dose has recent- heat dissipation and may worsen hyperther-
ly been increased. Supportive measures include mia.288,319,349,350 Pancuronium with concomitant
fluid, electrolyte, and acid–base management. diazepam administration was reported to be effec-
Rapid cooling measures, including cooled intra- tive for cessation of muscle rigidity in a patient
venous solutions, surface cooling, and ice water with NMS in whom treatment with anticholiner-
gastric lavage should be used for management of gics failed but who was not treated with dantro-
significant temperature elevation. lene.351 Carbidopa–levodopa may also be effective
Bromocriptine, amantadine, other dopamine because of its dopamine agonist properties.345,346,352
agonists and dantrolene have been used successful- Intravenous diazepam may be used to manage
ly in the management of NMS. Bromocriptine is involuntary movements, fever, tachycardia, hyper-
considered the drug of initial choice. Doses of 2.5 tension, muscle rigidity, tremor, and diaphoresis
to 5 mg (range, 2.5–20 mg) should be administered associated with NMS.353,354 Benzodiazepines may
orally three to four times daily for 10 days, be useful as adjunct therapy for suspected catato-
although a longer duration of treatment may be nia and for treatment of agitation.355-357
required.220,250,292,330-335 Treatment with bromocrip- Electroconvulsive therapy (ECT) may be consid-
tine should be continued until signs and symp- ered for the treatment of NMS refractory to other
toms resolve, after which the dose should be therapies, although there are no prospective com-
tapered gradually. Improvement in signs and parative studies.358-364 One retrospective review of
symptoms is usually observed within 24 to 72 NMS cases demonstrated a mortality rate of 10.3%
hours. in patients who underwent ECT, as compared with
Amantadine is a treatment alternative for NMS. 21% in patients who received no specific interven-
The recommended dose is 100 to 200 mg orally tion, a difference that did not reach statistical sig-
two to three times per day and should be contin- nificance.331 ECT should be considered the therapy
ued for 10 days after signs and symptoms are con- of choice in patients with suspected catatonia.
trolled, after which the dose should be tapered to Resolution of mental status changes, muscle
avoid rebound NMS.206,336-339 rigidity, serum creatine kinase concentrations,
Dantrolene has been used successfully to treat acid–base abnormalities and myoglobinuria should
NMS by relieving muscle rigidity and heat genera- be closely monitored. Progression of these signs
tion, via inhibition of calcium release from the and symptoms requires more aggressive manage-
endoplasmic reticulum.215,340-346 Often patients are ment. Monitoring parameters for patients with
unable to take oral medications during NMS, NMS are listed in Table 34–16.
necessitating use of the intravenous route. With appropriate care, patients with NMS gen-
Dantrolene therapy is recommended if the temper- erally fully recover within several days to weeks.
ature exceeds 40°C, rhabdomyolysis is suspected, Signs and symptoms may persist longer and may
cardiorespiratory or renal failure is imminent, and be more difficult to manage in patients who have
administration of dopamine agonists has not been received intramuscular (depot) antipsychotic
successful.289 These patients have severe NMS and agents.315 A residual catatonic state has been
are at high risk of serious morbidity or death and described in several patients for 1 to 6 months after
require the most rigorous intervention.315,347 resolution of hyperthermic signs and symptoms.326
Dantrolene should be administered at a dose of 2 Rigidity and mental status changes persisted in
to 3 mg/kg intravenously (up to 5 mg/kg) divided these patients for unknown reasons.
three to four times daily until signs and symptoms
have been adequately controlled.348 When the
patient is able to take oral medications, dantrolene INFORMATION FOR PATIENTS
may be administered at a dose of 1 mg/kg every 6
hours orally for another 10 days, and then the dose Patient education may be uniquely difficult in the
may be tapered. Although combination therapy of patient population treated with neuroleptic agents.
a dopamine agonist (bromocriptine or amanta- Despite the potential obstacles, patients and care-
TisdaleC34_644-685 1/12/10 3:35 PM Page 659
EPIDEMIOLOGY
givers should be alerted to the signs and symptoms
of NMS and instructed when to seek medical atten- The incidence of serotonin syndrome is not
tion. Patients and care givers should be instructed known. However, the incidence may be relatively
to call a health care professional or visit a health low, considering the widespread use of medica-
care facility in the event of sudden onset of muscle tions, alone and in combination, known to disrupt
rigidity, tachycardia, tachypnea, diaphoresis, or serotonin balance. One retrospective review exam-
mental status changes. It is particularly important ined the use of SSRIs and linezolid, a weak
to stress to patients that medications should not be inhibitor of MAO, and found that 3% of patients
discontinued if signs and symptoms develop, and had a high probability of serotonin syndrome.400
to seek medical attention to ensure that a proper In another retrospective review of the records of
diagnosis is achieved. 262 hospitalized patients who were treated with
meperidine, 10% were receiving concomitant
SSRIs; serotonin syndrome did not develop in any
of them.456 The sample size in this report was
HYPERTHERMIA DUE TO small, and the SSRI doses were not discussed.
SEROTONIN SYNDROME Although there is an increased awareness of the
Serotonin syndrome is a potentially serious and triggering factors for serotonin syndrome, the dis-
occasionally fatal complication of therapy associat- ease is still not commonly considered in patients
ed with drugs that cause an increase in serotoner- presenting with suspicious signs and symptoms.
gic activity. Fever is one common component of SSRIs are being prescribed with increased frequen-
the syndrome. With the significant increase in the cy, however there is declining use of MAOIs, result-
number of patients treated with selective serotonin ing in an unknown net effect on the true incidence
(5-hydroxytryptamine [5-HT]) reuptake inhibitors of this drug-induced disease.
(SSRIs), it may be expected that the prevalence of
this drug-induced disease will continue to increase.
MECHANISMS
CAUSATIVE AGENTS Mechanisms by which drugs cause serotonin syn-
drome are presented in Table 34–18. Excessive sero-
Any drug that causes a direct or indirect increase in tonergic activity is responsible for serotonin
the effective serotonin concentration in the central syndrome. Seven 5-HT receptor subtypes have
nervous system has the potential to induce sero- been identified, and it is believed that 5-HT1A and
tonin syndrome. Drugs that have been reported to 5-HT2A are involved specifically with the adverse
TisdaleC34_644-685 1/12/10 3:35 PM Page 660
Drug Mechanism
Hypericum perforatum (St. John’s Wort) Inhibit 5-HT reuptake
Inhibit 5-HT metabolism
Lithium Postsynaptic receptor stimulation
Metoclopramide + venlafaxine Inhibit 5-HT reuptake
HT = hydroxytryptamine; MAO = monoamine oxidase; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.
sequelae encountered with serotonin syn- syndrome manifests as a succession of signs and
drome.457,458 Controversy exists regarding which of symptoms that progress rapidly, over the course of
these two receptors is most responsible for the syn- hours, and may be highly variable, making identi-
drome. It is likely that both of these receptor sub- fication and diagnosis difficult. Serotonin syn-
types, and possibly others, are involved in the drome is most appropriately thought of as a
clinical manifestations of serotonin syndrome. The spectrum of diseases and has been classified into
syndrome generally occurs after initiating therapy severity categories to aid in earlier or more accurate
with, or increasing the dose of, a drug with one or diagnosis.457,459,460 Some of the signs and symp-
more of the following actions: (1) inhibition of toms associated with milder forms of serotonin
serotonin metabolism; (2) potentiation of sero- syndrome (tremor, confusion, incoordination)
tonin activity; (3) direct activation of serotonin may be difficult to distinguish from the underlying
receptors; (4) inhibition of serotonin uptake; and illness.457 The more severe symptoms of serotonin
(5) increase of substrate supply. Serotonin syn- toxicity (temperature of (38.5°C, myoclonus, diar-
drome has been associated with single-drug thera- rhea) are generally observed in overdose situations
py; however, because it is a dose-dependent or when an MAOI or a serotonin-releasing agent is
phenomenon, combinations of drugs in particular used in combination with an SSRI.457,461
are associated with the development of the syn- Signs and symptoms of serotonin syndrome may
drome. Pharmacodynamic (combinations of drugs be divided into three categories for patient assess-
that have a similar effect on serotonin) and phar- ment: autonomic dysfunction (fever, shivering,
macokinetic drug interactions result in an increase diaphoresis, diarrhea, tachycardia, labile blood pres-
in effect at the serotonin receptor, leading to exces- sure); neuromuscular hyperactivity (clonus,
sive serotonergic effects.406,425 Some drugs inhibit myoclonus, hyperreflexia, incoordination, tremor);
the metabolism of SSRIs while some SSRIs inhibit and mental status changes (confusion, agitation,
cytochrome P-450 2D6, which metabolizes other mania possibly progressing to hallucinations, obtun-
drugs with serotonergic effects, such as dex- dation, coma). The original criteria for diagnosis of
tromethorphan. In general, opioid analgesics are serotonin syndrome as proposed by Sternbach are
thought to inhibit the reuptake of serotonin, there- the presence of at least three symptoms temporally
by increasing the risk of serotonin syndrome when related to a suspect medication; other causes have
combined with agents that have serotonergic activ- been ruled out; and a neuroleptic agent has not been
ity. There may be other mechanisms involved, started or dose increased prior to the onset of signs
however, as serotonin syndrome has been reported and symptoms (indicating possible NMS).457
with oxycodone and buprenorphine, which do not Problems with the Sternbach criteria may exist and
inhibit the reuptake of serotonin.411,449 include the weight of mental status changes in the
criteria, causing patients with abnormal mental
states to be misdiagnosed and a diagnosis of sero-
CLINICAL PRESENTATION AND tonin syndrome to be missed in patients with mild
DIFFERENTIAL DIAGNOSIS serotonin toxicity. Others have determined that sero-
tonin syndrome may be misdiagnosed in patients
The onset of the signs and symptoms of serotonin with infection using Sternbach’s criteria.400 Because
syndrome may be almost immediate, with approx- of this lack of sensitivity, diagnostic decision rules
imately 60% of cases presenting within 6 hours have been developed based on the evaluation of
after the offending agent has been initiated, the 2,222 cases of serotonin overdose which were report-
dose increased, or the serum concentration ed to the Hunter Area Toxicology Service.461 These
increased by a drug–drug interaction. Serotonin criteria are simpler and include primarily clonus, agi-
TisdaleC34_644-685 1/12/10 3:35 PM Page 663
tation, diaphoresis, tremor, hyperreflexia, hyperto- tified, although increased age and female sex may
nia, and hyperthermia. The most important sign in be predisposing factors (Table 34–20). In addition,
the Hunter criteria is clonus and, if spontaneously risk factors may include endogenous or acquired
present in a patient taking a serotonergic agent, is by defects in MAO activity that lead to impairment in
itself adequate to make the diagnosis. Important to SSRI metabolism, such as those occurring in
note is that the diagnostics decision rules were devel- patients with cardiovascular diseases—including
oped from data in patients with overdoses and have hypertension and hyperlipidemia—liver disease,
not yet been validated to be sensitive and specific for and pulmonary disease and in those who smoke
patients with serotonin syndrome at therapeutic cigarettes. Genetic variation in the ability to
doses of serotonergic agents. Fulminant cases of sero- metabolize serotonergic drugs and activities of
tonin syndrome may progress to seizures, rhabdomy- MAO isoenzymes may predispose patients to sero-
olysis, renal failure, and death. Other conditions to tonin syndrome. Approximately 7% of individuals
consider in the differential diagnosis of serotonin are poor metabolizers of SSRIs.462 This genetic pre-
syndrome include infection, sepsis, heat stroke, and disposition may enhance a patient’s sensitivity to
NMS (Table 34–19) Although both NMS and sero- serotonergic agents and increase the propensity for
tonin syndrome may present with some common the development of serotonin syndrome.
symptoms—including catatonia, tremors, rigidity, Other potential risk factors for serotonin syn-
and hyperthermia—differences may aid in the diag- drome are drug-specific features, including drug
nosis. Proper diagnosis is essential, as bromocriptine potency, total daily dose, rapid dose escalation,
is a treatment considered for NMS but should be and use of concomitant agents that may increase
strictly avoided in patients with serotonin syndrome serotonin activity or interact with serotonergic
because it may worsen the condition. The rigidity agents.
associated with serotonin syndrome may be less pro-
nounced than that due to NMS and usually occurs in
the lower extremities, as compared with NMS, in MORBIDITY AND MORTALITY
which the rigidity is described as “lead pipe” and is
not usually limited to the lower extremities. With Most patients fully recover following discontinua-
NMS, the progression of signs and symptoms occurs tion of the causative agent and implementation of
over the course of days and there may be a lower supportive care; however, deaths have been report-
incidence of tremors, clonus, and myoclonus. There ed due to serotonin syndrome.368,369,376,379,385,391,445
are usually no gastrointestinal symptoms; however, Deaths are reported more often in association with
hyperthermia may be more common. The most reli- intentional overdose of SSRIs alone or in combina-
able method for appropriate diagnosis is an accurate tion with an MAOI. Death from serotonin syn-
medication history, including starting dates and drome generally occurs secondary to multiple
doses of medications that increase serotonergic activ- organ dysfunction, including rhabdomyolysis lead-
ity and specific information regarding dose escala- ing to renal failure, disseminated intravascular
tion, if available. coagulation, adult respiratory distress syndrome,
and cardiovascular collapse from muscular hyper- in those with renal or hepatic impairment, in addi-
activity and hyperthermia. With prompt interven- tion to closer monitoring of these patients for signs
tion, however, patients usually recover without or symptoms of toxicity.
long-term sequelae.
MANAGEMENT
PREVENTION
Discontinuation of the offending agent is impera-
Keys to the prevention of serotonin syndrome are tive, as is supportive care, which often results in
careful initiation and dose escalation of SSRIs, in resolution of signs and symptoms within 24
addition to appropriate patient education regard- hours without specific pharmacotherapeutic
ing drug-induced diseases, drug interactions, and intervention (Table 34–22). Fluid therapy should
recognition of signs and symptoms of toxicity be implemented in patients in whom diaphoresis
(Table 34–21). SSRI therapy should be initiated at a has been a significant clinical symptom, in addi-
low dosage and titrated upward slowly, particularly tion to those requiring cooling augmentation.
in elderly patients or those with impairment of Although there are no clinical trials that have
liver or renal function. specifically evaluated the efficacy of any thera-
Following discontinuation of the culprit drug, peutic intervention for serotonin syndrome, sev-
a washout period of at least 5 to 7 days prior to ini- eral drugs have anecdotally been reported to be
tiating therapy with an MAOI or another SSRI is successful.
important; the duration should be determined Cyproheptadine, a histamine1 (H1) antagonist
based on the half-life of the active compound. A with nonselective anti–5-HT and anticholinergic
washout period of 5 weeks or longer may be neces- properties, has been a successful treatment for sero-
sary for SSRIs with very long half-lives or those tonin syndrome. In some reports, cyproheptadine
with active metabolites such as fluoxetine, sertra- has not been found to alter the time course of sero-
line, and clomipramine. In addition, if delayed tonin syndrome but may relieve signs and symp-
elimination is suspected in selected patients, a toms.463 Others have indicated that
longer drug-free period is warranted. MAOIs inhib- cyproheptadine can shorten the duration of some
it the metabolism of SSRIs, and therefore directly symptoms of serotonin syndrome, including
increase serotonin concentrations at the site of tachycardia, tremor, neuromuscular features, and
activity. MAOIs should be discontinued at least 4 anxiety.366 The recommended dose of cyprohepta-
weeks prior to starting therapy with an SSRI.
Moclobemide, a reversible MAOI, requires a much
shorter washout period because of its very short
half-life; 24 hours may be sufficient. Concomitant
use of agents that increase serum serotonin con- TABLE 34–22 Management of Drug-Induced
centrations should be avoided. Appropriate dose Serotonin Syndrome
adjustments should be made in older patients and • Discontinue suspected agent
• Supportive care
• Surface cooling
• Cooled fluids
TABLE 34–21 Approaches to Help Prevent • Fluid replacement for patients with severe
Drug-Induced Serotonin Syndrome diaphoresis
• Cyproheptadine 4–12 mg orally every 8 hr up to 48
• Carefully initiate and titrate serotonergic agents
hr; 30 mg may be given as a single dose; single, small-
• Adjust dose appropriately for elderly patients and
er doses may also be effective
those with hepatic dysfunction or chronic kidney
• Chlorpromazine 12.5 mg as a single dose, up to 1
disease.
mg/kg, orally or intramuscularly; repeat dose if
• Ensure adequate washout period when switching
symptoms return
from MAOI to serotonergic agents or serotonergic
• Lorazepam, diazepam, or propranolol may be added
agents to MAOI.
to the above therapy in refractory cases as needed
• Carefully switch from one serotonergic agent to
to control signs and symptoms
another.
• Neuromuscular blocking agents may be considered
• Be aware of drug interactions and avoid if possible.
for patients with sustained myoclonus or severe
MAOI = monoamine oxidase inhibitor. hyperthermia
TisdaleC34_644-685 1/12/10 3:35 PM Page 665
ANESTHETICS, INHALED NK C
Desflurane468-476 NK C
Enflurane459-479 NK C
Halothane480-487 NK C
Isoflurane488-502 NK C
Methoxyflurane503 NK C
Sevoflurane485,504-511 NK C
DEPOLARIZING SKELETAL MUSCLE RELAXANTS NK C
Succinylcholine468-471,476,480,485,512-517 NK C
NK = not known.
TisdaleC34_644-685 1/12/10 3:35 PM Page 667
ommended.551,552 Dantrolene prophylaxis is not Dantrolene inhibits calcium release from the
expected to be completely successful and may cause endoplasmic reticulum, which alters the course of
significant muscle weakness resulting in temporary malignant hyperthermia. In one study of 11
disability, which should be considered in the deci- patients with malignant hyperthermia to whom
sion about whether to attempt prophylaxis.550,553,554 dantrolene was administered, 100% of patients sur-
Several cases have been reported in which patients vived.556 In one retrospective medical record review,
were successfully anesthetized without prophylac- the mortality rate was 8.9% in 79 patients who
tic administration of dantrolene, when triggering received intravenous dantrolene prior to cardiac
agents were not used and patients were monitored arrest, as compared with a mortality rate of 25.4%
very closely.546,555 Currently, the use of dantrolene in 375 patients who did not receive dantrolene—a
prophylaxis in susceptible patients is not recom- 16.6% absolute reduction in mortality.542 Rapid
mended because of the low risk of malignant hyper- dantrolene administration after recognition of the
thermia when triggering agents are avoided and the syndrome is critical, as outcome is related to a
potential adverse effects associated with dantro- shorter elapsed time from symptom onset to time
lene. of drug administration. Dantrolene should be
administered as an intravenous dose of 2 to 2.5
mg/kg initially, repeated as necessary up to 10
MANAGEMENT mg/kg until signs and symptoms begin to abate,
which is expected to occur within minutes of
Early recognition and intervention is crucial. All dantrolene administration. Higher doses of up to 30
suspected medications should be immediately dis- mg/kg may be administered in severe, refractory
continued, as should the surgical procedure, if fea- cases. These initial starting doses are higher than
sible (Table 34–28). Control of fever, acidosis, those that were recommended previously (1 mg/kg)
hypermetabolism, and hypercarbia is imperative. because of diminished circulation in patients with
Patients should receive intravenous fluid therapy malignant hyperthermia.482,557 The duration of
for prevention of acute tubular necrosis and meta- treatment in the cases reported has varied consider-
bolic acidosis from the hypermetabolic state, and ably, from single-dose therapy to multiple days of
to maintain cardiac output. Hypercarbia and therapy. After the patient has stabilized, dantrolene
hypoxemia should be treated with aggressive oxy- may be administered orally at a dose of 50 to 300
gen management and hyperventilation. Rapid mg per day in divided doses or 1 to 2 mg/kg four
cooling measures such as cooling blankets, ice times daily for several days (at least 36 hours) to
packs, ice water gastric lavage, and intravenous flu- prevent recurrence.558 Dantrolene has been used
ids should be implemented. Shivering may occur successfully and safely in pregnant patients who are
from rapid temperature decrease and should be susceptible to malignant hyperthermia and are
treated with chlorpromazine, benzodiazepines, undergoing caesarean section.559-566 Dantrolene
and paralysis with mechanical ventilation for may cause dizziness, diplopia, dysarthria, a sensa-
severe, refractory shivering. tion of swelling of the eyes and tongue, and subjec-
tive (but not objective) weakness.482,542,554
Prior to the first use of dantrolene, pro-
cainamide and procaine were found to be useful in
TABLE 34–28 Management of Drug-Induced reported cases.517,547,567-571 Procainamide is no
Malignant Hyperthermia longer recommended for management of malig-
nant hyperthermia unless tachyarrhythmia devel-
• Discontinue suspected agent
ops, in which case procainamide is considered the
• Cooling measures and other supportive care
drug of choice.
• Surface cooling
Benzodiazepines, opioid narcotic analgesics,
• Cooled intravenous fluids
and in severe cases, neuromuscular blockade with
• Ice water nasogastric or rectal lavage
mechanical ventilation may be required in patients
• Fluid and electrolyte replacement as needed
with severe shivering or refractory muscle contrac-
• Continuous ventilatory management
tion, in an effort to control oxygen utilization.
• Dantrolene 2.5 mg/kg intravenously as needed to
Close monitoring of improvement of signs and
control signs and symptoms (up to 10 mg/kg; doses
symptoms as well as any signs of recurrence is
up to 30 mg/kg may be used in severe, refractory cases)
important for a successful outcome for patients
• Nondepolarizing neuromuscular blocking drugs, ben-
with malignant hyperthermia. Appropriate moni-
zodiazepines, chlorpromazine as needed for refracto-
toring parameters for patients with malignant
ry shivering or rigidity
hyperthermia are listed in Table 34–29.
TisdaleC34_644-685 1/12/10 3:35 PM Page 670
EPIDEMIOLOGY
INFORMATION FOR PATIENTS
The incidence of drug-induced hypothermia
Patients should be questioned regarding a history of among those taking causative drugs is unknown.
malignant hyperthermia or a problem with anesthe- Sporadic cases are reported in the literature, but the
sia and should be instructed to alert all health care total number of individuals taking these drugs can-
professionals of this risk. In addition, family members not easily be determined.
of patients with a prior episode should be made aware
of their potential risk. Patients at risk should be given
the opportunity for an IVCT to determine susceptibil- MECHANISMS
ity to triggering agents. Various options for anesthe-
sia, as well as the risks and benefits of those options Temperature balance occurs via the anterior hypo-
in addition to prophylaxis with dantrolene should be thalamus, with stimulation and inhibition from a
discussed with patients at risk prior to any surgery. A variety of neurotransmitters in a complex process.
medical alerting device is recommended for those Dopamine and serotonin receptors are involved in
with a history of malignant hyperthermia or who thermoregulatory balance. Although both D1 and
have a significant family history and positive IVCT in D2 receptor subtypes are involved in temperature
the event that emergency surgery is needed. Finally, regulation, the more prominent effect of dopamine
patients should be offered the opportunity to register receptor stimulation is lowering of temperature,
with the Malignant Hyperthermia Association of the and the more prominent effect of dopamine recep-
United States (MHAUS) by calling 1-800-MHAUS or tor antagonism is that of elevating temperature.
visiting the Web site, at www.mhaus.org. The Web Cannabinoid and opioid-induced hypothermia is
site provides patient and health care professional mediated via dopaminergic pathways. In addition,
information in addition to resources for susceptibility opioids may decrease body temperature through
testing, hotline contact information, and for obtain- agonism of opiate receptors in the hypothalamus.
ing an Emergency Medical Identification Card. A relative increase in serotonin concentrations
increases temperature. GABA and baclofen inhibit
the release of excitatory neurotransmitters, includ-
HYPOTHERMIA ing serotonin and dopamine, resulting in a net
effect of hypothermia. Antipyretic agents such as
CAUSATIVE AGENTS acetaminophen, aspirin, and other nonsteroidal
antiinflammatory drugs decrease temperature in
Baclofen, gamma-hydroxybutyrate (GHB), and febrile patients in whom the thermoregulatory set
gamma-butyrolactone (GBL), which is converted point has been raised. However, these drugs have
to GHB after ingestion, are structurally related to no effect on temperature in afebrile patients. Table
TisdaleC34_644-685 1/12/10 3:35 PM Page 671
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Anesthesiology. 1973;39:450-451.
TisdaleC35_686-701 1/12/10 3:36 PM Page 686
CHAPTER 35
Sexual Dysfunction
in Males
serum testosterone concentrations that are below Theoretically, it follows then that supraphysio-
the normal range, exogenous administration of logic serum testosterone concentrations may
testosterone replacement agents restores libido.90 enhance male sexual drive in elderly patients.
Testicular testosterone production is controlled However, this has not been demonstrated clinical-
by the hypothalamic–pituitary–gonadal–adrenal ly. Administration of excessive doses of testos-
axis. Increased release of luteinizing- terone to elderly male patients, resulting in
hormone–releasing hormone or gonadotropin- supraphysiologic serum testosterone concentra-
releasing hormone from the hypothalamus tions, is not associated with increased libido.73 The
stimulates pituitary release of luteinizing hormone. mechanism for increased sexual drive is poorly
Luteinizing hormone stimulates the production of understood and may be due to a combination of
testosterone in Leydig cells. Therefore, drugs that causes, including a supratentorial component.
suppress hypothalamic release of luteinizing hor- In order for a penile erection to occur, a patient
mone–releasing hormone or pituitary release of must have intact penile vascular and neurologic sys-
luteinizing hormone, or that directly suppress tes- tems. The penis is composed of three vascular bod-
ticular testosterone production, may suppress ies: two dorsal corpora cavernosa and one corpus
libido. Similarly, drugs that increase serum pro- spongiosum. During an erection, the corpora fill
lactin concentrations, which results in a decrease with arterial blood, which must be trapped within
in testicular androgen production, can indirectly the corpora. Thus, arterial blood flow must be ade-
suppress libido. In addition to the stimulatory quate and the degree of arterial inflow must exceed
effect of testosterone on libido, males must be con- the degree of venous outflow for penile tumescence
scious and receptive to sexual stimuli, which can to occur. When compounded by contraction of the
be visual, auditory, olfactory, tactile, or gustatory. ischiocavernosus muscles surrounding the bulbous
As these stimuli are processed in the brain, drugs urethra, these effects produce a long, hard penile
that cause sedation or depress the sensorium can shaft suitable for vaginal penetration. Thus, sys-
suppress libido. temic antihypertensive agents, which decrease
TisdaleC35_686-701 1/12/10 3:36 PM Page 690
peripheral blood pressure, or diuretics, which urethra occurs at climax. Antegrade ejaculation
decrease blood volume, may compromise arterial requires emission (or the movement of seminal flu-
blood flow and cause erectile dysfunction.89 ids from the prostate, seminal vesicles, and vas def-
Both the central and peripheral nervous systems erens into the proximal urethra); contraction of the
can mediate a penile erection. With visual, olfactory, bladder neck sphincter (to prevent the retrograde
auditory, tactile, or gustatory sexual stimulation, the flow of seminal fluids into the bladder); and con-
brain sends nerve impulses down the spinal cord. traction of periurethral skeletal muscles to propel
Preganglionic sympathetic nerve fibers emerge from the ejaculate out of the urethra. Emission and blad-
the spinal cord at the thoracolumbar vertebra der neck closure are sympathetically mediated by
T11–L2; postganglionic neurotransmission to the cor- norepinephrine.92 Thus, postsynaptic ␣-adrenergic
pora is mediated by parasympathetic pathways in the receptor antagonists (e.g., tamsulosin) block norepi-
pelvic plexus. Tactile stimulation of the genitalia can nephrine at its receptor, and may lead to retrograde
also stimulate a somatic reflex nerve arc at the level of ejaculation or emission failure.92 The antegrade
the sacral vertebrae S2–S4. In either case, acetyl- propulsion of ejaculate from the posterior urethra
choline is the primary neurotransmitter responsible and out of the patient’s body is parasympathetically
for penile tumescence. Acetylcholine probably works mediated. Thus, drugs with anticholinergic effects
through noncholinergic, nonadrenergic neurotrans- may cause delayed ejaculation.44 In addition, stimu-
mitters, such as nitric oxide, and secondary messen- lation of central serotonin receptors appear to inhib-
gers, such as cyclic adenosine monophosphate and it ejaculation. Therefore selective serotonin reuptake
cyclic guanine monophosphate, to mediate corporal inhibitors are associated with anejaculation.94
relaxation and blood filling of cavernosal tissue sinus- The ejaculate is composed of three major compo-
es. Therefore, drugs that antagonize acetylcholine at nents: sperm-containing fluid from the vas deferens,
its receptor, producing anticholinergic effects, can fructose-containing fluid from the seminal vesicles,
cause erectile dysfunction.89 and prostatic secretions from the prostate. A normal
In male patients with normal sexual function, ejaculate volume is 2 ml or more. Contributors of
antegrade ejaculation of seminal fluids out of the ejaculate volume include the seminal vesicles
TisdaleC35_686-701 1/12/10 3:36 PM Page 691
(75–80% of the total volume) and prostate (10% of within and hypoxia of cavernosal tissue. Permanent
the total volume), both of which are androgen- cavernosal injury may develop if priapism does not
dependent tissues.44 Thus, medications that interfere resolve on its own or is not treated appropriately.
with testosterone stimulation of these target tissues The mechanism of drug-induced priapism is
(e.g., finasteride) can decrease ejaculate volume.18,36 poorly understood. Priapism may result from drug-
Following climax and ejaculation, the penis induced increased arteriolar inflow to the caver-
returns to a flaccid state. For detumescence to occur, nosa (e.g., hydralazine), drug-induced decreased
venous outflow must exceed arterial inflow. venous outflow mediated by inhibition of ␣-adren-
Detumescence is sympathetically mediated. ergic tone (e.g., phentolamine, phenothiazines,
Therefore, norepinephrine normally causes arterio- trazodone), blood sludging in the corpora because
lar vasoconstriction, thereby decreasing arteriolar of platelet or clotting factor dysfunction (e.g.,
inflow and causing cavernosal vasoconstriction. heparin, warfarin), or some other mechanism.
This improves venous outflow, and the penis even- The fertility of a male is dependent on multiple
tually becomes flaccid. 2-Adrenergic stimulation of physiologic functions: adequate quantitative and
peripheral blood vessels causes venodilation, which qualitative production of sperm and effective emis-
improves venous outflow and blood emptying from sion of sperm into the prostatic urethra. Luteinizing
the corpora cavernosa. When detumescence does hormone and follicle-stimulating hormone (FSH) are
not occur, and the penile erection is sustained in the essential for the induction of sperm production at
absence of sexual stimulation, priapism can devel- puberty. After puberty, maintenance of spermatogen-
op. Penile pain may result from blood sludging esis is dependent on FSH stimulation of Sertoli cells
TisdaleC35_686-701 1/12/10 3:36 PM Page 692
Drug Mechanism
Drug-Induced Decreased Libido
Estrogens Decreases pituitary LH secretion and testicular testosterone
production.
Gonadotropin-releasing hormone superagonists Decreases pituitary LH secretion and testicular
testosterone production.
Carbamazepine Decreases serum testosterone levels.
Ketoconazole Inhibits adrenal and testicular testosterone production.
Digoxin (Metabolite) Competes with androgen at receptors.
Spironolactone (Metabolite) Competes with androgen at receptor;
Inhibits testosterone synthesis.
Clofibrate Reduces cholesterol, a precursor for androgen synthesis.
Gemfibrozil
Antidepressants Causes sedation, which depresses libido.
Antipsychotics
Ethanol, high doses
Hypnotics
Metoclopramide Increases prolactin, which depresses androgen production.
Phenothiazines Increases prolactin, which depresses androgen production;
Has sedative effects.
Cimetidine Increases prolactin, which depresses androgen production;
May be an androgen receptor antagonist.
Drug-Induced Erectile Dysfunction
Antihistamine Sedative adverse effects cause decreases libido. Patients
Antidepressants develop erectile dysfunction secondary to decreased
Antiparkinsonian agents libido.
Antipsychotics
Ethanol, high doses
Hypnotics
Sedatives
Diuretics, thiazide or loop Decreased systemic blood pressure resulting in decreased
-Adrenergic antagonists blood flow to corpora cavernosa.
Centrally acting sympatholytics (e.g., clonidine)
Antihistamine Anticholinergic effects decrease arterial blood flow into
Antidepressants and filling of corpora cavernosa.
Antiparkinsonian agents
Antipsychotics
Haloperidol Blocks D1 and D2 receptors in the central nervous system.
Estrogens Decreased serum testosterone concentrations causing
Gonadotropin-releasing hormone superagonists decreased libido and secondary erectile dysfunction.
Phenothiazines Hyperprolactinemia causes decreased libido and secondary
erectile dysfunction.69
Drug-Induced Ejaculation Disorders
␣-Adrenergic antagonists Relaxation of bladder neck during coitus leads to
Phenothiazines retrograde or delayed emission.
Atypical antipsychotics
(Continued)
TisdaleC35_686-701 1/12/10 3:36 PM Page 693
Drug Mechanism
5␣-Reductase inhibitors Decrease in prostate volume leads to decrease in ability of
prostate to produce prostatic secretions; Decreased
semen volume results.
Tricyclic antidepressants Anticholinergic effects lead to delayed emission.
Anticholinergic agents
Phenothiazines
Guanethidine Blocks contraction of vas deferens which results in delayed
emission.
Selective serotonin reuptake inhibitors Stimulates central 5-HT2 receptors, which leads to emission
failure.
Trazodone Stimulates central serotonin receptors and causes peripheral
␣-adrenergic blockade, which leads to anejaculation.
Drug-Induced Priapism
Fat emulsion, intravenous Causes a hypercoagulable state.
Heparin
Warfarin
Phenothiazines24 ␣-Adrenergic blockade prevents detumescence of the penis
Clozapine
Risperidone
Quetiapine
Aripiprazole
Antidepressants, tricyclics
Trazodone ␣-Adrenergic blockade prevents
Selective serotonin reuptake detumescence of the penis. Central serotonin stimulation
inhibitors may also lead to low-flow priapism.
Bupropion
Hydralazine Arteriolar vasodilation increases blood flow to corpora
␣-Adrenergic antagonists cavernosa.
Papaverine Increases cyclic AMP in cavernosal tissue, which increases
Alprostadil blood filling of sinusoidal tissue.
Tadalafil Increases cyclic GMP in cavernosal tissue, which increases
Sildenafil blood filling of sinusoidal tissue.
Vardenafil
Drug-Induced Infertility
Antineoplastic agents Damages germinal epithelium in testes; sperm production is
impaired.
Estrogens Decrease serum testosterone concentration or block
Gonadotropin-hormone releasing hormone superagonists testosterone at receptors, which interferes with
Ketoconazole maturation of spermatagonia.
Spironolactone
Anabolic steroids Suppresses FSH and LH, which decreases sperm production
and maturation.
Cimetidine Blocks androgen receptor, which interferes with maturation
of spermatagonia.
Ethanol, chronic Decreases testosterone production, which interferes with
sperm maturation.
(Continued)
TisdaleC35_686-701 1/12/10 3:36 PM Page 694
Drugs Mechanism
Sulfasalazine Decreases sperm production, maturation, and motility.
Nitrofurantoin Inhibits sperm maturation and protein synthesis, which
interferes with sperm motility.
Erythromycin Decreases sperm motility and sperm number.
FSH = Follicle-stimulating Hormone; HT = Hydroxytryptamine; LH = Luteinizing hormone; AMP = Adenosine monophosphate; GMP =
Guanosine monophosphate
and the presence of adequate concentrations of libido present with a recent history of divorce, separa-
testosterone in the seminiferous tubules so that sper- tion from a loved one, death of a spouse, sudden job
matogonia can undergo differentiation and matura- loss, or performance anxiety. Patients with increased
tion into spermatozoa.94 Normal semen parameters libido usually do not come to the attention of a clini-
include a semen volume of 2 to 6 mL, a sperm con- cian unless the patient’s sexual desires are inappropri-
centration of at least 20 million per milliliter, at least ate, such as in precocious puberty.
50% to 60% motile sperm, and at least 30% of sperm Patients with erectile dysfunction present with
with normal morphology.94,95 Although variably failure to achieve a penile erection sufficient for
defined, infertility refers to the inability of the female vaginal penetration. Although periodic erectile
partner to become pregnant after 1 year or more of dysfunction is generally acceptable, a patient who
purposeful attempts to conceive.76 Infertility can be experiences erectile dysfunction in more than 50%
due to an inadequate number of sperm in the semen; of attempts at sexual intercourse should seek med-
abnormal sperm morphology, which interferes with ical treatment if he wishes to be sexually active.
their motility; or their ability to penetrate an egg. Patients with ejaculatory dysfunction may pres-
Thus, drug-induced infertility can result from dam- ent with a variety of symptoms, including prema-
age to the Sertoli cells (e.g., antineoplastic alkylating ture ejaculation, reduced ejaculation volume,
agents, radiation therapy), interference with the mat- retrograde ejaculation, delayed ejaculation, anejacu-
uration of sperm (e.g., antiandrogens), or motility of lation (no ejaculation), or emission failure. With
sperm (e.g., sulfasalazine, vaginal spermicides).14 The premature ejaculation, the patient ejaculates
extent of damage to the germinal epithelium by anti- within 1 minute of vaginal penetration or before cli-
neoplastic agents is dependent on the pharmacolog- max is reached, often rapidly followed by detumes-
ic class of agent used (alkylating agents are the most cence.44 A chief problem is spousal dissatisfaction
potent, followed by antimetabolites, vinca alkaloids, with the patient’s sexual performance. Alternatively,
procarbazine, and cisplatin), dose used (higher doses some patients report reduced ejaculatory volume.
cause worse damage than lower doses), combined Confirmation of the existence of the problem
use of alkylating agents (worse than monotherapy), requires measurement of ejaculatory volume prior
age of the patient (prepubertal males tend to be more to and after the supposed disorder developed, which
resistant to the effects of antineoplastic chemothera- is rarely performed in clinical practice. Thus, this is
py than adult patients), and combined use with radi- more often a subjective report by the patient. On
ation (worse than with chemotherapy alone). the other hand, in patients with retrograde ejacula-
tion, the patient usually reports “dry sex” and no
antegrade flow of seminal fluid during climax.
CLINICAL PRESENTATION AND Instead, during the first urine voiding after inter-
DIFFERENTIAL DIAGNOSIS course, the patient may produce cloudy urine,
which indicates the presence of seminal fluid in the
Symptoms of drug-induced sexual dysfunction in urine. The presence of sperm in the urine can be
males are similar to those of patients with dysfunc- confirmed by microscopic examination of a poste-
tion due to other causes (Table 35–7). With decreased jaculation urine sample. Anejaculation is a failure to
libido, patients may report no desire for or interest in ejaculate, which may be due to a disorder of emis-
sexual intercourse. Patients commonly profess to be sion or a delay in emission. The patient may present
busy with work, engaged in other activities, or to not similarly to those with retrograde ejaculation.
feel well, and use these as excuses for having no desire Patients with priapism often have a sickle cell
for sexual intercourse. Often, patients with decreased anemia or chronic granulocytic leukemia, use erec-
TisdaleC35_686-701 1/12/10 3:36 PM Page 695
performed to determine whether one specific treat- persistent drug-induced mutations to sperm, patients
ment is more effective than another. In addition, should be advised to delay conception for 6 months
implementation of drug therapy to treat a disease to 2 years after the last dose of chemotherapy.94,97,108
caused by another drug is never a preferred manage- Practitioners caring for patients with drug-
ment approach, as it adds to the patient’s drug costs induced sexual dysfunction should talk to these
and is usually associated with additional adverse patients, respond to their questions, and anticipate
effects. Pharmacotherapy for the purpose of treating their concerns. These cases must be handled with
sexual dysfunction induced by another drug should the utmost confidentiality. Counseling should take
be implemented only when other measures fail or place in a quiet, secure area. The practitioner should
are not feasible. Furthermore, a key component in project an attitude of caring and respect, and be
the treatment of patients with drug-induced sexual nonjudgmental in handling the patient’s issues.
dysfunction is replacing the causative agent with a Some patients find it difficult to discuss their con-
drug that is associated with a lower likelihood of cerns regarding drug-induced sexual dysfunction.
causing sexual dysfunction (Table 35–11). Practitioners can be helpful and proactive. For exam-
ple, pharmacists can initiate a follow-up consultation
session when refilling a prescription by stating, “This
INFORMATION FOR PATIENTS medication may cause changes to your sexual func-
tion when used in usual doses. Has this been a prob-
Practitioners who counsel patients with drug-induced lem for you?” Such a statement immediately puts the
sexual dysfunction should have a clear understanding patient at ease because the patient is reminded up
of the categories of sexual dysfunction, so there is no front that the problem is not unique and occurs com-
confusion in discussing the specific problem with the monly. Also, some patients who experience drug-
patient.105 Patients should be advised that drug- induced sexual dysfunction may refuse to continue to
induced sexual dysfunction (with the exception of take necessary medications. In this case, the pharma-
alkylating agent–induced infertility) is usually cist should discuss the benefits and risks of taking the
reversible following discontinuation of the culprit medication, notify the prescriber of the problem, and
drug. Patients who are taking drugs that may cause offer options for management of the patient’s primary
sexual dysfunction should be counseled regarding the problem and for his drug-induced sexual dysfunction.
specific type(s) of dysfunction that could occur and
the specific symptoms that may result. Patients
should be advised to implement lifestyle changes
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67. Klein EA, Montague DK, Steiger E. Priapism associated J Urol. 2006;13:1311-1316.
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and postulated pathogenesis. J Urol. 1985;133:857-859. does not change when serum testosterone levels are
68. Thomas A, Woodward C, Rover ES, et al. Urologic pharmacologically varied within the normal male range.
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North Am. 2003;30:123-131. 94. Schuster TG, Ohl DA. Diagnosis and treatment of
69. Bschleipfer TH, Hauck EW, Diemer TH, et al. Heparin ejaculatory dysfunction. Urol Clin North Am.
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70. Hashmat AI, Abrahams J, Fani K, et al. A lethal 95. Brugh VM, Lipshultz LI. Male factor infertility:
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1991;145:146-147. 2004;88:367-385.
71. Prasad K, el-Sherif A. Priapism following ingestion of 96. Rosen RC, Riley A, Wagner G, et al. The International
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72. Kotin J, Wilber DE, Verburg D. Thioridazine and sexual for assessment of erectile dysfunction. Urology
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73. King SH, Hallock M, Strote J, et al. Tadalafil-associated 97. Puscheck E, Philip PA, Jeyendran RS. Male fertility
priapism. Urology. 2005;66:432. preservation and cancer treatment. Cancer Treat Rev.
74. Sur RL, Kane CJ. Sildenafil citrate-associated priapism. 2004;30:173-180.
Urology. 2000;55:950. 98. Sadeghi-Nejad H, Seftel AD. The etiology, diagnosis, and
75. Kassim AA, Fabry ME, Nagel RL. Acute priapism treatment of priapism: review of the American
associated with the use of sildenafil in a patient with foundation for urologic disease consensus panel report.
sickle cell trait. Blood. 2000;95:1878-1879. Curr Urol Rep. 2002;3:492-498.
76. Javed MA. Priapism associated with fluoxetine therapy: a 99. Schrader M, Muller M, Straub B, et al. The impact of
case report. J Pak Med Assoc. 1996;46:45-46. chemotherapy on male fertility: a survey of the biologic
77. Rand EH. Priapism in a patient taking sertraline. J Clin basis and clinical aspects. Reprod Toxicol. 2001;15:611-617.
Psychiatry. 1998;59:538. 100. Bacon CG, Mittleman MA, Kawachi I, et al. Sexual
78. Mendelson WB, Franko T. Priapism with sertraline and function in men older than 50 years of age: results from
lithium. J Clin Psychopharmacol. 1994;14:434-435. the health professionals follow-up study. Ann Intern Med.
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complications of warfarin therapy: skin necrosis and 101. Litwin, MS, Nied RJ, Dhanani N. Health-related quality
priapism. J Pediatr. 2000;137:266-268. of life in men with erectile dysfunction. J Gen Intern Med.
80. Drife JO. The effect of drugs on sperm. Drugs 1998;13:159-166.
1987;33:610-622. 102. Ventegodt S. Sex and the quality of life in Denmark. Arch
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epilepsy and antiepileptic drugs on male reproductive 103. Berner MM, Hagen M, Kriston L. Management of sexual
health. Neurology. 2004;62:247-253. dysfunction due to antipsychotic drug therapy. Cochrane
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function in asymptomatic chronic alcoholics: relation to 105. Stimmel GL, Gutierrez MA. Counseling patients about
ethanol intake. Alcohol Clin Exp Res 1997;21:128-133. sexual issues. Pharmacotherapy. 2006;26:1608-1615.
84. Doelle GC, Alexander AN, Evans RM, et al. Combined 106. Althof SE, Levin SB, Corty EW, et al. A double blind
treatment with an LHRH agonist and testosterone in crossover trial of clomipramine for rapid ejaculation in
man: reversible oligospermia without impotence. J 15 couples. J Clin Psychiatry. 1995;56:401-407.
Androl 1983;4:298-302. 107. Waldinger MD, Berendsen HH, Block BF, et al. Premature
85. Nelson WO, Bunge RG. The effect of therapeutic dosages ejaculation and serotoninergic antidepressant-induced
of nitrofurantoin upon spermatogenesis in man. J Urol. delayed ejaculation: the involvement of the
1957;77:275. serotoninergic system. Behav Brain Res. 1998;92:111-118.
86. Albert PS, Mininberg DT, Davis JE. The nitrofurans as 108. Hayghe E, Matsuda T, Daudin M, et al. Fertility after
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clinical application. Br J Urol. 1975;47:459-462. study. Cancer. 2004;100:732-737.
TisdaleC36_702-726 1/20/10 11:46 PM Page 702
CHAPTER 36
Judith A. Smith
TABLE 36–1 Agents Implicated in Drug-Induced Gynecologic Diseases and Infertility in Women
Drug Incidence Level of Evidence
(see page xii for explanation)
1-36,a
OVARIAN HYPERSTIMULATION
Clomiphene citrate NK B
Gonadotropins NK B
Gonadotropin-releasing agonists NK B
Tamoxifen NK C
VULVOVAGINAL CANDIDIASIS37-42,b
Antibiotics (systemic) NK B
Corticosteroids NK C
Hormone-replacement therapy NK C
Oral contraceptives NK C
Tamoxifen NK C
VAGINAL BLEEDING DISORDERS: AMENORRHEA/OLIGOMENORRHEA55-61
Antiepileptic drugs 12–59% B
Antihypertensive agents NK C
Platinum analogues >60% B
Chlorambucil NK C
Alkylating agents >60% A
Danazol >50% C
Doxorubicin >60% B
Estrogen NK C
Etoposide >60% B
Goserelin NK C
Medroxyprogesterone NK C
Methyldopa NK C
Oral contraceptives NK C
Progesterone NK C
Spironolactone NK C
Tamoxifen NK C
Thalidomide NK C
VAGINAL BLEEDING DISORDERS: MENORRHAGIA/MENOMETRORRHAGIA81-88
Ginseng NK C
Human relaxin NK C
Levonorgestrol—intrauterine contraceptive devices 2–4% A
Methadone >50% B
Selective serotonin reuptake inhibitors <1% B
VAGINAL BLEEDING DISORDERS: DYSMENORRHEA102,c
Estrogen NK C
Oxytocin NK C
Progesterone NK C
Vasopressin NK C
(Continued)
TisdaleC36_702-726 1/20/10 11:46 PM Page 704
TABLE 36–1 Agents Implicated in Drug-Induced Gynecologic Diseases and Infertility in Women (Continued)
an capillaries into the peritoneal space.9 Drug- in similar symptoms, such as gastrointestinal compli-
induced ovarian hyperstimulation may be associated cations of ovarian cysts, endometriosis, and ectopic
with multiple nonspecific symptoms related to the pregnancy. Conditions to consider in the differential
accumulation of this peritoneal fluid and including diagnosis of ovarian hyperstimulation are presented
abdominal distention, pain or a pulling sensation in in Table 36–4.
the pelvis, nausea, vomiting, diarrhea, dyspnea, and
chest pain.4 In addition to enlargement of the ovary,
specific signs suggestive of ovarian hyperstimulation RISK FACTORS
include ascites, oliguria, tachycardia, and, in severe
cases, pleural effusion.6,11 These signs and symptoms Specific risk factors for the development of drug-
of drug-induced ovarian hyperstimulation must be induced ovarian hyperstimulation are not well-
differentiated from other conditions that may result established (Table 36–5). Younger patients tend to be
TisdaleC36_702-726 1/20/10 11:46 PM Page 705
TABLE 36–2 Mechanisms of Drug-Induced Gynecologic Diseases and Infertility in Women (Continued)
Drug Mechanism
Oral contraceptives Indirect inhibition of negative feedback loop of the
hypothalamic–pituitary pathway, decreasing FSH/LH
release and altering ovarian function
Progesterone Indirect inhibition of negative feedback loop of the hypothala-
mic–pituitary pathway, decreasing FSH/LH release and altering
ovarian function
Spironolactone Microvascular instability, inducing breakthrough bleeding
Tamoxifen Indirect inhibition of negative feedback loop of the hypothala-
mic–pituitary pathway, decreasing FSH/LH release and altering
ovarian function
Thalidomide Direct toxic effects on oocytes that halts ovulation, inducing
amenorrhea
VAGINAL BLEEDING DISORDERS: MENORRHAGIA/MENOMETRORRHAGIA81-88
Ginseng Unknown
Human relaxin Induction of vascular endothelial growth factor receptor
Levonorgestrol—intrauterine contraceptive devices Unknown; possible changes in prostaglandin concentrations in
uterine tissue
Methadone Unknown
Selective serotonin reuptake inhibitors Decreased clotting function
VAGINAL BLEEDING DISORDERS: DYSMENORRHEA102
Estrogen Rapid fluctuations in serum hormone concentrations;
Activation of inflammation cascade leading to pelvic
swelling and pain
Oxytocin Antidiuretic effect that alters uterine contractions to dysrhyth-
mic and painful pattern
Progesterone Rapid fluctuations in serum hormone concentrations;
Activation of inflammation cascade leading to pelvic
swelling and pain
Vasopressin Antidiuretic effect that alters uterine contractions to dysrhyth-
mic and painful pattern
SEXUAL DYSFUNCTION109-112, 117-122
Antiepileptic drugs Increase serum concentrations of hormone-binding globulin,
decreasing estradiol binding and altering the
hypothalamic–pituitary axis regulation of hormone release
Antihypertensive agents Decrease vaginal lubrication; Decrease libido via
antiandrogenic and antidopaminergic activity
Antidepressants Loss of libido and orgasm dysfunction by altering central sero-
tonergic activity that disrupts hypothalamic–pituitary axis regu-
lation of hormone release
Antipsychotics Elevate prolactin concentrations via inhibition of
dopamine-2 receptors which decreases libido and
disrupts orgasms
Amphetamines Loss of libido and orgasm dysfunction by altering central sero-
tonergic and dopaminergic activity and, indirectly, hypothalam-
ic–pituitary axis regulation of hormone release
(Continued)
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TABLE 36–2 Mechanisms of Drug-Induced Gynecologic Diseases and Infertility in Women (Continued)
Drug Mechanism
Bromocriptine Elevates prolactin concentrations, which decreases libido
and disrupts orgasms
Cimetidine Antiandrogenic effects
Digoxin Disrupts hypothalamic–pituitary axis regulation of hormone
release
Granisetron Unknown
Indinavir Unknown
Ketamine Unknown; Possible dissociation effects, altered muscle tone
Methadone Decrease in lutenizing hormone production and subsequent
testosterone concentrations
Methazolamide Unknown
Naproxen Unknown
Norethandrolone Disrupts hypothalamic–pituitary axis regulation of hormone
release
INFERTILITY131-144
Alkylating agents Direct toxic effect on oocytes, permanently halt ovulation
Antiepileptic drugs Increase serum concentrations of hormone binding
globulin decreasing estradiol binding and decreasing/
halting ovarian function
Anthracyclines Direct toxic effect on oocytes, permanently halt ovulation
Bleomycin Direct toxic effect on oocytes, permanently halts ovulation
Caffeine Unknown
Etoposide Direct toxic effect on oocytes, permanently halts ovulation
Fluorouracil Direct toxic effect on oocytes, permanently halts ovulation
Methotrexate Direct toxic effect on oocytes, permanently halts ovulation
Platinum analogues Direct toxic effect on oocytes, permanently halts ovulation
Thalidomide Direct toxic effect on oocytes, permanently halts ovulation
Vinca alkaloids Direct toxic effect on oocytes, permanently halts ovulation
LH = Luteinizing Hormone
FSH = Follicle-stimulating Hormone
at higher risk because they have a larger number of significant sequelae. However, severe cases of drug-
recruitable follicles and gonadotropin receptors.11,12 induced ovarian hyperstimulation and those which
Although some data suggest that women with a his- are diagnosed late can be life-threatening.4 In the
tory of polycystic ovarian syndrome may have an short term, the fluid shifts can result in significant
increased risk for drug-induced ovarian hyperstimu- ascites, intravascular volume depletion, and pleural
lation, in most cases this drug-induced disease is not effusion that may lead to significant breathing diffi-
predictable.13-16 Repeated or prolonged cycles as well culties and, in rare cases, acute respiratory distress
as high doses of clomiphene citrate and syndrome. Ascitic fluid can put pressure on the infe-
gonadotropins contribute to an increased risk of rior vena cava and lead to decreased cardiac output.4
drug-induced ovarian hyperstimulation.17-21 Severe cases of drug-induced ovarian hyperstimula-
tion have been associated with significant throm-
boembolic events.5,6 In addition, patients are at risk
MORBIDITY AND MORTALITY of ovarian torsion or cyst rupture that may lead to
potentially fatal hemorrhage.5,6 Ovarian hyperstimu-
Early or mild drug-induced ovarian hyperstimulation lation associated with fertility drugs may be associat-
typically resolves without intervention and with no ed with the development of ovarian cancer.18-29
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TABLE 36–3 Signs and Symptoms Associated TABLE 36–4 Conditions to Consider in the
with Drug-Induced Gynecologic Diseases and Differential Diagnosis of Drug-Induced
Infertility in Women Gynecologic Diseases and Infertility in Women
Ovarian hyperstimulation Ovarian hyperstimulation
• Abdominal distention • Endometriosis
• Ascites • Ectopic pregnancy
• Chest pain • Ovarian cysts
• Diarrhea Vulvovaginal candidiasis
• Dyspnea • Bacterial vaginosis
• Enlargement of ovary
• Chlamydia
• Nausea and vomiting
• Pelvic pain • Gonorrhea
Vulvovaginal candidiasis • Trichomoniasis
• Dyspareunia • Urinary tract infection
• Vaginal erythema Vaginal bleeding disorders
• Vaginal pruritus • Amenorrhea and oligomenorrhea
• Vaginal swelling (edema) • Anorexia nervosa
• White, curd-like vaginal discharge • Endocrine disorders
Vaginal bleeding disorders • Excessive physiological stress
• Amenorrhea and oligomenorrhea • Excessive psychological/emotional stress
• Decreased cervical mucus • Hypothalamus tumor
• Dyspareunia • Metabolic disorders
• Irregular menses • Pituitary tumor
• Irritability • Menorrhagia and menometrorrhagia
• Mood swings
• Abnormal endometrial hyperplasia
• No menses
• Vaginal dryness • Endometrial cancer
• Vaginal wall thinning • Endometriosis
• Menorrhagia and menometrorrhagia • Fibroids
• Heavy menses (>80 mL) • Uterine polyps
• Irregular menses • Dysmenorrhea
• Prolonged menses • Premenstrual syndrome
• Uterine fibroids Sexual dysfunction
• Uterine polyps • Anxiety/anger or fear
• Dysmenorrhea • Depression
• Abdominal cramping • Dyspareunia
• Backache • Fatigue
• Bloating Infertility
• Breast tenderness • Early menopause
• Fatigue
• Endocrine disorder
• Headache
• Mood changes • Metabolic disorder
• Nausea
• Pelvic pain
• Syncope
• Vomiting PREVENTION
Sexual dysfunction
• Anger or fear A few measures may prevent drug-induced ovar-
• Anxiety ian hyperstimulation, including suspending the
• Dyspareunia treatment cycle, extending the interval between
• Fatigue treatments, planning early follicular aspiration,
• Loss of libido or desire (may present as depression) and administration of albumin or concomitant
• Vaginismus progesterone therapy3,5,6 (Table 36–6). Patients
Infertility should be monitored closely while undergoing
• Frequent/recurrent miscarriages any type of ovarian stimulation therapy with
• Inability to conceive
serum estradiol concentrations obtained and
• Irregular menses
ultrasound performed at baseline and at least
• No menses
once after each treatment cycle; if serum estradi-
TisdaleC36_702-726 1/20/10 11:46 PM Page 709
TABLE 36–5 Risk Factors for Drug-Induced TABLE 36–6 Approaches to Help Prevent Drug-
Gynecologic Diseases and Infertility in Women Induced Gynecologic Diseases and Infertility in
Women
Ovarian hyperstimulation
• Polycystic ovarian syndrome Ovarian hyperstimulation
• Younger age • Add progesterone to treatment cycle.
Vulvovaginal candidiasis • Extend interval between treatment cycles.
• Diabetes • Monitor serum estradiol concentrations.
• Heat/moisture • Perform pelvic ultrasound.
• History of vulvovaginal candidiasis • Plan early follicular aspiration.
• Suspend treatment cycle.
• Obesity
Vulvovaginal candidiasis
• Pregnancy • Consume acidophilus/yogurt with activated cultures.
• Tight clothing • Douche with vinegar/water, yogurt, or potassium sor-
Vaginal bleeding disorders bate to restore acidic pH.
• Amenorrhea and oligomenorrhea • Take prophylactic antifungal treatment when taking
• Advancing age systemic antibiotics.
• Anorexia • Wear loose clothing and cotton undergarments.
• Excessive exercise • Wipe away from vulvovaginal area after bowel move-
• Perimenopause ment.
• Poor nutritional status Vaginal bleeding disorders
• Psychological (i.e., work/family/school) stress • Amenorrhea and oligomenorrhea
• Menorrhagia and menometrorrhagia • Eat a well-balanced diet and exercise.
• Unknown • Monitor the duration and frequency of menses
• Dysmenorrhea episodes.
• Preserve ovarian function during cytotoxic expo-
• Early menarche
sure (i.e., oral contraceptives).
• Family history • Menorrhagia and menometrorrhagia
• Heavy menses • Avoid aspirin use.
• High omega-6 fatty acid diets • Monitor for early indirect signs/symptoms.
Sexual dysfunction • Anemia
• Depression • Monitor for low hemoglobin
• Hypogonadism • Monitor serum iron concentrations
• Hypothyroidism • Use iron-replacement therapy.
• Hysterectomy • Increasing duration of menses
• Oophorectomy • Consider use of oral contraceptives to reduce
• Schizophrenia irregular bleeding
• Vulvovaginal resection • Dysmenorrhea
Infertility • Avoid uterine stimulants (oxytocin, vasopressin).
• Autoimmune diseases • Prophylactic use of antiinflammatory agents
(nonsteroidal antiinflammatory drugs, cyclooxy-
• Endocrine disorders
genase-2 inhibitors).
• Epilepsy Sexual dysfunction
• Older age • Identify and manage contributing symptoms (i.e.,
vaginal dryness)
• Offer alternative drug therapy options.
• Provide education to prepare patient.
ol concentrations increase rapidly at any time • Provide resources for development of communica-
during the treatment or if ultrasound reveals tion/coping skills for couples.
massive follicle recruitment, one of the interven- Infertility
tions described above should be undertaken to • Counsel patient and provide support resources.
prevent the development of drug-induced ovari- • Decrease consumption of caffeine-containing bev-
an hyperstimulation.30 In patients at increased erages.
risk for drug-induced ovarian hyperstimulation, • Offer interventions prior to initiation of offending
a lower dose of hCG (5000 IU instead of the agent.
standard 10,000 IU) may be administered. • Oocyte collection
• Frozen embryos
Alternatively, exogenous progesterone (50 mg
• Provide patient education.
intramuscularly, 100 mg intravaginal supposito-
• Consider use of oral contraceptives to halt ovu-
ry, or 8% intravaginal gel) may be administered lation during treatment with offending agent.
in place of additional doses of hCG to support
TisdaleC36_702-726 1/20/10 11:46 PM Page 710
the luteal phase.30,31 Another option is the intra- sis may be used, if necessary, to remove ascites fluid
venous administration of 25% albumin during to alleviate pelvic pain and dyspnea. Because these
follicular aspiration; however, the effectiveness patients are at risk for thromboembolic events,
of this approach for prevention of drug-induced anticoagulation therapy with heparin (5,000 U
ovarian hyperstimulation has been variable.30,32-34 subcutaneously every 12 hours) or low-molecular-
weight heparin (e.g., enoxaparin 40 mg subcuta-
neously once daily) with or without sequential
MANAGEMENT compression device therapy should be considered
for the duration of the patient’s confinement to
Treatment options for drug-induced ovarian hyper- bed. Surgical interventions may be required to pre-
stimulation are described in Table 36–7. Mild cases vent ovarian torsion or cyst rupture that may lead
in which patients present with some discomfort to intraperitoneal hemorrhage.4
and for which the only physical finding is mild When drug-induced ovarian hyperstimulation
abdominal distention will resolve without any is detected early and interventions and treatment
intervention.4 Fluid shifts can occur because of sig- can be performed on an outpatient basis, symp-
nificant ascites, intravascular volume depletion, toms usually resolve within 1 week.6 In moderate
and pleural effusions. To help prevent progression to severe cases, patients typically require hospital-
and adverse sequelae related to these fluid shifts, ization, and complete symptom resolution may
patients should be instructed to increase fluid take 10 days or more.6,36
intake. Patients with moderate drug-induced ovar-
ian hyperstimulation often present with increasing
abdominal girth, pain, nausea and vomiting, diar- INFORMATION FOR PATIENTS
rhea, shortness of breath, or any combination of
these. Moderate ovarian hyperstimulation can be Patients should be informed that while undergoing
treated on an outpatient basis, but close monitor- ovarian-stimulation therapy, they should be close-
ing and follow-up is required. These patients ly monitored by their physician. Patients should be
should be instructed to increase oral hydration and told that if symptoms such as abdominal discom-
may benefit from a short course of intravenous fort, shortness of breath, diarrhea, nausea, or vom-
hydration. Outpatients with moderate drug- iting occur, they should seek medical attention
induced ovarian hyperstimulation should be on immediately.
strict bed rest and should monitor oral intake,
weight, and urine output. Short term use of
antiemetic agents and analgesics can be used to
alleviate nausea and mild pelvic pain. The admin- VULVOVAGINAL CANDIDIASIS
istration of a gonadotropin-releasing–hormone
agonist (intramuscular leuprolide 7.5 mg once CAUSATIVE AGENTS
monthly) has been reported to be successful for the
treatment of tamoxifen-induced ovarian hyper- Drug-induced vulvovaginal candidiasis most often
stimulation.35 results from the use of systemic antibiotics that
Patient with life-threatening cases of ovarian alter the normal flora of the vaginal canal allowing
hyperstimulation present with significant ascites, for an overgrowth of Candida species. Drugs asso-
intravascular volume depletion, possible pleural ciated with drug-induced vulvovaginal candidiasis
effusions, severe hemoconcentration, potential are listed in Table 36–1.37–42
renal failure, risk for acute respiratory distress syn-
drome, or thromboembolic events. Hospital admis-
sion with immediate interventions is often EPIDEMIOLOGY
required. Aggressive intravenous fluid hydration is
required in patients with severe cases of drug- Vaginal symptoms are one of the most common
induced ovarian hyperstimulation characterized by reports of women during annual gynecologic office
dehydration with a hematocrit >45%.4 The rate of visits.42 Approximately 17% to 39% of these office
infusion should be adjusted to maintain urine out- visits are associated with cases of vulvovaginal can-
put >30 mL/hr. All diuretics, antihistamines, didiasis.43,44 The majority of women (>75%) experi-
angiotensin-converting enzyme inhibitors, and ence at least one case of vulvovaginal candidiasis
nonsteroidal antiinflammatory drugs (NSAIDs) during their lifetime and many (up to 50%) suffer
should be discontinued and avoided. Once the from recurrent or persistent cases of vulvovaginal
patient’s condition has been stabilized, paracente- candidiasis.42,45
TisdaleC36_702-726 1/20/10 11:46 PM Page 711
IM = Intramuscularly; IV = Intravenously; SC = subcutaneously; supp = vaginal suppository; SSRI = Selective serotonin reuptake inhibitor;
NSAID = Non-steroidal antiinflammatory drugs.
the vaginal canal and spreads to the vulva. The modification, such as wearing loose clothing and
vulva and vaginal tissue may develop erythema, cotton undergarments and wiping away from the
edema, or both because of local irritation and vulvovaginal area after bowel movements, can
inflammation. The onset of signs or symptoms of help prevent episodes of drug-induced disease.52 It
drug-induced vulvovaginal candidiasis varies. As has been suggested that consuming yogurt with
the infection progresses, symptoms increase and live bacteria or taking lactobacillus acidophilus
patients may report burning, soreness, and dys- capsules to maintain the balance of the normal
pareunia. flora in the vaginal tract may prevent drug-induced
When a patient presents with these vaginal vulvovaginal candidiasis infections.41 Patients with
symptoms, a vaginal smear (culture) should be a history of vulvovaginal candidiasis may choose
obtained to determine whether the symptoms are to eat yogurt “with activated cultures” when initi-
a result of bacterial vaginosis, trichomoniasis, or ating antibiotic therapy to help prevent drug-
candidiasis.51 Urinary tract infections should also induced vulvovaginal candidiasis. Therapy with
be ruled out. Patients are often tested for gonor- vitamin C (250 mg intravaginally for 6 days),
rhea or chlamydia, although neither has been which is available by prescription, may increase
closely associated with vaginal discharge.50,51 Table vaginal secretions and reduce infection53 and may
36–4 describes the conditions that should be con- help prevent drug-induced vulvovaginal candidia-
sidered in the differential diagnosis of drug- sis. Douching with vinegar and water, yogurt, or
induced vulvovaginal candidiasis. potassium sorbate may help prevent reinfection by
restoring the acidic pH to the vulvovaginal canal.41
For patients who routinely experience episodes
RISK FACTORS of vulvovaginal candidiasis when taking systemic
antibiotics, prophylactic antifungal treatment
A number of factors have been identified that pre- should be considered. Preventive treatment should
dispose women to drug-induced vulvovaginal can- be initiated simultaneously with the first dose of
didiasis (Table 36–5). These include comorbid antibiotics.45 A topical azole drug (miconazole,
diseases or conditions, including diabetes, obesity, clotrimazole, ticonazole, terconazole) may be
and pregnancy.46 Environmental factors such as administered for 3 to 7 days as indicated, or two
increased moisture and heat or tight clothing may doses of fluconazole 150 mg may be administered
also increase a women’s risk of drug-induced vulvo- 72 hours apart.47 Measures for prevention of drug-
vaginal candidiasis.52 Sexual intercourse has not induced vulvovaginal candidiasis may improve
been reported as a means of transmission of vulvo- adherence to and completion of prescribed antibi-
vaginal candidiasis.45 otic regimens.44,52
MANAGEMENT
MORBIDITY AND MORTALITY
Drug-induced vulvovaginal candidiasis can be
The majority of episodes of drug-induced vulvo- effectively treated with antifungal topical cream or
vaginal candidiasis are uncomplicated. In these vaginal suppositories administered for 1, 3, 7, or up
cases, symptoms resolve within 48 to 72 hours fol- to 14 days in severe cases when symptoms do not
lowing initiation of appropriate therapy. resolve after one course of treatment (Table
Uncomplicated vulvovaginal candidiasis is not 36–7).45 The most common topical antifungal
associated with morbidity. However, approximate- agents used in the treatment of vulvovaginal can-
ly 10% of cases of vulvovaginal candidiasis are didiasis include miconazole and clotrimazole, both
more severe and are associated with significant ery- of which are available without a prescription, and
thema, edema, pruritus, and dyspareunia. Left terconazole, which is currently available by pre-
untreated, drug-induced vulvovaginal candidiasis scription only.47 For both prescription and nonpre-
eventually resolves after the restoration of normal scription topical regimens, the recommended
vulvovaginal flora. duration of treatment ranges from 1 to 7 days,
depending on the dose and strength of the agent
selected. The treatment cycle may be repeated if
PREVENTION symptoms persist after one course. Another effec-
tive option is a single 150 mg oral dose of flucona-
Methods to prevent drug-induced vulvovaginal zole. This treatment approach also requires a
candidiasis are described in Table 36–6. Behavior prescription.45 The strategies discussed above for
TisdaleC36_702-726 1/20/10 11:46 PM Page 713
prevention of drug-induced vulvovaginal candidia- orrhea and oligomenorrhea are often symptoms of
sis may also have some benefit for treatment. more complex endocrine, gynecologic, or metabolic
Patients with significant erythema, edema, and disorders.70 Intermenstrual bleeding, often described
local irritation may require more prolonged treat- as “breakthrough bleeding,” is bleeding that occurs
ment (up to 14 days) to achieve a complete between regular menses and is usually associated
response and eradication of all symptoms.45,51 with nonadherence with oral contraceptives or
Although topical therapy provides more immedi- inadequate doses of oral contraceptives based on
ate relief of symptoms as compared with oral treat- endogenous, baseline hormone concentrations that
ment, either route will successfully eradicate may vary between individuals.70,71
vulvovaginal candidiasis.45,51,54 Antiepileptic drugs such as phenytoin, valproic
acid, and carbamazepine alter various aspects of
endocrine function, although endocrine dysfunc-
INFORMATION FOR PATIENTS tion has itself been associated with epilepsy. From
12% to 59% of women receiving antiepileptic
Patients can reduce the risk of drug-induced vulvo- drugs experience amenorrhea/oligomenorrhea.75
vaginal candidiasis by wearing loose clothing and More than 60% of women receiving cytotoxic
cotton undergarments to limit excessive moisture chemotherapy have experienced one or more
to the vulva area.51 Exposure to the Candida organ- symptoms of ovarian failure.64 The incidence of
isms can be minimized if patients remember to amenorrhea/oligomenorrhea associated with other
wipe away from the vulva area after a bowel move- drugs is unknown, as the evidence is published pri-
ment.51 Patients should seek medical attention for marily in the form of case reports.
diagnosis of their first vulvovaginal candidiasis
infection.44,45 However, patients with recurrent Mechanisms
drug-induced vulvovaginal candidiasis infections
should learn to recognize the symptoms and begin Drugs can affect uterine function through direct
early self-treatment with nonprescription medica- effects on the endometrium, such as causing
tions.41,44 microvascular instability that leads to break-
through bleeding.71 Antineoplastic drugs exert a
direct toxic effect on oocytes, decreasing follicular
VAGINAL BLEEDING DISORDERS formation and halting ovulation, leading to amen-
orrhea.56 Drugs can also indirectly inhibit the neg-
AMENORRHEA AND ative feedback loop of the hypothalamic–pituitary
pathway via modulation of serum hormone con-
OLIGOMENORRHEA centrations. This leads to decreased FSH and LH
release, resulting in decreased ovarian function and
Causative Agents induction of amenorrhea/oligomenorrhea.68-74
Agents that alter hormone balance directly or indi- Antiepileptic drugs such as phenytoin and car-
rectly are associated with drug-induced amenor- bamazepine have been reported to increase serum
rhea (cessation of menses), oligomenorrhea concentrations of hormone-binding globulin,
(irregular menses), or intermenstrual bleeding.55-61 resulting in decreased binding of estradiol, leading
Drugs that are known to be toxic to actively divid- to amenorrhea/oligomenorrhea.75-79 The mecha-
ing cells may induce premature or temporary ovar- nism of valproic acid–induced amenorrhea is not
ian failure that presents as drug-induced well understood, but it is thought to be related to
amenorrhea/oligomenorrhea.56 For example, drug- weight gain, elevated serum insulin concentra-
induced amenorrhea is an unfortunate long term tions, and decreased serum concentrations of
consequence of chemotherapy used to treat cancer insulin-like growth factor I, leading to decreased
and autoimmune disorders such as systemic lupus ovarian androgen synthesis.75,79-81 Mechanisms of
erythematosus.62-67 Other agents may affect drug-induced amenorrhea and oligomenorrhea are
microvascular stability or hormone production/ described in Table 36–2.55-61
release, causing drug-induced amenorrhea/oligo-
menorrhea (Table 36–1).55-61
Clinical Presentation
and Differential Diagnosis
Epidemiology Patients with drug-induced amenorrhea/oligomen-
A menstruation disorder is often the primary reason orrhea present with no menses or irregular bleed-
for a woman to seek medical attention. Both amen- ing. These symptoms may occur at any time after
TisdaleC36_702-726 1/20/10 11:46 PM Page 714
therapy with the causative drug is initiated. chemotherapy.60,61,64,83 The use of oral contracep-
Amenorrhea is a common presenting symptom of tives or GnRH-a during courses of cytotoxic
ovarian failure, and is typically not the only symp- chemotherapy has demonstrated some benefit in
tom that patients may experience related to the the prevention of drug-induced ovarian
hormonal imbalances. Other symptoms include failure/amenorrhea; this preventive strategy is suc-
mood swings, irritability, vaginal dryness, dyspare- cessful primarily in younger patients.60,61,80 GnRH-
unia, decreased cervical mucus, and thinning of a has shown limited benefit for the prevention of
the vaginal mucosa (Table 36-3).53 chemotherapy-induced amenorrhea/ovarian fail-
Drug-induced amenorrhea/oligomenorrhea ure in perimenopausal women.60,61 Maintenance of
must be distinguished from other causes, including a well-balanced diet with regular exercise may help
endocrine disorders, metabolic disorders, anorexia reduce the risk of developing drug-induced amen-
nervosa, pituitary or hypothalamus tumors, or orrhea/oligomenorrhea (Table 36–6).
excessive psychological or emotional stress (Table
36-4).60
Management
Treatment options for drug-induced amenorrhea/
Risk Factors oligomenorrhea vary depending on the causative
Women who have advanced in age to the peri- agent. Drug-induced amenorrhea/oligomenorrhea
menopausal stage are more susceptible to drug- associated with the use of progesterone implants
induced amenorrhea/oligomenorrhea.55 The can be reversed by discontinuation of the implant
probability of permanent chemotherapy-induced and selection of an alternative contraceptive agent,
amenorrhea or menopause increases proportional- such as oral contraceptives, or use of alternative
ly with advancing age.55 Poor nutritional status modes of contraception such as barrier meth-
caused by crash diets or anorexia nervosa can also ods.66,72 Breakthrough bleeding can be decreased
influence the susceptibility to drug-induced amen- by encouraging better patient adherence or use of
orrhea/oligomenorrhea.60 Physiologic stress such oral contraceptive agents with higher estrogen
as excessive exercise (i.e., marathon training pro- content (up to 50 mcg ethinyl estradiol).60 Once
grams) and psychological stress (i.e., anxiety, the causative agent is discontinued or doses modi-
work/school/family pressure) also increases the risk fied, drug-induced amenorrhea/oligomenorrhea
of drug-induced amenorrhea/oligomenorrhea usually resolves within 4 to 6 weeks (Table 36–7).
(Table 36–5).60 GnRH-a (e.g., leuprolide 7.5 mg intramuscular-
ly once monthly) may promote the reversal of
chemotherapy-induced amenorrhea/ovarian fail-
Morbidity and Mortality ure in some younger patients.61,64,80 However,
Drug-induced amenorrhea/oligomenorrhea is not because chemotherapy-induced amenorrhea (ovar-
associated with increased mortality but can signifi- ian failure) is often permanent, in most cases it is
cantly impact quality of life. Drug-induced amen- advisable to discuss alternative options to compen-
orrhea/oligomenorrhea may interfere with the sate for future infertility, such as cryopreservation
ability to plan conception as well as to conceive of embryos, unfertilized ova, or ovarian tissue
and can be associated with numerous other unde- before chemotherapy administration.60
sirable symptoms that interfere with daily activities
and relationships, including vaginal dryness,
moodiness, and painful intercourse.53,60,70 Drug-
Information for Patients
induced amenorrhea/oligomenorrhea may disguise Patients receiving drugs that may induce amenor-
underlying gynecologic and endocrine conditions rhea or oligomenorrhea should be counseled that
requiring medical evaluation, including polycystic amenorrhea is the absence of menstrual bleeding
ovarian syndrome and hypothyroidism.60,82 and oligomenorrhea is the presence of
infrequent/irregular menstrual cycles, and that if
these symptoms occur they should be evaluated by
Prevention a health care provider. Patients who will be receiv-
No specific studies have addressed the prevention ing cancer chemotherapy agents that may cause
of drug-induced amenorrhea/oligomenorrhea. Oral amenorrhea and ovarian failure should be
contraceptives and gonadotropin-releasing hor- informed of the potential for occurrence of this
mone (GnRH)-a inhibit ovarian function, primari- drug-induced disease and that options for future
ly ovulation, which, in theory, decreases child-bearing should be discussed before
susceptibility to the gonadotoxic effects of chemotherapy administration.64,65,80,81
TisdaleC36_702-726 1/20/10 11:46 PM Page 715
vent recurrent episodes of bleeding in patients dence and magnitude of drug-induced dysmenor-
with a history of menorrhagia/menometrorrha- rhea is unknown. It is possible that dysmenorrhea
gia.98 Avoidance of other platelet-inhibiting agents has been overlooked as a drug-induced condition,
such as aspirin, may decrease the risk of drug- and occurrences therefore may be under-reported.
induced menorrhagia or menometrorrhagia (Table
36–6).97
Mechanisms
Dysmenorrhea occurs often with normal ovulation
Management because of the release of arachidonic acid, which
Drug-induced menorrhagia can be effectively treat- promotes release of prostaglandins and
ed with combination oral contraceptive therapy. leukotrienes, initiating inflammation that pro-
Product selection is generally based on patient and duces cramps, bloating, and abdominal discom-
physician preference.86,96 Patients who have had fort.102 Elevations occur in serum concentrations of
menorrhagia for an extended time may also prostaglandin-2␣, which is an active metabolite of
require iron-replacement therapy until the hemo- arachidonic acid that mediates vasoconstriction
globin concentration returns to normal. In and uterine contractions which can result in
patients with IUDs, therapy with the antioxidant cramping.102 Drug-induced dysmenorrhea associat-
vitamin E (100 IU once every other day for 14 days) ed with the administration of the combination of
has been successful in attenuating menorrhagia.83 oxytocin and vasopressin occurs as a result of vaso-
Drug-induced menometrorrhagia can be effectively pressin-related antidiuretic effects that alter the
treated with GnRH agonists such as leuprolide (7.5 uterine contractions stimulated by oxytocin into a
mg intramuscularly once monthly) or goserelin dysrhythmic and painful pattern (Table 36–2).101
(3.6 mg intramuscularly once monthly).94,96 When The mechanism of estrogen- and progesterone-
a patient is experiencing drug-induced menorrha- induced dysmenorrhea is not well understood. It
gia or menometrorrhagia, the risks and benefits of has been suggested that the rapid fluctuations in
discontinuation of the causative agent should be serum hormone concentrations, primarily proges-
weighed. If the causative agent is discontinued, it terone withdrawal, activates the inflammation cas-
may take up to 3 months for symptoms to resolve cade, causing pelvic congestion (swelling) and
completely. contributing to the development of dysmenorrhea
(Table 36–2).103,104
Information for Patients
Patients receiving drugs that may cause menorrha-
Clinical Presentation
gia or menometrorrhagia should be counseled that
and Differential Diagnosis
heavy or prolonged menstrual cycles (at regular or Dysmenorrhea is a pelvic pain that occurs in rela-
irregular intervals) may occur and that this should tionship to menses. It is associated with a variety of
prompt them to seek medical attention. symptoms, including nausea, vomiting, diarrhea,
bloating, headache, backache, syncope, dizziness,
breast tenderness, abdominal cramping, mood
changes, nervousness, and fatigue (Table 36–3).
DYSMENORRHEA Symptoms typically present within 24 to 48 hours
before menstruation begins and usually continue
Causative Agents for 48 to 72 hours after menstruation com-
Drug-induced dysmenorrhea is associated with mences.101 Drug-induced dysmenorrhea must be
agents such as oxytocin, which is a known uterine distinguished from other causes of dysmenorrhea.
stimulant, and vasopressin (antidiuretic hormone), Pelvic pain with menses can be a natural physio-
a known vasoconstrictor (Table 36–1).102 Estrogen logic occurrence in association with ovulation or
and progesterone are also believed to be associated premenstrual syndrome or may have other primary
with some cases of drug-induced dysmenorrhea. or secondary causes, including adverse effects of
100,101
drugs (Table 36–4).101,102
Management EPIDEMIOLOGY
Management of drug-induced dysmenorrhea
should be individualized to the patient’s pain Drug-induced sexual dysfunction in women is
threshold, contraception goals, and overall health often underreported, but is one of the contributing
status. NSAIDs (e.g., ibuprofen 400 to 800 mg once factors to nonadherence to prescribed pharma-
every 6 hours) or COX-2 inhibitors (e.g., celecoxib cotherapy and decreased quality of life.111 It is dif-
200 mg once daily) are effective for alleviation of ficult to distinguish drug-induced sexual
pain, and therapy should be continued until the dysfunction from the effects of specific diseases on
end of menses (Table 36–7).102,105 In patients with sexual function. This is especially true with psychi-
lower pain thresholds, short term use of combina- atric disorders, where the disease itself has pro-
tion opioid products can be considered.103,105 found effects on social and sexual function.112
Acetaminophen is not as effective in controlling Since the success of sildenafil and similar drugs for
the inflammation and symptoms associated with the treatment of erectile dysfunction, there has
dysmenorrhea.106 been increased attention to the incidence of drug-
induced sexual dysfunction.112 Antidepressants
have been associated with decreased libido and
Information for Patients sexual dysfunction, with an incidence in women
Patients taking medications that may cause dys- ranging from 16.3% to 57%.113-115 Antipsychotic
menorrhea should be informed of the possibility agents such as haloperidol, risperidone, and thior-
and should be instructed to take antiinflammatory idazine have been associated with a 28% to 93%
medications at the first symptoms. Prompt treat- incidence of drug-induced sexual dysfunction in
ment will help control the pain and can prevent women.116-121 Antiretroviral agents are associated
the development or more significant discomfort. with an incidence of drug-induced sexual dysfunc-
Patients should take NSAIDs with food to avoid tion of 40%.110 The incidence of drug-induced sex-
development of gastrointestinal distress. Patients ual dysfunction associated with the use of
with sulfa allergies should avoid the use of COX-2 antihypertensive agents in women is approximate-
inhibitors. ly 11%.122
TisdaleC36_702-726 1/20/10 11:46 PM Page 718
cytotoxic chemotherapy regimen. However, lower infections.146-148 Epilepsy also has been associated
doses of these same cytotoxic agents are used in with an increased risk for endocrine disorders
treatment of systemic lupus erythematosus or resulting in infertility (Table 36–5).149
other autoimmune disorders and can cause drug-
induced infertility in these situations as well. In
addition, the prevalent use of caffeine in today’s MORBIDITY AND MORTALITY
society could put many women at risk for
reversible drug-induced infertility. As with drug-induced sexual dysfunction, the
physical complications of drug-induced infertility
are not life-threatening. However, finite and pre-
MECHANISMS dictable infertility can be associated with signifi-
cant psychological stress reflected in a diminished
Antineoplastic drugs have a direct toxic effect on mental health (i.e., depression, reduced self-
oocytes, decreasing follicular formation and halt- esteem) and quality of life associated with relation-
ing ovulation resulting in permanent drug-induced ships with partners, family, and friends.
infertility.56 This also leads to decreased FSH and
LH release, resulting in decreased ovarian function
and induction of infertility.68–74 The class of
antiepileptic drugs has been reported to increase
PREVENTION
the serum concentration of hormone-binding
Drug-induced infertility associated with caffeine
globulin, resulting in decreased binding of estradi-
can be prevented simply by reducing or eliminat-
ol, which can result in drug-induced infertility.75-79
ing the frequent consumption of caffeine-contain-
The mechanism of drug-induced infertility is not
ing beverages and medications. Patients will find
as well understood for caffeine (Table 36–2).
that fertility is regained within months after the
discontinuation of caffeine consumption.
Permanent drug-induced infertility is less likely to
CLINICAL PRESENTATION AND be prevented. Some studies have suggested the use
DIFFERENTIAL DIAGNOSIS of oral contraceptives during chemotherapy in
younger patients may help prevent permanent
Drug-induced infertility associated with cytotoxic drug-induced infertility by temporarily halting
agents is fairly easy to recognize, since it is associ- ovulation.144 Another pharmacologic option that
ated with a majority of these drugs. Conversely, the has been proposed, although still controversial, is
diagnosis of reversible drug-induced infertility the prophylactic use of GnRH analogs to prevent
associated with caffeine is more difficult to estab- permanent drug-induced infertility (Table
lish and requires a detailed medication and diet 36–6).61,150,151
history. The obvious and primary symptoms of
drug induced infertility include inability to con-
ceive and/or frequent miscarriages (Table 36–3). MANAGEMENT
Patients may also have cessation of menses or irreg-
ular menses. Underlying or contributing endocrine Management strategies for drug-induced infertili-
or metabolic conditions should be ruled out as well ty are listed in Table 36–7. Prior to receiving cyto-
as possible early menopause. Conditions to consid- toxic chemotherapy, patients need to be made
er in the differential diagnosis of drug-induced aware of the high risk and likelihood of drug-
infertility are presented in Table 36–4. induced infertility, which in most cases will be
permanent. These patients need to consider mul-
tiple options for cryopreservation to preserve fer-
RISK FACTORS tility options once treatment is completed.
Factors that can influence this decision include
The probability of permanent drug-induced infer- time restraints (how quickly treatment needs to
tility after chemotherapy increases proportionally be initiated), the type of cancer or disease being
with advancing age.144,145 In patients with autoim- treated (specifically if estrogen-sensitive),
mune disorders, there are specific disease-related whether or not the patient has a partner, desire to
factors that may increase the risk of drug-induced have (more) children, and the patient’s age. For
infertility, including the presence of antiovarian those with a partner and enough time before
antibodies, polyglandular insufficiency, and viral cytotoxic therapy begins, cryopreservation of
TisdaleC36_702-726 1/20/10 11:46 PM Page 721
embryos is preferred and has the highest success 4. Mitchell SY, Fletcher HM, Williams E. Ovarian
rate.152 Other cryopreservation options include hyperstimulation syndrome associated with clomiphene
citrate. West Indian Med J. 2001;50:227-229.
freezing of oocytes, ovarian cortex, or folli- 5. Dourron NE, Williams DB. Prevention and treatment of
cles.152,153 Although these options do not require ovarian hyperstimulation syndrome. Semin Reprod
a partner and can be accomplished in less time Endocrinol. 1996;14(4):355-365.
than cryopreservation of embryos, the potential 6. Brinsden PR, Wada I, Tan SL, et al. Diagnosis, prevention
of achieving viable pregnancies is less than with and management of ovarian hyperstimulation syndrome.
Br J Obstet Gynaecol. 1995;102:767-772.
cryopreservation of embryos. 7. Derman SG, Adashi EY. Adverse effects of fertility drugs.
For patients receiving antiepileptic drugs, infer- Drug Saf. 1994;11:408-421.
tility is often, but not always, reversible once the 8. Elchalal U, Schenker JG. The pathophysiology of ovarian
culprit agent is removed and endocrine function is hyperstimulation syndrome: views and ideas. Hum
allowed to normalize. Unfortunately, the option to Reprod. 1997;12:1129-1137.
9. Rutkowski A, Dubinsky I. Ovarian hyperstimulation
discontinue medications is generally available only syndrome: imperatives for the emergency physician. J
for patients whose seizure disorder can be managed Emerg Med. 1999;17:669-672.
effectively by an alternative, newer antiepileptic 10. Thakur R, EL-Menabawey M. Combined intra-uterine
agent.149 and extra-uterine pregnancy associated with mild
hyperstimulation syndrome after clomiphene ovulation
induction. Hum Reprod. 1996;11:1583-1584.
11. Navot D, Relou A, Birkenfeld A, et al. Risk factors and
INFORMATION FOR PATIENTS prognostic variables in the ovarian hyperstimulation
syndrome. Am J Obstet Gynecol. 1988;159:210-215.
12. Delvigne A, Demoulin A, Smitz J, et al. The ovarian
Infertility is a highly sensitive and emotional topic hyperstimulation syndrome in in-vitro fertilization: a
for most women. In some cases, fertility is the Belgian multicentric study: I. Clinical and biological
essence of a women’s identity. Patients about to features. Hum Reprod. 1993;8:1353-1360.
receive cytotoxic chemotherapy need to be educat- 13. Cremisi HD, Mitch WE. Profound hypotension and
ed regarding the multiple methods available to pre- sodium retention with the ovarian hyperstimulation
syndrome. Am J Kidney Dis. 1994;24:854-857.
serve child-bearing options after completion of 14. Buyalos RP, Lee CT. Polycystic ovary syndrome:
treatment. Once treatment is completed and resid- pathophysiology and outcome with in vitro fertilization.
ual treatment-related toxicities have resolved, Fertil Steril. 1996;65:1-10.
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Reprod. 1992;7:597-600.
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antiepileptic drugs, the potential for infertility syndrome in novel reproductive technologies:
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undergone multiple ovulation induction cycles. Hum
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preservation of fertility during cancer treatment in
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SECTION VIII
DRUG-INDUCED
GASTROINTESTINAL DISEASES
CHAPTER 38 Diarrhea
CHAPTER 39 Constipation
CHAPTER 41 Pancreatitis
C H A P T E R 37
Upper Gastrointestinal
Ulceration
729
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NSAIDs has been reported to be as high as 2.2% they can cause esophageal damage as well. One
annually in patients with rheumatoid arthritis.5 review of medications associated with drug-
The highest risk for upper GI ulceration in induced esophageal injury showed NSAIDs, includ-
patients receiving NSAIDS appears to occur when ing aspirin, to be responsible for 40% of cases. This
these agents are used in combination with other was followed by tetracyclines (22%), potassium
medications also known to cause GI ulceration. chloride (10%), and bisphosphonates (9%).
When combined with even low doses of aspirin Antimicrobials, quinidine, and ascorbic acid were
(less than 325 mg/day), the risk of upper GI bleed- responsible for the remainder of cases.2
ing in patients receiving NSAIDs may be increased
as much as 12-fold. While the incidence of drug-
induced upper GI ulceration is relatively low in MECHANISMS
patients receiving corticosteroids and selective
serotonin reuptake inhibitors alone, the combina- Various mechanisms are responsible for drug-
tion of these drugs with an NSAID increases the induced upper GI ulceration, ranging from simple
risk for ulceration considerably. Patients taking a direct irritation of the GI lining to more complex
selective serotonin reuptake inhibitor concurrent- interactions with mucosal cells and prostaglandin
ly with an NSAID had as much as a 3.6-fold inhibition. Since ulceration can occur in the
increase in the risk of upper GI bleeding.6 The inci- absence of direct contact with the GI tract, no
dence of ulceration appears to be least common route of administration can be considered com-
with ibuprofen, especially at doses <1,200 mg/24 pletely safe with respect to this drug-induced dis-
hours. Selective cyclooxygenase (COX)-2 NSAIDs ease. An understanding of mechanisms is
also are associated with a lower incidence of med- important in preventing or minimizing adverse
ication-induced ulceration ranging from 5% to effects in patients at greatest risk. Table 37-2 lists
8%.7 causative agents with their proposed mechanism.
While GI damage due to NSAIDs and aspirin With some drugs, more than one mechanism may
are most common at sites distal to the esophagus, be involved.
TisdaleC37_727-737 1/20/10 11:35 PM Page 731
Aspirin and NSAIDs have long been thought gastric ulcers have a lower incidence of recur-
to cause upper GI ulceration through their inhibi- rence if they are Helicobacter pylori-positive.10,11
tion of COX, a major enzyme needed for the syn- Whether the presence of one affects the mecha-
thesis of prostaglandins. Prostaglandins have a nism of ulceration of the other is unknown.
strong cytoprotective effect on the GI mucosa. These are likely independent risk factors for
They help maintain mucosal blood flow, increase ulceration.12
secretion of mucus and bicarbonate, and augment Corticosteroids have been implicated in GI
epithelial defense against cytotoxic injury.2 There ulceration, but the exact mechanism is unclear.
are at least two subtypes of the COX enzyme, These drugs may impair mucosal healing through
COX-1 and COX-2. COX-1 is the predominant the reduction of epithelial regeneration.13
subtype found in the stomach. NSAIDs that pref- Corticosteroids may pose a greater risk to the lower
erentially inhibit COX-2, therefore, might be GI tract than to the upper GI tract.2 Studies have
expected to cause fewer adverse GI effects than failed to confirm the mechanism or quantify the
those that inhibit COX-1. Indeed, when COX-1 actual risk.14
inhibitors were directly compared with COX-2 “Pill-induced” esophagitis, a localized ulcer of
inhibitors, it was found that patients experienced variable depth, can occur when capsules or tablets
fewer minor GI problems with the COX-2 do not clear the esophagus in a timely manner.
inhibitors.8 Unfortunately, the long-term use of Gelatin capsules can become sticky and lodge in
COX-2 inhibitors is limited because they have the esophagus if not taken with adequate water. In
also been associated with greater cardiovascular addition, tablets may be difficult to swallow or
toxicity. Nonacetylated salicylates, such as sal- contain a caustic coating that causes direct mucos-
salate, are weaker inhibitors of cyclooxygenase al irritation. The pH and concentration of the med-
activity and therefore less damaging to the GI ication may also be contributing factors.
tract. Pill-induced esophagitis occurs commonly with
The relationship between Helicobacter pylori oral bisphosphonates, such as alendronate.
positivity and the incidence of NSAID ulceration Potassium chloride may induce irritation in a local-
appears to depend on when NSAID therapy was ized area of the esophagus or stomach because of
started. New users of NSAIDs have been shown the high salt concentration. The slow-release, wax
to have fewer ulcers and ulcer-associated com- matrix formulations are more likely to cause dam-
plications if they are Helicobacter pylori-nega- age than the microencapsulated forms. In most
tive. 9 However, long-term users with healed cases the esophageal injury is caused by the pro-
TisdaleC37_727-737 1/20/10 11:35 PM Page 732
uncomplicated peptic ulcer; age >75 years; con- defects or scarring. Clinicians should be alert to the
comitant use of aspirin, corticosteroids, or warfarin; fact that patients with a history of aspirin-induced
the dose of NSAID; a history of dyspepsia; and the GI bleeding are at high risk for the development of
disease being treated (e.g., patients treated for the same outcome with clopidogrel.
rheumatoid arthritis have higher prevalence of GI Clopidogrel has been reported to have a favor-
events than those treated for osteoarthritis).23 The able GI safety profile as compared with aspirin,
duration of NSAID use may also be an important although patients who were studied received only
factor in the development of GI toxicity. Short-term 325 mg doses of nonbuffered and nonenteric coat-
use (<1 week) in healthy patients is unlikely to be ed aspirin. In addition, prescribers were permitted
problematic, but longer-term use is associated with to exclude any patient they defined as being
increased GI toxicity. GI complications are most “aspirin-intolerant.”28
common within the first 3 months of the initiation Patients at risk for pill-induced esophagitis are
of NSAID therapy. those who do not take enough fluids with their
Because COX-1 produces prostaglandins that medications, those with swallowing abnormalities
are known to protect the GI mucosa, it is thought due to stroke or esophageal dysmotility, and those
that NSAIDs with greater COX-1 inhibitory activi- with anatomic abnormalities such as strictures.20
ty would present a greater risk of GI toxicity. This Other risk factors include fasting, decreased pro-
idea is supported by evidence that ketorolac, the duction of saliva, age > 70 years, and polypharma-
NSAID with the greatest COX-1 inhibitory effects, cy.1 In most case reports of bisphosphonate-related
produces the highest risk for GI bleeding of all the ulcerative esophagitis or esophageal stricture, the
medications in this class.25,26 COX-2 inhibiting patient took alendronate with little to no water or
agents (e.g., celecoxib) have a minimal effect on returned to a supine position too soon after swal-
COX-1 and theoretically present a lower risk of GI lowing the tablet.29 Women with a history of upper
bleeding. However, no NSAID is completely free of GI disease or patients with gastroesophageal reflux
ulceration risks and associated complications. Most disease also appear to be at greater risk for
of the factors that raise the risk for GI complica- esophageal complications from bisphosphonates.30
tions in patients taking NSAIDs also increase the When used in combination, NSAIDs and bisphos-
likelihood of GI complications in non-NSAID- phonates appear to have a synergistic effect on the
treated patients.7 As a result, patients may be at risk for the development of gastric ulceration.31
continued risk for GI complications even after
being switched to alternative medications. In addi-
tion, the incidence of cardiovascular toxicities has MORBIDITY AND MORTALITY
been shown to be higher with COX-2 inhibitors, so
proper patient selection following evaluation of While some drug-induced upper GI ulceration may
the risks and benefits is extremely important. be relatively insignificant and transient, there is
Patients who have undergone transplantation always a risk of severe complications including per-
have multiple risk factors for GI ulceration, includ- foration, penetration of an ulcer from the stomach
ing the stress of surgery, use of NSAIDs and corti- or duodenum into an adjacent organ, GI obstruc-
costeroids, and increased gastric acid secretion tion, and bleeding. Any of these complications can
during dialysis post-transplantation.27 Also con- necessitate hospitalization with possible surgical
tributing is the possible impairment of native GI intervention and can be life-threatening.
cytoprotection due to azathioprine or mycopheno- The highest rates of complication are associat-
late-induced slowing of intestinal cell turnover. ed with aspirin and the NSAIDs. Problems range
Ulcers can be asymptomatic with the symptoms from minor but common side effects such as dys-
masked by the use of corticosteroids. Risk factors pepsia and abdominal pain to the more severe
for bleeding following transplantation include complications of ulceration, perforation, and
NSAID use for at least 1 week post-transplantation, bleeding. While the more serious complications are
high-dose intravenous corticosteroids used for relatively uncommon, they are a major public
acute rejection, and cyclosporine use.27 health concern because of the large numbers of
Patients with a history of GI bleeding may also patients who are exposed each year to aspirin and
be at increased risk of rebleeding when taking clopi- NSAIDs. With an estimated 60 million Americans
dogrel.17 Nine of 70 such patients (14%) had signif- taking NSAIDs, the reported 1% to 2% rate of sig-
icant GI bleeding after a median follow-up of 1 year. nificant upper GI events results in a large number
All except one lesion was identical to the previous of patients requiring care.32,33 Although estimates
lesion, suggesting that clopidogrel causes rebleed- vary, NSAID-related mortality has been reported to
ing only in patients with underlying mucosal be as high as 16,500 per year in the United States.5
TisdaleC37_727-737 1/20/10 11:35 PM Page 735
microencapsulated form may be preferable to a noted, one of the biggest risk factors for drug-
slow-release, wax-matrix form. Patients requiring a induced upper GI ulceration is the concomitant
bisphosphonate for osteoporosis may tolerate rise- use of aspirin or NSAIDs with any other medica-
dronate better than alendronate, since it appears to tion known to cause upper GI ulceration. Because
be less ulcerogenic. many NSAIDs are available over the counter under
Education is important in pill-induced a variety of brand names and as combination
esophagitis. Patients should sit or stand upright products, an informed patient may be the best
and take medications with ample fluids. They protection against these adverse events. Patients
should remain upright for at least 15 minutes after should be reminded to carefully read labels of
taking the medication. Careful selection of the non-prescription medications to avoid inadver-
dosage form of the medication may also help pre- tently purchasing products containing NSAIDs. A
vent mucosal injury. Liquid or tablet formulations discussion of potentially harmful non-prescription
may be less problematic than capsules. medications should be conducted with all patients
In addition to the steps outlined above, receiving a prescription for any of the causative
patients at risk for upper GI ulceration should be drugs.
educated regarding important lifestyle modifica- For NSAIDs, patients should take the recom-
tions, including avoidance of acidic beverages (e.g., mended dose for the indicated length of time. If
citrus juices) and irritating foods (e.g., onions, prescribed for a chronic condition, patients should
spicy foods). be regularly reminded of the warning signs of
ulceration. They should report any nausea, abdom-
inal pain or tenderness, or coffee-ground or bloody
MANAGEMENT emesis or stools immediately to their health care
provider. Patients must realize that even low-dose
The first step in the management of drug-induced aspirin can result in complications.
upper GI ulceration is to reassess the need for the Patients taking bisphosphonates should strictly
offending agent. Changing to an alternative med- adhere to recommendations regarding administra-
ication is often ideal; however, if this is not possi- tion, including taking the medication first thing in
ble, the lowest possible dose of the offending agent the morning at least 30 minutes before eating or
should be used. Gastric ulceration should be con- drinking anything, taking the medication with a
firmed via endoscopy and, when present, treated full glass of water, and staying in a sitting or stand-
with acid-suppressing therapy such as a proton- ing position for at least 30 minutes following
pump inhibitor. Treatment of Helicobacter pylori ingestion. Any medication known to cause pill-
infections should be considered. Surgery may be induced esophagitis should be taken with suffi-
necessary to treat strictures. cient fluid every time a dose is administered.
Treatment of pill-induced esophagitis damage
consists mostly of supportive therapy, and acid
suppression may be used as an adjunct. Symptoms References
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6. Dalton SO, Johansen C, Mellemkjaer L, et al. Use of
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gastrointestinal tract bleeding: a population- based
cohort study. Arch Intern Med. 2003;163(1):59-64.
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pylori and risk of peptic ulcers in patients starting long- anti inflammatory drugs, calcium antagonists, and
term treatment with non-steroidal anti inflammatory other antihypertensive drugs. Arch Intern Med.
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10. Yeomans ND, Tulassay Z, Juhasz L, et al. A comparison of 26. Llorente MJ, Tenias JM, Zaragoza A. Comparative
omeprazole with ranitidine for ulcers associated with incidence of upper gastrointestinal bleeding associated
non-steroidal anti inflammatory drugs. N Engl J Med. with individual non-steroidal anti inflammatory drugs.
1998;338:719-726. Rev Esp Enferm Dig. 2002;94:7-18.
11. Hawkey CJ, Karrasch JA, SzczepanskiL, et al. Omeprazole 27. Helderman JH, Goral S. Gastrointestinal complications of
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13. Gore RM, Levine MS, Ghahremani GG. Drug-induced 29. DeGroen AC, Lube DF, Hirsch LJ, et al. Esophagitis
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14. Carpani DK, Rentsch R, Levi S, et al. Corticosteroids 30. Cryer B, Bauer D. Oral bisphosphonates and upper
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15. Boyce HW. Drug-induced esophageal damage: diseases of 31. Graham D, Malatya H. Alendronate and naproxen are
medical progress. Gastrointest Endosc. 1998;47:547-550. synergistic for the development of gastric ulcers. Arch
16. Parfitt JR, Driman DK. Pathological effects of drugs on Intern Med. 2001;161:107-110.
the gastrointestinal tract: a review. Hum Pathol. 32. Dai C, Stafford RS, Alexander GC. National trends in
2007;38:527-536. cyclooxygenase-2 inhibitor use since market release: non-
17. Ng FH, Wong SY, Chang CM, et al. High incidence of selective diffusion of a selectively cost-effective
clopidogrel-associated gastrointestinal bleeding in innovation. Arch Intern Med. 2005;165:171-177.
patients with previous peptic ulcer disease. Aliment 33. Silverstein FE, Faich G, Goldstein JL, et al.
Pharmacol Ther. 2003;18:443-449. Gastrointestinal toxicity with celecoxib versus
18. Yuan Y, Tsoi K, Hunt RH. Selective serotonin reuptake nonsteroidal anti inflammatory drugs for osteoarthritis
inhibitors and risk of upper GI bleeding: confusion or and rheumatoid arthritis: the CLASS study: a randomized
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19. McCord GS, Clouse RE. Pill-induced esophageal 34. Blower AL, Brooks A, Fenn GC, et al. Emergency
strictures: clinical features and risk factors for admissions for upper gastrointestinal disease and their
development. Am J Med. 1990;88:512-518. relation to NSAID use. Aliment Pharmacol Ther.
20. Tolstoi LG. Drug-induced gastrointestinal disorders. 1997;11:283-291.
Medscape Pharmacotherapy. 2002;4(1):1-9. 35. MacDonald TM, Morant SV, Robinson GC, et al.
21. Lanas A, Scheiman J. Low-dose aspirin and upper Association of upper gastrointestinal toxicity of non-
gastrointestinal damage: epidemiology, prevention and steroidal anti inflammatory drugs with continued
treatment. Curr Med Res Opin. 2007;23(1):163-173. exposure: cohort study. BMJ. 1997;315:1333-1337.
22. Laine L. Gastrointestinal bleeding with low-dose aspirin- 36. Laporte JR, Lbanez L, Vidal X, et al. Upper
what’s the risk? Aliment Pharmacol Ther. 2006;24(6):897-908. gastrointestinal bleeding associated with the use of
23. Lanas A, Hunt R. Prevention of anti inflammatory drug- NSAIDs. Drug Saf. 2004;27(6):411-420.
induced gastrointestinal damage: benefits and risks of 37. Lanas A, Perez-Asia MA, Feu F, et al. A nationwide study
therapeutic strategies. Ann Med. 2006;38:415-428. of mortality associated with hospital admission due to
24. Chan FK, Graham DY. Review article: prevention of non- severe gastrointestinal events and those associated with
steroidal anti inflammatory drug gastrointestinal nonsteroidal randomized anti inflammatory drug use.
complications-review and recommendations based on Am J Gastroenterol. 2005;100:1685-1693.
TisdaleC38_738-759 1/12/10 3:40 PM Page 738
CHAPTER 38
Diarrhea
Jane M. Gervasio
gut and promote retention of water and elec- can result in diarrhea. Prokinetic medications
trolytes. Drug-induced secretory diarrhea occurs including metoclopramide and the antibiotic
when a medication increases secretions or decreas- erythromycin are associated with this type of direct
es absorption of large amounts of water and elec- effect on the intestine.344,345
trolytes in the gut lumen.344,345 Drug-induced diarrhea has been attributed to
Drugs that decrease the amount of time during fat malabsorption, or steatorrhea. Drugs can pre-
which chyme is exposed to intestinal epithelium vent absorption of fatty acids in the small intes-
cause abnormal absorption and secretion, which tine. When non-absorbed fatty acids reach the
TisdaleC38_738-759 1/12/10 3:40 PM Page 744
sorption include acidic stool pH, stool osmotic gap, result from drug therapy started as long as 4 weeks
and increased breath hydrogen. The D-xylose test prior to the onset of symptoms and 8 weeks follow-
and lactose-tolerance test may also be used to iden- ing discontinuation, the temporal relationship
tify malabsorption and lactose intolerance.351 Drug between onset and changes in drug therapy must
formulations containing sucrose, lactose, or fruc- be carefully and thoroughly explored. Additive or
tose may cause or exacerbate diarrhea in patients synergistic effects from possible drug–drug interac-
who have carbohydrate malabsorption. tions must also be considered. To help rule out
Chemotherapeutic agents, particularly fluo- common non-drug causes of diarrhea, eating
rouracil and irinotecan, are well recognized to habits, alcohol and caffeine consumption, and
cause drug-induced diarrhea.326-328 Two National illicit drug use as well as psychosocial factors that
Cancer Institute–sponsored cooperative group tri- might be affecting the patient all must be consid-
als of irinotecan plus high-dose fluorouracil and ered. Any environmental changes in the patient’s
leucovorin for advanced colorectal cancer led to home or office, recent travel or exposure to possi-
the recognition of a life-threatening GI syndrome, ble sources of bacterial or viral pathogens, disease
with symptoms including severe diarrhea, nausea, processes or comorbid complications must all be
vomiting, anorexia, and abdominal cramping.326- identified. Conditions to consider in the differen-
328
These symptoms were associated with severe tial diagnosis of drug-induced diarrhea are listed in
dehydration, neutropenia, fever and electrolyte Table 38–4.
imbalance. Severe abdominal cramping appeared
to be an important early warning sign of imminent
diarrhea. Early detection and treatment of diarrhea RISK FACTORS
is imperative to prevent life-threatening complica-
tions.326 General risk factors for diarrhea are listed in Table
AAD and CDAD may occur from a few days 38–5. Although specific risk factors for drug-
after antibiotic therapy is initiated to 8 weeks after induced diarrhea have not been identified, it can
discontinuation of the drug. Patients with CDAD reasonably be assumed that patients are at
present with profuse diarrhea (rarely with blood) increased risk for drug-induced diarrhea when one
consisting of mucoid, greenish, foul-smelling,
watery stools, abdominal pain, bloating, low-grade
fever, leukocytosis, and a frank altered general sta-
tus.332 Although endoscopy is the most definitive TABLE 38–4 Conditions to Consider in the
way to diagnosis CDAD, it is extremely costly and Differential Diagnosis of Drug-Induced Diarrhea
should generally not be used as a first-line diag-
• Celiac disease
nostic test for most patients. On endoscopy, C. diff
• Crohn’s disease
lesions appear as raised white to yellow plaques
• Diverticulitis
covering a normal or moderately erythematous
• Gastroenteritis
colonic mucosa.305 Diagnostic tests should initial-
• Infectious diarrhea/traveler’s diarrhea
ly include testing a stool specimen for C. diff and
• Campylobacter
its toxin. The standard for the laboratory diagno-
• Cryptosporidium
sis of C. diff is a cell culture to detect the specific
• Cyclospora infections
cytopathic effects of toxin B.332,333 In addition,
• Enterotoxigenic Escherichia coli
many institutions use enzyme immunoassay (EIA)
• Giardia lamblia
tests for detection of toxin A or B. Unfortunately,
• Isospora belli
the accuracy of these tests is not optimal, and a
• Microsporidia
negative EIA test for toxin A or B does not rule out
• Plesiomonas shigelloides
the diagnosis of CDAD. A second or third stool
• Rotavirus
specimen should be sent to the laboratory when
• Salmonellosis
initial results are negative but diarrhea persists.331-
333 • Shigella
• Irritable bowel syndrome
Differentiating between drug-induced diarrhea
• Ischemic bowel disease
and non–drug-induced diarrhea can be challeng-
• Malabsorption syndrome
ing. Practitioners should seek to identify any
• Microbial foodborne disease
changes in drug therapy that have occurred recent-
• Psychiatric disease
ly and any new drugs (prescription, nonprescrip-
• Psychosocial/psychological disorders
tion, herbal and nutritional supplements) to which
• Ulcerative colitis
the patient has been exposed. Since diarrhea may
TisdaleC38_738-759 1/12/10 3:40 PM Page 746
TABLE 38–5 Risk Factors for Drug-Induced TABLE 38–6 Approaches to Help Prevent Drug-
Diarrhea Induced Diarrhea
• Age (pediatric and elderly) • Adjust dosage to patient-specific parameters (e.g.,
• Diet (high-fat, high-fiber) age, weight, renal/hepatic function).
• Female sex • Avoid foods with artificial sweeteners (e.g., sorbitol,
• Malnutrition mannitol, fructose).
• Pain • Encourage fluid and proper diet.
• Poor/unsanitary conditions • Encourage rational antimicrobial use; prescribe
antibiotics only when necessary; reserve broad-spec-
trum antibiotics where possible.
• Identify any drug intolerance or allergy previously
or more of the general risk factors are present or if experienced.
multiple agents known to cause diarrhea are used • Identify liquid medications with high-sorbitol content
concomitantly. Furthermore, since changes in and substitute the tablet/capsule form when possible.
bowel function or a developing GI tract put the • Implement probiotic therapy (further investigation
elderly and infants at increased risk for diarrhea, necessary).
health care providers must recognize that the • Instruct patient to eat low-residual diet (e.g. bananas,
potential for drug-induced diarrhea is increased in rice, applesauce, toast).
these populations as well. • Instruct patients to consume low-fat meals (e.g., with
orlistat).
• Instruct patients to eat frequent, small meals.
MORBIDITY AND MORTALITY • Instruct patients to take medication with meals (if
not contraindicated).
The morbidity and mortality of drug-induced diar- • Progressively increase dose (if able).
rhea is unknown. Severe diarrhea may result in • Use alternative medications with a lower risk of diar-
dehydration, electrolyte abnormalities, and shock, rhea when available.
leading to hospitalization and even death. Two
National Cancer Institute–sponsored cooperative
group studies reported mortality rates of 0.6% and
1.9% due to severe diarrhea and subsequent com- In addition to general measures, drug-specific
plications secondary to the use of irinotecan, fluo- preventive measures are sometimes available.
rouracil, and leucovorin in cancer patients.327,328 Patients prescribed orlistat may decrease the inci-
dence of diarrhea by consuming low-fat meals.
Patients experiencing GI cramping and diarrhea
PREVENTION associated with iron therapy or multivitamins
may benefit from taking these preparations with
Techniques for decreasing the risk of drug-induced meals. Smaller, more frequent meals may be help-
diarrhea are listed in Table 38–6. Although proper ful in patients with chemotherapy-induced diar-
diet and adequate fluid intake should be encour- rhea.
aged in all individuals, implementing specific pre- Probiotics have been investigated for the pre-
ventive measures in all patients receiving a drug vention of AAD.353-356 A meta-analysis of nine ran-
with the potential to induce diarrhea may be domized, double-blind, placebo-controlled studies
overzealous. It is more effective for health care found probiotics to be effective for the prevention,
providers to implement preventive measures in but not treatment, of antibiotic-induced diar-
patients with a history of intolerance to medica- rhea.353 While these biologic agents may have a
tions or in patients receiving medications associat- place in therapy, larger trials and further investiga-
ed with a high incidence of diarrhea. Whenever tion are needed before their routine use can be rec-
possible, health care providers should attempt to ommended.
minimize drug-induced diarrhea in their patients
by avoiding the use of medications with high sor-
bitol content or high tonicity,352 using alternative MANAGEMENT
medications with lower incidences of causing diar-
rhea, using low doses and slowly increasing the Approximately 90% of cases of acute diarrhea
dose of drugs known to cause diarrhea, and judi- require no intervention and are self-limiting.342
ciously prescribing antibiotics. Drug-induced diarrhea usually spontaneously
TisdaleC38_738-759 1/12/10 3:40 PM Page 747
resolves within a few days after withdrawal of the cation for which vigilant monitoring and aggres-
drug and, in some cases, resolves even with contin- sive therapy is warranted.324,325 An expert multidis-
ued use of the causative agent.306 ciplinary panel developed guidelines for the
When diarrhea persists, identification of the treatment of CTID in 2000, and even more aggres-
offending agent is imperative to direct appropriate sive recommendations were published in
therapy. Patients should be asked specifically 2004.324,325 Patients with uncomplicated, grade 1 or
about new medications, including antibiotics 2 CTID (Table 38–7) should be treated with lop-
taken within the previous 4 weeks, any nonpre- eramide 4 mg initially followed by 2 mg every 4
scription medications, herbal medications, illicit hours (or after every unformed stool). Patients
drugs, alcohol, and caffeine. The content of sor- should be reassessed after 12 to 24 hours, and, if
bitol or other sugar substitutes in liquid medica- diarrhea persists, the loperamide dose should be
tions or “sugar-free” formulations, as well as the increased to 2 mg every 2 hours and therapy with
tonicity, usually found in the product labeling, an oral antibiotic (see below) initiated. For patients
should be identified. with unresolved diarrhea after an additional 12- to
Whenever possible, the culprit drug should be 24-hour period, loperamide should be discontin-
discontinued or changed to an agent less likely to ued and octreotide 100 to 150 mcg given subcuta-
cause diarrhea. Solid oral dosage forms may be con- neously three times daily. The dose may be
sidered when sorbitol-containing liquid medica- increased up to 500 mcg three times daily as
tions or high-tonicity formulations are associated required based on the patient’s response.
with diarrhea. Another option, if a formulation Patients presenting with grade 3 or 4 CTID
change is not feasible, is to dilute the liquid med- should be admitted to the hospital and given intra-
ication with water. When therapy with the offend- venous fluids and antibiotics (see below).
ing agent must be continued, some of the Octreotide in subcutaneous doses as outlined
preventive measures described in Table 38–6 may above or intravenously in a dose of 25 to 50 mcg
be helpful. Antidiarrheal medications should gen- per hour should be administered. Cytotoxic
erally not be thought of as first-line therapy for chemotherapy should be discontinued until all
drug-induced diarrhea; however, if the culprit drug symptoms have resolved; afterward, chemotherapy
cannot be changed or discontinued and preventive should be at reinstituted at reduced dosages.
measures do not resolve the diarrhea, antidiarrheal Oral antibiotics are used in CTID to prevent
drugs may be used. superinfections from widespread necrosis of crypt
Patients with chemotherapy-induced diarrhea stem cells, especially in patients with immunosup-
are a population in which antidiarrheal medica- pression or neutropenia. Superinfections can wors-
tions may be indicated as first-line therapy, espe- en diarrhea via direct secretory effects on the
cially in situations in which it would be intestinal mucosa and destruction of the intestinal
detrimental to discontinue or lower the dose of the epithelium. Antibiotic therapy should be targeted
culprit chemotherapeutic agent. CTID has been at opportunistic pathogens, including C. diff,
recognized as a severe and life-threatening compli- Clostridium perfringens, Bacillus cereus, Giardia lam-
blia, Cryptosporidium, Salmonella, Shigella, and diarrhea, including CDAD. A meta-analysis361 evalu-
Campylobacter and guided by local patterns of sen- ating studies using probiotics for CDAD treatment
sitivity and resistance.325 showed a significant therapeutic benefit; however,
Oral metronidazole or vancomycin should be the Cochrane Review362 suggested only a modest ben-
used to treat patients with C. diff and resulting efit with Saccharomyces boulardii when this probiotic
CDAD. Metronidazole is considered first-line ther- was used as an adjunct to antibiotics. Lactobacillus
apy, and it should be given orally in doses of 250 rhamnosus GG and Lactobacillus plantarum did not
mg four times a day or 500 mg three times a day for appear to provide any benefit.362 The Cochrane
7 to 10 days. Although oral metronidazole is pre- Review concluded that evidence is insufficient to rec-
ferred, intravenous metronidazole may be used ommend probiotic therapy as an adjunct to antibiot-
when the oral route is not available. Vancomycin ic therapy and that no evidence supports the use of
may be used as a second-line agent or as a first-line probiotics alone in the treatment of CDAD.362
agent in severe disease and is given orally in doses In patients with CDAD, antidiarrheal medica-
of 125 to 500 mg four times daily.330-333 tions that inhibit peristalsis (e.g., diphenoxylate)
Intravenous vancomycin is not indicated in treat- are contraindicated, since these agents may pro-
ment of CDAD. Rifampin has been used alone and long the course of illness and have been associated
in combination with oral metronidazole but has with the serious complication of toxic megacolon.
lost favor after a study demonstrating increased Agents such as bismuth subsalicylate are preferred
mortality in patients receiving the combination of in CDAD if antidiarrheal treatment is necessary.
rifampin and metronidazole as compared with The most common complication of severe diar-
metronidazole alone.357 Other antibiotic agents rhea is dehydration. Patients with mild or moder-
that have been used to treat CDAD include rifax- ate dehydration can nearly always be rehydrated
imin, an antibiotic similar to rifampin but lacking with oral rehydration solution (ORS). An appropri-
the GI absorption (making it a safer treatment) and ate ORS contains sodium, potassium, chloride, cit-
nitazoxanide, a synthetic antibiotic and antipara- rate, and glucose to address electrolyte and
sitic. Both antibiotics are considered as adjunctive bicarbonate losses.363 The rehydration volume for
treatment in recurrent C. diff infections. Rifaximin mildly dehydrated patients is approximately 50
is administered orally at 400 to 800 mg two to mL/kg and approximately 75 mL/kg for those with
three times daily and nitazoxanide, also given oral- moderate dehydration. Additional volumes may be
ly, is administered at 500 mg twice daily. necessary to account for continuing stool losses. 363
Additional antibiotics under investigation for the Intravenous fluid is recommended for patients
treatment of CDAD include ramoplanin, with severe dehydration or when oral rehydration
teicoplanin, and oritavancin.358 is contraindicated. Volumes of 100 mL per kilo-
Treatment directed at binding the C. diff toxin gram of body weight or more may be required for
has included use of the bile acid–binding resin rehydration. Rapid replacement of fluid and elec-
cholestyramine. Studies, however, failed to show a trolyte losses is necessary to prevent shock and sub-
high success rate with cholestyramine, and it has sequent death. A poly-electrolyte solution such as
been relegated to adjunct treatment status for Ringer’s lactate is considered appropriate for this
patients who have no response to antibiotics. purpose. Normal saline is a poorer choice for rehy-
Cholestyramine is administered at 4 g three to four dration in these patients because it does not correct
times a day. If given with vancomycin, administra- the acidosis or hypokalemia that may result from
tion should be separated by 2 hours.358 severe diarrhea.363
Intravenous immunoglobulin (IVIG) has been
used to bolster the immune response to C. diff tox-
ins.358 Although case reports have described its INFORMATION FOR PATIENTS
effectiveness randomized trials have not been con-
ducted. Smaller studies have reported 100% and Patients who are prescribed drugs that may cause
60% response rates to IVIG in children and adults, clinically relevant diarrhea should be warned of
respectively, with recurrent C. diff infections.359,360 the potential for this adverse effect prior to the ini-
The usual dosing regimen of IVIG is 300 to 500 tiation of therapy. To help anticipate and avoid
mg/kg daily until resolution or to a maximum of complications, patients should always be carefully
six doses. IVIG is reserved for patients as an questioned regarding any adverse drug reactions
adjunct to antibiotic therapy in severe refractory or previously experienced.
recurrent C. diff infections.358 Adequate fluid intake and a proper diet should
Probiotics have also been studied for the treat- be recommended for any patient who might expe-
ment of diarrhea, specifically treatment of infectious rience drug-induced diarrhea. Patients should be
TisdaleC38_738-759 1/12/10 3:40 PM Page 749
advised to avoid “sugar-free” foods containing sor- regimen for treatment of acute bacterial sinusitis.
bitol or mannitol sweeteners. Patients at risk for Antimicrob Agents Chemother. 2003;47:2770-2774.
12. Bucher HC, Tschudi P, Young J, et al. Effect of
drug-induced diarrhea should be cautioned to amoxicillin-clavulanate in clinically diagnosed acute
avoid or at least reduce the consumption of alco- rhinosinusitis: a placebo-controlled, double-blind,
hol, which may itself cause diarrhea. Patients with randomized trial in general practice. Arch Intern Med.
drug-induced diarrhea should take medication 2003;163:1793-1798
with food if not contraindicated. If the patient is 13. Iravani A, Richard GA. Amoxicillin-clavulanic acid versus
cefaclor in the treatment of urinary tract infections and
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advised. Agents Chemother. 1986;29:107-111.
Patients should be aware that most inci- 14. Gold JA, Hegarty CP, Deitch MW, et al. Double-blind
dences of drug-induced diarrhea are self-limiting clinical trials of oral cyclacillin and ampicillin. Antimicrob
and resolve within a few days. However, if symp- Agents Chemother. 1979;15:55-58.
15. Gotz V, Romankiewicz JA, Moss J, et al. Prophylaxis
toms are chronic or severe (e.g., presence of against ampicillin-associated diarrhea with a lactobacillus
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1977;53:324-326.
17. Hakkal HG. Pseudomembranous colitis associated with
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C H A P T E R 39
Constipation
Jane M. Gervasio
function increases colonic transit time.111 Under tion are met when two or more of the following are
these circumstances, colon contents may not be present: straining during ≥25% of defecations,
expelled for 10 days or longer.116 Drug-induced lumpy or hard stools in ≥25% of defecations, sen-
constipation may be multifactorial, and common sation of incomplete evacuation in ≥25% of defeca-
mechanisms are listed in Table 39–2. tions, sensation of anorectal obstruction/blockage
in ≥25% of defecations, manual maneuver to facil-
itate defecation (digital manipulations, pelvic floor
CLINICAL PRESENTATION AND support) is required in ≥25% of defecations, less
DIFFERENTIAL DIAGNOSIS than three evacuations per week, or loose stools are
rarely present without use of laxatives.118,119
Constipation may be defined as hard stools, fewer Patients must experience these symptoms for at
than three bowel movements per week, or inabil- least 3 months, and onset must occur ≥6 months
ity to expel stool. Patients may report too infre- prior to diagnosis.118,119 Chronic constipation in
quent defecation, stools too hard or too small, patients receiving long-term opioid therapy is
and incomplete rectal evacuation. Discomfort, termed “opioid-induced bowel dysfunction” and is
pain, and straining may also accompany poor often diagnosed in oncology patients. A subset of
defecation. The American Gastroenterological these patients presenting with worsening, severe
Association, in their Medical Position Statement: constipation, abdominal pain and distention, nau-
Guidelines on Constipation, state that practition- sea, and vomiting from large, chronic doses of nar-
ers must also consider straining, stools that are cotics are said to have narcotic bowel syndrome
excessively hard, unproductive urges, infrequency (NBS).86 NBS is due to a prolonged intestinal tran-
and a feeling of incomplete evacuation when sit time combined with increased electrolyte and
evaluating patients for constipation.117 Signs and water absorption and an impaired defecation
symptoms associated with drug-induced constipa- response and/or increased anal sphincter tone.
tion are presented in Table 39–3. Drug-induced constipation rarely requires hos-
Constipation may be acute or chronic.89 The pitalization unless the complications of bowel
Rome III diagnostic criteria for functional constipa- obstruction or perforation occur. Patients with
TABLE 39–3 Signs and Symptoms Associated TABLE 39–4 Conditions to Consider in the
with Drug-Induced Constipation Differential Diagnosis of Drug-Induced
Constipation
• Abdominal pain
• Anal or perianal pain • Dehydration
• Anal prolapse/hemorrhoids • Disorders of bowel structure/function
• Anorexia • Diverticulitis
• Bad taste in mouth • Gastrointestinal obstruction
• Bloating • Gastrointestinal pseudo-obstruction (Ogilvie syn-
• Cramping drome)
• Discomfort • Gastroparesis/small bowel ileus
• Feeling of fullness • Hernia
• Headache • Hypercalcemia
• Hypoperistalsis • Hypothyroidism
• Ineffective straining • Irritable bowel syndrome
• Infrequent bowel movements • Ischemic bowel disease
• Lack of bowel sounds • Pregnancy
• Local tenderness /distention • Psychiatric disease
• Malaise • Psychosocial/psychological disorders
• Nausea/vomiting
• No urge to defecate
• Sense of incomplete defecation
• Stools difficult to pass (small, hard, dry) irritable bowel syndrome, inflammatory bowel dis-
• Weakness ease, gastrointestinal perforation/obstruction, or
• Weight loss gastrointestinal cancer. A rectal examination can
help identify some anatomical complications (e.g.,
pelvic floor dysfunction) associated with constipa-
tion.87,118,119
bowel obstruction or perforation may present with
fever, leukocytosis, abdominal pain and distention,
and general malaise.
Differentiating between drug-induced consti-
RISK FACTORS
pation and other common functional or anatom-
Patient parameters and comorbid disease states
ic causes is important but can be difficult. Table
that place patients at increased risk for constipa-
39–4 lists conditions to consider in the differen-
tion are listed in Table 39–5. Certain drugs are con-
tial diagnosis of drug-induced constipation. A
sidered “notorious” for causing constipation (e.g.,
careful medication history that documents the
opioids).88 The incidence of drug-induced consti-
patient’s use of prescription drugs, nonprescrip-
pation may be increased in the elderly because of
tion drugs, herbal products, and nutritional sup-
an associated decline in bowel function (e.g.,
plements should be completed and reviewed for
decreased transit time).89
the presence of a temporal relationship between
changes in therapy and onset of symptoms.
Additive or synergistic effects resulting from
potential drug–drug interactions must be consid-
ered and ruled out. Assessment of the patient’s TABLE 39–5 Risk Factors for Drug-Induced
eating habits, hydration status, and mobility can Constipation
help rule out other common causes of constipa-
• Age (pediatric and elderly)
tion. Psychosocial factors, changes in the home or
• Concurrent medications
office environment, other disease processes or
• Dehydration
comorbid conditions can also lead to constipa-
• Female sex
tion and must be identified.
• Immobility
Patients presenting with severe abdominal
• Inactivity/decreased physical activity
pain, fever, unintended weight loss (>10 lb), hema-
• Pain
tochezia, positive occult-blood test, anemia, or a
• Poor diet
family history of colorectal cancer (or a combina-
• Pregnancy
tion of any of these) must be evaluated for possible
TisdaleC39_760-770 1/12/10 3:41 PM Page 764
health care providers to use this class of laxatives. in a given patient (e.g., a history of anorexia or
However, stimulant laxatives offer a generally safe bulimia), their use should be not be avoided.117,122
and effective means to treat constipation, and For patients with opioid-induced constipation
unless there is a valid concern for abuse or misuse not relieved by standard measures, opioid receptor
TisdaleC39_760-770 1/12/10 3:41 PM Page 766
antagonists have been successfully used, though bowel habits and to not ignore the urge to defe-
their place in therapy is still being debated. cate. Increased activity and exercise should be
Nonselective opioid receptor antagonists, such as encouraged. Laxatives may be necessary if and
naloxone and nalmefene, reverse both peripheral when these lifestyle and dietary measures do not
and central opioid effects, thereby relieving symp- resolve constipation. If symptoms of abdominal
toms of opioid-induced constipation but may also distention, severe pain, or fever occur, the patient
reverse the intended opioid analgesic effects.123,124 should notify a health care provider immediately
The bioavailability of oral naloxone is approxi- for evaluation and assistance.
mately 2% because of an extensive first-pass
metabolism.123,124 Oral administration of naloxone
theoretically allows selective blocking of intestinal
opioid receptors without blocking the desired sys-
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CHAPTER 40
Hepatic and
Cholestatic Diseases
Robert MacLaren
ANALGESICS/ANTIINFLAMMATORY AGENTS
Acetaminophen1-14,28,36 NK B
Aspirin1-16,28,36 NK C
Celecoxib17,18,28,36 NK C
Diclofenac1-14,21,23,28,36 0.001–0.005% B
Erythromycin17,18,28,34 NK C
Etodolac1-14,28,36 NK C
Ibuprofen1-18,28,36 NK C
Indomethacin21 NK C
Ketorolac21 NK C
Leflunamide1-14,28,36 4.4% A
Naproxen17,18 NK C
Nimesulide1-14,28,36 NK C
Oxaprozin1-14,28,36 NK C
Phenylbutazone1-14,17,18,28,34 NK C
Piroxicam1-16,28,36 NK C
Propoxyphene NK C
Propionic acid derivatives1-16,28,36 NK B
Sulindac17,18,28,34 NK C
Tienilic acid1-14,28,36 NK C
Tolmetin1-16,28,36 NK C
ANTIMICROBIAL AGENTS
Amoxicillin/ampicillin1-14,17,18,21,22,24,25 0.0011–0.02% B
Amphotericin1-14,22,24,25 NK C
Antimonial antiparasitics 1-16,24,25 NK C
Azole antifungals1-14,17,18,21,22,24,25 0.2% C
Azole antiparasitics1-14,24,25 5% B
Carbapenems17,18,24,25 NK C
Caspofungin1-14,24,25 NK C
Ceftriaxone17,18,24,25 NK C
Chloramphenicol1-14,17,18.24,25 NK C
Chloroquine1-16,24,25 NK C
Clindamycin1-14,17,18,24,25 NK C
Cloxacillin/nafcillin1-14,24,25 ≤0.01% C
Cotrimoxazole1-18,24,25 NK C
Dapsone1-14,17,18,24,25 ≤1.3% C
Ethionamide1-14,20,22,24-26 NK C
Flucytosine1-14,17,1824,25 NK C
Fluoroquinolones1-14,23-25 NK C
Fusidic acid17,18 NK C
(Continued)
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TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)
TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)
TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)
TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)
TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)
TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)
TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)
and phospholipases) causing cell membrane break- of ingested acetaminophen is conjugated through
down and localized inflammation. Apoptosis is glucuronidation and sulfation to nontoxic inactive
characterized by cell shrinkage, nuclear disassem- metabolites that are excreted in the urine. About
bly, and cell fragmentation into discrete bodies 5% to 10% undergoes oxidative conversion by CYP
with intact cell membranes.1-3,42-44,60-63 to the toxic metabolite, N-acetyl-p-benzo-
Phagocytosis of these bodies occurs so that local- quinoneimine (NAPQI). NAPQI is a highly reactive
ized inflammation is minimized. Histologically, two-electron moiety that can act as an electrophile
cell death may be zonal or nonzonal (diffuse).1-3,42- or oxidant. It is rapidly metabolized by conjuga-
44,60-63
Zonal injury means that necrosis/apoptosis tion to intracellular glutathione.42,43,45 Excessive
is limited to specific zones of the hepatic acinus, doses of acetaminophen saturate the conjugation
which is determined by the relative concentration pathways, shunting more acetaminophen into the
of the enzyme system responsible for degrading CYP system to generate more NAPQI. Hepatic glu-
the xenobiotic. Diffuse injury causes lobules to col- tathione stores may be depleted in an attempt to
lapse so that lobular arrangements disappear. Most detoxify NAPQI. In the absence of glutathione,
idiosyncratic reactions produce centrilobular or NAPQI binds covalently to the cysteine residues of
nonzonal injuries. hepatocyte macromolecules such as mitochondrial
Immune-mediated cytotoxicity results from the proteins. Mitochondrial destruction and loss of
biotransformation of the xenobiotic to produce ATP occurs, resulting in altered calcium homeosta-
adducts or haptens (known as haptenization) that sis, DNA damage, and intracellular protein modifi-
migrate to the cell membrane of Kupffer cells to cation.42,43,45 Glutathione depletion further
evoke an immune response via major histocompati- contributes to cellular oxidative stress.42,43,45
bility complexes I and II.1-3,42-46,60-63 Both humoral Covalent binding to hepatic proteins in isolation
and cellular immune responses of innate and adap- does not produce hepatotoxicity. Evidence suggests
tive immunity lead to inflammation and produce that inflammatory mediators (e.g., interferon-␥)
liver damage. Several recognized antibodies exist: trigger the innate immune system, leading to an
anti–liver/kidney microsomal (LKM) antibody that influx of Kupffer cells, non-Kupffer cells, neu-
specifically targets CYP2C9 of the liver and kidney; trophils, and macrophages that participate in the
anti–liver microsomal (LM) antibody (e.g., as development and propagation of injury.42,43,45
induced by carbamazepine) that targets CYP1A2, an The accumulation of fatty acids in the mito-
isoenzyme not found in the kidney; antimitochon- chondria is termed “steatosis.”15,16,64,65 The two
drial antibody (e.g., as induced by isoniazid); antimi- major pathways of fatty acid elimination are
crosomal epoxide hydrolase (e.g., as induced by microsomal triglyceride transfer protein (MTP) that
germander); anti-CYP 1A2 (e.g., as induced by forms triglyceride-rich very-low-density lipopro-
hydralazine); and anti-CYP 2E1 (e.g., as induced by tein particles that are secreted and mitochondrial
halothane). The inflammatory reaction is mediated oxidation.15,16,64,65 Xenobiotics can cause steatosis
by several inflammatory cytokines, including inter- by inhibiting MTP activity to block the movement
leukin (IL)-1, TNF, nitric oxide, and interferon-␥.1- of fat from the liver or impairing fatty acid oxida-
3,42-46,60-63
Other cytokines, such as IL-6, IL-10, and tion through various mechanisms, including the
some prostaglandins are hepatoprotective. All sequestration of coenzyme A, the inhibition of
cytokines may be expressed differently according to mitochondrial -oxidation, the disruption of
genetic polymorphisms. Animal models have oxidative phosphorylation to deplete cellular ATP,
demonstrated hepatotoxicity to nontoxic doses of or the formation of reactive oxygen species.15,16,64,65
agents when inflammation is present, suggesting Impaired hepatic protein synthesis or cross linking
that the inflammatory state at baseline may precipi- of structural proteins contribute to steatohepatitis.
tate or enhance the risk of immune-mediated hepa- For example, malondialdehyde and 4-hydrox-
totoxicity.42-46 Some agents activate macrophages to ynoneal, two products of lipid peroxidation, are
produce fibrosis or form granulomas. Immune- capable of cross linking structural proteins in the
mediated toxicity causes cell death by apoptosis that hepatocyte and may explain the transition from
produces piecemeal zonal injury (regions of inflam- steatosis to hepatitis.15 Steatosis may occur in the
mation surrounded by fibrous strands that extend vicinity of zonal necrosis or may be associated with
into the periportal area).1-3,42-46,60-63 inflammation and apoptosis.15,16,64,65 Steatosis is
Acetaminophen is the classic example of an described as microvesicular (hepatocytes that are
agent that causes cytotoxicity and, as understand- occupied by many tiny fat droplets that do not dis-
ing of its mechanisms of injury continues to place the nucleus) or macrovesicular (hepatocytes
evolve, is a good example of the complexity of that are occupied by few large fat droplets that dis-
drug-induced hepatotoxicity. Approximately 90% place the nucleus).15,16,64,65 Typically, microvesicu-
TisdaleC40_771-799 1/12/10 3:42 PM Page 783
lar steatosis is indicative of acute injury whereas antithyroid agents (except propylthiouracil), and
the coalescence of small fat vesicles to form some antidiabetic agents produce predominantly
macrovesicular steatosis usually represents chronic cholestatic injury.2 The diversity of agents used in
injury.15,16,64,65 Phospholipidosis is the trapping cardiovascular and infectious diseases precludes
and accumulation of phospholipids in the lyso- generalizations. Some agents produce mixed hepa-
somes of hepatocytes by xenobiotics.15,16 tocholestatic injuries. However, even mixed
Cholestatic injury is frequently due to selective injuries usually have a predominant cytotoxic or
interference with excretion of substances into the cholestatic feature.
bile canaliculus or direct bile duct injury from a In patients with acute drug-induced hepatoc-
xenobiotic or its metabolite.17-19,47,66 Some xenobi- holestatic injury, the onset of symptoms and labo-
otics or metabolites disable ATP-dependent bile salt ratory abnormalities may occur within days,
transport proteins (e.g., bile salt export protein) by weeks, or months following initiation of therapy.67-
disrupting actin filaments to cause cholestasis.17- 71
Near-immediate onset is typical of direct hepatic
19,47,66
Several ATP-dependent transport pumps injury. An onset of several days to weeks is typical
(multidrug-resistant polypeptide and multidrug- of immune-mediated injuries or microvesicular
resistant P-glycoprotein) located on the canalicular steatosis, and a delayed onset of months is indica-
domain of the hepatocyte are responsible for the tive of metabolic idiosyncrasies or macrovesicular
excretion of bilirubin and other organic substances steatosis.1-19,67-71 Some agents, however, have a
including xenobiotics and their conjugates. latency of 3 to 12 months between exposure and
Cholestatic injury may be caused when these trans- onset of symptoms (e.g., isoniazid or troglitazone)1-
port pumps are disrupted.17-19,47,66 Few agents pro- 19,67-71
and in some cases, injury may even occur
duce pure cholestatic injuries. Mixed weeks after the medication is discontinued (e.g.,
hepatocholestatic injury is usually the result of an amoxicillin/clavulanic acid, erythromycin,
immune-mediated reaction with parenchymal trovafloxacin).1-19,67-71 A chronic injury is defined
injury and portal inflammation or the failure of as 3 months of consistent hepatic or cholestatic
canalicular pumps to allow toxic bile acids to accu- injury.1-19
mulate and cause secondary hepatocyte injury. Signs and symptoms of hepatocholestatic
Direct injury to cells lining the bile duct causes injuries are presented in Table 40–31-19 and patterns
cholangiodestructive cholestasis and is character- of biochemical features of acute hepatocholestatic
ized by interlobular bile duct destruction (vanish- injuries are presented in Table 40–4.1-19,67-71 Many
ing bile duct syndrome).17-19,47,66 agents are associated with asymptomatic, mild ele-
Drug-induced vascular injuries may produce vations (<3 times the upper limit of the normal
hepatotoxicity by blocking the efferent blood flow range) of aspartate aminotransferase (AST) and ala-
(veno-occlusion) and causing congestive hepatopa- nine aminotransferase (ALT) concentrations that
thy or by dilation of hepatic sinusoids producing return to normal over time while continuing the
blood-filled cavities within the liver (peliosis agent. This has been termed “hepatic adaptation”
hepatis).1-3,42-44,60-63 Congestive hepatopathy may and potentially represents minor degrees of non-
result from thrombosis of the hepatic veins or progressive injury to organelles that do not induce
occlusion of the hepatic venules.1-3,42-44,60-63 Some cell death or inflammation but rather activate pro-
agents may alter DNA to produce benign or malig- tective mechanisms such as antioxidant and anti-
nant neoplasms.1-3,42-44,60-63 apoptotic pathways.1-19,67-71
Early cytotoxic injury may also be associated
with asymptomatic elevations of AST and ALT con-
CLINICAL PRESENTATION AND centrations; however, in most cases of injury, AST
DIFFERENTIAL DIAGNOSIS and ALT are substantially elevated (>10 times the
upper limit of the normal range).1-19,67-71 Serum
Drug-induced hepatocholestatic injury is best cate- alkaline phosphatase (ALP) and 5´-nucleotidase,
gorized according to the predominant type of two enzymes that reflect cholestasis, may be mini-
injury: hepatocellular (cytotoxic), cholestatic, vas- mally elevated, and serum bilirubin concentrations
cular, or neoplastic (Table 40–2).1-19,42-48 Several are variably elevated. If hyperbilirubinemia is pres-
general relationships exist between the pharmaco- ent with hepatocellular injury, usually unconjugat-
logic category and the pattern of hepatic injury. ed (indirect) bilirubin concentration is elevated
General anesthetics, drugs used to treat rheumatic rather than conjugated (direct) because bilirubin
or musculoskeletal diseases, hydrazine antidepres- undergoes hepatic conjugation. Depressed concen-
sants, and most anticonvulsants produce hepato- trations of plasma coagulation factors are charac-
cellular injury.2 Neuroleptic agents, most teristic of necrosis or apoptosis. More severe injury
TisdaleC40_771-799 1/12/10 3:42 PM Page 784
TABLE 40–4 Patterns of Biochemical Features of Acute Hepatocholestatic Injuries as Fold Deviations from Baseline.
Pathologic Injury ALP 5NC GGT AST ALT ALT/ULN ÷
ALP/ULN LDH Tbili Ibili Dbili
CYTOTOXIC1-16,67-71
Necrosis/apoptosis 1–2⫻ 1–2⫻ 1–2⫻ 10–500⫻ 10–500⫻ ⱖ5 10–500⫻ 1–10⫻ 1–10⫻ Normal
Steatosis
Microvesicular 1–2⫻ 1–2⫻ 1–2⫻ 5–20⫻ 5–20⫻ ⱖ5 5–20⫻ 1–10⫻ 1–10⫻ Normal
Macrovesicular 1–2⫻ 1–2⫻ 1–2⫻ 2–5⫻ 2–5⫻ Variable 2–5⫻ 1–3⫻ 1–3⫻ Normal
CHOLESTASIS18,19,67-71
Pure cholestasis 3–20⫻ 3–20⫻ 3–20⫻ 1–2⫻ 1–2⫻ ⱕ2 1 –4⫻ 2–20⫻ 1–2⫻ 2–20⫻
Canalicular 3–20⫻ 3–20⫻ 3–20⫻ 1 –4⫻ 1 –4⫻ ⱕ2 1 –4⫻ 2–20⫻ 1–2⫻ 2–20⫻
Hepatocanalicular 3–20⫻ 3–20⫻ 3–20⫻ 10–100⫻ 10–100⫻ 2–5 1–20⫻ 2–20⫻ 1–10⫻ 2–20⫻
Cholangiodestructive 3–10⫻ 3–10⫻ 3–10⫻ 1 –4⫻ 1 –4⫻ ⱕ2 1 –4⫻ 2–20⫻ 1–2⫻ 2–20⫻
Vascular1-14,67-71 1–5⫻ 1–5⫻ 1–5⫻ 2–100⫻ 2–100⫻ Variable but 2–100⫻ 1–5⫻ 1–5⫻ 1–2⫻
often ⱖ5
Page 785
NEOPLASM1-14,67-71 1–2⫻ 1–2⫻ 1–2⫻ 2–10⫻ 2–10⫻ Variable 2–10⫻ 1–3⫻ 1–3⫻ 1–2⫻
ALP = alkaline phosphatase (normal range, 38–126 U/L); ALT = alanine aminotransferase (normal range, 7–53 U/L); AST = aspartate aminotransferase (normal range, 11–47 U/L); Dbili =
direct (conjugated) bilirubin (normal range, 0–0.2 mg/dL); 5NC = 5´-nucleotidase (normal range, 2–16 U/L); GGT = ␥-glutamyltransferase (normal range, 12–76 U/L); Ibili = indirect
(unconjugated) bilirubin (normal range. 0–1.1 mg/dL); LDH = lactate dehydrogenase (normal range, 90–280 U/L); Tbili = total bilirubin (normal range, 0.2–1.3 mg/dL); ULN = upper limit
3:42 PM
exist for the conjugative and CYP systems that may agent is the best preventive measure. A patient
influence the metabolism of acetaminophen and reporting that a new medicine “does not agree
alter the risk of toxicity.42,43,45 with him” may be all that is required for early
detection of a preventable toxic exposure. Patients
with risk factors should not receive hepatotoxic
MORBIDITY AND MORTALITY agents if and when alternative agents are available.
Many manufacturers of drugs known to cause
Drug-induced liver diseases account for 2% to 3% hepatic injury provide guidelines for monitoring
of all hospital admissions.76 Only 20% to 25% of liver enzymes while patients are receiving the
patients with acute idiosyncratic fulminant hepat- potential hepatotoxin (e.g., isoniazid, etretinate,
ic failure survive 3 weeks without liver transplanta- synthetic retinoids, ketoconazole, methotrexate,
tion.56 The causes of death include cerebral edema, pemoline, tacrine). Monthly monitoring of liver-
sepsis, multiorgan failure, cardiac arrhythmia or associated biochemistry may be cost-effective for
arrest, and respiratory failure.56 As suggested by drugs that produce serious liver dysfunction in 1%
associated signs and symptoms (Table 40–3), mild- to 2% of exposures, but not for drugs that are less
to-moderate liver dysfunction can cause significant frequently associated with this drug-induced dis-
morbidity, however, mortality is rare.1-19 Patients ease.54
with preexisting liver disease, however, have
increased morbidity and mortality.72-74 Prognosis is
worse the longer a patient is exposed to the hepa- MANAGEMENT
totoxin. AST, bilirubin, female sex, and age are
associated with higher mortality in patients who Most cases of drug-induced hepatocholestatic dys-
experience hepatocellular reactions, whereas only function are reversible. In general, discontinuation
bilirubin is predictive of mortality in patients with of the hepatotoxin results in rapid reversal of signs
cholestatic injuries.72-74 and symptoms if the injury is mild to moderate. A
50% reduction of hepatic-associated enzymes can
be expected within 1 week if the injury is hepato-
PREVENTION cellular, but this degree of improvement may take
6 months or longer if the injury is cholestatic.1-19,72-
74
Table 40–9 lists approaches to help prevent drug- Recovery following discontinuation of drugs
induced hepatic and cholestatic diseases.1-9,76,77 with long half-lives may be prolonged or incom-
Recognition and rapid discontinuation of the plete.
TisdaleC40_771-799 1/12/10 3:42 PM Page 789
TABLE 40–8 Risk Factors for Drug-Induced Hepatic and Cholestatic Diseases54,70
Factor Examples
AGE
Older Acetaminophen, amoxicillin/clavulanic acid, isoniazid,
halothane, nitrofurantoin, troglitazone
Younger Erythromycin, salicylates, valproic acid
SEX
Male Amoxicillin/clavulanic acid, azathioprine
Female Diclofenac, halothane, isoniazid, methyldopa, minocycline,
nitrofurantoin, sulindac, propoxyphene
Obesity Halothane, methotrexate, tamoxifen, drug-induced
steatohepatitis
Diabetes mellitus Methotrexate, drug-induced steatohepatitis
Juvenile rheumatoid arthritis, systemic lupus erythematosus Salicylates
Pregnancy Acetaminophen, isoniazid, tetracycline
Renal dysfunction Allopurinol, intravenous tetracycline, methotrxate
Hyperthyroidism Halothane
Hyperlipidemic Drug-induced steatohepatitis
Acquired immunodeficiency syndrome Cotrimoxazole, dapsone, isoniazid
Chronic hepatitis B or C Flutamide, ibuprofen, isoniazid, ritonavir
Fasting, malnutrition Acetaminophen, methimazole, rifampin
Alcohol consumption Acetaminophen, halothane, isoniazid, methotrexate, vitamin A
Cumulative dose Amiodarone, bromfenac, methotrexate, oral contraceptives
Increased dose Acarbose, acetaminophen, cocaine, cyclophosphamide,
cyclosporine, methotrexate, niacin, perhexiline, phencycli-
dine, salicylates, tacrine, tetracycline, valproic acid, vitamin A
Pharmacokinetic interaction Phenobarbital or phenytoin enhances valproic acid toxicity;
isoniazid enhances acetaminophen toxicity
Pharmacodynamic interaction Pyrazinamide or isoniazid enhances rifampin toxicity;
acetaminophen and pennyroyal oil enhance toxicity of one
another; valproic acid and chlorpromazine enhance toxicity
of one another; isoniazid, zidovudine, trimethoprim–
sulfamethoxazole, phenytoin, carbamazepine, barbiturates
enhance acetaminophen toxicity
GENETIC PREDISPOSITION
CYP2C19 deficiency Phenobarbital carbonate derivatives
CYP2E1 or CYP1A2 deficiency Isoniazid, sulfonamides
N-acetyltransferase 2 deficiency Hydralazine, isoniazid, sulfonamides
Sulfoxidation deficiency Chlorpromazine
Epoxide hydrolase inhibition or deficiency Carbamazepine, halothane, phenobarbital, phenytoin
Glutathione synthetase or transferase deficiency Acetaminophen, tacrine, troglitazone
Glucuronosyl transferase deficiency Diclofenac, tolcapone
Unknown Amineptine
CYP = cytochrome P450.
Cautious rechallenge should be considered only able and only after all signs and symptoms have
if the diagnosis of drug-induced hepatocholestatic resolved. The rechallenge dose should be reduced
injury is questionable, the condition being treated by at least one-half and titrated upward to the
is serious, and no other treatment options are avail- desired dose over several months.1-19,75-77 Hepatic-
TisdaleC40_771-799 1/12/10 3:42 PM Page 790
macrovesicular steatosis caused by agents other showed that L-carnitine therapy at unspecified
than alcohol, including methotrexate, parenteral doses improved survival from 10% to 48% in
lipids, and warfarin. patients receiving standard treatment.103,104 It
Typically, corticosteroids are initiated in should be noted, however, that specific data
patients with chronic hepatitis who show minimal describing the patients, severity of liver injury, and
or slow clinical or biochemical improvement morphologic and histologic pathologies were not
despite other therapies. Approximately one-third presented. Moreover, the beneficial effect of
of patients with acute hepatic failure, irrespective increased survival was observed only when L-carni-
of the cause, have concomitant relative adrenal tine was administered intravenously (67% vs. 29%
insufficiency. This condition can be diagnosed with enteral administration). The typical dose of
with the adrenocorticotropic hormone–stimula- intravenous L-carnitine is 50 to 100 mg/kg/day
tion test, where a serum cortisol increase of ≤9 given in divided doses every 6 to 8 hours, and ther-
mg/dL 60 minutes after the administration of 0.25 apy should be initiated as soon as possible after
mg of corticotrophin is considered positive.100 exposure. Silymarin, an herbal supplement com-
These patients may benefit from short-term admin- monly used by patients to protect the liver when
istration of supplemental corticosteroid (daily they are taking known hepatotoxic agents, is
administration of hydrocortisone 200–300 mg or reported to possess antioxidant, antiinflammatory,
equivalent). and antifibrotic activities that protect hepatocytes
Other agents that have been successfully used from lipid peroxidation. However, a meta-analysis
in the treatment of alcohol-induced hepatitis or of 14 trials of silymarin used in patients with
reported to be of benefit in the treatment of other chronic liver disease (two studies of drug-induced
causes of hepatitis include colchicine, propylth- liver diseases) found that ALT was reduced by only
iouracil, gemfibrozil, betaine glucuronate, ursodi- 9 U/L (P = 0.05).105 AST, albumin, and prothrombin
ol, pentoxifylline, ␣-tocopherol, nitric oxide, time were not altered. Silymarin, therefore, should
methionine, vitamin E, L-carnitine, and silymarin not be used to treat cases of hepatotoxicity until
(milk thistle).101,102 Only L-carnitine and silymarin additional information supports its use for this
have been studied for reversal of drug-induced liver indication. Only case reports or in vitro data sup-
dysfunction. L-Carnitine induces ureagenesis, port the use of other agents for drug-induced liver
reduces inflammation by inhibiting TNF, and facil- failure.
itates fatty acyl transport. The results of a retro- Drug-induced cholestasis may require long-term
spective study of 92 patients with apparent daily treatment with ursodiol 300–600 mg, which
fulminant liver failure secondary to valproic acid aids in the dissolution of cholesterol gallstones and
TisdaleC40_771-799 1/12/10 3:42 PM Page 793
interaction.123,124 Hepatic injury prevents efficient sure forces the passage of fluid from the sinusoidal
use of vitamin K, and a dose of 10 mg of vitamin K lumen into the interstitial spaces because the
reverses coagulopathy to some extent in many endothelial cells that line the sinusoids are com-
patients with mild-to-moderate liver dysfunc- promised.138-144 Therefore, ascites should be treated
tion.125-132 However, the treatment of coagulopathy with fluid restriction (1–2 L/day), sodium restric-
secondary to drug-induced hepatic dysfunction tion (1–2 g/day), and the administration of diuret-
frequently necessitates the administration of ics, preferably furosemide and spironolactone in
exogenous clotting factors such as fresh-frozen doses of 40 mg and 100 mg daily, respectively.127-
132,138-144
plasma or cryoprecipitate.127-132 Exogenous These doses may be increased to 160 mg
platelets should only be administered when throm- and 400 mg, respectively. The goal of diuretic ther-
bocytopenia is present.133 Intravenous desmo- apy is to remove fluid at a rate of 0.5 kg/day in
pressin acetate at 0.4 mcg/kg promotes the release patients without peripheral edema and 2 kg/day in
of factor VIII from platelets and reverses coagu- patients with peripheral edema. Large-volume
lopathy with variable success.133 Intravenous paracentesis (>5 L) may be performed if the patient
recombinant factor VIIa in a dose of 40 mcg/kg has severe abdominal pain or breathing difficul-
rapidly reverses coagulopathy and may alleviate ty.138-144 Albumin (8 g for each liter of ascitic fluid
hemorrhagic episodes, but these effects last less removed) administered during or immediately
than 6 hours and, since the agent is extremely after paracentesis can help prevent circulatory and
expensive, it is usually reserved for cases of refrac- renal dysfunction.127-132,139-144
tory hemorrhage.134,135 Higher doses may be associ- A small-volume paracentesis (<2 L) is used to
ated with thrombosis.136 In general, the evaluate patients with new-onset ascites for the
international normalized ratio should be kept <1.5 presence of SBP, and an ascitic fluid polymor-
and the platelet count ≥50,000 per cubic millime- phonuclear count of ≥250 cells per cubic millime-
ter. However, reversing coagulopathy may require ter is considered diagnostic.138-147 SBP occurs when
substantial fluid administration that can induce bacteria translocate from the intestinal tract to the
ascites and intracranial hypertension and may peritoneum via the mesenteric lymphatic system.
negate the ability to use coagulopathy as a prog- This complication of hepatic disease is secondary
nostic marker.127-132 Although the production of to impaired gastrointestinal motility, damage to
endogenous thrombopoietin is frequently dimin- the intestinal mucosa, gastrointestinal bacterial
ished in patients with severe liver dysfunction, overgrowth, low concentrations of protein and
additional evidence is needed before the routine complement in the ascitic fluid, impaired activity
use of exogenous thrombopoietin can be recom- of the reticuloendothelial system including Kupffer
mended in these patients.133 Fat-soluble vitamins cells, and reduced neutrophil function.146,147
(A, D, E, K) should be administered with careful Antibiotic therapy for 5 to 7 days is indicated for
attention to the dose of vitamin A, since it may the treatment of patients with SPB.138-147 Therapy
induce liver failure at high doses or worsen existing should be designed to cover the most likely organ-
injury at therapeutic doses by producing hepatic isms and penetrate the ascitic fluid. Coverage for
inflammation and depleting the antioxidant Escherichia coli, Streptococcus pneumoniae, Klebsiella
capacity of the liver.137 species, and other enteric gram-negative organisms
Hypoglycemia is a common manifestation of should be provided. Third-generation cephalo-
liver dysfunction because the production of sporins (cefotaxime, ceftriaxone), extended-spec-
glucagon is impaired and hepatic glycogen stores trum penicillins (ampicillin/sulbactam), and
are minimal.127-132 Patients with fulminant liver fluoroquinolone agents are all effective in eradicat-
dysfunction are often hypervolemic, so the intra- ing these organisms, with resolution rates
venous administration of high concentrations of ≥90%.146,147 Albumin in a dose of 1.5 g/kg given at
dextrose (50%) may be needed to correct hypo- the time of diagnosis and 1 g/kg 3 days later has
glycemia without adding volume. Patients may been shown to reduce the incidences of renal
have hyperglycemia due to peripheral insulin impairment and hospital mortality in patients
resistance and the inability of the liver to convert with SBP.148 Prophylactic antibiotics for the preven-
glucose to glycogen.127-132 Short-acting insulin can tion of SBP in patients with ascites may be warrant-
be used to control hyperglycemia. ed when fulminant liver failure is present.142-147
Portal hypertension and arterial vasodilation Encephalopathy is a metabolic disorder of
produce ascites by activating the renin–angio- mentation, neuromuscular function, and con-
tensin–aldosterone–vasopressin system to increase sciousness associated with hepatic disease. It is
intravascular blood volume.138-144 Peritoneal fluid believed to be caused by the accumulation of sub-
collects when an elevated hepatosplanchnic pres- stances such as ammonia that are efficiently
TisdaleC40_771-799 1/12/10 3:42 PM Page 795
metabolized under normal conditions but accumu- compromising cerebral blood flow, but the effect is
late with liver dysfunction.149-151 Single measure- limited to several hours.127-132,162 Intravenous
ments of serum ammonia concentrations do not thiopental or pentobarbital 250 mg may be used if
reflect the degree of encephalopathy, but trends in mannitol is unsuccessful or contraindicated.127-
132,158,159
serial measurements correlate with the progression Mild hypothermia (32–35°C) is also used
or reversal of encephalopathy.149-151 Initial treat- in the treatment of elevated ICP; this therapy
ment of encephalopathy should include the rever- maintains hepatic function by decreasing
sal of precipitating factors, including hemorrhage, ischemic-reperfusion injury and the inflammatory
excess dietary protein, azotemia (as induced by response; however; it is associated with coagulopa-
diuretics or renal failure), infection, constipation, thy, electrolyte abnormalities, altered hemody-
and metabolic/electrolyte disturbances and the dis- namics, variable glucose control, and rebound
continuation of central nervous system depres- intracranial hypertension during rewarming.163,164
sants.149-151 Pharmacotherapy of encephalopathy Variceal hemorrhage and HRS are rarely associ-
may be initiated with enteral/rectal lactulose (30 ated with idiosyncratic drug reactions. Varices are
mL as often as hourly until stool is produced and caused by portal hypertension and develop when
then 3–4 times daily as needed to produce 2–3 soft the portal pressure gradient exceeds 10 mm Hg,
stools per day) and/or enteral rifaximin (200–400 resulting in the development of portosystemic col-
mg 3 times daily) or metronidazole (500 mg 2–4 lateral circulation.143-145,165,166 A variceal hemor-
times daily).127-132,149-152 Meta-analysis has shown rhage should be treated with endoscopic
that lactulose improves encephalopathy.153 procedures (banding is preferred) followed by the
Neomycin (1–2 g 4 times daily) may be used, but administration of octreotide (50-U bolus followed
caution is warranted, as it may be associated with by intravenous infusion of 25–50 U/hr for 3–5
nephrotoxicity.152 Daily protein should be restrict- days).143-145,165,166 Octreotide reduces the rate of
ed to 1 g/kg in patients with encephalopathy, and rebleeding and transfusion requirements.167 Acute
nutritional products containing branched-chain renal failure may require renal dialysis, but HRS
amino acids may further reduce the degree of may be temporarily alleviated by intravenous vaso-
encephalopathy, although other outcomes such as pressin infusion (0.1–0.4 U/min) or the combina-
returning to baseline mental status, length of hos- tion of octreotide and midodrine (2.5–10 mg 3
pital stay, and survival are not affected.154-156 times daily).168
Intravenous flumazenil (0.2–0.5 mg) temporarily Common electrolyte abnormalities associated
reduces the extent of encephalopathy.157 with liver dysfunction include hypophos-
Altered mental status should be investigated phatemia, hypokalemia, and hypomagnesemia,
using computed tomography to rule out intracra- and electrolyte replacement may be required.
nial hemorrhage. Insertion of an ICP monitoring Hypervolemic hyponatremia is common and usu-
device should be considered but may constitute an ally asymptomatic even when sodium concentra-
unacceptable risk for the patient when coagulopa- tions are profoundly low; however, it may indicate
thy is present.158,159 The use of an ICP monitor is the onset of HRS.169 Diuretic therapy combined
associated with hemorrhage but enhances the rate with fluid restriction usually improves serum sodi-
of successful transplantation.160 Treatment of um concentrations.169 Intravenous sodium chlo-
increased ICP should include minimizing agitation ride should be administered only when patients
with short-acting benzodiazepine agents, provid- are symptomatic (e.g., when seizures are present),
ing analgesia with short-acting opioid agents, con- as increases in serum sodium concentrations are
trolling hyperthermia, and minimizing acidosis transient and the excess fluid may precipitate
and hypoxia.127-132,158,159 Cerebral edema and ascites. In the future, therapy for hyponatremia
increased ICP may be treated with intravenous may involve the administration of antagonists to
mannitol 25–50 g as needed to keep the ICP <20 vasopressin receptor2 (antidiuretic hormone) to
mm Hg and the serum osmolarity between reduce hypervolemia, but these approaches have
310–320 mOsm/kg.149-151,158,159 Mannitol may accu- not been evaluated for hyponatremia associated
mulate in astrocytes if renal failure is present and with acute liver disease.169
may cause rebound cerebral edema. Hypertonic
saline (3%) to a target serum sodium concentration
of 145–155 mEq/L may be used as an alternative to INFORMATION FOR PATIENTS
mannitol but may contribute to serum sodium
irregularities.161 Hyperventilation to maintain the Patients taking agents that may cause hepatoc-
partial pressure of arterial carbon dioxide near 35 holestatic injury should be instructed to consult
mm Hg should reduce ICP without substantially their physician or pharmacist if they experience
TisdaleC40_771-799 1/12/10 3:42 PM Page 796
nausea, vomiting, unexplained weight loss, or 18. Levy C, Lindor KD. Drug-induced cholestasis. Clin Liver
abdominal pain that lasts several days and cannot Dis. 2003;7:311-330.
19. Chitturi S, Farrell GC. Drug-induced cholestasis. Semin
be attributed to other causes. Patients with altered Gastrointest Dis. 2001;12:113-124.
mental status, increased abdominal girth, peripher- 20. Norris W, Paredes AH, Lewis JH. Drug-induced liver
al edema, bleeding episodes, protracted pruritus, injury in 2007. Curr Opin Gastroenterol. 2008;24:287-297.
jaundice, or reduced urine production should 21. Arundel C, Lewis JH. Drug-induced liver diseases in 2006.
receive immediate medical attention. Patients Curr Opin Gastroenterol. 2007;23:244-254.
22. Lewis JH, Ahmed M, Shobassy A, et al. Drug-induced
should be instructed not to take any nonprescrip- liver disease. Curr Opin Gastroenterol. 2006;22:223-233.
tion medications or herbal products without first 23. Lazerow SK, Abdi MS, Lewis JH. Drug-induced liver
consulting their physician or pharmacist. Patients disease in 2004. Curr Opin Gastroenterol. 2005;21:283-292.
should inform their physician and pharmacist of 24. Brown SJ, Desmond PV. Hepatotoxicity of antimicrobial
all agents (including herbal remedies) they are tak- agents. Semin Liver Dis. 2002;22:157-168.
25. Thiim M, Friedman LS. Hepatotoxicity of antibiotics and
ing to avoid interactions and should be cautioned antifungals. Clin Liver Dis. 2003;7:381-399.
about risk factors including ethanol use, illicit-drug 26. Tostmann A, Boeree MJ, Aarnouste RE, et al.
use, and environmental exposures. Finally, appro- Antituberculosis drug-induced hepatotoxicity: concise
priate monitoring to avoid the development of up-to-date review. J Gastroenterol Hepatol. 2008;23:192-
hepatocholestatic injury or to prevent further dam- 202.
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CHAPTER 41
Pancreatitis
DEFINITE ASSOCIATION
5-Acetylsalicylic acid83,136-139,141-153,282 NK B
L-Asparaginase90-93,99-101,103-108,110-114,116-118 2–16% C
Azathioprine74-78,80-82,84,87,88 4.5–5.3% B
Didanosine14,15,19-22,24-31,33-35,327 1.5–9% C
Estrogen205-211,213 NK C
Furosemide214-219 NK C
6-Mercaptopurine73,85,86 3.3% C
Methyldopa201-204 NK C
Metronidazole62-70 NK C
Pentamidine184-199,280 NK C
Sulfonamide (sulfamethoxazole)140,170-172 NK C
Sulindac126-131,134,135,283 NK C
Tetracycline174-179 NK C
Thiazides (hydrochlorothiazide)222,223,225,226,231,232 NK C
Valproic acid237-241,243-257,259-269 0.0025% B
PROBABLE ASSOCIATION
Angiotensin-converting enzyme inhibitors 38-48,54,295,296,320,328,329 0.3–1.07% B
Ampicillin200,224 NK C
Angiotensin-receptor blockers49,50,330,331 NK C
Bezafibrate332 NK C
Bumetanide220 NK C
Calcium122-125,312,314,316 7–11% C
Chlorthalidone233,234 NK C
Cimetidine57-60 NK C
Cisplatin161-163 NK C
Clozapine270-276 NK C
Corticosteroids304,333-344 NK C
Cytarabine154,160 NK C
Ethacrynic acid221 NK C
Ifosfamide155,345 NK C
Olanzapine346-348 NK C
Omeprazole60,61 NK C
Piroxicam126,298 NK C
Procainamide349 NK C
Salicylates350 NK C
Sodium stibogluconate351-355 NK C
Sorafenib356,357 NK C
Statins71,72,358-368 NK B
Tigecycline182,183 NK C
Vinblastine167 NK C
Vincristine167 NK C
Zalcitabines <1% C
NK = Not known
801
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209 of the 2749 reports of drug-induced pancreati- tion based case–control Danish study reported a
tis received by the World Health Organization threefold increased risk of acute pancreatitis in
(WHO) from 1968 to 1993.36 More recently, over patients receiving metronidazole.70
300 cases of drug-induced pancreatitis were associ- There are numerous reports of 3-hydroxy-3-
ated with enalapril or captopril.37 The estimated methyl-glutaryl-CoA (HMG-CoA) reductase
incidence of ACE inhibitor-associated pancreatitis inhibitor (or statin)–induced pancreatitis in the lit-
ranges from 0.3% to 1.07%.38 A retrospective erature.71,72 A meta-analysis of two pooled studies
cohort study of 174,824 elderly patients prescribed showed an odds ratio of 1.41 (95% confidence
ACE inhibitors reported an incidence of 9 per interval, 1.15–1.74) for the risk of pancreatitis
10,000 person-years, which was not significantly developing while a patient is receiving statins.72
different from that in control groups receiving war- Pancreatitis can occur at any time, but may be
farin or calcium-channel blockers (classes of drugs more likely after many months of treatment with
with either a weak association or with no associa- statins.
tion with pancreatitis).39 Several cases of ACE Azathioprine and 6-mercaptopurine are potent
inhibitor and angiotensin II receptor immunosuppressive agents that are associated with
antagonist–induced pancreatitis have been report- pancreatitis.73-88 The incidence of pancreatitis with
ed.40-53 In one such case, pancreatitis developed 6-mercaptopurine is approximately 3.3%,73 where-
with no known cause other than a 10-month his- as the incidence of azathioprine-induced pancre-
tory of lisinopril therapy and mildly elevated atitis ranges from 4.4% to 5.3%.73–75 Pancreatitis
serum triglyceride concentrations, highlighting the developed within approximately 1 month of initi-
possibility that pancreatitis may develop several ation of 6-mercaptopurine therapy, with a range of
months after the initiation of ACE inhibitor thera- 8 to 32 days. Pancreatitis developed within 2
py.38 In another case, pancreatitis developed three weeks, often within 1 to 2 days, in all 7 of the 13
times after initiation and rechallenge with lisino- patients who were rechallenged. Three additional
pril. The latency period ranged from 4 to 25 patients with azathioprine-induced pancreatitis
months.54 ACE inhibitors are associated with an subsequently did well with 6-mer- captopurine.89
increased risk of acute pancreatitis (approximately L-asparaginase induces pancreatitis in 2% to
50%), particularly in the first 6 months of thera- 16% of patients, and approximately 2% to 5% of
py.55 children treated with L-asparaginase experience
During the period from 1968 to 1993, the life-threatening pancreatitis.90-94 Two other prepa-
WHO received reports of 127 cases of pancreatitis rations of asparaginase have become available:
associated with histamine-2 (H2) receptor antago- Erwinia carotovora-derived L-asparaginase and poly-
nists.56 The association between cimetidine and ethylene glycol-L-asparaginase (PEG-asparaginase,
pancreatitis is probable, and there are numerous Oncaspar). Erwinia asparaginase may be associated
published case reports.57-59 A retrospective cohort with a lower incidence of pancreatitis as compared
study of patients taking acid-suppressive therapies with the native L-asparaginase product (0% vs. 2%,
(cimetidine, famotidine, nizatidine, ranitidine, respectively) although this has not been thorough-
lansoprazole, omeprazole) identified 36 cases of ly investigated.95-97 There are numerous case
acute pancreatitis, 5 of which occurred in patients reports of L-asparaginase-induced pancreatitis with
taking cimetidine.60 One case report of ompera- or without fatalities.98-110 Pancreatitis induced by L-
zole-induced pancreatitis has been reported in the asparaginase usually occurs during administration
literature.61 Pancreatitis developed 2 months after of the drug, but in some cases pancreatitis second-
the initiation of therapy and recurred after rechal- ary to L-asparaginase therapy may occur as long as
lenge with omeprazole. However, a retrospective, 10 weeks after therapy has been discontin-
case-control study including more than 180,000 ued.3,90,92,99,110-112 The incidence of pancreatitis
subjects did not find an increased risk associated associated with PEG-asparaginase is similar to that
with acid-suppressive therapy.60 with native L-asparaginase (0–15%).113-118 The
There are at least six well-documented cases of onset of pancreatitis associated with PEG-asparagi-
metronidazole-induced pancreatitis.62-67 In these nase is within a few days or up to 6 weeks after
cases, the onset of symptoms ranged from 12 hours PEG-asparaginase administration.
to 7 days after initiation of therapy and resolved The incidence of hypercalcemia-induced pan-
after discontinuation of the drug. Metronidazole- creatitis is approximately 7%.119 Two of 112 cases
induced acute pancreatitis was reported in a 46- (1.8%) of drug-induced pancreatitis reported
year-old female.68 Another case of metronida- through 1977 were attributed to calcium thera-
zole-related acute pancreatitis occurred during a py.120 Intravenous calcium administration has
relapse of ulcerative colitis.69 In addition, a popula- been associated with pancreatitis in at least two
TisdaleC41_800-818 1/12/10 3:43 PM Page 803
published reports, and hypercalcemia secondary to treated with vincristine, methotrexate, mitomycin
total parenteral nutrition has also been report- C, fluorouracil, and cyclophosphamide for
ed.121-124 In a prospective study of patients who had advanced-stage ovarian carcinoma. Pancreatitis
undergone cardiopulmonary bypass, the risk of recurred during the sixth cycle, although cholecys-
pancreatic injury correlated with a dose of calcium tography confirmed gallbladder disease, a con-
chloride >800 mg/m2, and calcium chloride admin- founding variable.158 Another patient who received
istration was an independent predictor of pancre- cisplatin, bleomycin, and vinblastine experienced
atic injury.121 Hypercalcemia-related pancreatitis is recurrence of pancreatitis during the second cycle
more common in patients who have undergone of chemotherapy.164 Pancreatitis developed in a
renal transplantation, with an approximate inci- patient treated with cyclophosphamide, doxoru-
dence of 11%.125 bicin, vincristine, and prednisone for immunoblas-
The incidence of pancreatitis induced by nons- tic lymphoma before the initiation of prednisone;
teroidal antiinflammatory drugs (NSAIDs) appears pancreatitis recurred during later cycles of treat-
low. In a population-based study of over 100,000 ment, and asymptomatic hyperamylasemia also
users of piroxicam, naproxen, or diclofenac, only occurred during a later chemotherapy cycle.156
one case of pancreatitis occurred (in a patient During the 1950s, corticosteroids became the
receiving piroxicam).126 In contrast, there are first drugs to be implicated in drug-induced pan-
numerous reports of sulindac-induced pancreatitis, creatitis. Steroids and adrenocorticotropic hor-
including reports of recurrence after rechal- mone (ACTH) accounted for 51 of 112 (45.5%)
lenge.127-134 Pancreatitis may develop within 2 cases of pancreatitis reported in the literature as of
weeks to 9 months after the initiation of sulindac 1977.120 A more recent report described a patient
therapy.134,135 being treated with hydrocortisone for exacerbation
Salicylate-induced pancreatitis has also been of ulcerative colitis in whom pancreatitis later
reported, particularly in poisonings.136,137 Of 112 developed.168 This patient experienced a second
cases of drug-induced pancreatitis reported exacerbation of ulcerative colitis and was again
through 1977, 1 (0.9%) was attributed to salicylate treated with hydrocortisone; acute pancreatitis
therapy.120 Sulfasalazine is composed of sulfapyri- developed again.
dine and 5-aminosalicylic acid (5-ASA). Intestinal In 1963, Barrett and Their reported the first
bacteria cleave the diazo bond between the two case of sulfonamide-induced pancreatitis.169 More
components, releasing the active moiety, 5-ASA. recently, there have been three reported cases of
Pancreatitis has been reported in association with pancreatitis secondary to trimethoprim–sul-
both sulfapyridine and 5-ASA.138-151 Sulfasalazine- famethoxazole treatment, in which the disease
induced pancreatitis has recurred after rechallenge developed within 5 days to 10 weeks after the ini-
with 5-ASA. Although serum 5-ASA concentrations tiation of therapy.17,140,170-172
are higher when the drug is administered orally, Ober and Lecompte reported the earliest case of
pancreatitis has been reported in association with tetracycline-induced pancreatitis in a patient in
5-ASA administered by either the oral or the rectal whom acute fatty liver of pregnancy also devel-
route. In a retrospective analysis of serious adverse oped.173 Other reports of pancreatitis secondary to
events, pancreatitis was reported seven times more tetracycline have also been associated with liver
frequently with mesalamine than with sul- disease.174-176 There are three other reports of tetra-
fasalazine.152 However, in a retrospective study, cycline-induced pancreatitis in patients without
patients with inflammatory bowel disease who liver disease.177-179 Also, two reports of minocy-
received 5-ASA and sulfasalazine did not show an cline-induced pancreatitis have been des-
increased risk of pancreatitis.153 cribed.180,181 Tigecycline, a newer agent related to
Cisplatin, cytarabine, ifosfamide, and the vinca the tetracyclines, has been implicated in drug-
alkaloids have been associated with pancreatitis, induced pancreatitis in two case reports.182,183
but the incidence is unknown.154-167 Many cases of A number of cases of aerosolized and injectable
drug-induced pancreatitis have been reported dur- pentamidine-induced pancreatitis have been
ing concurrent cytarabine and L-asparaginase reported, the majority of which have been in the
administration. Pancreatitis developed within 10 HIV/AIDS population, including a report of recur-
days after the first cytarabine dose in 7 of 134 rence after rechallenge.17,184-199 Pancreatitis second-
patients undergoing treatment for acute myeloge- ary to pentamidine typically occurs in the second
nous leukemia at two tertiary care centers; recur- week of treatment and resolves within 10 days after
rent pancreatitis developed in one of six patients discontinuation, although there have been some
who were rechallenged.160 Another case described reports of pancreatitis persisting after the discon-
the development of acute pancreatitis in a patient tinuation of therapy. Persistence may be explained
TisdaleC41_800-818 1/12/10 3:43 PM Page 804
by the lipophilic properties of pentamidine, a case reports and the potential severity of this drug-
cumulative dose effect on the pancreas, or induced disease the United States Food and Drug
both.190,192 In a report of five cases of pentamidine- Administration (FDA) instituted new “black box”
induced pancreatitis, all patients experienced warnings regarding the risk of pancreatitis in pack-
episodes of hypoglycemia or hyperglycemia. Sepsis age inserts for valproic acid in July, 2000.258
developed in four of the five.192 Glucose abnormal- Although valproic acid induced pancreatitis is
ities, renal insufficiency, nonspecific abdominal most common during the first year of therapy, in
pain, and nausea and/or vomiting after the initia- some cases the disease has appeared more than 1
tion of pentamidine may be early warning signs of year after the initiation of treatment. There have
pancreatitis.184 also been cases suggestive of valproic acid induced
One case report supports a probable association chronic pancreatitis.260,261 In a retrospective, case-
between pancreatitis and ampicillin.200 Pancreatitis control trial, valproic acid significantly increased
developed 6 days after the initiation of therapy; the risk for pancreatitis; however, the risk was no
the patient recovered 5 days after discontinuation different from that of other antiepileptic agents.269
and had a relapsed 4 days after ampicillin therapy There are at least five case reports of drug-
was reinstituted. induced pancreatitis with clozapine.270-274 In one of
The incidence of methyldopa-induced pancre- these reports, pancreatitis remitted upon clozapine
atitis is unknown. Symptoms of methyldopa- withdrawal but recurred when clozapine was reini-
induced pancreatitis generally occur within 1 week tiated.272 In another report, pancreatitis resolved
after the initiation of therapy.201-204 after withdrawal of clozapine but did not recur
There are numerous reports of estrogen- after a rechallenge with a lower dose.273 Other
induced pancreatitis (with and without concomi- reports describe a syndrome of “asymptomatic”
tant progesterone therapy).205-211 Estrogen-induced pancreatitis and eosinophilia induced by clozap-
pancreatitis begins 2 to 78 weeks after the initia- ine, although asymptomatic hyperamylasemia
tion of therapy, and symptoms usually resolve usually is not diagnostic of pancreatitis.275,276
approximately 10 days after discontinuation.17 In
addition, there is a case report of clomiphene (an
estrogen analogue)-induced pancreatitis.212 MECHANISMS
Although there are case reports of estrogen-
induced pancreatitis, a population-based case–con- The pancreas has two functions: endocrine and
trol study did not support a substantial association exocrine.1 The endocrine function is to secrete
between pancreatitis and postmenopausal hor- insulin, glucagon, somatostatin and other
mone therapy.213 polypeptides via the pancreatic -cells. The
Several cases of furosemide-induced pancreati- exocrine pancreas consists of lobular subunits
tis have been reported.214-219 The doses that were called acini, which secrete pancreatic fluid that
administered in these cases ranged from 40 to 1000 contains water, electrolytes, and enzymes for diges-
mg daily, and symptoms occurred within 2 to 5 tion. The major enzymes secreted by the pancreas
weeks after the initiation of therapy.17 In one case, include proteolytic (trypsinogen, chymotrypsino-
pancreatitis occurred in a patient with malignant gen, proelastase, procarboxypeptidases A and B),
hypertension within 24 hours of the initiation of amylolytic (amylase), lipolytic (lipase, prophos-
therapy with furosemide 750 mg per day.218 pholipase A1 and A2, esterase), nucleolytic
Pancreatitis resolved after the discontinuation of (deoxyribonuclease and ribonuclease), and others,
furosemide and recurred upon rechallenge. In such as trypsin inhibitor. The proteolytic enzymes
addition, other loop diuretics, bumetanide and are secreted as zymogens (enzymes requiring acti-
ethacrynic acid, have been associated with pancre- vation, such as proenzymes) in the pancreas and
atitis.218,220,221 require an extrapancreatic trigger for activation.
Chlorothiazide, hydrochlorothiazide, and Enterokinase in the duodenum transforms
chlorthalidone have all been reported to cause trypsinogen to trypsin, which activates all other
pancreatitis.222-236 Thiazide-induced pancreatitis zymogens. The pancreas protects itself from
develops within 2 weeks to as long as 1 year or autodigestion by secreting proenzymes and low
more after the initiation of therapy. concentrations of trypsin inhibitor. Acute pancre-
Pancreatitis associated with valproic acid was atitis results from premature activation of prote-
first recognized in 1979,237 and since then there olytic enzymes within the pancreas.
have been many reports of valproic acid induced Drugs may induce pancreatitis through several
pancreatitis, in both adults and children.238-267 The mechanisms, including pancreatic duct hyperten-
estimated incidence is 1 in 40,000.268 In view of the sion secondary to intraluminal or extraluminal
TisdaleC41_800-818 1/12/10 3:43 PM Page 805
duct blockage, increased viscosity of pancreatic aerobic conditions, yielding hydrogen peroxide
fluid leading to peripheral duct rupture, and proen- and other oxygen free radicals.277,278 These redox
zyme release.2 Data from studies in animals have active compounds are toxic to pancreatic -cells
shown that reduced exocytosis and premature and cause pancreatitis in animal models. The exact
fusion of zymogen granules to lysosomes in pan- mechanism of tetracycline-induced pancreatitis is
creatic exocrine cells may activate pancreatic not completely understood; however, it may be
proenyzmes and lead to cellular autodigestion. related to a toxic metabolite of tetracycline.279 The
Drugs could play a role in this process. precise mechanism of pentamidine-induced pan-
Predisposition to infection through immunosup- creatitis likewise is not known, but animal studies
pression may also be involved in pancreatitis suggest a direct toxic effect on the pancreas.280
caused by drugs such as corticosteroids and other Pentamidine is known to cause hypoglycemia or
immunosuppressants.2 Table 41–2 lists additional hyperglycemia, which is possibly due to damaged
mechanisms that have been proposed for drugs pancreatic -cells.17
known to be associated with pancreatitis.
Estrogen
Antimicrobial Agents A possible mechanism of estrogen-induced pancre-
Metronidazole-induced pancreatitis may occur as a atitis is hyperlipidemia, a well-known cause of pan-
result of a redox cycling reaction that occurs under creatitis. In a report by Glueck and colleagues,
Calcium
grade fever. The presentation may also include
It is possible that hypercalcemia may induce pain that radiates to the back, hypotension, men-
chronic pancreatic exocrine secretion changes that tal aberrations, and jaundice. Complications may
may affect ductal epithelium.120 Intracellular calci- include the development of pancreatic abscess,
um in pancreatic zymogen granules is important in pseudocyst formation and the development of
the maintenance of granule stability, and factors subcutaneous fat necrosis and bluish discoloration
disrupting this delicate balance may contribute to of the abdominal wall (Grey-Turner’s or Cullen’s
calcium-induced pancreatitis.303 sign).306
Diagnosis is usually based on clinical and lab-
Corticosteroids oratory data. Typical laboratory parameter abnor-
malities that may occur in patients with
Corticosteroids may induce pancreatitis through drug-induced pancreatitis include leukocytosis,
toxic effects, immune suppression, or increased vis- hyperglycemia, hypoalbuminemia, mild hyper-
cosity of pancreatic fluids.120 The viscosity of pan- bilirubinemia, elevated blood urea nitrogen and
creatic secretions was greater in steroid-treated serum creatinine concentrations, elevated hemo-
glands in an ex vivo study of perfused canine pan- globin, elevated hematocrit, hypocalcemia,
creas exposed to high doses of methylpred- thrombocytopenia, and prolongation of pro-
nisolone.304 Steroids stimulate both exocrine and thrombin time and the international normalized
endocrine pancreatic secretions, which may con- ratio (INR).1 Serum amylase concentrations usual-
tribute to the development of drug-induced pan- ly increase within 24 hours of the onset of symp-
creatitis.305 toms and return to normal over a period of 3 to 4
days. Persistent elevation is suggestive of exten-
Statins sive pancreatic necrosis or related complications
or both. Serum amylase concentrations do not
The exact mechanism of statin-induced pancreati- correlate with severity of disease or cause. In con-
tis is not clear. Some hypothesized mechanisms trast, lipase originates in the pancreas, making it
include an immune-mediated inflammatory a more specific marker for pancreatitis than serum
response, a metabolic effect, or direct cellular toxi- amylase. Serum lipase concentrations are usually
city.72 The safety profile among the statins may dif- elevated in patients with pancreatitis. Elevations
fer based on their inhibitory effects on cytochrome of serum lipase concentration persist longer (7 to
P-450 and their lipophilicity. 10 days) than serum amylase elevations. Imaging
techniques such as ultrasound may be indicated
in patients with suspected biliary involvement.
CLINICAL PRESENTATION AND Contrast-enhanced computed tomography may
DIFFERENTIAL DIAGNOSIS be useful in determining the severity of the
inflammatory process, and it also provides an esti-
The clinical presentation of drug-induced pancre- mate of risk for systemic and local complica-
atitis is similar to that of acute pancreatitis second- tions.307,308
ary to other causes.2 Table 41–3 summarizes the Because the clinical presentation of drug-
usual signs and symptoms associated with drug- induced pancreatitis is similar to that of pancreatitis
induced pancreatitis. Typically, patients with due to other causes, drug-induced pancreatitis is
acute pancreatitis present with abdominal pain, usually diagnosed after other, more common causes
nausea, vomiting, abdominal distention, and low- have been ruled out. A careful medication history
TisdaleC41_800-818 1/12/10 3:43 PM Page 808
• Cholelithiasis
• Abdominal trauma
• Toxins
MORBIDITY AND MORTALITY
• Hyperlipidemia
Drug-induced pancreatitis may be mild to severe.
• Pancreatic tumor
The majority of patients recover without any long-
• Surgery
term morbidity, but 5% to 15% of patients ex-
• Endoscopic retrograde cholangiopancreatography
perience life-threatening complications. 2 A
• Infection
retrospective study including data from 42 Ger-
• Vascular abnormalities
man centers of gastroenterology found that the
TisdaleC41_800-818 1/12/10 3:43 PM Page 809
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